Janet L Funk

Interests

No activities entered.

Courses

Scholarly Contributions

Chapters

• Funk, J. L. (2017). Humoral Manifestations of Malignancy.. In Greenspan’s Basic and Clinical Endocrinology (10th ed.). McGraw Hill.
• Shoback, D., & Funk, J. L. (2016). Humoral Manifestations of Malignancy. In Greenspan’s Basic and Clinical Endocrinology (10th ed.). McGraw Hill,.
  More info

  DG Gardner & D Shoback (eds.)
• Funk, J. L. (2014). Disorders of the Endocrine Pancreas. In Pathophysiology of Disease: An Introduction to Clinical Medicine (7th ed.).
  More info

  S McPhee, GD Hammer (eds.),
• Funk, J. L., & Timmermann, B. N. (2012). Multidisciplinary Studies of Anti-Inflammatory Botanicals: Ginger and Turmeric. In Phytochemicals: Health Promotion and Therapeutic Potential. CRC Press.
  More info

  eds: Carkeet C, Grann K, Randolph RK, Venzon DS, Izzy S.
• 11. Shoback, D., & Funk, J. L. (2011). Humoral Manifestations of Malignancy. In Greenspan’s Basic and Clinical Endocrinology (9th ed.). McGraw Hill.
  More info

  DG Gardner & D Shoback (eds.),
• Funk, J. L. (2010). Disorders of the Endocrine Pancreas. In Pathophysiology of Disease: An Introduction to Clinical Medicine (6th ed.).
  More info

  S McPhee, GD Hammer (eds.)
• Funk, J. L. (2010). Turmeric.. In Encyclopedia of Dietary Supplements, 2nd edition. Informa Healthcare.
  More info

  Editors, Paul Coates, Marc Blackman
• Funk, J. L. (2007). PTHrP and Inflammation. In Novel Aspects of PTHrP Physiology. Nova.
  More info

  C Luparello (ed.),
• Funk, J. L., & 8. Shoback, D. (2007). Humoral Manifestations of Malignancy. In Greenspan’s Basic and Clinical Endocrinology (8th ed.). McGraw Hill.
  More info

  DG Gardner & D Shoback (eds.)
• 6. Shoback, D., & Funk, J. L. (2004). Humoral Manifestations of Malignancy. In Basic and Clinical Endocrinology (7th ed.). McGraw Hill.
  More info

  Greenspan FS & DG Gardner (eds.)
• Funk, J. L. (2004). Disorders of the Endocrine Pancreas. In Pathophysiology of Disease: An Introduction to Clinical Medicine (5th ed.). McGraw Hill.
  More info

  S McPhee, VR LIngappa, WF Ganong (eds.)
• Funk, J. L. (2003). Disorders of the Endocrine Pancreas. In Pathophysiology of Disease: An Introduction to Clinical Medicine (4th ed.). Lange Medical Books/McGraw Hill.
  More info

  S McPhee, VR Lingappa, WF Ganong, (eds.)
• 4. Shoback, D., & Funk, J. L. (2001). Humoral Manifestations of Malignancy. In Basic and Clinical Endocrinology (6th ed.). McGraw Hill.
  More info

  Greenspan FS & DG Gardner (eds.)
• Funk, J. L., & 3. Feingold, K. R. (2000). Disorders of the Endocrine Pancreas. In Pathophysiology of Disease: An Introduction to Clinical Medicine (3rd ed.). Lange Medical Books/McGraw Hill.
  More info

  S McPhee, VR Lingappa, WF Ganong, JD Lange (eds.)
• Funk, J. L., & Feingold, K. (1997). Disorders of the Endocrine Pancreas. In Pathophysiology of Disease: An Introduction to Clinical Medicine (2nd ed.). Appleton and Lange.
  More info

  S McPhee, (eds.),
• Funk, J. L., & Feingold, K. R. (1995). Disorders of the Endocrine Pancreas. In Pathophysiology of Disease: An Introduction to Clinical Medicine (1st ed.). Appleton and Lange.
  More info

  S McPhee, VR LIngappa, WF Ganong, JD Lange (eds.)

Journals/Publications

• Barakati, N., Bustos, R. Z., Coletta, D. K., Langlais, P. R., Kohler, L. N., Luo, M., Funk, J. L., Willis, W. T., & Mandarino, L. J. (2023). Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals. Metabolic syndrome and related disorders, 21(1), 16-24.
  More info

  Resting skeletal muscle in insulin resistance prefers to oxidize carbohydrate rather than lipid, exhibiting metabolic inflexibility. Although this is established in resting muscle, complexities involved in directly measuring fuel oxidation using indirect calorimetry across a muscle bed have limited studies of this phenomenon in working skeletal muscle. During mild exercise and at rest, whole-body indirect calorimetry imperfectly estimates muscle fuel oxidation. We provide evidence that a method termed "ΔRER" can reasonably estimate fuel oxidation in skeletal muscle activated by exercise. Completely sedentary volunteers ( = 20, age 31 ± 2 years, V̇O 24.4 ± 1.5 mL O per min/kg) underwent glucose clamps to determine insulin sensitivity and graded exercise consisting of three periods of mild steady-state cycle ergometry (15, 30, 45 watts, or 10%, 20%, and 30% of maximum power) with measurements of whole-body gas exchange. ΔRER, the RER in working muscle, was calculated as (V̇CO2 -V̇CO)/(V̇O - V̇O), from which the fraction of fuel accounted for by lipid was estimated. Lactate levels were low and stable during steady-state exercise. Muscle biopsies were used to estimate mitochondrial content. The rise of V̇O at onset of exercise followed a monoexponential function, with a time constant of 51 ± 7 sec, typical of skeletal muscle; the average O cost of work was about 12 mL O/watt/min, representing a mechanical efficiency of about 24%. At work rates of 30 or 45 watts, active muscle relied predominantly on carbohydrate, independent of insulin sensitivity within this group of very sedentary volunteers. The fraction of muscle fuel oxidation from fat was predicted by power output ( 
• Barakati, N., Zapata Bustos, R., Coletta, D. K., Langlais, P. R., Kohler, L. N., Luo, M., Funk, J. L., Willis, W. T., & Mandarino, L. J. (2023). Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals. Metabolic Syndrome and Related Disorders.
• Bland, V. L., Bea, J. W., Going, S. B., Yaghootkar, H., Arora, A., Ramadan, F., Funk, J. L., Chen, Z., & Klimentidis, Y. C. (2023). Metabolically favorable adiposity and bone mineral density: a Mendelian randomization analysis. Obesity (Silver Spring, Md.), 31(1), 267-278.
  More info

  This analysis assessed the putative causal association between genetically predicted percent body fat and areal bone mineral density (aBMD) and, more specifically, the association between genetically predicted metabolically "favorable adiposity" (MFA) and aBMD at clinically relevant bone sites.
• Bucchireddigari, B., Funk, J. L., Hauer, M., Howe, C. L., Panknin, T. M., & Rossi, A. M. (2023).

  Curcumin Supplementation and Human Disease: A Scoping Review of Clinical Trials

  . International Journal of Molecular Sciences, 24(5), 4476. doi:10.3390/ijms24054476
• Funk, J. L., Wertheim, B. C., Frye, J. B., Blew, R. M., Nicholas, J. S., Chen, Z., & Bea, J. W. (2023). Association of ß-glucuronidase activity with menopausal status, ethnicity, adiposity, and inflammation in women. Menopause (New York, N.Y.), 30(2), 186-192.
  More info

  Many dietary polyphenols with potential health-promoting benefits undergo hepatic conjugation and circulate as inactive glucuronides that can be cleaved by ß-glucuronidase to reform the bioactive aglycone. Although indirect evidence suggests estrogen may induce ß-glucuronidase, little is known about ß-glucuronidase regulation across women's reproductive lifespan. Correlates of serum ß-glucuronidase activity in healthy premenopausal versus postmenopausal women were therefore examined.
• Funk, J., Frye, J., Whitman, S., Thomas, A., Ameneni, G., Magee, A., & Cheng, J. (2023).

  Unraveling the role of estrogen signaling in the breast cancer-bone connection

  . Physiology, 38(S1). doi:10.1152/physiol.2023.38.s1.5793712
• Hauer, M., Rossi, A. M., Wertheim, B. C., Kleppel, H. B., Bea, J. W., & Funk, J. L. (2023). Corrigendum to 'Dietary Supplement Use in Women Diagnosed with Breast Cancer' [J Nutrition 2023 January;153(3):301-311]. The Journal of nutrition, 153(5), 1656-1657.
• Hauer, M., Rossi, A. M., Wertheim, B. C., Kleppel, H. B., Bea, J. W., & Funk, J. L. (2023). Dietary Supplement Use in Women Diagnosed with Breast Cancer. The Journal of nutrition, 153(1), 301-311.
  More info

  Vitamins, minerals, and natural product (NP)-derived dietary supplements are commonly used among women with breast cancer, where interactions with treatments and the disease are possible, emphasizing the importance for health care providers to be aware of supplement use.
• Panknin, T. M., Howe, C. L., Hauer, M., Bucchireddigari, B., Rossi, A. M., & Funk, J. L. (2023). Curcumin Supplementation and Human Disease: A Scoping Review of Clinical Trials. International journal of molecular sciences, 24(5).
  More info

  Medicinal properties of turmeric ( L.), a plant used for centuries as an anti-inflammatory, are attributed to its polyphenolic curcuminoids, where curcumin predominates. Although "curcumin" supplements are a top-selling botanical with promising pre-clinical effects, questions remain regarding biological activity in humans. To address this, a scoping review was conducted to assess human clinical trials reporting oral curcumin effects on disease outcomes. Eight databases were searched using established guidelines, yielding 389 citations (from 9528 initial) that met inclusion criteria. Half focused on obesity-associated metabolic disorders (29%) or musculoskeletal disorders (17%), where inflammation is a key driver, and beneficial effects on clinical outcomes and/or biomarkers were reported for most citations (75%) in studies that were primarily double-blind, randomized, and placebo-controlled trials (77%, D-RCT). Citations for the next most studied disease categories (neurocognitive [11%] or gastrointestinal disorders [10%], or cancer [9%]), were far fewer in number and yielded mixed results depending on study quality and condition studied. Although additional research is needed, including systematic evaluation of diverse curcumin formulations and doses in larger D-RCT studies, the preponderance of current evidence for several highly studied diseases (e.g., metabolic syndrome, osteoarthritis), which are also clinically common, are suggestive of clinical benefits.
• Zapata Bustos, R., Coletta, D. K., Galons, J., Davidson, L., Langlais, P. R., Funk, J. L., Willis, W. T., & Mandarino, L. J. (2023). Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle. Front Physiol.
• Barakati, N., Coletta, D. K., Funk, J. L., Mandarino, L. J., Willis, W. T., Luo, M., Kohler, L. N., Langlais, P. R., & Bustos, R. Z. (2022). Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals. Metabolic Syndrome and Related Disorders. doi:10.1089/met.2022.0062
  More info

  Background: Resting skeletal muscle in insulin resistance prefers to oxidize carbohydrate rather than lipid, exhibiting metabolic inflexibility. Although this is established in resting muscle, complexities involved in directly measuring fuel oxidation using indirect calorimetry across a muscle bed have limited studies of this phenomenon in working skeletal muscle. During mild exercise and at rest, whole-body indirect calorimetry imperfectly estimates muscle fuel oxidation. We provide evidence that a method termed "ΔRER" can reasonably estimate fuel oxidation in skeletal muscle activated by exercise. Methods: Completely sedentary volunteers (n = 20, age 31 ± 2 years, V̇O2peak 24.4 ± 1.5 mL O2 per min/kg) underwent glucose clamps to determine insulin sensitivity and graded exercise consisting of three periods of mild steady-state cycle ergometry (15, 30, 45 watts, or 10%, 20%, and 30% of maximum power) with measurements of whole-body gas exchange. ΔRER, the RER in working muscle, was calculated as (V̇CO2exercise -V̇CO2rest)/(V̇O2exercise - V̇O2rest), from which the fraction of fuel accounted for by lipid was estimated. Results: Lactate levels were low and stable during steady-state exercise. Muscle biopsies were used to estimate mitochondrial content. The rise of V̇O2 at onset of exercise followed a monoexponential function, with a time constant of 51 ± 7 sec, typical of skeletal muscle; the average O2 cost of work was about 12 mL O2/watt/min, representing a mechanical efficiency of about 24%. At work rates of 30 or 45 watts, active muscle relied predominantly on carbohydrate, independent of insulin sensitivity within this group of very sedentary volunteers. Conclusions: The fraction of muscle fuel oxidation from fat was predicted by power output (P < 0.001) and citrate synthase activity (P < 0.05), indicating that low mitochondrial content may be the main driver of fuel choice in sedentary people, independent of insulin sensitivity.
• Funk, J. L., Bea, J. W., Mattick, L. J., Singh, L., Hovey, K. M., Banack, H. R., Wactawski-Wende, J., Manson, J. E., & Ochs-Balcom, H. M. (2022). Serum Follicle-Stimulating Hormone and 5-Year Change in Adiposity in Healthy Postmenopausal Women. The Journal of Clinical Endocrinology & Metabolism, 107(8), e3455-e3462. doi:10.1210/clinem/dgac238
• Klimentidis, Y. C., Chen, Z., Funk, J. L., Going, S. B., Bea, J. W., Bland, V. L., Yaghootkar, H., Arora, A., & Ramadan, F. (2022). Metabolically favorable adiposity and bone mineral density: a Mendelian randomization analysis. Obesity, 31(1), 267-278. doi:10.1002/oby.23604
  More info

  This analysis assessed the putative causal association between genetically predicted percent body fat and areal bone mineral density (aBMD) and, more specifically, the association between genetically predicted metabolically "favorable adiposity" (MFA) and aBMD at clinically relevant bone sites.Mendelian randomization was used to assess the relationship of MFA and percent body fat with whole-body, lumbar spine, femoral neck, and forearm aBMD. Sex-stratified and age-stratified exploratory analyses were conducted.In all MR analyses, genetically predicted MFA was inversely associated with aBMD for the whole body (β = -0.053, p = 0.0002), lumbar spine (β = -0.075; p = 0.0001), femoral neck (β = -0.045; p = 0.008), and forearm (β = -0.115; p = 0.001). This negative relationship was strongest in older individuals and did not differ by sex. The relationship between genetically predicted percent body fat and aBMD was nonsignificant across all Mendelian randomization analyses. Several loci that were associated at a genome-wide significance level (p < 5 × 10-8 ) in opposite directions with body fat and aBMD measures were also identified.This study did not support the hypothesis that MFA protects against low aBMD. Instead, it showed that MFA may result in lower aBMD. Further research is needed to understand how MFA affects aBMD and other components of bone health such as bone turnover, bone architecture, and osteoporotic fractures.
• Kunihiro, A. G., Brickey, J. A., Frye, J. B., Cheng, J. N., Luis, P. B., Schneider, C., & Funk, J. L. (2022). Curcumin Inhibition of TGFβ signaling in bone metastatic breast cancer cells and the possible role of oxidative metabolites. The Journal of nutritional biochemistry, 99, 108842.
  More info

  TGFβ signaling promotes progression of bone-metastatic (BMET) breast cancer (BCa) cells by driving tumor-associated osteolysis, a hallmark of BCa BMETs, thus allowing for tumor expansion within bone. Turmeric-derived bioactive curcumin, enriched in bone via local enzymatic deconjugation of inactive circulating curcumin-glucuronides, inhibits osteolysis and BMET progression in human xenograft BCa BMET models by blocking tumoral TGFβ signaling pathways mediating osteolysis. This is a unique antiosteolytic mechanism in contrast to current osteoclast-targeting therapeutics. Therefore, experiments were undertaken to elucidate the mechanism for curcumin inhibition of BCa TGFβ signaling and the application of this finding across multiple BCa cell lines forming TGFβ-dependent BMETs, including a possible role for bioactive curcumin metabolites in mediating these effects. Immunoblot analysis of TGFβ signaling proteins in bone tropic human (MDA-SA, MDA-1833, MDA-2287) and murine (4T1) BCa cells revealed uniform curcumin blockade of TGFβ-induced Smad activation due to down-regulation of plasma membrane associated TGFβR2 and cellular receptor Smad proteins that propagate Smad-mediated gene expression, resulting in downregulation of PTHrP expression, the osteolytic factor driving in vivo BMET progression. With the exception of early decreases in TGFβR2, inhibitory effects appeared to be mediated by oxidative metabolites of curcumin and involved inhibition of gene expression. Interestingly, while not contributing to changes in Smad-mediated TGFβ signaling, curcumin caused early activation of MAPK signaling in all cell lines, including JNK, an effect possibly involving interactions with TGFβR2 within lipid rafts. Treatment with curcumin or oxidizable analogs of curcumin may have clinical relevancy in the management of TGFβ-dependent BCa BMETs.
• Bland, V. L., Bea, J. W., Blew, R. M., Roe, D. J., Lee, V. R., Funk, J. L., & Going, S. B. (2021). Influence of Changes in Soft Tissue Composition on Changes in Bone Strength in Peripubertal Girls: The STAR Longitudinal Study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 36(1), 123-132.
  More info

  Obesity and osteoporosis remain two major public health concerns. Soft tissue composition and bone are interrelated; however, it is still not well understood how changes in adiposity during adolescence affect bone development. The aim of this study was to assess how changes in DXA-derived total body lean mass (TBLM) and total body fat mass (TBFM) associate with 2-year changes in bone outcomes at the 20% femur, 66% tibia, 66% radius, and 4% tibia, as measured by pQCT, during the years surrounding the onset of menarche in a cohort of 9- to 12-year-old (baseline) adolescent girls (70% Hispanic). From baseline to 2-year follow-up, girls showed statistically significant increases in all bone outcomes, except radial endosteal circumference. In separate linear regression models, change in TBLM and change in TBFM were both positively associated with 2-year changes in bone outcomes at all measured bone sites, after controlling for relevant covariates. However, when change in TBLM and change in TBFM were included in the same model, change in TBLM was the predominant predictor of bone outcomes, explaining 4% to 14% of the variance in bone strength outcomes. Change in TBFM remained a positive predictor of tibia polar strength strain index (SSI (2% variance explained). A significant interaction between change in TBFM and menarcheal status was identified at the radius for SSI and indicated that greater gains in TBFM were beneficial for SSI in girls that were premenarcheal at baseline but detrimental for girls who were postmenarcheal at baseline. The overall findings suggest that changes in TBLM during the peripubertal years have a greater influence on bone outcomes than changes in TBFM. While gains in TBFM might benefit the weight bearing 66% tibia, greater gains in TBFM may be detrimental to bone development at the non-weight bearing 66% radius after the onset of menarche. © 2020 American Society for Bone and Mineral Research (ASBMR).
• Bland, V. L., Klimentidis, Y. C., Bea, J. W., Roe, D. J., Funk, J. L., & Going, S. B. (2021). Cross-sectional associations between adipose tissue depots and areal bone mineral density in the UK Biobank imaging study. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA.
  More info

  The relationship between obesity and osteoporosis is poorly understood. In this study, we assessed the association between adiposity and bone. The fat-bone relationship was dependent on sex, body mass index classification, and menopausal status. Results highlight the importance of accounting for direct measures of adiposity (beyond BMI) and menopause status.
• Cheng, J. N., Frye, J. B., Whitman, S. A., Kunihiro, A. G., Brickey, J. A., & Funk, J. L. (2021). Osteolytic effects of tumoral estrogen signaling in an estrogen receptor-positive breast cancer bone metastasis model. Journal of cancer metastasis and treatment, 7.
  More info

  Estrogen receptor α-positive (ER+) subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases (BMETs). Because tumor-derived factors mediate osteolysis, a possible role for tumoral ERα signaling in driving ER+ BMET osteolysis was queried using an estrogen (E)-dependent ER+ breast cancer BMET model.
• Cheng, J. N., Frye, J. B., Whitman, S. A., Kunihiro, A. G., Pandey, R., & Funk, J. L. (2021). A Role for TGFβ Signaling in Preclinical Osteolytic Estrogen Receptor-Positive Breast Cancer Bone Metastases Progression. International journal of molecular sciences, 22(9).
  More info

  While tumoral Smad-mediated transforming growth factor β (TGFβ) signaling drives osteolytic estrogen receptor α-negative (ER-) breast cancer bone metastases (BMETs) in preclinical models, its role in ER+ BMETs, representing the majority of clinical BMETs, has not been documented. Experiments were undertaken to examine Smad-mediated TGFβ signaling in human ER+ cells and bone-tropic behavior following intracardiac inoculation of estrogen (E)-supplemented female nude mice. While all ER+ tumor cells tested (ZR-75-1, T47D, and MCF-7-derived) expressed TGFβ receptors II and I, only cells with TGFβ-inducible Smad signaling (MCF-7) formed osteolytic BMETs in vivo. Regulated secretion of PTHrP, an osteolytic factor expressed in >90% of clinical BMETs, also tracked with osteolytic potential; TGFβ and E each induced PTHrP in bone-tropic or BMET-derived MCF-7 cells, with the combination yielding additive effects, while in cells not forming BMETs, PTHrP was not induced. In vivo treatment with 1D11, a pan-TGFβ neutralizing antibody, significantly decreased osteolytic ER+ BMETs in association with a decrease in bone-resorbing osteoclasts at the tumor-bone interface. Thus, TGFβ may also be a driver of ER+ BMET osteolysis. Moreover, additive pro-osteolytic effects of tumoral E and TGFβ signaling could at least partially explain the greater propensity for ER+ tumors to form BMETs, which are primarily osteolytic.
• Coletta, D. K., Hlusko, L. J., Scott, G. R., Garcia, L. A., Vachon, C. M., Norman, A. D., Funk, J. L., Shaibi, G. Q., Hernandez, V., De Filippis, E., & Mandarino, L. J. (2021). Association of EDARV370A with breast density and metabolic syndrome in Latinos. PloS one, 16(10), e0258212.
  More info

  The ectodysplasin receptor (EDAR) is a tumor necrosis factor receptor (TNF) superfamily member. A substitution in an exon of EDAR at position 370 (EDARV370A) creates a gain of function mutant present at high frequencies in Asian and Indigenous American populations but absent in others. Its frequency is intermediate in populations of Mexican ancestry. EDAR regulates the development of ectodermal tissues, including mammary ducts. Obesity and type 2 diabetes mellitus are prevalent in people with Indigenous and Latino ancestry. Latino patients also have altered prevalence and presentation of breast cancer. It is unknown whether EDARV370A might connect these phenomena. The goals of this study were to determine 1) whether EDARV370A is associated with metabolic phenotypes and 2) if there is altered breast anatomy in women carrying EDARV370A. Participants were from two Latino cohorts, the Arizona Insulin Resistance (AIR) registry and Sangre por Salud (SPS) biobank. The frequency of EDARV370A was 47% in the Latino cohorts. In the AIR registry, carriers of EDARV370A (GG homozygous) had significantly (p < 0.05) higher plasma triglycerides, VLDL, ALT, 2-hour post-challenge glucose, and a higher prevalence of prediabetes/diabetes. In a subset of the AIR registry, serum levels of ectodysplasin A2 (EDA-A2) also were associated with HbA1c and prediabetes (p < 0.05). For the SPS biobank, participants that were carriers of EDARV370A had lower breast density and higher HbA1c (both p < 0.05). The significant associations with measures of glycemia remained when the cohorts were combined. We conclude that EDARV370A is associated with characteristics of the metabolic syndrome and breast density in Latinos.
• Funk, J. L., & Schneider, C. (2021). Perspective on Improving the Relevance, Rigor, and Reproducibility of Botanical Clinical Trials: Lessons Learned From Turmeric Trials. Frontiers in nutrition, 8, 782912.
  More info

  Plant-derived compounds, without doubt, can have significant medicinal effects since many notable drugs in use today, such as morphine or taxol, were first isolated from botanical sources. When an isolated and purified phytochemical is developed as a pharmaceutical, the uniformity and appropriate use of the product are well defined. Less clear are the benefits and best use of plant-based dietary supplements or other formulations since these products, unlike traditional drugs, are chemically complex and variable in composition, even if derived from a single plant source. This perspective will summarize key points-including the premise of ethnobotanical and preclinical evidence, pharmacokinetics, metabolism, and safety-inherent and unique to the study of botanical dietary supplements to be considered when planning or evaluating botanical clinical trials. Market forces and regulatory frameworks also affect clinical trial design since in the United States, for example, botanical dietary supplements cannot be marketed for disease treatment and submission of information on safety or efficacy is not required. Specific challenges are thus readily apparent both for consumers comparing available products for purchase, as well as for commercially sponsored vs. independent researchers planning clinical trials to evaluate medicinal effects of botanicals. Turmeric dietary supplements, a top selling botanical in the United States and focus of over 400 clinical trials to date, will be used throughout to illustrate both the promise and pitfalls associated with the clinical evaluation of botanicals.
• Funk, J., Howe, C., Panknin, T., Bucchireddigari, B., Hauer, M., & Rossi, A. (2021). A Scoping Review: Clinical Trials Assessing Turmeric Dietary Supplement Use in Cancer. The FASEB Journal, 35(S1). doi:10.1096/fasebj.2021.35.s1.05233
• Funk, J., Howe, C., Panknin, T., Bucchireddigari, B., Hauer, M., & Rossi, A. (2021). Curcumin-Containing Turmeric Dietary Supplement Clinical Trials: A Scoping Review. Current Developments in Nutrition, 5(Supplement_2), 357-357. doi:10.1093/cdn/nzab037_067
• Going, S. B., Funk, J. L., Lee, V. L., Roe, D., Blew, R., Bea, J. W., & Bland, V. (2021). Influence of Changes in Soft Tissue Composition on Changes in Bone Strength in Peripubertal Girls: The STAR Longitudinal Study. Journal of Bone and Mineral Research, 36, 123-132. doi:10.1002/jbmr.4168
• Mandarino, L. J., Willis, W. T., Luo, M., Coletta, D. K., Zapata Bustos, R., Funk, J. L., Langlais, P. R., Barakati, N., & Finlayson, J. (2021). Site-specific acetylation of adenine nucleotide translocase 1 at lysine 23 in human muscle. Analytical biochemistry, 630, 114319.
  More info

  Evidence suggests acetylation of human adenine nucleotide translocase 1 (ANT1) at lysine 23 (Lys23) reduces binding of ADP. Lys23 contributes to the positive charge that facilitates this interaction. This study was undertaken to characterize ANT1 abundance and acetylation by a novel method using small amounts of human skeletal muscle biopsies. Lysates of whole muscle or mitochondria from the same tissue were prepared from needle biopsies of vastus lateralis muscle of healthy volunteers. Lysed proteins were resolved on gels, the section containing ANT1 (surrounding 30 Kd) was excised, digested with trypsin, spiked with labeled unacetylated and acetylated synthetic standard peptides and analyzed by mass spectrometry. Natural logarithm transformation of data linearized ion intensities over a 10-fold range of peptide mass. Coefficients of variation ranged from 7 to 30% for ANT1 abundance and Lys23 acetylation. In three volunteers, ANT1 content was 8.36 ± 0.33 nmol/g wet weight muscle and 0.64 ± 0.05 nmol/mg mitochondria, so mitochondrial content was 13.3 ± 2.4 mg mitochondria per gram muscle. Acetylation of Lys23 averaged 14.3 ± 4.2% and 4.87 ± 1.84% in whole muscle and mitochondria, respectively. This assay makes it possible to assess effects of acetylation on the function of ANT1 in human muscle.
• Rossi, A. M., Panknin, T. M., Howe, C. L., Hauer, M., Funk, J. L., & Bucchireddigari, B. (2021). Clinical Trials Evaluating Turmeric Dietary Supplement Treatment of Obesity-Associated Disorders of Glucose Metabolism or Bone. Journal of the Endocrine Society, 5(Supplement_1), A329-A330. doi:10.1210/jendso/bvab048.673
  More info

  Abstract Curcumin-enriched turmeric dietary supplements (DS) are one of the top selling botanicals in the United States. Recent observational studies by our research group have documented turmeric DS use by almost a quarter of breast cancer survivors concurrent with anti-estrogen therapy and a third of those with rheumatoid arthritis. However, some recent reviews have suggested that there is no evidence of any biological effect of curcumin in humans, albeit without rigorous review of published reports. A scoping review of the literature was therefore undertaken to identify clinical trials testing oral curcumin-containing turmeric dietary supplements in humans. Using a defined search strategy, eight databases were reviewed (thru 05/29/2019), identifying 4767 potential English language reports for inclusion, from which all but n = 315 were excluded after review by three independent observers. The majority of studies reported significant effects of turmeric DS on clinical endpoints. Obesity-associated disorders of glucose and lipid metabolism (n =69, including type 2 diabetes mellitus [T2DM], metabolic syndrome and/or hyperlipidemia) or musculoskeletal disorders (n = 46), of which half related to osteoarthritis, were among the most commonly studied diseases in turmeric DS clinical trials, with reported benefits related to inhibition of inflammation, amelioration of hyperlipidemia, increases in adiponectin, and improved glucose control. As is common for botanical clinical trials, the quality of the studies were variable due to lack of clarity about product content as well as study design (e.g. only 60% of T2DM trials and 74% of osteoarthritis trials were randomized, placebo-controlled and double-blinded). However, particularly with respect to treatment of osteoarthritis and metabolic consequences of insulin resistance, the preponderance of the data were suggestive of beneficial physiologic effects. Given the current widespread use of turmeric DS by Americans and existing evidence of possible clinical benefits, further evaluation of turmeric DS efficacy and safety may be warranted.
• Whitman, S. A., Pandey, R., Kunihiro, A. G., Funk, J. L., Frye, J. B., & Cheng, J. N. (2021). A Role for TGFβ Signaling in Preclinical Osteolytic Estrogen Receptor-Positive Breast Cancer Bone Metastases Progression.. International journal of molecular sciences, 22(9), 4463. doi:10.3390/ijms22094463
  More info

  While tumoral Smad-mediated transforming growth factor β (TGFβ) signaling drives osteolytic estrogen receptor α-negative (ER-) breast cancer bone metastases (BMETs) in preclinical models, its role in ER+ BMETs, representing the majority of clinical BMETs, has not been documented. Experiments were undertaken to examine Smad-mediated TGFβ signaling in human ER+ cells and bone-tropic behavior following intracardiac inoculation of estrogen (E2)-supplemented female nude mice. While all ER+ tumor cells tested (ZR-75-1, T47D, and MCF-7-derived) expressed TGFβ receptors II and I, only cells with TGFβ-inducible Smad signaling (MCF-7) formed osteolytic BMETs in vivo. Regulated secretion of PTHrP, an osteolytic factor expressed in >90% of clinical BMETs, also tracked with osteolytic potential; TGFβ and E2 each induced PTHrP in bone-tropic or BMET-derived MCF-7 cells, with the combination yielding additive effects, while in cells not forming BMETs, PTHrP was not induced. In vivo treatment with 1D11, a pan-TGFβ neutralizing antibody, significantly decreased osteolytic ER+ BMETs in association with a decrease in bone-resorbing osteoclasts at the tumor-bone interface. Thus, TGFβ may also be a driver of ER+ BMET osteolysis. Moreover, additive pro-osteolytic effects of tumoral E2 and TGFβ signaling could at least partially explain the greater propensity for ER+ tumors to form BMETs, which are primarily osteolytic.
• Cheng, J. N., Frye, J. B., Whitman, S. A., & Funk, J. L. (2020). Skeletal impact of 17β-estradiol in T cell-deficient mice: age-dependent bone effects and osteosarcoma formation. Clinical & experimental metastasis, 37, 269-281.
  More info

  Estrogen (E)-dependent ER+ breast cancer, the most common breast cancer subtype, is also the most likely to metastasize to bone and form osteolytic lesions. However, ER+ breast cancer bone metastasis human xenograft models in nude mice are rarely studied due to complexities associated with distinguishing possible tumoral vs. bone microenvironmental effects of E. To address this knowledge gap, we systematically examined bone effects of E in developing young (4-week-old) vs. skeletally mature (15-week-old) female Foxn1 nude mice supplemented with commercial 60-day slow-release E pellets and doses commonly used for ER+ xenograft models. E pellets (0.05-0.72 mg) were implanted subcutaneously and longitudinal changes in hind limb bones (vs. age-matched controls) were determined over 6 weeks by dual-energy X-ray absorptiometry (DXA), microCT, radiographic imaging, and histology, concurrent with assessment of serum levels of E and bone turnover markers. All E doses tested induced significant and identical increases in bone density (BMD) and volume (BV/TV) in 4-week-old mice with high bone turnover, increasing bone mineral content (BMC) while suppressing increases in bone area (BA). E supplementation, which caused dose-dependent changes in circulating E that were not sustained, also led to more modest increases in BMD and BV/TV in skeletally mature 15-week-old mice. Notably, E-supplementation induced osteolytic osteosarcomas in a subset of mice independent of age. These results demonstrate that bone effects of E supplementation should be accounted for when assessing ER+ human xenograft bone metastases models.
• Edwards, R. L., Luis, P. B., Nakashima, F., Kunihiro, A. G., Presley, S. H., Funk, J. L., & Schneider, C. (2020). Mechanistic Differences in the Inhibition of NF-κB by Turmeric and Its Curcuminoid Constituents. Journal of agricultural and food chemistry, 68(22), 6154-6160.
  More info

  Turmeric extract, a mixture of curcumin and its demethoxy (DMC) and bisdemethoxy (BDMC) isomers, is used as an anti-inflammatory preparation in traditional Asian medicine. Curcumin is considered to be the major bioactive compound in turmeric but less is known about the relative anti-inflammatory potency and mechanism of the other components, their mixture, or the reduced in vivo metabolites. We quantified inhibition of the NF-κB pathway in cells, adduction to a peptide mimicking IκB kinase β, and the role of cellular glutathione as a scavenger of electrophilic curcuminoid oxidation products, suggested to be the active metabolites. Turmeric extracts (IC 14.5 ± 2.9 μM), DMC (IC 12.1 ± 7.2 μM), and BDMC (IC 8.3 ± 1.6 μM), but not reduced curcumin, inhibited NF-κB similar to curcumin (IC 18.2 ± 3.9 μM). Peptide adduction was formed with turmeric and DMC but not with BDMC, and this correlated with their oxidative degradation. Inhibition of glutathione biosynthesis enhanced the activity of DMC but not BDMC in the cellular assay. These findings suggest that NF-κB inhibition by curcumin and DMC involves their oxidation to reactive electrophiles, whereas BDMC does not require oxidation. Because it has not been established whether curcumin undergoes oxidative transformation in vivo, oxidation-independent BDMC may be a promising alternative to test in clinical trials.
• Funk, J. L., Kunihiro, A. G., Edwards, R. L., Luis, P. B., Nakashima, F., Presley, S., & Schneider, C. (2020). Mechanistic Differences in the Inhibition of NF-κB by Turmeric and Its Curcuminoid Constituents. Journal of Agricultural and Food Chemistry, 68(22), 6154-6160. doi:10.1021/acs.jafc.0c02607
• Funk, J. L., Luis, P. B., Kunihiro, A. G., & Schneider, C. (2020). Incomplete Hydrolysis of Curcumin Conjugates by β‐Glucuronidase: Detection of Complex Conjugates in Plasma. Molecular Nutrition & Food Research, 64(6), 1901037. doi:10.1002/mnfr.201901037
• Going, S. B., Funk, J. L., Roe, D. J., Bland, V. L., Bea, J. W., Blew, R. M., & Lee, V. R. (2020). Influence of Changes in Soft Tissue Composition on Changes in Bone Strength in Peripubertal Girls: The STAR Longitudinal Study. Journal of Bone and Mineral Research, 36(1), 123-132. doi:10.1002/jbmr.4168
• Kunihiro, A. G., Luis, P. B., Frye, J. B., Chew, W., Chow, H. H., Schneider, C., & Funk, J. L. (2020). Bone-Specific Metabolism of Dietary Polyphenols in Resorptive Bone Diseases. Molecular nutrition & food research, 64(14), e2000072.
  More info

  Curcumin prevents bone loss in resorptive bone diseases and inhibits osteoclast formation, a key process driving bone loss. Curcumin circulates as an inactive glucuronide that can be deconjugated in situ by bone's high β-glucuronidase (GUSB) content, forming the active aglycone. Because curcumin is a common remedy for musculoskeletal disease, effects of microenvironmental changes consequent to skeletal development or disease on bone curcumin metabolism are explored.
• Luis, P. B., Kunihiro, A. G., Funk, J. L., & Schneider, C. (2020). Incomplete Hydrolysis of Curcumin Conjugates by β-Glucuronidase: Detection of Complex Conjugates in Plasma. Molecular nutrition & food research, 64(6), e1901037.
  More info

  The diphenol curcumin from turmeric is rapidly metabolized into phase II conjugates following oral administration, resulting in negligible plasma concentration of the free compound, which is considered the bioactive form. Total plasma concentration of curcumin is often quantified after treatment with β-glucuronidase to hydrolyze curcumin-glucuronide, the most abundant conjugate in vivo. The efficiency of enzymatic hydrolysis has not been tested.
• Skiba, M. B., Hopkins, L. L., Hopkins, A. L., Billheimer, D., & Funk, J. L. (2020). Nonvitamin, Nonmineral Dietary Supplement Use in Individuals with Rheumatoid Arthritis. The Journal of nutrition, 150(9), 2451-2459.
  More info

  Over-the-counter, natural product-based (nonvitamin, nonmineral) dietary supplement (NVNM DS) use is common in adults with rheumatoid arthritis (RA), a group at risk for drug-DS interactions, due to polypharmacy, but this use is underreported to health care providers. Recent dramatic changes in US sales of specific NVNM DS suggest that the prevalence and types of NVNM DS used in RA populations may also have shifted.
• Bea, J. W., Hetherington-rauth, M., Kohler, L. N., Funk, J. L., Lee, V. R., Kohler, L., Hetherington-rauth, M., Going, S. B., Funk, J. L., Carranza, N., Blew, R. M., & Bea, J. W. (2019). Low Cruciferous Vegetable Intake is Associated with Elevated Inflammation in Preadolescent Girls: 3140 Board #186 May 31 2:00 PM - 3:30 PM. Medicine and Science in Sports and Exercise, 51(6S), 869-869. doi:10.1249/01.mss.0000563098.53539.a8
• Hetherington-rauth, M., Bea, J. W., Funk, J. L., Sardinha, L. B., Roe, D. J., Lee, V. R., Hetherington-rauth, M., Going, S. B., Funk, J. L., Blew, R. M., & Bea, J. W. (2019). Relationship of cardiometabolic risk biomarkers with DXA and pQCT bone health outcomes in young girls.. Bone, 120, 452-458. doi:10.1016/j.bone.2018.12.013
  More info

  Excess weight exerts the positive effect of mechanical loading on bone during development whereas obesity-related metabolic dysfunction may have a detrimental impact. In adults, the presence of metabolic syndrome and type 2 diabetes has been associated with compromised bone density, quality, and strength, and an increased incidence of fractures. The few studies that have investigated the role of cardio-metabolic disease risk biomarkers (CMR) on bone strength in children have given conflicting results. The aim of this study was to assess the combined and independent relationships of cardio-metabolic biomarkers with total body and regional bone parameters in young girls..In 306, 9-12 year old girls, measures of whole body fat and lean mass, areal bone mineral density (aBMD), bone mineral content (BMC), and bone area (BA) were obtained by dual-energy x-ray absorptiometry (DXA). Bone mineral density (vBMD), geometry, and strength of metaphyseal and diaphyseal regions of the femur and tibia and a diaphyseal region of the radius were measured using peripheral quantitative computed tomography (pQCT). Fasting serum measures of CMRs included, fasting glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), systolic and diastolic blood pressure (SBP and DBP), and C-reactive protein (CRP). Multiple linear regression was used to assess the independent associations of a single CMR with total body and peripheral measures of bone strength after controlling for the other CMRs, plus total body soft tissue, and other relevant covariates. Also, a standardized total CMR composite score, calculated by standardizing to z-scores and then summing z-scores of each CMR biomarker, was regressed with total body and regional bone measures to assess the relationship of a cluster of risk factors with bone health..Total CMR composite score had inverse associations (p < 0.001) with DXA total BMC and BA. Inverse associations (p < 0.05) of CMR risk score with pQCT regional bone measures occurred with total and trabecular BA at the 4% tibia. Of the individual CMRs, HOMA-IR and CRP were significant predictors of total body bone measures by DXA accounting for ~1-5% of the variance in BMC, BA, and/or aBMD. HOMA-IR was the main predictor of regional pQCT bone outcomes, accounting for the most variance in trabecular vBMD (2.6%) and BSI (3.8%) at the 4% tibia. Most markers of dyslipidemia (TG, HDL-C, LDL-C) and hypertension (SBP, DBP) were not associated (p > 0.05) with any total body or regional bone outcomes with the exception of the inverse relationship of LDL-C with total and trabecular BA and the positive relationship of DBP with cortical vBMD at the radius..Of the obesity-related metabolic impairments, insulin resistance and chronic inflammation may compromise whole body bone development in young girls. In particular, trabecular bone, such as that found at the metaphysis of long bones, may be more susceptible to the detrimental effects associated with obesity-related metabolic dysfunction.
• Howe, C. L., Funk, J. L., Skiba, M. B., Howe, C. L., Haiber, K. E., Funk, J. L., & Desalvo, J. C. (2019). Natural Product Dietary Supplement Use by Individuals With Rheumatoid Arthritis: A Scoping Review.. Arthritis care & research, 71(6), 787-797. doi:10.1002/acr.23696
  More info

  Natural product dietary supplements (NDS), defined as non-mineral, non-vitamin, ingested, natural product-derived, substances, are the most frequently used complementary and alternative medicine modality in the US, with musculoskeletal disease being the most frequent reason for their use. Because NDS usage is frequently unreported, and patients with RA may be at higher risk for NDS-related side effects due the underlying nature of the disease and frequent use of complex pharmaceutical regimens, a scoping review of the literature was undertaken to examine population-based patterns of NDS use for RA self-management..Using guidelines for scoping reviews, Allied and Complementary Medicine, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, Embase, Ovid/Medline, and Web of Science databases were searched to identify references presenting primary data related to the prevalence or patterns of use of NDS in RA populations..Twenty-three studies, which were published between 1980 and 2015 and conducted in 11 countries, met the inclusion criteria. The overall prevalence of NDS use in patients with RA was 47% worldwide and did not differ by geographic region. On average, 47% of patients found NDS to be effective and 13% reported adverse side effects, with only 30% informing their physicians about the use of NDS, which in a majority of cases were used concomitantly with RA pharmaceuticals. Marine oils, glucosamine, vinegar, and chondroitin were among the most commonly reported NDS worldwide..Given the apparent communication gap between patients and providers regarding NDS use and higher potential risks associated with this usage in RA, ongoing surveillance of population-based practices may help facilitate RA management and direct future NDS research.
• Kunihiro, A. G., Brickey, J. A., Frye, J. B., Luis, P. B., Schneider, C., & Funk, J. L. (2019). Curcumin, but not curcumin-glucuronide, inhibits Smad signaling in TGFβ-dependent bone metastatic breast cancer cells and is enriched in bone compared to other tissues. The Journal of nutritional biochemistry, 63, 150-156.
  More info

  Breast cancer (BCa) bone metastases (BMETs) drive osteolysis via a feed-forward loop involving tumoral secretion of osteolytic factors (e.g., PTHrP) induced by bone-matrix-derived growth factors (e.g., TGFβ). In prior experiments, turmeric-derived curcumin inhibited in vivo BMET progression and in vitro TGFβ/Smad-signaling in a TGFβ-stimulated PTHrP-dependent human xenograft BCa BMET model (MDA-SA cells). However, it is unclear whether curcumin or curcumin-glucuronide mediates in vivo protection since curcumin-glucuronide is the primary circulating metabolite in rodents and in humans. Thus, effects of curcumin vs. curcumin-glucuronide on Smad-dependent TGFβ signaling were compared in a series of BCa cell lines forming TGFβ-dependent BMET in murine models, and tissue-specific metabolism of curcumin in mice was examined by LC-MS. While curcumin inhibited TGFβ-receptor-mediated Smad2/3 phosphorylation in all BCa cells studied (human MDA-SA, MDA-1833, MDA-2287 and murine 4T1 cells), curcumin-glucuronide did not. Similarly, curcumin, but not curcumin-glucuronide, blocked TGFβ-stimulated secretion of PTHrP from MDA-SA and 4T1 cells. Because the predominant serum metabolite, curcumin-glucuronide, lacked bioactivity, we examined tissue-specific metabolism of curcumin in mice. Compared to serum and other organs, free curcumin (both absolute and percentage of total) was significantly increased in bone, which was also a rich source of enzymatic deglucuronidation activity. Thus, curcumin, and not curcumin-glucuronide, appears to inhibit bone-tropic BCa cell TGFβ-signaling and to undergo site-specific activation (deconjugation) within the bone microenvironment. These findings suggest that circulating curcumin-glucuronide may act as a prodrug that preferentially targets bone, a process that may contribute to the bone-protective effects of curcumin and other highly glucuronidated dietary polyphenols.
• Kunihiro, A. G., Kunihiro, A. G., Brickey, J. A., Frye, J. B., Luis, P. B., Schneider, C., & Funk, J. L. (2019). Abstract 3002: Bone-protective curcumin circulates as a pro-drug conjugate that is activated in bone by β-glucuronidase. Cancer Research, 79, 3002-3002. doi:10.1158/1538-7445.sabcs18-3002
  More info

  Curcumin (CURC), a turmeric-derived dietary polyphenol, prevents osteoclast formation and bone resorption in murine models of arthritis, post-menopausal osteoporosis, and bone metastatic breast cancer despite being rapidly conjugated upon ingestion in both rodents and humans to form curcumin-glucuronide (G-CURC). However, recent studies from our laboratory demonstrate that aglycone CURC is enriched in bone relative to the circulation. Studies were therefore undertaken to compare the anti-resorptive effects of aglycone CURC vs G-CURC and to elucidate mechanisms responsible for enrichment of aglycone CURC in bone, including clinically relevant influences of age, sex, and reproductive status. CURC dose-dependently inhibited RANKL-stimulated osteoclast formation in RAW264.7 cell cultures, while G-CURC was without effect. Likewise, CURC dose-dependently inhibited TGFβ-stimulated PTHrP secretion from MDA-MB-231 breast cancer cells, which readily form PTHrP-driven osteolytic bone metastases in vivo. In wild type (WT) C57BL/6J mice, heparanase (HPSE) and β-glucuronidase (GUSB) were the only enzymes with reported deglucuronidation activity expressed in bone (Western). However, only GUSB was able to recognize G-CURC as a substrate, deconjugating G-CURC to form CURC (LC/MS). Consistent with these findings, tissue-specific levels of CURC were highest in bone (vs. heart, muscle, or kidney) and proportional to tissue specific GUSB enzyme activity. To verify the role of GUSB in CURC bone enrichment, CURC metabolism and GUSB enzyme expression and activity were compared among mice with normal levels of GUSB (C57BL/6J) vs. partial (C3H/HeJ) or complete (mucopolysaccharidosis VII (mps/mps]) deficiencies in GUSB expression. As expected, partial (55% of WT) or complete deficiencies in GUSB expression significantly reduced CURC enrichment in bone. While GUSB can be positively regulated by pharmacologic doses of androgens, neither male sex nor ovariectomy (OVX) altered GUSB activity (per protein) in bone relative to intact females, although a small but statistically significant increase in free curcumin was demonstrated in males (17%) and OVX females (10%). Age did not significantly change the enrichment of CURC in bone of 4 vs 28-week mice. These findings suggest bio-inactive G-CURC acts as pro-drug that is converted to active CURC within bone, independent of sex, age or reproductive status, where it can inhibit the formation of bone resorbing osteoclasts or secretion of osteolytic PTHrP from breast cancer bone metastases. Citation Format: Andrew Kunihiro, Julia A. Brickey, jennifer B. Frye, Paula B. Luis, Claus Schneider, Janet L. Funk. Bone-protective curcumin circulates as a pro-drug conjugate that is activated in bone by β-glucuronidase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3002.
• Kunihiro, A. G., Luis, P. B., Brickey, J. A., Frye, J. B., Chow, H. S., Schneider, C., & Funk, J. L. (2019). Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone. Journal of natural products, 82(3), 500-509.
  More info

  The biological basis for documented in vivo bone-protective effects of turmeric-derived curcumin is unclear since curcumin is barely detectable in serum, being rapidly conjugated to form what is thought to be an inactive glucuronide. Studies were therefore undertaken to test the postulate that antiresorptive effects of curcumin require deconjugation within bone to form the bioactive aglycone and that β-glucuronidase (GUSB), a deconjugating enzyme expressed by hematopoietic marrow cells, facilitates this site-specific transformation. Consistent with this postulate, aglycone, but not glucuronidated, curcumin inhibited RANKL-stimulated osteoclastogenesis, a key curcumin target in bone. Aglycone curcumin, expressed relative to total curcumin, was higher in bone marrow than in serum of curcumin-treated C57BL/6J mice, while remaining a minor component. Ex vivo, under conditions preventing further metabolism of the unstable aglycone, the majority of curcumin-glucuronide delivered to marrow in vivo was hydrolyzed to the aglycone, a process that was inhibited by treatment with saccharolactone, a GUSB inhibitor, or in mice having reduced (C3H/HeJ) or absent (mps/mps) GUSB activity. These findings suggest that curcumin, despite low systemic bioavailability, may be enzymatically activated (deconjugated) within GUSB-enriched bone to exert protective effects, a metabolic process that could also contribute to bone-protective effects of other highly glucuronidated dietary polyphenols.
• Kunihiro, A. G., Whitman, S. A., Kunihiro, A. G., Funk, J. L., Frye, J. B., Egan, M. M., Cheng, J. N., Brickey, J. A., & Alvord, L. A. (2019). Abstract 2042: Modeling estrogen receptor-positive breast cancer bone metastasis to query osteolytic effects of tumor ER signaling. Tumor Biology, 79, 2042-2042. doi:10.1158/1538-7445.am2019-2042
  More info

  Estrogen receptor α-positive (ER+) breast cancers (BrCAs) have the greatest predilection for forming clinically evident bone metastases (BMETs). To query ERα’s role in osteolytic BrCA BMET progression, tumoral vs bone microenvironment effects of 17β-estradiol (E2) were determined in a human xenograft murine model of ER+ BrCA BMET. Female athymic mice aged 4 weeks (young) or 15 weeks (mature) were inoculated with 1x105 human ER+ MCF-7 BrCA cells via the left cardiac ventricle 2 days post-placement of 60-day release E2 pellets (0.05, 0.10, 0.18, 0.36, & 0.72 mg E2). Osteolytic BMET formation was assessed radiographically and E2effects on bone were determined by DXA and microCT at various time points. The BMET size and proliferation were assessed by immunohistochemical (IHC) analyses at the end of the experiment (42 days). The effect of E2 on tumoral secretion of the osteolytic factor, parathyroid hormone related protein (PTHrP), was determined using a commercially available radioimmunoassay. The incidence and size of osteolytic BMET, which were not evident in the absence of E2 supplementation, were E2 dose-dependent in young mice. In contrast, E2 effects on the bone microenvironment were not dose-dependent, and resulted in identical increases in bone mineral density (BMD) and bone volume (BV/TV). In skeletally immature (young) mice vs skeletally mature mice treated with an identical E2 dose (0.72 mg), which caused significantly different effects on bone turnover, progression of E2-dependent BMET was identical. These results suggest that E2 effects on the tumor, rather than bone, were driving E2-dependency of BMET progression. IHC analysis demonstrated that neither the size of human cytokeratin-positive tumors nor the proportion of Ki67-positive proliferating tumor cells in bone were E2 dose-dependent, suggesting that proliferative effects of E2 could not explain E2-dose dependent differences in osteolytic BMET formation. PTHrP, an osteolytic factor expressed in most clinical BrCA BMET, was E2-inducible ex vivo and secreted in higher levels by tumor cells isolated from BMETs. These results suggest that during ER+ BrCA BMET progression, tumoral effects of E2 not only support ER+ BMET proliferation, but may also have bone-specific effects due to the induction of PTHrP, which may explain the marked osteolytic capacity of the ER+ tumor cells in this model despite a microenvironment where bone volume is markedly increased. Citation Format: Julia N. Cheng, Jennifer B. Frye, Susan A. Whitman, Andrew G. Kunihiro, Madison M. Egan, Julia A. Brickey, Lily A. Alvord, Janet L. Funk. Modeling estrogen receptor-positive breast cancer bone metastasis to query osteolytic effects of tumor ER signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2042.
• Brickey, J. A., Frye, J. B., Funk, J. L., Kunihiro, A. G., & Kunihiro, A. G. (2018). Abstract 2685: Targeting TGFβ signaling pathways in bone metastatic breast cancer cells to limit metastatic progression using curcuminoids, a turmeric-derived natural product. Cancer Research, 78, 2685-2685. doi:10.1158/1538-7445.am2018-2685
  More info

  Tumor-cell TGFβ signaling has been demonstrated to drive osteolytic breast cancer bone metastases (BrCa BMET) in mouse models. This established an important link between the microenvironment and tumor cells in bone, wherein osteoclast-mediated bone resorption stimulates the release of TGFβ from bone matrix, which induces tumoral secretion of osteolytic factors, such as parathyroid-related protein (PTHrP) that drive further osteoclast-mediated bone destruction in a positive feedback loop. These findings have prompted interest in the use of pharmacologic TGFβ inhibitors, currently under development, for the treatment of BrCa BMET. Interestingly, studies have demonstrated antagonistic effects of a natural product, turmeric-derived polyphenols called curcuminoids (CURC), on BrCa BMET progression and TGFβ-inducible, Smad-dependent signaling in a TGFβ-dependent human xenograft model (human MDA-MB-231 [MDA-SA]).The studies described here were undertaken to determine whether this inhibitory effect is generalizable to other BrCa cells that form TGFβ-dependent BMETs (human MDA-1833 and MDA-2287; murine 4T1) and to begin to elucidate the mechanism by which CURC block BrCa cell TGFβ signaling. Analogous to prior findings using MDA-SA cells forming BMET that are dependent on TGFβ-inducible tumoral secretion of PTHrP via Smad and non-Smad (specifically, p38) dependent pathways, CURC inhibited TGFβ inducible activation (phosphorylation) of receptor Smad2 (Western) in all TGFβ-dependent BrCa cell lines tested.In MDA-SA cells, CURC inhibition of TGFβ-stimulated Smad2 phosphorylation was time- and dose-dependent (Western), and associated with decreased expression of a Smad-dependent luciferase reporter gene in transiently transfected cells. In both MDA-SA and 4T1 cells, these changes were accompanied by decreased TGFβ-stimulated PTHrP secretion (RIA). These effects in MDA-SA cells were not associated with changes in the expression of canonical TGFβ signaling proteins, such as Smad anchor for receptor activation (SARA), which is involved in Smad phosphorylation, or Smad4, a required cofactor for Smad-mediated gene transcription. Also unchanged were noncanonical TGFβ-stimulated, Smad-independent signaling pathways (e.g., p38, ERK1/2 or JNK). Of note, however, in all cell lines tested, CURC inhibition of Smad2 phosphorylation was accompanied by a decrease in constitutive Smad2 levels, with variable decreases in the ratio of phosphorylated vs. total Smad levels. These results suggest that CURC can specifically and uniformly inhibit Smad-regulated TGFβ signaling in bone metastatic BCa cells forming TGFβ-dependent osteolytic lesions, an effect that may be mediated, at least in part, by changes in constitutive levels of receptor-regulated Smad expression. Citation Format: Andrew Kunihiro, Julia A. Brickey, Jen B. Frye, Janet L. Funk. Targeting TGFβ signaling pathways in bone metastatic breast cancer cells to limit metastatic progression using curcuminoids, a turmeric-derived natural product [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2685.
• Cheng, J. N., Frye, J. B., Whitman, S. A., Kunihiro, A. G., Kunihiro, A. G., Egan, M. M., Brickey, J. A., & Funk, J. L. (2018). Abstract 2116: Tumor-specific effects of estrogen drive a murine model of human estrogen receptor-positive breast cancer bone metastasis independent of bone microenvironment changes. Cancer Research, 78, 2116-2116. doi:10.1158/1538-7445.am2018-2116
  More info

  Estrogen receptor α-positive (ER+) breast cancers (BrCAs) have the greatest predilection for forming bone metastases (BMETs). To begin to query ERα9s role in osteolytic BrCA BMET progression, tumoral vs bone microenvironment effects of 17β-estradiol (E2) were determined in a human xenograft murine model of ER+ BrCA BMET. For these studies, naive or 17β-estradiol (E2)-treated female athymic mice aged 4 weeks (young) or 15 weeks (mature) were inoculated with 1x105 human ER+ MCF-7 BrCA cells via the left cardiac ventricle 2 days post-placement of 60-day release E2 pellets (0.05, 0.10, 0.18, 0.36, & 0.72 mg E2). For studies examining E2 effects on bone, MCF-7 cells were not inoculated. Osteolytic lesion formation was assessed by hind limb radiographs, and E2 effects on bone were assessed by DXA (Faxitron), μCT (Scanco), and biochemical markers of bone formation or resorption (P1NP and TRAcP, respectively; Immunodiagnostic Systems). BMET incidence and lesion size in young mice were E2 dose-dependent, achieving 100% incidence at the highest dose tested, with smaller lesions and lower incidence occurring in response to lower doses, and no lesions forming in the absence of E2 even after 8 months. In contrast, E2 effects on the bone microenvironment were not dose dependent, and resulted in identical increases in bone mineral density (BMD) and bone volume (BV/TV), primarily via an increase in bone formation. To further query the importance of tumoral vs bone effects of E2 in driving ER+ BrCA progression, the tumoral effects of an identical E2 dose (0.72 mg) were compared in the skeletally immature young mice, which accrued increased bone (BV/TV) due to increases in bone formation in response to E2, vs skeletally mature mice, where E2-induced increases in bone were less marked and primarily driven by decreases in bone resorption. In these two very different bone milieus, progression of E2-dependent BMET was identical. While the relative roles of E2-induced tumor cell proliferation vs osteolytic factor secretion cannot be distinguished here, the development of osteolytic lesions similar in size to those occurring in ER- models driven by tumoral secretion of osteolytic factors, despite a marked increase in bone volume, suggests that tumoral effects of E2 may drive osteolytic ER+ BrCA BMET progression in a bone-specific fashion. Citation Format: Julia N. Cheng, Jennifer B. Frye, Susan A. Whitman, Andrew G. Kunihiro, Madison M. Egan, Julia A. Brickey, Janet L. Funk. Tumor-specific effects of estrogen drive a murine model of human estrogen receptor-positive breast cancer bone metastasis independent of bone microenvironment changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2116.
• DeSalvo, J. C., Skiba, M. B., Howe, C. L., Haiber, K. E., & Funk, J. L. (2018). Natural Product Dietary Supplement Use by Individuals with Rheumatoid Arthritis: A Scoping Review. Arthritis care & research.
  More info

  Natural-product dietary supplements (NDS), defined as non-mineral, non-vitamin, ingested natural product-derived substances, are the most frequently used CAM modality in the United States, with musculoskeletal disease being the most frequent reason for their use. Because NDS usage is frequently unreported and individuals with RA may be at higher risk for NDS-related side effects due the underlying nature of the disease and frequent use of complex pharmaceutical regimens, a scoping review of the literature was undertaken to examine population-based patterns of NDS use for RA self-management.
• Going, S. B., Funk, J. L., Bea, J. W., Hetherington-Rauth, M., Lee, V. R., Blew, R. M., & Lohman, T. G. (2018). Relationship between fat distribution and cardiometabolic risk in Hispanic girls. American Journal of Human Biology, 30(5), e23149. doi:10.1002/ajhb.23149
• Going, S. B., Going, S. B., Roe, D., Roe, D., Funk, J. L., Funk, J. L., Blew, R., Blew, R., Lee, V., Lee, V., Bea, J. W., Bea, J. W., Hetherington-Rauth, M., & Hetherington-Rauth, M. (2018). Relationship between fat distribution and cardiometabolic risk in preadolescent Hispanic girls. American Journal of Human Biology.
• Going, S. B., Lohman, T. G., Wheeler, M. D., Lee, V. R., Roe, D., Hingle, M. D., Funk, J. L., Blew, R. M., Bea, J. W., & Hetherington-Rauth, M. C. (2018). Relative contributions of lean and fat mass to bone strength in young Hispanic and non-Hispanic girls. Bone, 113, 144-150. doi:10.1016/j.bone.2018.05.023
• Going, S. B., Roe, D., Lohman, T. G., Blew, R., Lee, V., Thuraisingam, R., Mosquiera, L., Wertheim, B. C., Hetherington-Rauth, M. C., Funk, J. L., & Bea, J. W. (2018). Anthropometry versus imaging for the prediction of inflammation among Hispanic girls. Obesity (Silver Spring), 26(10), 1594-1602. doi:10.1002/oby.22265
• Hetherington-Rauth, M., Bea, J. W., Blew, R. M., Funk, J. L., Hingle, M. D., Lee, V. R., Roe, D. J., Wheeler, M. D., Lohman, T. G., & Going, S. B. (2018). Relative contributions of lean and fat mass to bone strength in young Hispanic and non-Hispanic girls. Bone, 113, 144-150.
  More info

  With the high prevalence of childhood obesity, especially among Hispanic children, understanding how body weight and its components of lean and fat mass affect bone development is important, given that the amount of bone mineral accrued during childhood can determine osteoporosis risk later in life. The aim of this study was to assess the independent contributions of lean and fat mass on volumetric bone mineral density (vBMD), geometry, and strength in both weight-bearing and non-weight-bearing bones of Hispanic and non-Hispanic girls.
• Hetherington-Rauth, M., Bea, J. W., Blew, R. M., Funk, J. L., Lee, V. R., Roe, D. J., Sardinha, L. B., & Going, S. B. (2018). Relationship of cardiometabolic risk biomarkers with DXA and pQCT bone health outcomes in young girls. Bone, 120, 452-458.
  More info

  Excess weight exerts the positive effect of mechanical loading on bone during development whereas obesity-related metabolic dysfunction may have a detrimental impact. In adults, the presence of metabolic syndrome and type 2 diabetes has been associated with compromised bone density, quality, and strength, and an increased incidence of fractures. The few studies that have investigated the role of cardio-metabolic disease risk biomarkers (CMR) on bone strength in children have given conflicting results. The aim of this study was to assess the combined and independent relationships of cardio-metabolic biomarkers with total body and regional bone parameters in young girls.
• Hetherington-Rauth, M., Bea, J. W., Lee, V. R., Blew, R. M., Funk, J. L., Lohman, T. G., & Going, S. B. (2018). Relationship between fat distribution and cardiometabolic risk in Hispanic girls. American journal of human biology : the official journal of the Human Biology Council, 30(5), e23149.
  More info

  In adults, certain body fat depots have greater impact on cardiometabolic risk than total adiposity. Whether similar relationships exist in children is uncertain. The aim of this study was to examine the relationships among dual x-ray absorptiometry (DXA) measures of body fat distribution and total body adiposity with cardiometabolic risk factors in Hispanic girls.
• Lukefahr, A. L., McEvoy, S., Alfafara, C., & Funk, J. L. (2018). Drug-induced autoimmune hepatitis associated with turmeric dietary supplement use. BMJ case reports, 2018.
  More info

  Turmeric dietary supplement sales, which accounted for US$69 million in spending in 2016, have been increasing exponentially in the USA, making this one of the most popular botanical supplements sold in the USA. Herbal supplement use, which is generally regarded as safe by consumers, is not usually reported to healthcare providers. We reported here on a case of autoimmune hepatitis, occurring in a 71-year-old woman taking turmeric dietary supplements for the maintenance of cardiovascular health, which resolved rapidly following discontinuation of the turmeric supplements. Of particular note, turmeric use was not documented in the patient's medical records and the potential causative role of the turmeric supplementation was ultimately identified by the patient rather than the healthcare providers. To our knowledge, this is the first documented report of turmeric supplement-induced autoimmune hepatitis.
• Roe, D. J., Funk, J., Bea, J. W., Hetherington‐Rauth, M., Wertheim, B. C., Mosquiera, L., Thuraisingam, R., Lee, V., Blew, R., Lohman, T., & Going, S. (2018). Anthropometry Versus Imaging for Prediction of Inflammation Among Hispanic Girls. Obesity, 26(10), 1594-1602. doi:10.1002/oby.22265
• Skiba, M. B., Luis, P. B., Alfafara, C., Billheimer, D., Schneider, C., & Funk, J. L. (2018). Curcuminoid Content and Safety-Related Markers of Quality of Turmeric Dietary Supplements Sold in an Urban Retail Marketplace in the United States. Molecular nutrition & food research, e1800143.
  More info

  Turmeric is a top selling dietary supplement (DS) in the United States with rapidly expanding usage. Therefore, turmeric DS formulations available for sale in an urban US retail marketplace are analyzed, and point of sale information is related to measures of quality relevant to safety.
• Funk, J. L., Alfafara, C., Mcevoy, S., Strom, M., & Lukefahr, A. L. (2017). Turmeric Dietary Supplement-Induced Autoimmune Hepatitis: A Case Report. The FASEB Journal, 31. doi:10.1096/fasebj.31.1_supplement.lb354
  More info

  Autoimmune hepatitis (AIH), a chronic disorder of unknown etiology characterized by hypergammaglobulinemia and autoantibody positivity, is induced by drug injury in a minority of cases. Herbal supp...
• Hetherington-Rauth, M. C., Bea, J. W., Blew, R., Lee, V., Funk, J. L., Going, S. B., Lohman, T. G., Hetherington-Rauth, M. C., Bea, J. W., Blew, R., Lee, V., Funk, J. L., Going, S. B., & Lohman, T. G. (2017). Comparison of direct measures of adiposity with indirect measures for predicting cardiometabolic risk factors in preadolescent girls. Nutrition Journal.
  More info

  In Press
• Hetherington-Rauth, M., Bea, J. W., Lee, V. R., Blew, R. M., Funk, J., Lohman, T. G., & Going, S. B. (2017). Comparison of direct measures of adiposity with indirect measures for assessing cardiometabolic risk factors in preadolescent girls. Nutrition journal, 16(1), 15.
  More info

  Childhood overweight and obesity remains high, contributing to cardiometabolic risk factors at younger ages. It is unclear which measures of adiposity serve as the best proxies for identifying children at metabolic risk. This study assessed whether DXA-derived direct measures of adiposity are more strongly related to cardiometabolic risk factors in children than indirect measures.
• Hopkins, A. L., Funk, J. L., Strom, M., Hopkins, A. L., Haiber, K. E., Funk, J. L., Feng, L., & Desalvo, J. (2017). Natural Product Supplement Use for Rheumatoid Arthritis Self-Management in the United States: A Literature Review. The FASEB Journal, 31. doi:10.1096/fasebj.31.1_supplement.lb365
  More info

  Natural-product dietary supplements (NDS) are a frequently used complementary and alternative medicine (CAM) modality in the United States (U.S.), with complaints of musculoskeletal symptoms being ...
• Hopkins, A. L., Funk, J. L., Strom, M., Hopkins, L. L., Hopkins, A. L., Groff, R., Funk, J. L., & Feng, L. (2017). Dietary Supplements and Nutritional Approaches Used for Rheumatoid Arthritis Self‐Management. The FASEB Journal, 31. doi:10.1096/fasebj.31.1_supplement.lb396
  More info

  The autoimmune disease, rheumatoid arthritis (RA), leads to joint pain and inflammation. Pharmaceutical drugs, including methotrexate, as well as antibodies directed against inflammatory cytokines ...
• Kunihiro, A. G., Whitman, S. A., Kunihiro, A. G., Funk, J. L., Frye, J. B., & Cheng, J. N. (2017). Abstract P4-06-08: Characterization of an estrogen-dependent murine model of human estrogen receptor-positive breast cancer bone metastasis. Cancer Research, 77. doi:10.1158/1538-7445.sabcs16-p4-06-08
• Schneider, C., Kunihiro, A. G., Luis, P. B., Kunihiro, A. G., Funk, J. L., Frye, J. B., & Brickey, J. A. (2017). Abstract P6-18-01: Site-specific activation of curcuminoids in the breast cancer bone metastases microenvironment. Cancer Research, 77. doi:10.1158/1538-7445.sabcs16-p6-18-01
• Strom, M., Alfafara, C., Desalvo, J., Mccallum, M., Pace, T. W., Chow, S., Levinsky, D., Ruderman, E., Billheimer, D., Funk, J. L., & Hopkins, L. C. (2017). Eligibility of Rheumatoid Arthritis Patients for a Phase 1b Clinical Trial Evaluating Turmeric Supplementation. The FASEB Journal, 31. doi:10.1096/fasebj.31.1_supplement.lb353
  More info

  Rheumatoid arthritis (RA) is an autoimmune disease that primarily targets the joints, leading to synovial inflammation. Turmeric supplementation markedly reduces joint inflammation in pre-clinical ...
• Cheng, J. N., Frye, J. B., Whitman, S. A., & Funk, J. L. (2016). Characterizing Bone Tropism of Human ER+ Breast Cancer Cell Lines in a Murine Bone Metastasis Model. The FASEB Journal, 30.
  More info

  IntroductionBreast cancer patients with estrogen receptor-positive (ER+) tumors have the highest rate of developing clinically evident osteolytic bone metastasis. However, pre-clinical models of ER...
• Funk, J. L., Frye, J. B., Oyarzo, J. N., Chen, J., Zhang, H., & Timmermann, B. N. (2016). Anti-Inflammatory Effects of the Essential Oils of Ginger (Zingiber officinale Roscoe) in Experimental Rheumatoid Arthritis. PharmaNutrition, 4(3), 123-131.
  More info

  Ginger and its extracts have been used traditionally as anti-inflammatory remedies, with a particular focus on the medicinal properties of its phenolic secondary metabolites, the gingerols. Consistent with these uses, potent anti-arthritic effects of gingerol-containing extracts were previously demonstrated by our laboratory using an experimental model of rheumatoid arthritis, streptococcal cell wall (SCW)-induced arthritis. In this study, anti-inflammatory effects of ginger's other secondary metabolites, the essential oils (GEO), which contain terpenes with reported phytoestrogenic activity, were assessed in female Lewis rats with SCW-induced arthritis. GEO (28 mg/kg/d ip) prevented chronic joint inflammation, but altered neither the initial acute phase of joint swelling nor granuloma formation at sites of SCW deposition in liver. Pharmacologic doses of 17-β estradiol (200 or 600 μg/kg/d sc) elicited the same pattern of anti-inflammatory activity, suggesting that GEO could be acting as a phytoestrogen. However, contrary to this hypothesis, GEO had no in vivo effect on classic estrogen target organs, such as uterus or bone. En toto, these results suggest that ginger's anti-inflammatory properties are not limited to the frequently studied phenolics, but may be attributable to the combined effects of both secondary metabolites, the pungent-tasting gingerols and as well as its aromatic essential oils.
• Kunihiro, A. G., Kunihiro, A. G., Frye, J. B., Luis, P. B., Schneider, C., & Funk, J. L. (2016). Site-Specific Deglucuronidation of Turmeric-Derived Curcuminoids in Bone. The FASEB Journal.
  More info

  IntroductionThe majority of women with advanced breast cancer (BCa) develop osteolytic bone metastases. Our laboratory has previously demonstrated that curcuminoids, bioactive components isolated f...
• Bea, J., Lee, V., Blew, R., Funk, J., & Going, S. (2015). Cardiovascular Risk Related to Body Fat and Physical Activity in Young Girls. FASEB JOURNAL, 29.
• Funk, J. L. (2018). From bedside to bench and back again: investigating medicinal effects of turmeric on bone.. Entorno UDLAP.
• Going, S., Funk, J., Thomson, C., Vassallo, D., Jacobs, E., Blew, R., & Lee, V. (2015). Physical Activity is Associated with Lower Adiposity Independent of Diet Quality in Adolescent Girls. The FASEB Journal, 29(S1). doi:10.1096/fasebj.29.1_supplement.135.8
• Hetherington-Rauth, M., Bea, J. W., Lee, V., Blew, R., Funk, J. L., Roe, D., & Going, S. B. (2017). Relationship between fat distribution and cardiometabolic risk in preadolescent Hispanic girls. The Journal of Pediatrics.
• Vassallo, D., Thomson, C., Funk, J., Jacobs, E., Blew, R., Lee, V., & Going, S. (2015). Physical Activity is Associated with Lower Adiposity Independent of Diet Quality in Adolescent Girls. FASEB JOURNAL, 29.
• Funk, J. L., Frye, J. B., Davis-Gorman, G., Spera, A. L., Bernas, M. J., Witte, M. H., Weinand, M. E., Timmermann, B. N., McDonagh, P. F., & Ritter, L. (2013). Curcuminoids Limit Neutrophil-Mediated Reperfusion Injury in Experimental Stroke by Targeting the Endothelium. MICROCIRCULATION, 20(6), 544-554.
• Funk, J. L., Frye, J. B., Davis-Gorman, G., Spera, A. L., Bernas, M. J., Witte, M. H., Weinand, M. E., Timmermann, B. N., McDonagh, P. F., & Ritter, L. (2013). Curcuminoids limit neutrophil-mediated reperfusion injury in experimental stroke by targeting the endothelium. Microcirculation (New York, N.Y. : 1994), 20(6), 544-54.
  More info

  We sought to test the hypothesis that turmeric-derived curcuminoids limit reperfusion brain injury in an experimental model of stroke via blockade of early microvascular inflammation during reperfusion.
• Hopkins, A. L., Lamm, M. G., Funk, J. L., & Ritenbaugh, C. (2013). Hibiscus sabdariffa L. in the treatment of hypertension and hyperlipidemia: A comprehensive review of animal and human studies. FITOTERAPIA, 85, 84-94.
• Hopkins, A. L., Lamm, M. G., Funk, J. L., & Ritenbaugh, C. (2013). Hibiscus sabdariffa L. in the treatment of hypertension and hyperlipidemia: a comprehensive review of animal and human studies. Fitoterapia, 85, 84-94.
  More info

  The effectiveness of Hibiscus sabdariffa L. (HS) in the treatment of risk factors associated with cardiovascular disease is assessed in this review by taking a comprehensive approach to interpreting the randomized clinical trial (RCT) results in the context of the available ethnomedical, phytochemical, pharmacological, and safety and toxicity information. HS decoctions and infusions of calyxes, and on occasion leaves, are used in at least 10 countries worldwide in the treatment of hypertension and hyperlipidemia with no reported adverse events or side effects. HS extracts have a low degree of toxicity with a LD50 ranging from 2,000 to over 5,000mg/kg/day. There is no evidence of hepatic or renal toxicity as the result of HS extract consumption, except for possible adverse hepatic effects at high doses. There is evidence that HS acts as a diuretic, however in most cases the extract did not significantly influence electrolyte levels. Animal studies have consistently shown that consumption of HS extract reduces blood pressure in a dose dependent manner. In RCTs, the daily consumption of a tea or extract produced from HS calyxes significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults with pre to moderate essential hypertension and type 2 diabetes. In addition, HS tea was as effective at lowering blood pressure as the commonly used blood pressure medication Captropril, but less effective than Lisinopril. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides were lowered in the majority of normolipidemic, hyperlipidemic, and diabetic animal models, whereas high-density lipoprotein cholesterol (HDL-C) was generally not affected by the consumption of HS extract. Over half of the RCTs showed that daily consumption of HS tea or extracts had favorable influence on lipid profiles including reduced total cholesterol, LDL-C, triglycerides, as well as increased HDL-C. Anthocyanins found in abundance in HS calyxes are generally considered the phytochemicals responsible for the antihypertensive and hypocholesterolemic effects, however evidence has also been provided for the role of polyphenols and hibiscus acid. A number of potential mechanisms have been proposed to explain the hypotensive and anticholesterol effects, but the most common explanation is the antioxidant effects of the anthocyanins inhibition of LDL-C oxidation, which impedes atherosclerosis, an important cardiovascular risk factor. This comprehensive body of evidence suggests that extracts of HS are promising as a treatment of hypertension and hyperlipidemia, however more high quality animal and human studies informed by actual therapeutic practices are needed to provide recommendations for use that have the potential for widespread public health benefit.
• Hutchison, J., Cohen, Z., Onyeagucha, B. C., Funk, J. L., & Nelson, M. A. (2013). How microRNAs influence both hereditary and inflammatory-mediated colon cancers. Cancer Genet, 206(9-10):309-16.
• Hutchison, J., Cohen, Z., Onyeagucha, B. C., Funk, J., & Nelson, M. A. (2013). How microRNAs influence both hereditary and inflammatory-mediated colon cancers. CANCER GENETICS, 206(9-10), 309-316.
• Hutchison, J., Cohen, Z., Onyeagucha, B. C., Funk, J., & Nelson, M. A. (2013). How microRNAs influence both hereditary and inflammatory-mediated colon cancers. Cancer genetics, 206(9-10), 309-16.
  More info

  MicroRNAs have emerged as important post-translational regulators of gene expression and are involved in several physiological and pathological states including the pathogenesis of human colon cancers. In regards to tumor development, microRNAs can act as oncogenes or tumor suppressors. Two hereditary predispositions (i.e., Lynch syndrome and familial adenomatous polyposis) contribute to the development of colon cancer. In addition, individuals who suffer from inflammatory bowel diseases such as Crohn's disease or ulcerative colitis have a higher risk of developing colon cancer. Here, we discuss the occurrence of the deregulated expression of microRNAs in colon cancer that arise as a result of hereditary predisposition and inflammatory bowel disease.
• Wright, L. E., Frye, J. B., Gorti, B., Timmermann, B. N., & Funk, J. L. (2013). Bioactivity of Turmeric-derived Curcuminoids and Related Metabolites in Breast Cancer. CURRENT PHARMACEUTICAL DESIGN, 19(34), 6218-6225.
• Wright, L. E., Frye, J. B., Gorti, B., Timmermann, B. N., & Funk, J. L. (2013). Bioactivity of turmeric-derived curcuminoids and related metabolites in breast cancer. Current pharmaceutical design, 19(34), 6218-25.
  More info

  While the chemotherapeutic effect of curcumin, one of three major curcuminoids derived from turmeric, has been reported, largely unexplored are the effects of complex turmeric extracts more analogous to traditional medicinal preparations, as well as the relative importance of the three curcuminoids and their metabolites as anti-cancer agents. These studies document the pharmacodynamic effects of chemically-complex turmeric extracts relative to curcuminoids on human breast cancer cell growth and tumor cell secretion of parathyroid hormone-related protein (PTHrP), an important driver of cancer bone metastasis. Finally, relative effects of structurallyrelated metabolites of curcuminoids were assessed on the same endpoints. We report that 3 curcuminoid-containing turmeric extracts differing with respect to the inclusion of additional naturally occurring chemicals (essential oils and/or polar compounds) were equipotent in inhibiting human breast cancer MDA-MB-231 cell growth (IC50=10-16µg/mL) and secretion of osteolytic PTHrP (IC50=2-3µg/mL) when concentrations were normalized to curcuminoid content. Moreover, these effects were curcuminoid-specific, as botanically-related gingerol containing extracts had no effect. While curcumin and bis-demethoxycurcumin were equipotent to each other and to the naturally occurring curcuminoid mixture (IC50=58µM), demethoxycurcumin did not have any effect on cell growth. However, each of the individual curcuminoids inhibited PTHrP secretion (IC50=22-31µM) to the same degree as the curcuminoid mixture (IC50=16µM). Degradative curcuminoid metabolites (vanillin and ferulic acid) did not inhibit cell growth or PTHrP, while reduced metabolites (tetrahydrocurcuminoids) had inhibitory effects on cell growth and PTHrP secretion but only at concentrations ≥10-fold higher than the curcuminoids. These studies emphasize the structural and biological importance of curcuminoids in the anti-breast cancer effects of turmeric and contradict recent assertions that certain of the curcuminoid metabolites studied here mediate these anti-cancer effects.
• Wright, L. E., Frye, J. B., Lukefahr, A. L., Timmermann, B. N., Mohammad, K. S., Guise, T. A., & Funk, J. L. (2013). Curcuminoids Block TGF-beta Signaling in Human Breast Cancer Cells and Limit Osteolysis in a Murine Model of Breast Cancer Bone Metastasis. JOURNAL OF NATURAL PRODUCTS, 76(3), 316-321.
• Wright, L. E., Frye, J. B., Lukefahr, A. L., Timmermann, B. N., Mohammad, K. S., Guise, T. A., & Funk, J. L. (2013). Curcuminoids block TGF-β signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis. Journal of natural products, 76(3), 316-21.
  More info

  Effects of curcuminoids on breast cancer cell secretion of the bone-resorptive peptide parathyroid hormone-related protein (PTHrP) and on lytic breast cancer bone metastasis were evaluated. In vitro, transforming growth factor (TGF)-β-stimulated PTHrP secretion was inhibited by curcuminoids (IC50 = 24 μM) in MDA-MB-231 human breast cancer cells independent of effects on cell growth inhibition. Effects on TGF-β signaling revealed decreases in phospho-Smad2/3 and Ets-1 protein levels with no effect on p-38 MAPK-mediated TGF-β signaling. In vivo, mice were inoculated with MDA-MB-231 cells into the left cardiac ventricle and treated ip every other day with curcuminoids (25 or 50 mg/kg) for 21 days. Osteolytic bone lesion area was reduced up to 51% (p < 0.01). Consistent with specific effects on bone osteolysis, osteoclast number at the bone-tumor interface was reduced up to 53% (p < 0.05), while tumor area within bone was unaltered. In a separate study, tumor mass in orthotopic mammary xenografts was also unaltered by treatment. These data suggest that curcuminoids prevent TGF-β induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells.
• Chandra, S., Romero-Aleshire, M. J., Cai, Q. i., Funk, J., & Brooks, H. L. (2012). Role of Estrogen in the Urinary Concentrating Mechanism. FASEB JOURNAL, 26.
• Frye, J. B., Lukefahr, A. L., Wright, L. E., Marion, S. L., Hoyer, P. B., & Funk, J. L. (2012). Modeling Perimenopause in Sprague-Dawley Rats by Chemical Manipulation of the Transition to Ovarian Failure. COMPARATIVE MEDICINE, 62(3), 193-202.
• Frye, J. B., Lukefahr, A. L., Wright, L. E., Marion, S. L., Hoyer, P. B., & Funk, J. L. (2012). Modeling perimenopause in Sprague-Dawley rats by chemical manipulation of the transition to ovarian failure. Comparative medicine, 62(3), 193-202.
  More info

  Various age-related diseases increase in incidence during perimenopause. However, our understanding of the effects of aging compared with hormonal changes of perimenopause in mediating these disease risks is incomplete, in part due to the lack of an experimental perimenopause model. We therefore aimed to determine whether manipulation of the transition to ovarian failure in rats via the use of 4-vinylcyclohexene diepoxide (VCD) could be used to model and accelerate hormonal changes characteristic of perimenopause. We examined long-term (11 to 20 mo), dose-dependent effects of VCD on reproductive function in 1- and 3-mo-old female Sprague-Dawley rats. Twenty-five daily doses of VCD (80 or 160 mg/kg daily compared with vehicle alone) depleted ovarian follicles in a dose-dependent fashion in rats of both ages, accelerated the onset of acyclicity, and caused dose-dependent increases in follicle-stimulating hormone that exceeded those naturally occurring with age in control rats but left serum levels of 17β-estradiol unchanged, with continued ovarian production of androstenedione. High-dose VCD caused considerable nonovarian toxicities in 3-mo-old Sprague-Dawley rats, making this an unsuitable model. In contrast, 1-mo-old rats had more robust dose-dependent increases in follicle-stimulating hormone without evidence of systemic toxicity in response to either VCD dose. Because perimenopause is characterized by an increase in follicle-stimulating hormone with continued secretion of ovarian steroids, VCD acceleration of an analogous hormonal milieu in 1-mo-old Sprague-Dawley rats may be useful for probing the hormonal effects of perimenopause on age-related disease risk.
• Funk, J. L., Frye, J. B., Wright, L. E., & Timmermann, B. N. (2012). Effects of Ginger (Zingiber officialis L) on Inflammation-Induced Bone Loss. FASEB JOURNAL, 26.
• Lukefahr, A. L., Frye, J. B., Wright, L. E., Marion, S. L., Hoyer, P. B., & Funk, J. L. (2012). Decreased bone mineral density in rats rendered follicle-deplete by an ovotoxic chemical correlates with changes in follicle-stimulating hormone and inhibin A. Calcified tissue international, 90(3), 239-49.
  More info

  Bone loss during perimenopause, an estrogen-sufficient period, correlates with elevated serum follicle-stimulating hormone (FSH) and decreased inhibins A and B. Utilizing a recently described ovotoxin-induced animal model of perimenopause characterized by a prolonged estrogen-replete period of elevated FSH, we examined longitudinal changes in bone mineral density (BMD) and their association with FSH. Additionally, serum inhibin levels were assessed to determine whether elevated FSH occurred secondary to decreased ovarian inhibin production and, if so, whether inhibins also correlated with BMD. BMD of the distal femur was assessed using dual-energy X-ray absorptiometry (DXA) over 19 months in Sprague-Dawley rats treated at 1 month with vehicle or 4-vinylcyclohexene diepoxide (VCD, 80 or 160 mg/kg daily). Serum FSH, inhibins A and B, and 17-ß estradiol (E(2)) were assayed and estrus cyclicity was assessed. VCD caused dose-dependent increases in FSH that exceeded values occurring with natural senescence, hastening the onset and prolonging the duration of persistent estrus, an acyclic but E(2)-replete period. VCD decreased serum inhibins A and B, which were inversely correlated with FSH (r(2) = 0.30 and 0.12, respectively). In VCD rats, significant decreases in BMD (5-13%) occurred during periods of increased FSH and decreased inhibins, while BMD was unchanged in controls. In skeletally mature rats, FSH (r(2) = 0.13) and inhibin A (r(2) = 0.15) correlated with BMD, while inhibin B and E(2) did not. Thus, for the first time, both the hormonal milieu of perimenopause and the association of dynamic perimenopausal changes in FSH and inhibin A with decreased BMD have been reproduced in an animal model.
• Timmermann, B. N., Funk, J. L., & Frye, J. B. (2012). P01.55. Turmeric inhibits parathyroid hormone-related protein (PTHrP) secretion from human rheumatoid synoviocytes. BMC Complementary and Alternative Medicine, 12(1). doi:10.1186/1472-6882-12-s1-p55
  More info

  Purpose Excessive production of parathyroid hormone-related protein (PTHrP) by tumor-like synoviocytes contributes to joint destruction in rheumatoid arthritis (RA). Having previously demonstrated that curcuminoid-only and essential oil-only fractions of turmeric prevent joint destruction in an animal model of RA, we hypothesized that synoviocyte PTHrP production could be one signaling pathway targeted by turmeric (Curcuma longa L.) in RA.
• Farr, J. N., Funk, J. L., Chen, Z., Lisse, J. R., Blew, R. M., Lee, V. R., Laudermilk, M., Lohman, T. G., & Going, S. B. (2011). Skeletal Muscle Fat Content Is Inversely Associated With Bone Strength in Young Girls. JOURNAL OF BONE AND MINERAL RESEARCH, 26(9), 2217-2225.
• Farr, J. N., Funk, J. L., Chen, Z., Lisse, J. R., Blew, R. M., Lee, V. R., Laudermilk, M., Lohman, T. G., & Going, S. B. (2011). Skeletal muscle fat content is inversely associated with bone strength in young girls. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 26(9), 2217-25.
  More info

  Childhood obesity is an established risk factor for metabolic disease. The influence of obesity on bone development, however, remains controversial and may depend on the pattern of regional fat deposition. Therefore, we examined the associations of regional fat compartments of the calf and thigh with weight-bearing bone parameters in girls. Data from 444 girls aged 9 to 12 years from the Jump-In: Building Better Bones study were analyzed. Peripheral quantitative computed tomography (pQCT) was used to assess bone parameters at metaphyseal and diaphyseal sites of the femur and tibia along with subcutaneous adipose tissue (SAT, mm(2) ) and muscle density (mg/cm(3) ), an index of skeletal muscle fat content. As expected, SAT was positively correlated with total-body fat mass (r = 0.87-0.89, p 
• Morrison, H., Frye, J., Davis-Gorman, G., Funk, J., McDonagh, P., Stahl, G., & Ritter, L. (2011). The Contribution of Mannose Binding Lectin to Reperfusion Injury after Ischemic Stroke. CURRENT NEUROVASCULAR RESEARCH, 8(1), 52-63.
• Morrison, H., Frye, J., Davis-Gorman, G., Funk, J., McDonagh, P., Stahl, G., & Ritter, L. (2011). The contribution of mannose binding lectin to reperfusion injury after ischemic stroke. Current neurovascular research, 8(1), 52-63.
  More info

  After complement system (CS) activation, the sequential production of complement products increases cell injury and death through opsonophagocytosis, cytolysis, adaptive, and inflammatory cell responses. These responses potentiate cerebral ischemia-reperfusion (IR) injury after ischemic stroke and reperfusion. Activation of the CS via mannose binding lectin (MBL)-initiated lectin pathway is known to increase tissue damage in response to IR in muscle, myocardium and intestine tissue. In contrast, the contribution of this pathway to cerebral IR injury, a neutrophil-mediated event, is less clear. Therefore, we investigated the potential protective role of MBL deficiency in neutrophil-mediated cerebral injury after IR. Using an intraluminal filament method, neutrophil activation and cerebral injury were compared between MBL-deficient and wild type C57Bl/6 mice subjected to 60 minutes of MCA ischemia and reperfusion. Systemic neutrophil activation was not decreased in MBL-deficient animals after IR. In MBL-deficient animals, cerebral injury was significantly decreased only in the striatum (p < 0.05). Despite MBL deficiency, C3 depositions were evident in the injured hemisphere during reperfusion. These results indicate that while MBL deficiency results in a modest protection of a sub-cortical brain region during IR, redundant complement pathway activation may overwhelm further beneficial effects of MBL deficiency during reperfusion.
• Ritter, L., Davidson, L., Henry, M., Davis-Gorman, G., Morrison, H., Frye, J. B., Cohen, Z., Chandler, S., McDonagh, P., & Funk, J. L. (2011). Exaggerated Neutrophil-Mediated Reperfusion Injury after Ischemic Stroke in a Rodent Model of Type 2 Diabetes. MICROCIRCULATION, 18(7), 552-561.
• Ritter, L., Davidson, L., Henry, M., Davis-Gorman, G., Morrison, H., Frye, J. B., Cohen, Z., Chandler, S., McDonagh, P., & Funk, J. L. (2011). Exaggerated neutrophil-mediated reperfusion injury after ischemic stroke in a rodent model of type 2 diabetes. Microcirculation (New York, N.Y. : 1994), 18(7), 552-61.
  More info

  We tested the hypothesis that both chronic and acute inflammatory processes contribute to worse reperfusion injury and stroke outcome in an experimental model of T2DM.
• Wright, L. E., Frye, J. B., Lukefahr, A. L., Marion, S. L., Hoyer, P. B., Besselsen, D. G., & Funk, J. L. (2011). 4-Vinylcyclohexene diepoxide (VCD) inhibits mammary epithelial differentiation and induces fibroadenoma formation in female Sprague Dawley rats. REPRODUCTIVE TOXICOLOGY, 32(1), 26-32.
• Wright, L. E., Frye, J. B., Lukefahr, A. L., Marion, S. L., Hoyer, P. B., Besselsen, D. G., & Funk, J. L. (2011). 4-Vinylcyclohexene diepoxide (VCD) inhibits mammary epithelial differentiation and induces fibroadenoma formation in female Sprague Dawley rats. Reproductive toxicology (Elmsford, N.Y.), 32(1), 26-32.
  More info

  4-Vinylcyclohexene diepoxide (VCD), an occupational chemical that targets ovarian follicles and accelerates ovarian failure in rodents, was used to test the effect of early-onset reproductive senescence on mammary fibroadenoma formation. One-month female Sprague Dawley rats were dosed with VCD (80 mg/kg or 160 mg/kg) and monitored for 22 months for persistent estrus and tumor development. Only high-dose VCD treatment accelerated the onset of persistent estrus relative to controls. However, both doses of VCD accelerated mammary tumor onset by 5 months, increasing incidence to 84% (vs. 38% in controls). Tumor development was independent of time in persistent estrus, 17 β-estradiol, androstenedione and prolactin. Delay in VCD administration until after completion of mammary epithelial differentiation (3 months) did not alter tumor formation despite acceleration of ovarian senescence. VCD administration to 1-month rats acutely decreased mammary alveolar bud number and expression of β-casein, suggesting that VCD's tumorigenic effect requires exposure during mammary epithelial differentiation.
• Craig, Z. R., Marion, S. L., Funk, J. L., Bouxsein, M. L., & Hoyer, P. B. (2010). Retaining Residual Ovarian Tissue following Ovarian Failure Has Limited Influence on Bone Loss in Aged Mice. Journal of osteoporosis, 2010.
  More info

  Previous work showed that retaining residual ovarian tissue protects young mice from accelerated bone loss following ovarian failure. The present study was designed to determine whether this protection is also present in aged animals. Aged (9-12 months) C57BL/6Hsd female mice were divided into: CON (vehicle), VCD (160 mg/kg; 15d), or OVX (ovariectomized). Lumbar BMD was monitored by DXA and μCT used to assess vertebral microarchitecture. BMD was not different between VCD and CON at any time point but was lower (P < .05) than baseline, starting 1 month after ovarian failure in VCD and OVX mice. Following μCT analysis there were no differences between CON and VCD, but OVX mice had lower bone volume fraction, trabecular thickness, and a trend for decreased connectivity density. These findings provide evidence that retention of residual ovarian tissue may protect aged follicle-depleted mice from accelerated bone loss to a lesser extent than that observed in young mice.
• Funk, J. L., Craig, Z. R., Marion, S. L., Bouxsein, M. L., & Hoyer, P. B. (2010). Retaining Residual Ovarian Tissue following Ovarian Failure Has Limited Influence on Bone Loss in Aged Mice. Journal of Osteoporosis, 2010, 1-6. doi:10.4061/2010/157323
• Funk, J. L., Frye, J. B., Oyarzo, J. N., Zhang, H., & Timmermann, B. N. (2010). Anti-Arthritic Effects and Toxicity of the Essential Oils of Turmeric (Curcuma longa L.). JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 58(2), 842-849.
• Funk, J. L., Frye, J. B., Oyarzo, J. N., Zhang, H., & Timmermann, B. N. (2010). Anti-arthritic effects and toxicity of the essential oils of turmeric (Curcuma longa L.). Journal of agricultural and food chemistry, 58(2), 842-9.
  More info

  Turmeric (Curcuma longa L., Zingiberaceae) rhizomes contain two classes of secondary metabolites, curcuminoids and the less well-studied essential oils. Having previously identified potent anti-arthritic effects of the curcuminoids in turmeric extracts in an animal model of rheumatoid arthritis (RA), studies were undertaken to determine whether the turmeric essential oils (TEO) were also joint protective using the same experimental model. Crude or refined TEO extracts dramatically inhibited joint swelling (90-100% inhibition) in female rats with streptococcal cell wall (SCW)-induced arthritis when extracts were administered via intraperitoneal injection to maximize uniform delivery. However, this anti-arthritic effect was accompanied by significant morbidity and mortality. Oral administration of a 20-fold higher dose TEO was nontoxic, but only mildly joint-protective (20% inhibition). These results do not support the isolated use of TEO for arthritis treatment but, instead, identify potential safety concerns in vertebrates exposed to TEO.
• Funk, J. L., Wright, L. E., Frye, J. B., & Timmermann, B. N. (2010). Protection of Trabecular Bone in Ovariectomized Rats by Turmeric (Curcuma longa L.) Is Dependent on Extract Composition. Journal of Agricultural and Food Chemistry, 58(17), 9498-9504. doi:10.1021/jf101873f
• Wright, L. E., Frye, J. B., Timmermann, B. N., & Funk, J. L. (2010). Protection of Trabecular Bone in Ovariectomized Rats by Turmeric (Curcuma longa L.) Is Dependent on Extract Composition. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 58(17), 9498-9504.
• Wright, L. E., Frye, J. B., Timmermann, B. N., & Funk, J. L. (2010). Protection of trabecular bone in ovariectomized rats by turmeric (Curcuma longa L.) is dependent on extract composition. Journal of agricultural and food chemistry, 58(17), 9498-504.
  More info

  Extracts prepared from turmeric (Curcuma longa L., [Zingiberaceae]) containing bioactive phenolic curcuminoids were evaluated for bone-protective effects in a hypogonadal rat model of postmenopausal osteoporosis. Three-month female Sprague-Dawley rats were ovariectomized (OVX) and treated with a chemically complex turmeric fraction (41% curcuminoids by weight) or a curcuminoid-enriched turmeric fraction (94% curcuminoids by weight), both dosed at 60 mg/kg 3x per week, or vehicle alone. Effects of two months of treatment on OVX-induced bone loss were followed prospectively by serial assessment of bone mineral density (BMD) of the distal femur using dual-energy X-ray absorptiometry (DXA), while treatment effects on trabecular bone microarchitecture were assessed at two months by microcomputerized tomography (microCT). Chemically complex turmeric did not prevent bone loss, however, the curcuminoid-enriched turmeric prevented up to 50% of OVX-induced loss of trabecular bone and also preserved the number and connectedness of the strut-like trabeculae. These results suggest that turmeric may have bone-protective effects but that extract composition is a critical factor.
• Funk, J. L., Frye, J. B., Oyarzo, J. N., & Timmermann, B. N. (2009). Comparative Effects of Two Gingerol-Containing Zingiber officinale Extracts on Experimental Rheumatoid Arthritis. JOURNAL OF NATURAL PRODUCTS, 72(3), 403-407.
• Funk, J. L., Frye, J. B., Oyarzo, J. N., & Timmermann, B. N. (2009). Comparative effects of two gingerol-containing Zingiber officinale extracts on experimental rheumatoid arthritis. Journal of natural products, 72(3), 403-7.
  More info

  Ginger (Zingiber officinale) supplements are being promoted for arthritis treatment in western societies on the basis of ginger's traditional use as an anti-inflammatory in Chinese and Ayurvedic medicine. However, scientific evidence of ginger's antiarthritic effects is sparse, and its bioactive joint-protective components have not been identified. Therefore, the ability of a well-characterized crude ginger extract to inhibit joint swelling in an animal model of rheumatoid arthritis, streptococcal cell wall-induced arthritis, was compared to that of a fraction containing only gingerols and their derivatives. Both extracts were efficacious in preventing joint inflammation. However, the crude dichloromethane extract, which also contained essential oils and more polar compounds, was more efficacious (when normalized to gingerol content) in preventing both joint inflammation and destruction. In conclusion, these data document a very significant joint-protective effect of these ginger samples and suggest that nongingerol components are bioactive and can enhance the antiarthritic effects of the more widely studied gingerols.
• Morrison, H. W., Davis-Gorman, G., Frye, J., McDonagh, P., Funk, J., & Ritter, L. (2009). Neutrophil activation during reperfusion after ischemic stroke in mice. FASEB JOURNAL, 23.
• Funk, J. L., Chen, J., Downey, K. J., & Clark, R. A. (2008). Bone protective effect of simvastatin in experimental arthritis. JOURNAL OF RHEUMATOLOGY, 35(6), 1083-1091.
• Funk, J. L., Chen, J., Downey, K. J., & Clark, R. A. (2008). Bone protective effect of simvastatin in experimental arthritis. The Journal of rheumatology, 35(6), 1083-91.
  More info

  Emerging evidence suggests that clinically important antiinflammatory effects of HMG-CoA reductase inhibition may extend beyond cardiovascular disease to other inflammatory disorders, such as rheumatoid arthritis (RA). Protective bone-specific anabolic and antiresorptive effects of HMG-CoA reductase inhibitors have also been evaluated in normal and osteoporotic bone. The specific effect of statins on inflammation-induced bone loss has not previously been a focus of evaluation. We investigated whether simvastatin, a potent HMG-CoA reductase inhibitor, alters bone turnover in an animal model of RA, thus preventing periarticular bone loss.
• Ritter, L., Funk, J., Schenkel, L., Tipton, A., Downey, K., Wilson, J., Coull, B., & McDonagh, P. (2008). Inflammatory and hemodynamic changes in the cerebral microcirculation of aged rats after global cerebral ischemia and reperfusion. Microcirculation (New York, N.Y. : 1994), 15(4), 297-310.
  More info

  Effects of aging on inflammation and blood flow in the brain are unclear. Young (three to six months) and aged (19-22 months) male Brown Norway Fisher rats were used to compare (i) leukocyte function in nonischemic conditions and (ii) leukocyte function and hemodynamic changes after ischemia-reperfusion (I-R). In nonischemic studies, polymorphonuclear (PMN) CD11b expression and reactive oxygen species (ROS) production were measured with flow cytometry and PMN chemotaxis was measured with a Boyden chamber (+/-fMLP). In I-R studies, ischemia was induced by bilateral carotid artery occlusion and hypotension (20 minutes). During early reperfusion (30 minutes), leukocyte adhesion and rolling and blood-shear rates were measured using fluorescence microscopy. During late reperfusion (48 hours), mortality, neurological function, and leukocyte infiltration were measured. Stimulated PMN chemotaxis was increased in nonischemic aged rats (p < 0.05). In early reperfusion, there was a significant increase in leukocyte rolling and adhesion in the cerebral microcirculation and a significant decrease in shear rate in aged rats, compared to the young (p < 0.05). During late reperfusion, neurologic function was worse in aged vs. young rats (p < 0.05). These findings suggest that increased intravascular PMN adhesion and vascular dysfunction may contribute to poor neurologic outcome after cerebral I-R in the aged brain.
• Ritter, L., Funk, J., Schenkel, L., Tipton, A., Downey, K., Wilson, J., Coull, B., & Mcdonagh, P. (2008). Inflammatory and hemodynamic changes in the cerebral microcirculation of aged rats after global cerebral ischemia and reperfusion. MICROCIRCULATION, 15(4), 297-310.
• Timmermann, B. N., Funk, J. L., & Frye, J. B. (2008). Turmeric reduces cardiovascular disease risk factors in rheumatoid arthritis. Planta Medica, 74(09). doi:10.1055/s-0028-1084886
• Wright, L. E., Christian, P. J., Rivera, Z., Van Alstine, W. G., Funk, J. L., Bouxsein, M. L., & Hoyer, P. B. (2008). Comparison of skeletal effects of ovariectomy versus chemically induced ovarian failure in mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 23(8), 1296-303.
  More info

  Bone loss associated with menopause leads to an increase in skeletal fragility and fracture risk. Relevant animal models can be useful for evaluating the impact of ovarian failure on bone loss. A chemically induced model of menopause in which mice gradually undergo ovarian failure yet retain residual ovarian tissue has been developed using the chemical 4-vinylcyclohexene diepoxide (VCD). This study was designed to compare skeletal effects of VCD-induced ovarian failure to those associated with ovariectomy (OVX). Young (28 day) C57Bl/6Hsd female mice were dosed daily with vehicle or VCD (160 mg/kg/d, IP) for 15 days (n = 6-7/group) and monitored by vaginal cytology for ovarian failure. At the mean age of VCD-induced ovarian failure (approximately 6 wk after onset of dosing), a different group of mice was ovariectomized (OVX, n = 8). Spine BMD (SpBMD) was measured by DXA for 3 mo after ovarian failure and OVX. Mice were killed approximately 5 mo after ovarian failure or OVX, and bone architecture was evaluated by microCT ex vivo. In OVX mice, SpBMD was lower than controls 1 mo after OVX, whereas in VCD-treated mice, SpBMD was not lower than controls until 2.9 mo after ovarian failure (p < 0.05). Both VCD-induced ovarian failure and OVX led to pronounced deterioration of trabecular bone architecture, with slightly greater effects in OVX mice. At the femoral diaphysis, cortical bone area and thickness did not differ between VCD mice and controls but were decreased in OVX compared with both groups (p < 0.05). Circulating androstenedione levels were preserved in VCD-treated mice but reduced in OVX mice relative to controls (p < 0.001). These findings support that (1) VCD-induced ovarian failure leads to trabecular bone deterioration, (2) bone loss is attenuated by residual ovarian tissue, particularly in diaphyseal cortical bone, and (3) the VCD mouse model can be a relevant model for natural menopause in the study of associated bone disorders.
• Wright, L. E., Christian, P. J., Rivera, Z., Van, A., Funk, J. L., Bouxsein, M. L., & Hoyer, P. B. (2008). Comparison of skeletal effects of ovariectomy versus chemically induced ovarian failure in mice. JOURNAL OF BONE AND MINERAL RESEARCH, 23(8), 1296-1303.
• Wright, L. E., Timmermann, B. N., Funk, J. L., & Frye, J. B. (2008). Medicinal Zingiberaceae in the prevention of menopausal bone loss. Planta Medica, 74(09). doi:10.1055/s-0028-1084855
• Funk, J. L., & Sowers, J. R. (2006). Commentary: Women with type 2 diabetes have increased risk of fracture. North American Menopause Society, First to Know.
• Funk, J. L., & Timmermann, B. N. (2006). Translational investigation of turmeric for arthritis treatment: a review of lessons learned. NATURAL PRODUCT COMMUNICATIONS, 1(11), 1061-1066.
• Funk, J. L., & Timmermann, B. N. (2006). Translational investigation of turmeric for arthritis treatment: a review of lessons learned.. Natural Product Communication, 1, 1061-1066.
• Funk, J. L., Frye, J. B., Oyarzo, J. N., Kuscuoglu, N., Wilson, J., McCaffrey, G., Stafford, G., Chen, G., Lantz, R. C., Jolad, S. D., Solyom, A. M., Kiela, P. R., & Timmermann, B. N. (2006). Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis. ARTHRITIS AND RHEUMATISM, 54(11), 3452-3464.
• Funk, J. L., Frye, J. B., Oyarzo, J. N., Kuscuoglu, N., Wilson, J., McCaffrey, G., Stafford, G., Chen, G., Lantz, R. C., Jolad, S. D., Sólyom, A. M., Kiela, P. R., & Timmermann, B. N. (2006). Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis. Arthritis and rheumatism, 54(11), 3452-64.
  More info

  Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA).
• Funk, J. L., Oyarzo, J. N., Frye, J. B., Chen, G. J., Lantz, R. C., Jolad, S. D., Solyom, A. M., & Timmermann, B. N. (2006). Turmeric extracts containing curcuminoids prevent experimental rheumatoid arthritis. JOURNAL OF NATURAL PRODUCTS, 69(3), 351-355.
• Funk, J. L., Oyarzo, J. N., Frye, J. B., Chen, G., Lantz, R. C., Jolad, S. D., Sólyom, A. M., & Timmermann, B. N. (2006). Turmeric extracts containing curcuminoids prevent experimental rheumatoid arthritis. Journal of natural products, 69(3), 351-5.
  More info

  Turmeric has been used for centuries in Ayurvedic medicine as a treatment for inflammatory disorders including arthritis. On the basis of this traditional usage, dietary supplements containing turmeric rhizome and turmeric extracts are also being used in the western world for arthritis treatment and prevention. However, to our knowledge, no data are available regarding antiarthritic efficacy of complex turmeric extracts similar in composition to those available for use as dietary supplements. Therefore, the studies described here were undertaken to determine the in vivo efficacy of well-characterized curcuminoid-containing turmeric extracts in the prevention or treatment of arthritis using streptococcal cell wall (SCW)-induced arthritis, a well-described animal model of rheumatoid arthritis (RA). Arthritic index, a clinical measure of joint swelling, was used as the primary endpoint for assessing the effect of extracts on joint inflammation. An essential oil-depleted turmeric fraction containing 41% of the three major curcuminoids was efficacious in preventing joint inflammation when treatment was started before, but not after, the onset of joint inflammation. A commercial sample containing 94% of the three major curcuminoids was more potent in preventing arthritis than the essential oil-depleted turmeric fraction when compared by total curcuminoid dose per body weight. In conclusion, these data (1) document the in vivo antiarthritic efficacy of an essential oil-depleted turmeric fraction and (2) suggest that the three major curcuminoids are responsible for this antiarthritic effect, while the remaining compounds in the crude turmeric extract may inhibit this protective effect.
• Lantz, R. C., Funk, J. L., Oyarzo, J. N., Frye, J. B., Chen, G., Jolad, S. D., Sólyom, A. M., & Timmermann, B. N. (2006). Turmeric Extracts Containing Curcuminoids Prevent Experimental Rheumatoid Arthritis. Journal of Natural Products, 69(3), 351-355. doi:10.1021/np050327j
• Funk, J. L., Chen, J., Downey, K. J., Davee, S. M., & Stafford, G. (2003). Blockade of parathyroid hormone-related protein prevents joint destruction and granuloma formation in streptococcal cell wall-induced arthritis. Arthritis and rheumatism, 48(6), 1721-31.
  More info

  To determine whether parathyroid hormone-related protein (PTHrP), an interleukin-1beta-inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA.
• Funk, J. L., Migliati, E., Chen, G., Wei, H., Wilson, J., Downey, K. J., Mullarky, P. J., Coull, B. M., McDonagh, P. F., & Ritter, L. S. (2003). Parathyroid hormone-related protein induction in focal stroke: a neuroprotective vascular peptide. American journal of physiology. Regulatory, integrative and comparative physiology, 284(4), R1021-30.
  More info

  Parathyroid hormone-related protein (PTHrP) is a multifunctional peptide that enhances blood flow in non-central nervous system (CNS) vascular beds by causing vasodilation. PTHrP expression is induced in non-CNS organs in response to ischemia. Experiments were therefore undertaken to determine whether PTHrP can be induced in brain in response to ischemic injury and whether PTHrP can act locally as a vasodilator in the cerebral vasculature, an effect that could be neuroprotective in the setting of stroke. PTHrP expression was examined by Northern analysis and immunohistochemical staining in male Sprague-Dawley rats subjected to permanent middle cerebral artery occlusion (MCAO). Vasodilatory effects of superfused PTHrP(1-34) on pial arterioles were determined by intravital fluorescence microscopy. Effects of PTHrP(1-34) peptide administration on MCAO infarction size reduction were assessed. PTHrP expression was induced in the ischemic hemisphere as early as 4 h after MCAO and remained elevated for up to 24 h. Increased immunoreactive PTHrP at sites of ischemic tissue injury was located in the cerebral microvessels. Superfusion with PTHrP(1-34) peptide for up to 25 min increased pial arteriolar diameter by 30% in normal animals. In animals with permanent MCAO, PTHrP(1-34) peptide treatment significantly decreased cortical infarct size (-47%). In summary, PTHrP expression increases at sites of ischemic brain injury in the cerebrovasculature. This local increase in PTHrP could be an adaptive response that enhances blood flow to the ischemic brain, thus limiting cell injury.
• Funk, J. L., Wei, H., Downey, K. J., Yocum, D., Benjamin, J. B., & Carley, W. (2002). Expression of PTHrP and its cognate receptor in the rheumatoid synovial microcirculation. Biochemical and biophysical research communications, 297(4), 890-7.
  More info

  Parathyroid hormone-related protein (PTHrP), a multifunctional peptide that acts as a vasodilator as well as possible regulator of vascular development, is produced in increased amounts in the rheumatoid synovium. To understand whether PTHrP can contribute to the development and function of the rheumatoid microcirculation, studies were undertaken to identify and compare vascular sites of expression of PTHrP and its cognate receptor in the rheumatoid synovium and/or in cultured rheumatoid synovial endothelial cells. Endothelial cells, including apoptotic cells, as determined by TUNEL staining, were the primary site of vascular PTHrP expression in the rheumatoid synovium, a result confirmed in vitro in rheumatoid synovial microvascular endothelial cells. In contrast, the PTH/PTHrP receptor was primarily located in pericytes and smooth muscle cells within the vasculature. These results are consistent with a possible paracrine pathway for PTHrP action in the synovial microcirculation, wherein PTHrP peptides secreted by the synovial endothelium could act on surrounding PTH1R-positive pericytes and smooth muscle cells.
• Funk, J. L. (2001). A role for parathyroid hormone-related protein in the pathogenesis of inflammatory/autoimmune diseases. International immunopharmacology, 1(6), 1101-21.
  More info

  Our increased understanding of the critical role of cytokines in chronic inflammatory/autoimmune diseases has led to the recent development of effective anti-cytokine treatments. In particular, agents blocking the function of TNF-alpha, a cytokine first identified as an endotoxin-inducible mediator of tumor cell necrosis, are now licensed for the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease. However, TNF-alpha is but one member of a cytokine network that is responsible for mediating these inflammatory disorders. Therefore, as our understanding of the pathophysiologic role of other members of this inflammatory network increases, other cytokines may similarly be identified as effective targets for treatment. In this article, we will review evidence which suggests that parathyroid hormone-related protein (PTHrP), a peptide which, like TNF-alpha, was first identified because of its effects in the setting of malignancy, may in fact serve an important non-neoplastic, physiologic function by mediating the inflammatory/autoimmune host response. Data identifying PTHrP as a member of the cytokine network induced in multi-organ inflammation and rheumatoid arthritis will be summarized, initial evidence comparing the therapeutic efficacy of PTHrP- vs. TNF-alpha-blockade in the treatment of endotoxemia will be reviewed, and potential future areas of research, including assessment of the effects of PTHrP blockade in the treatment of RA, will be discussed.
• Funk, J. L., Trout, C. R., Wei, H., Stafford, G., & Reichlin, S. (2001). Parathyroid hormone-related protein (PTHrP) induction in reactive astrocytes following brain injury: a possible mediator of CNS inflammation. Brain research, 915(2), 195-209.
  More info

  PTHrP, a peptide induced in parenchymal organs during endotoxemia and in the synovium in rheumatoid arthritis, has recently been shown to be expressed in immature or transformed human astrocytes, but not in normal cells. This finding has led us to postulate that PTHrP might also be induced in reactive astrocytes in inflamed brain and, thus, act as a mediator of CNS inflammation. To test this hypothesis, PTHrP expression was examined following cortical stab wound injury in rats, a classical model of reactive gliosis. To determine whether PTHrP was induced in glia by TNF-alpha, a known mediator of inflammation in brain and of PTHrP induction in peripheral tissues, and to determine whether PTHrP, in turn, mediated inflammatory changes in glia, in vitro studies with rat astrocytes and glial-enriched mixed brain cells were also undertaken. Consistent with previous reports of PTHrP expression in normal brain, neurons were the primary site of immunoreactive PTHrP expression in the injured cortex 1 day after stab wound injury. Over the subsequent 3 days, specific immunostaining for PTHrP and for GFAP, a marker of reactive astrocytes, appeared in reactive astrocytes at the wound edge and in perivascular astrocytes, reaching a maximum level of expression at the last time point examined (day 4). TNF-alpha induced PTHrP expression in astrocyte and glial-enriched brain cells in vitro, suggesting that this pro-inflammatory peptide was a possible mediator of PTHrP expression in CNS inflammation. PTHrP(1-34) acted in an additive fashion with TNF-alpha to induced astrocyte expression of IL-6, a cytokine with demonstrated neuroprotective effects. Astrocyte proliferation was inhibited by PTHrP(1-34) and PTHrP(1-141), acting via a PTH/PTHrP receptor cAMP signaling pathway. These studies suggest that PTHrP, analogous to its regulatory functions in other non-CNS models of inflammation, may be an important mediator of the inflammatory response in brain.
• Shankar, P. P., Wei, H., Davee, S. M., & Funk, J. L. (2000). Parathyroid hormone-related protein is expressed by transformed and fetal human astrocytes and inhibits cell proliferation. Brain research, 868(2), 230-40.
  More info

  Parathyroid hormone-related protein (PTHrP) and the PTH/PTHrP receptor are expressed in most normal tissues, including brain, where PTHrP is though to act locally in an autocrine or paracrine fashion. Previous in situ localization studies in adult rodents have documented CNS PTHrP expression in neurons but not in glial cells. However, a recent report describing immunoreactive PTHrP in human astrocytomas suggests that PTHrP expression may be a marker of dedifferentiation and/or malignant transformation in glial cells. To begin to test this hypothesis, constitutive and regulated PTHrP expression were examined in cultured fetal and transformed (U-373 MG) human astrocytes. PTHrP was expressed in untreated fetal astrocytes and U-373 MG cells, as determined by Northern analysis, immunocytochemical staining, and detection of PTHrP(1-84) protein in conditioned media. Epidermal growth factor and tumor necrosis factor, important growth factors in astrocyte development and malignant transformation, stimulated PTHrP expression in both cell types. Treatment of U-373 MG cells or fetal astrocytes with PTHrP(1-34) consistently inhibited cellular proliferation, as measured by [(3)H]-thymidine incorporation. These findings suggest that PTHrP, a peptide whose expression is induced by mitogens in both immature and transformed human astrocytes, may feedback inhibit cellular proliferation, an effect that may be of importance during malignant transformation as well as CNS development. Furthermore, when combined with previous evidence of PTHrP expression by PTH/PTHrP receptor-positive neurons, our demonstration of regulated PTHrP expression by receptor-positive astrocytes identifies PTHrP as a potential peptide mediator of cross-talk between glial cells and neurons.
• Funk, J. L., Jones, G. V., Botham, C. A., Morgan, G., Wooding, P., & Kendall, M. D. (1999). Expression of parathyroid hormone-related protein and the parathyroid hormone/parathyroid hormone-related protein receptor in rat thymic epithelial cells. Journal of anatomy, 194 ( Pt 2), 255-64.
  More info

  Thymic epithelial cells are an important source of cytokines and other regulatory peptides which guide thymocyte proliferation and maturation. Parathyroid hormone-related protein (PTHrP), a cytokine-like peptide, has been reported to affect the proliferation of lymphocytes in vitro. The studies presented here were undertaken to test the hypotheses that PTHrP is produced locally within the thymus where it could influence thymocyte maturation and, more specifically, that thymic epithelial cells (TEC) could be the intrathymic source of PTHrP expression. To this end, immunohistochemical studies were performed to localise PTHrP and the PTH/PTHrP receptor within the adult rat thymus. Antibodies directed against 2 different PTHrP epitopes, PTHrP(1-34) and PTHrP(34-53), demonstrated prominent specific PTHrP immunoreactivity in both subcapsular and medullary TEC. In addition, faint but specific staining for PTHrP was seen in the cortex, interdigitating between cortical lymphocytes while sparing epithelial-free subcapsular areas, thus suggesting that cortical TEC could also be a source of PTHrP immunoreactivity. In contrast, PTH/PTHrP receptor immunoreactivity was only seen in medullary and occasional septal TEC; no evidence of cortical or lymphocytic PTH/PTHrP receptor immunoreactivity was detected. Immunohistochemical studies of cultured cytokeratin-positive rat TEC confirmed the results of these in situ studies as cultured TEC were immunoreactive both for PTHrP and the PTH/PTHrP receptor. Thus these results demonstrate that PTHrP is produced by the epithelial cells of the mature rat thymus. This suggests that PTHrP, a peptide with known cytokine, growth factor and neuroendocrine actions, could exert important intrathymic effects mediated by direct interactions with TEC, or indirect effects on PTH/PTHrP receptor-negative thymocytes.
• Funk, J. L., & Wei, H. (1998). Regulation of parathyroid hormone-related protein expression in MCF-7 breast carcinoma cells by estrogen and antiestrogens. Biochemical and biophysical research communications, 251(3), 849-54.
  More info

  Expression of parathyroid hormone-related protein (PTHrP) in breast carcinoma is a frequent cause of the paraneoplastic syndrome of hypercalcemia. In response to treatment with estrogen or tamoxifen, some breast cancer patients also develop a transient hypercalcemia. Therefore, the effect of 17beta-estradiol (E2), tamoxifen, or its more potent metabolite, 4-hydroxytamoxifen (OH-tamoxifen), on PTHrP expression in an estrogen receptor (ER)-positive breast carcinoma cell line (MCF-7) was evaluated. E2 increased PTHrP mRNA levels in MCF-7 cells and stimulated PTHrP(1-86) release in a dose-dependent fashion (10(-10)-10(-6) M). Tamoxifen and OH-tamoxifen also stimulated PTHrP release in a concentration-dependent fashion that paralleled their relative ER binding affinities (10(-6) or 10(-8)-10(-6) M, respectively). Combined treatment with the partial estrogen agonist, OH-tamoxifen, and E2 decreased E2-stimulated PTHrP secretion in MCF-7 cells to the levels seen with OH-tamoxifen treatment alone. These results suggest that transient estrogen- or tamoxifen-induced hypercalcemia in patients with breast carcinoma may be a PTHrP-mediated effect that is a marker of ER positivity.
• Funk, J. L., Cordaro, L. A., Wei, H. B., Benjamin, J. B., & Yocum, D. E. (1998). Synovium as a source of increased amino-terminal parathyroid hormone-related protein expression in rheumatoid arthritis - A possible role for locally produced parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis. JOURNAL OF CLINICAL INVESTIGATION, 101(7), 1362-1371.
• Funk, J. L., Cordaro, L. A., Wei, H., Benjamin, J. B., & Yocum, D. E. (1998). Synovium as a source of increased amino-terminal parathyroid hormone-related protein expression in rheumatoid arthritis. A possible role for locally produced parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis. The Journal of clinical investigation, 101(7), 1362-71.
  More info

  Proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin 1 (IL-1), mediate the joint destruction that characterizes rheumatoid arthritis (RA). Previous studies have shown that parathyroid hormone-related protein (PTHrP) is a member of the cascade of proinflammatory cytokines induced in parenchymal organs during lethal endotoxemia. To test the hypothesis that NH2-terminal PTHrP, a potent bone resorbing agent, could also be a member of the synovial cascade of tissue-destructive cytokines whose expression is induced in RA, PTHrP expression was examined in synovium and synoviocytes obtained from patients with RA and osteoarthritis (OA). PTHrP production, as determined by measurement of immunoreactive PTHrP(1-86) in tissue explant supernatants, was increased 10-fold in RA versus OA synovial tissue. Synovial lining cells and fibroblast-like cells within the pannus expressed both PTHrP and the PTH/PTHrP receptor, findings that were confirmed by in vitro studies of cultured synoviocytes. TNF-alpha and IL-1beta stimulated PTHrP expression in synoviocytes, while dexamethasone and interferon-gamma, agents with some therapeutic efficacy in the treatment of RA, inhibited PTHrP release. Treatment of synoviocytes with PTHrP(1-34) stimulated IL-6 secretion. These results suggest that proinflammatory cytokine-stimulated production of NH2-terminal PTHrP by synovial tissue directly invading cartilage and bone in RA may mediate joint destruction through direct effects on cartilage or bone, or, indirectly, via the induction of mediators of bone resorption in the tumor-like synovium.
• Funk, J. L., Moser, A. H., Grunfeld, C., & Feingold, K. R. (1997). Parathyroid hormone-related protein is induced in the adult liver during endotoxemia and stimulates the hepatic acute phase response. Endocrinology, 138(7), 2665-73.
  More info

  Previously, we reported that PTH-related protein (PTHrP) gene expression is induced in vital organs, including the liver, during endotoxemia. The liver plays a central role in the acute phase response (APR), a cytokine-mediated host defense against infection and inflammation that includes increased production of acute phase proteins and lipids by hepatocytes. Because PTHrP is thought to act locally at its site of production, in vivo studies were carried out to determine whether PTHrP could contribute to the induction of the hepatic APR. Hepatic PTHrP messenger RNA (mRNA) levels were induced acutely in rat liver in response to a near lethal dose of endotoxin. PTHrP protein, which was located by immunohistochemical staining in hepatocytes from both control and LPS-treated rats, was markedly induced in periportal hepatocytes in response to LPS treatment. Co-incident with this transient increase in PTHrP gene expression, PTH/PTHrP receptor mRNA levels were down-regulated. Administration of PTHrP(1-34), a PTH/PTHrP receptor agonist, to mice increased hepatic serum amyloid A (SAA) mRNA levels as well as circulating levels of SAA. In addition, PTHrP(1-34) increased serum triglyceride (TG) levels in rats and mice in a dose-dependent fashion. The hypertriglyceridemic effect of PTHrP(1-34) was accompanied by an increase in hepatic fatty acid synthesis. In contrast, PTHrP(7-34) amide, a receptor antagonist, had no effect on serum SAA or TG levels. These results, which provide evidence for the regulated expression of PTHrP in adult liver, suggest that PTHrP may be one additional member of the cytokine cascade produced locally in liver that can act to stimulate the hepatic acute phase response.
• Funk, J. L., Moser, A. H., Strewler, G. J., Feingold, K. R., & Grünfeld, C. (1996). Parathyroid hormone-related protein is induced during lethal endotoxemia and contributes to endotoxin-induced mortality in rodents. Molecular medicine (Cambridge, Mass.), 2(2), 204-10.
  More info

  Parathyroid hormone-related protein (PTHrP) is a ubiquitous and highly conserved vasoactive peptide whose role and regulation in normal physiology remain an enigma. Recently, we demonstrated that low-dose endotoxin (LPS) induces intrasplenic, but not systemic, levels of PTHrP; and that tumor necrosis factor, a pro-inflammatory cytokine, is the major mediator of this effect. We have therefore hypothesized that, with higher, lethal doses of endotoxin, PTHrP could be induced in multiple tissues to such a degree that it could contribute to the lethality of septic shock.
• FEINGOLD, K. R., FUNK, J. L., MOSER, A. H., SHIGENAGA, J. K., RAPP, J. H., & GRUNFELD, C. (1995). ROLE FOR CIRCULATING LIPOPROTEINS IN PROTECTION FROM ENDOTOXIN TOXICITY. INFECTION AND IMMUNITY, 63(5), 2041-2046.
• FUNK, J. L., SHOBACK, D. M., & GENANT, H. K. (1995). TRANSIENT OSTEOPOROSIS OF THE HIP IN PREGNANCY - NATURAL-HISTORY OF CHANGES IN BONE-MINERAL DENSITY. CLINICAL ENDOCRINOLOGY, 43(3), 373-382.
• Feingold, K. R., Funk, J. L., Moser, A. H., Shigenaga, J. K., Rapp, J. H., & Grunfeld, C. (1995). Role for circulating lipoproteins in protection from endotoxin toxicity. Infection and immunity, 63(5), 2041-6.
  More info

  Previous studies have shown that endotoxin (lipopolysaccharide [LPS])-induced death can be prevented by preincubating LPS with lipoproteins in vitro or by infusing large quantities of lipids into animals prior to LPS administration. In the present study we determined whether physiological levels of lipids also provide protection. Serum lipid levels were decreased by two different mechanisms: administration of 4-aminopyrolo-(3,4-D)pyrimide, which prevents the hepatic secretion of lipoproteins, and administration of pharmacological doses of estradiol, which increases the number of hepatic low-density lipoprotein receptors, leading to increased lipoprotein clearance. In both hypolipidemic models, LPS-induced mortality is markedly increased compared with that of controls with normal serum lipid levels. In both hypolipidemic models, administration of exogenous lipoproteins, which increase levels of serum lipids into the physiological range, reduces the increased mortality to levels similar to that seen in normal animals. In normal lipidemic animals, 63% of 125I-LPS in plasma is associated with lipoproteins, where it would not be capable of stimulating cytokine production. In contrast, in hypolipidemic animals, very little LPS (12 to 17%) is associated with lipoproteins. Rather, more LPS is in the lipoprotein-free plasma compartment, where it could exert biological effects. In both hypolipidemic models, LPS produces a greater increase in serum tumor necrosis factor levels than it does in controls (three- to fivefold increase), and administration of exogenous lipoproteins prevents this increase. Cytokines, in particular tumor necrosis factor, are responsible for most of the toxic effects of LPS. These data provide evidence that physiological levels of serum lipids protect animals from LPS toxicity. Thus, lipoproteins, in addition to playing a role in lipid transport, may have protective functions. Moreover, as part of the immune response, cytokine-induced increases in serum lipid levels may play a role in host defense by decreasing the toxicities of biological and chemical agents.
• Funk, J. L., Lausier, J., Moser, A. H., Shigenaga, J. K., Huling, S., Nissenson, R. A., Strewler, G. J., Grunfeld, C., & Feingold, K. R. (1995). Endotoxin induces parathyroid hormone-related protein gene expression in splenic stromal and smooth muscle cells, not in splenic lymphocytes. Endocrinology, 136(8), 3412-21.
  More info

  PTH-related protein (PTHrP), the peptide that is responsible for most cases of hypercalcemia of malignancy, is also produced under normal circumstances by a variety of tissues. Its role and regulation at these sites are not well understood. Recently, we have shown that PTHrP is induced in the spleen during the host response to endotoxin (LPS) and that tumor necrosis factor (TNF) is a major mediator of this effect. Given the large body of in vitro evidence suggesting that PTHrP can be produced by lymphocytes and act in an autocrine loop to alter their function, studies were undertaken to determine whether lymphocytes were the cells responsible for PTHrP production in the spleen. Both constitutive and LPS-induced PTHrP messenger RNA (mRNA) levels were the same in mice lacking mature T cells (nude mice) and in mice lacking natural killer (NK) cells (due to pretreatment with antibody against NK 1.1) compared to levels in normal mice, suggesting that neither mature T cells nor NK cells were the splenic source of PTHrP. Even scid mice that lack functioning T and B cells responded to TNF with the induction of splenic PTHrP mRNA levels comparable to those in control mice. Localization of PTHrP mRNA in subfractions of rat spleens after in vivo treatment with LPS confirmed the results of the murine studies; PTHrP mRNA was barely detectable in the lymphocyte-rich single cell fraction of the spleen. In contrast, the stromal fraction of the spleen was enriched with PTHrP mRNA both in the basal state and in response to LPS. A similar pattern of distribution was seen for interleukin-6; LPS only increased mRNA levels of this TNF-inducible cytokine in the splenic stroma. In addition, mRNA for the PTH/PTHrP receptor, which decreased in response to LPS, colocalized with PTHrP mRNA in the stromal fraction of the spleen. Immunohistochemical studies identified PTHrP in two populations of splenic cells: 1) smooth muscle cells located in the splenic capsule and trabeculae and 2) a subpopulation of stromal cells located in the red pulp of the spleen, primarily in a subcapsular distribution. Consistent with the localization of PTHrP mRNA, lymphocytes in the white pulp of the spleen did not stain for PTHrP.
• Funk, J. L., Shoback, D. M., & Genant, H. K. (1995). Transient osteoporosis of the hip in pregnancy: natural history of changes in bone mineral density. Clinical endocrinology, 43(3), 373-82.
  More info

  A 31-year-old white female developed severe bilateral hip pain during the third trimester of pregnancy that persisted after parturition. Laboratory abnormalities (elevated alkaline phosphatase and erythrocyte sedimentation rate) and radiographic changes (faint demineralization of the femur in the more symptomatic hip on plain films with evidence of bone marrow oedema and small joint effusions bilaterally on MRI) in the absence of other causes of focal osteoporosis were consistent with the diagnosis of transient osteoporosis of the hip in pregnancy. Although loss of bone mineral density (BMD) characterizes this syndrome, serial BMD measurements in symptomatic transient osteoporosis of the hip in pregnancy have not previously been reported. In the case reported here, serial bone density measurements were obtained over a 4-year period following the onset of symptoms. BMD in both femoral necks, which initially was approximately 20% lower than the average for age matched controls, increased markedly during the first year, plateaued during the following year, and then rapidly increased again following cessation of lactation. Unexpectedly, BMD in the lumbar spine, an asymptomatic site, was also markedly decreased at the time of presentation (31% lower than the mean of age-matched controls). Recovery of spinal density did not occur during the first year. However, spinal BMD did begin to increase during the second year and continued to rise after the cessation of lactation. In contrast to the marked reduction in bone density at these site of trabecular bone, cortical bone density in the forearm was normal. Possible aetiologies of pregnancy associated osteoporosis are discussed.
• Funk, J. L., Shigenaga, J. K., Moser, A. H., Krul, E. J., Strewler, G. J., Feingold, K. R., & Grunfeld, C. (1994). Cytokine regulation of parathyroid hormone-related protein messenger ribonucleic acid levels in mouse spleen: paradoxical effects of interferon-gamma and interleukin-4. Endocrinology, 135(1), 351-8.
  More info

  Under normal physiological conditions, PTH-related protein (PTHrP) is produced in a wide variety of tissues and is thought to act locally in an autocrine or paracrine fashion more analogous to cytokines than to classic hormones such as PTH. In addition, we have recently shown that, like cytokines, PTHrP is induced in the spleen during the response to sublethal doses of endotoxin [lipopolysaccharide (LPS)] an effect that is mediated by tumor necrosis factor (TNF). As complex cytokine cascades are induced in response to infectious or inflammatory stimuli, the effects of other prototypical inflammatory [interferon-gamma (IFN gamma)] or antiinflammatory [interleukin-4 (IL-4)] cytokines on PTHrP gene expression were studied. Paradoxically, IFN gamma (50 micrograms), a cytokine that usually synergizes with TNF, inhibited LPS induction of splenic PTHrP messenger RNA (mRNA) levels in LPS-sensitive C3H/OuJ (OuJ) and LPS-resistant C3H/HeJ (HeJ) mice. The stimulation of splenic PTHrP mRNA levels caused by the administration of TNF alpha or interleukin-1 beta was similarly inhibited by IFN gamma, a type II interferon. In contrast, IFN alpha (50 micrograms), a type I interferon, stimulated splenic levels of PTHrP mRNA. IL-4, a prototypical antiinflammatory cytokine, also had a paradoxical effect on LPS induction of splenic PTHrP mRNA levels. Instead of inhibiting LPS induction of splenic PTHrP mRNA levels in OuJ or HeJ mice, IL-4 (200 ng) actually stimulated PTHrP mRNA levels. These complex cytokine interactions suggest that the expression of PTHrP in response to infectious or inflammatory stimuli depends on the counterbalancing effects of the specific cytokine networks induced by each stimulus.
• FUNK, J. L., FEINGOLD, K. R., MOSER, A. H., & GRUNFELD, C. (1993). LIPOPOLYSACCHARIDE STIMULATION OF RAW 264.7 MACROPHAGES INDUCES LIPID-ACCUMULATION AND FOAM CELL-FORMATION. ATHEROSCLEROSIS, 98(1), 67-82.
• Funk, J. L., Feingold, K. R., Moser, A. H., & Grunfeld, C. (1993). Lipopolysaccharide stimulation of RAW 264.7 macrophages induces lipid accumulation and foam cell formation. Atherosclerosis, 98(1), 67-82.
  More info

  A role for immune and inflammatory processes in the induction of atherosclerotic lesions is emerging. These studies were undertaken to determine whether activation by lipopolysaccharide (LPS) enhances the ability of macrophages to become foam cells. Since LPS activation inhibits scavenger receptor activity, we studied the ability of LPS-activated RAW 264.7 macrophages to accumulate lipid from a variety of lipid particles that are not ligands for the scavenger receptor. Macrophages activated by LPS, in the absence of lipid particles, accumulated triglyceride, but not cholesterol ester (CE). The addition of Soyacal, a triglyceride-rich particle, further enhanced this LPS-stimulated triglyceride accumulation. LPS activation similarly enhanced CE accumulation almost 3-fold from two CE-rich lipoproteins, beta VLDL and LDL, as compared with controls. The unstimulated control cells only accumulated significant CE from beta VLDL and not LDL. LPS-enhanced lipid accumulation was dependent on LPS dose and began after 8-12 h of incubation. LPS increased the degradation of 125I-labelled LDL and the cell-associated 125I-labelled LDL at 37 degrees C by 1.8-fold. Degradation remained saturable, consistent with a receptor-mediated process. Antioxidants did not inhibit LPS-induced CE accumulation from LDL. Thus, activation of RAW 264.7 macrophages enhanced their ability to accumulate lipid from a variety of lipid particles and to become foam cells. These data suggest a potential role for infections, and LPS in particular, in atherogenesis.
• Funk, J. L., Krul, E. J., Moser, A. H., Shigenaga, J. K., Strewler, G. J., Grunfeld, C., & Feingold, K. R. (1993). Endotoxin increases parathyroid hormone-related protein mRNA levels in mouse spleen. Mediation by tumor necrosis factor. The Journal of clinical investigation, 92(5), 2546-52.
  More info

  Parathyroid hormone-related protein (PTHrP) causes hypercalcemia in malignancy. However, the role and regulation of PTHrP in normal physiology is just beginning to be explored. PTHrP is found in the spleen and has several other features common to cytokines. Since endotoxin (LPS) causes many of its effects indirectly by inducing cytokines, studies were undertaken to determine whether LPS might also induce splenic PTHrP expression. LPS (100 ng/mouse) increased splenic PTHrP mRNA levels 3.6-fold in C3H/OuJ mice. This effect was maximal at 2 h and returned to baseline by 4 h. PTHrP peptide levels also increased 3.3-fold in splenic extracts in response to LPS (1 microgram/mouse). Murine TNF-alpha and human IL-1 beta, cytokines that mediate many of the effects of LPS, also increased splenic PTHrP mRNA levels. LPS-resistant C3H/HeJ mice, which produce minimal amounts of TNF and IL-1 in response to LPS, were resistant to LPS induction of splenic PTHrP mRNA, while TNF-alpha and IL-1 beta readily increased PTHrP mRNA levels in C3H/HeJ mice. Anti-TNF antibody blocked LPS induction of splenic PTHrP mRNA in C3H/OuJ mice by 68%, indicating that TNF is a mediator of the LPS induction of PTHrP levels. In contrast, an IL-1 receptor antagonist (IL-1ra) was ineffective. The increase in PTHrP in the spleen during the immune response suggests that PTHrP may play an important role in immune modulation, perhaps by mediating changes in lymphocyte proliferation and/or function.

Proceedings Publications

• Going, S. B., Blew, R., Lee, V., Carranza, N., Funk, J. L., Hetherington-Rauth, M., Kohler, L. N., & Bea, J. W. (2019, June 2019). Low Cruciferous Vegetable Intake is Associated with Elevated Inflammation in Preadolescent Girls. In ACSM, 51.
• Kunihiro, A., Kunihiro, A., Brickey, J. A., Frye, J. B., Luis, P. B., Schneider, C., & Funk, J. L. (2019). Abstract 3002: Bone-protective curcumin circulates as a pro-drug conjugate that is activated in bone by β-glucuronidase. In Experimental and Molecular Therapeutics.
• Funk, J. L. (2016, Janaury). “Approach to the Evaluation of the Medicinal Effects of Turmeric”. In Universidad de las Américas Puebla, Puebla, Mexico, 1st Colloquium on Molecular Biomedicine.
  More info

  invited

Presentations

• Funk, J. L., Hauer, M., & Rossi, A. (2021, Jan 2018uary 2020). Use of natural products and other over the counter supplements in breast cancer. WAFMR/WSPR Joint Western Medical Research Conference. virtual.
• Rossi, A., Hauer, M., & Funk, J. L. (2020, Nov). Use of Dietary Supplements by Breast Cancer Patients. Arizona Physiological Society. virtual: APS.
• Funk, J. L., Cheng, J., Frye, J., Whitman, S., Kunihiro, A., Eagan, M., Brickey, J., & Alvord, L. (2019, spring). Modeling estrogen receptor-positive breast cancer bone metastasis to query osteolytic effects of tumor ER signaling. American Association for Cancer Research.
• Funk, J. L., Kunihiro, A., Brickey, J., Luis, P., Frye, J., & Schneider, C. (2019, summer). The Curcumin-Glucuronide Deconjugation Capacity of Bone is Unaffected by Common Age-Related Perturbations to the Bone Marrow Microenvironment.. American Society of Pharmacognosy.
• Hetherington-Rauth, M. C., Bea, J. W., Blew, R., Lee, V., Funk, J. L., & Going, S. B. (2016, October 31). Comparison of direct measures of adiposity with indirect measures for predicting cardiometabolic risk factors in preadolescent girls. The Obesity Society, Obesity Week.

Poster Presentations

• Funk, J. L., Kunihiro, A., Brickey, J., Luis, P., & Schneider, C. (2019, spring). Bone-protective curcumin circulates as a pro-drug conjugate that is activated in bone by β-glucuronidase. American Association for Cancer Research.
• Going, S. B., Blew, R., Lee, V., Carranza, N., Funk, J. L., Hetherington-Rauth, M., Kohler, L. N., & Bea, J. W. (2019, May). Cruciferous vegetable intake association with inflammation in preadolescent girls. American College of Sports Medicine Annual Meeting. Orlando, FL: ACSM.
• Hetherington-Rauth, M., Bea, J. W., Lee, V., Funk, J. L., Blew, R., & Going, S. B. (2017, October). Effect of cardiometabolic risk factors on relationship between adiposity and bone measures in girls. Obesity Week. Washington, DC: The Obesity Society.
• Cheng, J. N., Frye, J. B., Whitman, S. A., & Funk, J. L. (2016, January). Characterizing Bone Tropism of Human ER+ Breast Cancer Celll Lines in a Murine Bone Metastasis Model. Experimental BiologyAm Soc Nutrition.
• Cheng, J. N., Frye, J. B., Whitman, S. A., Funk, J. L., & Kunihiro, A. G. (2016, December). Characterization of an estrogen-dependent murine model of human estrogen receptor positive breast cancer bone metastasis. Bone Tropism of Human ER+ Breast Cancer Celll Lines in a Murine Bone Metastasis Model.. San Antonio Breast Cancer Symposium.
• Hetherington-Rauth, M. C., Bea, J. W., Blew, R., Lee, V., Funk, J. L., & Going, S. B. (2016, October 31). Comparison of direct measures of adiposity with indirect measures for predicting cardiometabolic risk factors in preadolescent girls. The Obesity Society, Obesity Week. New Orleans, LA.
• Kunihiro, A. G., Frye, J. B., Brickey, J. A., Luis, P. B., Schneider, C., & Funk, J. L. (2016, December). Site-specific activation of curcuminoids in the breast cancer bone metastases microenvironment.. San Antonio Breast Cancer Symposium.
• Kunihiro, A. G., Frye, J. B., Luis, P. B., Schneider, C., & Funk, J. L. (2016, April). Site-Specific Deglucuronidation of Turmeric-Derived Curcuminoids in Bone. Experimental Biology. San Diego: Am Soc Nutrition.
• Bea, J. W., Kohler, L. N., Hetherington-Rauth, M., Funk, J. L., Carranza, N., Lee, V., Blew, R., & Going, S. B. (2019, May). Cruciferous vegetable intake association with inflammation in preadolescent girls. American College of Sports Medicine Annual Meeting. Orlando, FL: ACSM.

Others

• Funk, J. L. (2016, January). Spicy New Treatment for Rheumatoid Arthritis Moves to Clinical Trials. BIO5 Public Media Video.
  More info

  BIO5 Public Media VideoSpicy New Treatment for Rheumatoid Arthritis Moves to Clinical Trials(to be released in early 2016)
• Bea, J., Lee, V., Blew, R. B., Funk, J. L., & Going, S. B. (2015, January). Cardiovascular Risk Related to Body Fat and Physical Activity in Young Girls. Experimental Biology.
• Funk, J. L. (2015, April). Physical Activity is Associated with Lower Adiposity Independent of Diet Quality in Adolescent Girls. Federation of American Societies for Experimental Biology Journal.
  More info

  FASEB J April 2015 29:135.8
• Funk, J. L. (2015, April). Survey of Herbal Dietary Supplement Use in Rheumatoid Arthritis. IRB Protocol # 1503767303.
  More info

  Approval Date: 4/2/2015, ongoing research
• Funk, J. L. (2015, Janaury). “Pharmacologic Effects of Turmeric in Bone: Moving from practice to theory, and back again”. Vanderbilt University, Department of Pharmacology.
• Funk, J. L. (2015, January). Media Recognition of Research. radio interviews.
  More info

  radio interviews, 8DEC15 KTAR-Phoenix (Sharon Mittleman); 16DEC15 KQTH-Tucson (Mike Rapp); 30DEC15 KUAT-Tucson (Sara Hammond)
• Frye, J. B., Lukefahr, A. L., & Funk, J. L. (2013, January). Longitudinal Changes in Ovarian Function with Aging in Sprague Dawley Rats. Endocrine Society National Meeting.
• Funk, J. L. (2013, January). Dietary Supplements and Arthritis: What Every Consumer Should Know. Tucson Arthritis Support League.
  More info

  Speaker
• Chandra, S., Romero-Aleshire, M. J., Cai, Q., Funk, J. L., & Brooks, H. L. (2012, January). Role of estrogen in the urinary concentrating mechanism. Experimental Biology.
• Funk, J. L. (2012, January). Winning the Battle over Heart Disease: Diet/Exercise. Public Library Series.
  More info

  Speaker
• Funk, J. L. (2012, January). “Adioposity: Advantageous or Detrimental to Bone?”. Research Frontiers in Nutritional Sciences Conference.
  More info

  The University of Arizona , invited
• Funk, J. L. (2012, January). “Effects of ginger (Zingiber officialis L.) on inflammation-induced bone loss.. Experimental Biology National Meeting.
• Funk, J. L. (2012, Jnauary). Winning the Battle over Heart Disease: The Role of Diet & Exercise. Green Valley Lecture Series.
  More info

  speaker
• Funk, J. L., Frye, J. B., & Timmermann, B. N. (2012, January). Turmeric Inhibits parathyroid hormone-related protein (PTHrP) secretion from human rheumatoid synoviocytes. BMC Complementary and Alternative Medicine.
  More info

  BMC Complementary and Alternative Medicine 12(supplement): p55, 2012.
• Funk, J. L., Frye, J. B., Wright, L. E., & Timmermann, B. N. (2012, January). Effects of Ginger (Zingiber officialis L.) on Inflammation-induced bone loss. Experimental Biology.
• Farr, J. N., Funk, J. L., Chen, Z., Lisse, J. R., Blew, R. M., Lee, V. R., Laudermilk, M., Lohman, T. G., & Going, S. B. (2011, January). Skeletal Muscle Fat Content is Inversely Associated with Bone Strength in Young Girls. American Society for Bone and Mineral Research National Meeting.
• Funk, J. L. (2011, January). Ethical Use of Animals. Greenfields School.
• Funk, J. L. (2011, January). Media Recognition of Research. Television Interview, Arizona Illustrated, KUAT. https://media.azpm.org/master/video/2011/4/25/qrhd/0511_Tumeric.mp4
• Funk, J. L. (2011, January). Speaker, Academy Village.
• Funk, J. L., Frye, J. B., Zhang, H., & Timmermann, B. N. (2011, January). Anti-inflammatory effects of the essential oils of ginger in an experimental model of rheumatoid arthritis. The American Society of Pharmacognosy.
• Funk, J. L., Lukefahr, A. L., Frye, J. B., Wright, L. E., Marion, S. L., & Hoyer, P. B. (2011, January). FSH Correlates with Trabecular Bone Loss in Rats Transitioning to Ovarian Failure.. American Society for Bone and Mineral Research.
• Funk, J. L., Wright, L. E., Guise, T. A., & Mohammad, K. S. (2011, January). Curcuminoids Decrease Osteolytic Breast Cancer Bone Metastases Separate from Effects on Tumor Cell Growth. American Society for Bone and Mineral Research National Meeting.
• Ritter, L., Gorman, G., Frye, J. B., McDonagh, P., Timmermann, B. N., & Funk, J. L. (2011, January). Oral administration of curcuminoids with turmeric oils after experimental stroke prevents reperfusion injury. The American Society of Pharmacognosy.
• Wright, L. E., Guise, T. A., Mohammad, K. S., Timmermann, B. N., & Funk, J. L. (2011, January). Curcuminoids inhibit PTHrP-mediated breast cancer osteolysis separate from effects on tumor cell growth. The American Society of Pharmacognosy.
• Funk, J. L. (2010, January). Tapping into the Power of Plants as Medicines. Desert Leaf.
• Funk, J. L. (2010, January). Turmeric and Inflammation. UA Health Sciences Center Public Media Video. https://www.youtube.com/watch?v=0lxV6jowuJ4
• Funk, J. L., & Ritter, L. (2010, January). Turmeric and Stroke. UA Health Sciences Center Public Media Video. https://www.youtube.com/watch?v=reQM1epROXk
• Funk, J. L., Wright, L. E., Lukefahr, A. L., Frye, J. B., & Hoyer, P. B. (2010, January). 4-Vinylcyclohexene Diepoxide (VCD)-induced Fibroadenomas: A Novel Rat Model of Mammary Tumorigenesis. Endocrine Society National Meeting.
• Lukefahr, A. L., Frye, J. B., Wright, L. E., Marion, S. L., Hoyer, P. B., & Funk, J. L. (2010, January). Comparison of skeletal changes in rat models of ovary-intact vs. surgical menopause. Endocrine Society National Meeting.
• Wright, L. E., Guise, T. A., Mohannad, K. S., & Funk, J. L. (2010, January). Curcuminoids prevent MDA-MB-231 cell expression of PTHrP in vitro and osteolytic lesion formation in a mouse model of breast cancer bone metastasis. Endocrine Society National Meeting.
• Dickerson, M., Frye, J., Wright, L., Ritter, L., & Funk, J. L. (2009, September). Skeletal development in male ZDF rats, a rodent model of type 2 diabete. American Society for Bone and Mineral Research Annual Meeting.
• Funk, J. L. (2009, January). Living Healthy with Arthritis (speaker). Living Healthy with Arthritis Community Lecture Series.
• Funk, J. L. (2009, January). “Botanicals and Stroke: A novel therapeutic approach.”. American Society of Pharmacognosy National Meeting.
  More info

  invited
• Funk, J. L., Beischel-Frye, J., Morrison, H., & Ritter, L. (2009, June). Botanicals and Stroke: A novel therapeutic approach. The American Society of Pharmacognosy Meeting.
• Funk, J. L., Lukefahr, A. L., Frye, J. B., Wright, L. E., Marion, S. L., & Hoyer, P. B. (2009, September). Characterizing Bone Loss in an Ovary-intact Murine Model of Menopause.. American Society for Bone and Mineral Research Annual Meeting.
• Morrison, H., Gorman, G., Frye, J., McDonagh, P., Funk, J. L., & Ritter, L. (2009, January). Neutrophil activation during reperfusion after ischemic stroke in mice. Experimental Biology.
• Ritter, L., Funk, J. L., McDonagh, P., Spera, A., Gorman, G., & Beischel, J. (2009, October). Turmeric targets neutrophil-endothelial interactions during reperfusion after ischemic stroke. International Microcirculatory Society.
  More info

  Oct. 2009 (abstract
• Wright, L. E., Beischel-Frye, J., Timmermann, B. N., & Funk, J. L. (2009, June). Curcuma Longa L., Zingiberaceae Prevents Osteoporotic Bone Loss. The American Society of Pharmacognosy Meeting.
• Wright, L. E., Frye, J. B., Timmermann, B. N., & Funk, J. L. (2009, September). Curcuminoid-Containing Turmeric Protects Bone Mass and Microarchitecture in Ovariectomized Rats. American Society for Bone and Mineral Research Annual Meeting.
• Wright, L. E., Timmermann, B. N., & Funk, J. L. (2009, June). Differential effects of medicinal Zingiberaceae on the prevention of bone loss. The American Society of Pharmacognosy Meeting.
• Wright, W. E., Frye, J. B., Timmermann, B. N., & Funk, J. L. (2009, Janaury). Effects of Medicinal Zingiberaceae on Bone Loss in Musculoskeletal Disease. 2009 North American Research Conference on Complementary and Integrative Medicine..
• Funk, J. L. (2008, August). Turmeric Reduces Cardiovascular Disease Risk Factors in Rheumatoid Arthritis. 7th Joint Meeting of the Association Francophone pour l'Enseignement de la Recherche en Pharmacognosie (AFERP), American Society of Pharmacognosy (ASP), Society for Medicinal Plant Research (GA), Phytochemical Society of Europe (PSE), and Societa Italiana di Fitochimica (SIF),.
  More info

  7th Joint Meeting of AFERP, ASP, GA, PSE & SIF; August 3-8, 2008, Athens, Greece,
• Funk, J. L. (2008, January). Speaker, Rotary Club of Tucson.
• Wright, L. E., Beischel Frye, J., Timmermann, B., & Funk, J. L. (2008, January). Turmeric and Ginger Extracts in the Prevention of Menopausal Bone Loss. Endocrine Society National Meeting.
• Wright, L. E., Beischel-Frey, J. A., Timmermann, B. N., & Funk, J. L. (2008, January). Zingiberaceae plant species in the prevention of OVX-induced bone loss. Natural Supplements: An evidence-based Update. Scripps Center for Integrative Medicine.
  More info

  First Place Award: Best Abstract
• Wright, L. E., Christian, P. J., Rivera, Z., & Funk, J. L. (2008, January). Skeletal Deterioration in an Ovary-Intact Mouse Model of Menopause. Endocrine Society National Meeting.
• Funk, J. L. (2007, Janaury). “Botanical Medicine in Clinical Practice”. 15th Annual Congress of Women’s Health.
  More info

  Hilton Head, South Carolina; invited
• Funk, J. L., Beischel-Frey, J. A., & Oyarzo–Somoza, J. N. (2007, January). Efficacy of Turmeric Essential Oils in Treatment of Experimental Arthritis. The American Society of Pharmacognosy National Meeting.
• Wright, L. E., Frye, J. B., Henderson, T., Bouxsein, M. L., Marion, S. L., Hoyer, P. B., & Funk, J. L. (2007, January). Turmeric Extracts for Postmenopausal Osteoporosis Treatment: An Initial Evaluation. Journal of Bone and Mineral Research.
  More info

  J Bone Min Res. 22:S449, 2007.
• Funk, J. L. (2006, Janaury). “Turmeric supplements for arthritis treatment: translational investigation of mechanism and efficacy.”. American Society of Pharmacognosy National Meeting.
  More info

  invited
• Funk, J. L. (2006, January). Arthritis and Rheumatism. Reuters, UPI, Associated Press, CBS News, BBC News, Time Magazine, USA Today, Washington Post, Chicago Tribune, Arizona Republic, Tucson Citizen, Medpage Today and other media outlets.
  More info

  Media Recognition: International and national press coverage of Arthritis and Rheumatism 2006 publication (Reuters, UPI, Associated Press, CBS News, BBC News, Time Magazine, USA Today, Washington Post, Chicago Tribune, Arizona Republic, Tucson Citizen, Medpage Today and other media outlets)
• Funk, J. L. (2006, January). “Anti-arthritic effects of turmeric”. NIH/NCCAM Symposium, Experimental Biology.
  More info

  San Francisco, CA; invited
• Funk, J. L., Beischel, J. A., Oyarzo-Somoza, J. N., Kiela, P. R., Kuscuoglu, N., Chen, G., Lantz, R. C., Solyom, A. M., Jolad, S. D., & Timmermann, B. N. (2006, May). Turmeric Prevents Arthritis and Bone Resorption by Blocking Multiple Inflammatory Pathways.. North American Research Conference on Complementary and Integrative Medicine.
• Funk, J. L., Beischel-Frye, J. A., Oyarzo, J. N., Kuscuoglu, K., Kiela, P. R., Jolad, S. D., & Timmermann, B. N. (2006, January). Turmeric supplements for arthritis treatment: translational investigation of mechanism and efficacy. The American Society of Pharmacognosy National Meeting.
• Hoyer, P. B., Christian, P. J., Rivera, Z., Funk, J. L., Glatt, V., & Bouxsein, M. L. (2006, Janaury). Monitoring Bone Integrity in a Murine Model for Perimenopause. Endocrine Society National Meeting.
• Funk, J. L. (2005, January). “PTHrP in Brain Injury”. International Symposium on Basic & Clinical Aspects of PTH & PTHrP.
  More info

  Yale University, Invited
• Funk, J. L., Beischel, J. A., Oyarzo, J. N., Chen, G., Lantz, R. C., Solyom, A. M., Jolad, S. D., & Timmermann, B. N. (2005, January). Protective effect of Zingiber officinale roscoe [Zingiberaceae] in an animal model of RA. The American Society of Pharmacognosy National Meeting.
• Funk, J. L., Beischel, J. A., Oyarzo, J. N., Chen, G., Lantz, R. C., Solyom, A. M., Jolad, S. D., & Timmermann, B. N. (2005, July). Protective effect of Zingiber officinale roscoe [Zingiberaceae] in an animal model of rheumatoid arthritis. The American Society of Pharmacognosy.
• Funk, J. L., Beischel, J. A., Oyarzo-Somoza, J. N., Chen, G., Lantz, R. C., Solyom, A. M., Jolad, S. D., & Timmermann, B. N. (2005, January). Botanical Extracts Isolated from Turmeric or Ginger Prevent Joint Swelling and Associated Joint Destruction in an Animal Model of RA. Journal of Bone and Mineral Research.
  More info

  J Bone Min Res. 20:S303, 2005.
• Funk, J. L., Chen, G., McCaffrey, G., Stafford, G., Beischel, J., Oyarzo, J., Wilson, J., & Lantz, R. C. (2005, January). Turmeric prevents rheumatoid arthritis in an animal model. Natural Supplements: An evidence-based Update. Scripps Center for Integrative Medicine.
  More info

  First Place Award: Best Abstract
• Rivera, Z., Funk, J. L., Christian, P. J., & Hoyer, P. B. (2005, July). Early ovarian failure accelerates the rate of bone mineral density loss in aged C57BL/6 mice.. Society for the Study of Reproduction Annual Meeting.
• Funk, J. L. (2004, Janaury). “Evaluating anti-inflammatory activity of a turmeric extract in an animal model”. NIH/NCCAM Educational Seminar, Supply Side West International Trade Show.
  More info

  Las Vegas, NV (invited)
• Funk, J. L. (2004, January). hyperlipidemia in women (speaker). community lecture on hyperlipidemia in women.
• Funk, J. L. (2004, January). postmenopausal osteoporosis (Speaker). community lecture on postmenopausal osteoporosis.
• Funk, J. L. (2004, January). “In vivo efficacy of turmeric extracts in the treatment of arthritis”. ODS/NCCAM Botanical Center Directors Annual Meeting.
  More info

  St. Louis, MO (Invited)
• Funk, J. L., Chen, G., McCaffrey, G., Stafford, G., Beischel, J., Wilson, J., Lantz, R. C., Solyom, A. M., Jolad, S. D., & Timmermann, B. N. (2004, January). Curcuminoid-enriched turmeric extract prevents arthritis in Lewis rats. Journal of Bone and Mineral Research.
  More info

  J. Bone Min Res 19:S473, 2004.
• Mayer, L. P., Dyer, C. A., Kitten, A. M., Christian, P. J., Funk, J. L., & Hoyer, P. B. (2004, January). Loss of Bone Mineral Density in B6C3F1 Ovariectomized and Ovary-Intact Follicle-Deplete Mice.. Endocrine Society Annual Meeting.
• Chen, J., Downey, K. J., Clark, R. A., & Funk, J. L. (2003, January). Simvastatin Prevents Joint inflammation and Joint Destruction in Lewis Rats with SCW-Induced Arthritis.. Journal of Bone and Mineral Research.
  More info

  J. Bone Min. Res.18:S397, 2003.
• Funk, J. L., Chen, J., Downey, K. J., & Clark, R. A. (2003, January). Effect of Simvastatin on Joint Inflammation and Bone Mineral Density in SCW-Induced Arthritis in Lewis Rats. Endocrine Society Annual Meeting.
• Funk, J. L., Downey, K. J., Migliati, E., Wilson, J., & Ritter, L. (2003, January). Increase in PTHrP Immunoreactivity in Rat Brain at Site of Neuronal Death Following Transient Global Ischemia. Endocrine Society Annual Meeting.
• Chen, J., Downey, K. J., & Funk, J. L. (2002, January). Estrogen inhibits T cell mediated arthritis and RANK-mediated bone resorption in rats with SCW-induced arthritis. Journal of Bone and Mineral Research.
  More info

  J. Bone Min. Res. 17(S1):S387, 2002.
• Chen, J., Downey, K. J., Stafford, G., & Funk, J. L. (2002, January). PTHrP neutralizing antibody inhibits bone resorption but not SCW-induced joint inflammation in SCW-induced arthritis in Lewis rats. Arthritis & Rheumatology.
  More info

  Arth. Rheum 46:(abst.), 2002.
• Ritte, L., Migliati, E., Wilson, J., Chen, G., Wei, H., Downey, K., Mullarkey, P., Coull, B., McDonagh, P., & Funk, J. L. (2002, January). PTHrP induction after permanent middle cerebral artery occlusion: a vasodilator with neuroprotective effects.. Society for Neuroscience.
  More info

  Soc. Neuroscience Abstr., Vol. 28, Program No. 392.16, 2002.
• Ritter, L., Funk, J. L., Schenke, L., Migliati, E., Wilson, J., McDonagh, P., & Coull, B. (2002, January). Global cerebral ischemia and reperfusion in aged rats is associated with an exaggerated inflammatory response and decreased blood flow. federation of american societies for experimental biology.
  More info

  The FASEB Journal, 16: A121-A122, 2002
• Chen, J., Davee, S., Stafford, G., & Funk, J. L. (2001, January). PTHrP neutralizing antibody inhibits streptococcal cell wall (SCW)-induced bone resorption and granuloma formation, but not SCW-induced joint inflammation in Lewis rats. Journal of Bone and Mineral Research.
  More info

  J. Bone Min. Res. 16(S1); S424, 2001
• Funk, J. L., Trout, C. R., Wei, H., Stafford, G., & Reichlin, S. (2001, January). Brain injury induces parathyroid hormone-related protein expression in reactive astrocytes. Endocrine Society Annual Meeting.
• Funk, J. L., Wei, H., Chen, J., & Carley, W. (2001, January). Expression of PTHrP and its cognate receptor in the microcirculation of the human rheumatoid synovium. Journal of Bone and Mineral Research.
  More info

  J. Bone Min. Res. 16(S1):S423, 2001
• Funk, J. L. (2000, January). postmenopausal osteoporosis (Speaker). community lecture on postmenopausal osteoporosis.
• Funk, J. L., Davee, S. M., & Stafford, G. (2000, January). PTHrP Expression in Rat Thymus. Journal of Bone and Mineral Research.
  More info

  J. Bone Min. Res., 15(S1): S569, 2000.
• Funk, J. L. (1999, January). Speaker. Friends of the Arthritis Center Community Luncheon.
• Shankar, P. P., Wei, H., Davee, S. M., & Funk, J. L. (1999, Janaury). PTHrP and PTH/PTHrP receptor expression in transformed and fetal human astrocytes. Journal of Bone and Mineral Research.
  More info

  J. Bone Min. Res. 14(S1): S545, 1999.
• Funk, J. L., & Wei, H. (1998, January). Regulation of PTHrP expression in MCF-7 breast carcinoma cells by estrogen and antiestrogens. Bone.
  More info

  Bone 23: S445, 1998
• Funk, J. L., Leidy, Jr, J. W., & Reichlin, S. (1998, January). Regulated expression of neuropeptide Y and PTHrP by cultured rat astrocytes.. Society for Neuroscience Annual Meeting.
• Funk, J. L., Trout, C. R., Wei, H., & Reichlin, S. (1998, January). Parathyroid hormone-related protein: a glial cell neuroimmunomodulator. Endocrine Society Annual Meeting.
• Cordaro, L. C., Cordaro, L. C., Benjamin, J. B., Benjamin, J. B., Marson, B. M., Yocum, D. E., Willingham, C. H., Funk, J. L., Yocum, D. E., & Funk, J. L. (1997, January). A possible role for parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis. Journal of Investigative Medicine.
  More info

  J. Investigative Med. 45:141A, 1997.
• Funk, J. L. (1997, January). “Splenic parathyroid hormone-related protein expression: a locally induced proinflammatory cytokine?”. Immunology Division, Babraham Institute, Cambridge, United Kingdom.
  More info

  invited
• Trout, C. R., Sherman, T., Reichlin, S., & Funk, J. L. (1997, January). Parathyroid hormone-related protein: a previously unrecognized neuroimmunomodulator. Journal of Investigative Medicine.
  More info

  J. Investigative Med. 45:109A, 1997.
• Trout, C. R., Sherman, T., Reichlin, S., & Funk, J. L. (1997, January). Parathyroid hormone-related protein: a previously unrecognized neuroimmunomodulator. Journal of Investigative Medicine.
  More info

  J. Investigative Med. 45:237A, 1997.
• Funk, J. L., Moser, A. H., Grunfeld, C., & Feingold, K. R. (1996, January). Parathyroid hormone-related protein induces the acute phase response. Endocrine Society Annual Meeting.
  More info

  Abstract #OR9-8, Endocrine Society Annual Meeting, 1996
• Funk, J. L., Nissenson, R. A., Strewler, G. J., Grunfeld, C., & Feingold, K. R. (1996, January). Parathyroid hormone-related protein is induced during the host response to endotoxin in splenic stromal and smooth muscle cells--not in splenic lymphocytes. Endocrine Society Annual Meeting.
  More info

  Abstract # OR41-4, Endocrine Society Annual Meeting, 1995
• Funk, J. L. (1994, January). “Cytokine regulation of splenic parathyroid hormone-related protein”. Division of Endocrinology & Metabolism and the Program in Human Molecular Biology & Genetics, University of Utah School of Medicine.
  More info

  Invited
• Funk, J. L., Shigenaga, J. K., Moser, A. H., Strewler, G. J., Feingold, K. R., & Grunfeld, C. (1994, January). Paradoxical regulation of splenic parathyroid hormone-related protein by interferon-gamma during the host response to endotoxin. Clinical Research.
  More info

  Clin. Res. 42:210A, 1994
• Funk, J. L. (1993, January). “Cytokine regulation of parathyroid hormone-related protein”. Endocrinology and Metabolism Division, West Los Angeles VA Medical Center.
  More info

  invited
• Funk, J. L. (1994, January). “In vivo regulation of splenic PTHrP by endotoxin, TNF, and IL-1”. Endocrinology and Metabolism Division, Long Beach VA Medical Center.
  More info

  Invited
• Funk, J. L. (1992, January). “In vivo regulation of splenic parathyroid hormone-related protein mRNA levels by LPS”. Endocrinology and Metabolism Division, San Francisco VA Medical Center.
• Funk, J. L., Feingold, K. R., & Grunfeld, C. (1992, Janaury). Lipopolysaccharide stimulation of macrophages induces foam cell formation. Clinical Research.
  More info

  Clin. Res. 40:311A, 1992.
• Funk, J. L., Strewler, G. L., Grunfeld, C., & Grunfeld, K. R. (1992, January). In vivo induction of parathyroid hormone-related protein mRNA levels by endotoxin: mediation by tumor necrosis factor. Endocrine Society Annual Meeting.
  More info

  Abstract #1977, Endocrine Society Annual Meeting,