Dietary Supplement Use in Women Diagnosed with Breast Cancer.

BACKGROUND: 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. OBJECTIVES: The study aimed to investigate current vitamin/mineral (VM) and NP supplement use among those diagnosed with breast cancer, including usage based on tumor type or concurrent breast cancer treatments and primary information sources for specific supplements. METHODS: Social media recruiting to complete an online questionnaire self-reporting current VM and NP use and breast cancer diagnosis and treatment information primarily attracted US participants. Analyses, including multivariate logistic regression, were performed on 1271 women who self-reported breast cancer diagnosis and completed the survey. RESULTS: Most participants reported current VM (89.5%) and NP (67.7%) use, with 46.5% (VM) and 26.7% (NP) using at least 3 products concurrently. Top-reported (>15% prevalence) products were vitamin D, calcium, multivitamin, and vitamin C for VM and probiotics, turmeric, fish oil/omega-3 fatty acids, melatonin, and cannabis for NP. Overall, VM or NP use was higher among those with hormone receptor-positive tumors. Although overall NP use did not differ according to current breast cancer treatments, VM use was significantly less common among those currently undergoing chemotherapy or radiation, but higher with current endocrine therapy. Among current chemotherapy users, specific VM and NP supplements with possible adverse effects were still used by 23% of respondents. Medical providers were the primary information source for VM, whereas NP information sources were more varied. CONCLUSIONS: Because women diagnosed with breast cancer commonly reported concurrent use of multiple VM and NP supplements, including those with known or underexplored risks (or benefits) in breast cancer, it is important for health care providers to inquire about and facilitate discussions regarding supplement use in this population.

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

Medicinal properties of turmeric (Curcuma longa 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.

A Role for TGFß Signaling in Preclinical Osteolytic Estrogen Receptor-Positive Breast Cancer Bone Metastases Progression.

While tumoral Smad-mediated transforming growth factor ß (TGFß) 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 TGFß 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 TGFß receptors II and I, only cells with TGFß-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; TGFß 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-TGFß neutralizing antibody, significantly decreased osteolytic ER+ BMETs in association with a decrease in bone-resorbing osteoclasts at the tumor-bone interface. Thus, TGFß may also be a driver of ER+ BMET osteolysis. Moreover, additive pro-osteolytic effects of tumoral E2 and TGFß signaling could at least partially explain the greater propensity for ER+ tumors to form BMETs, which are primarily osteolytic.

Nonvitamin, Nonmineral Dietary Supplement Use in Individuals with Rheumatoid Arthritis.

BACKGROUND: 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. OBJECTIVES: A study was undertaken to identify current and past use of specific NVNM DS for RA disease treatment and to examine associations between use of NVNM DS, RA pharmaceuticals, and/or vitamin or mineral (VM) DS. METHODS: We developed a survey instrument to capture current and ever use of specific NVNM DS, VM DS, and RA pharmaceuticals, with 696 subjects self-reporting an RA diagnosis recruited online or in clinic for survey participation. Analyses were limited to 611 subjects reporting RA diagnosis after age 18 y and treatment with specific RA pharmaceuticals. RESULTS: Most participants reported DS use, with current usage prevalence 49.6% (n = 303), 83.5% (n = 510), or 87.6% (n = 535) for NVNM, VM, or any DS, respectively. While not having appeared in previous RA surveys, turmeric and ginger were among the top 3 NVNM DS in current use, along with fish oil/ω-3 (n-3) PUFA. Concurrent NVNM DS use was reported by 48.2% (n = 243) of participants currently using RA pharmaceuticals (n = 504) and was more common in those using disease-modifying antirheumatic drugs only (no biologics). Most methotrexate users (83%) reported concurrent folate supplementation, with one-third also using turmeric, which is notable because methotrexate and turmeric have been associated with hepatotoxicity. CONCLUSION: Individuals with RA commonly use NVNM DS in combination with RA pharmaceuticals, including a previously undocumented but popular use of turmeric or ginger supplements with an unclear risk/benefit ratio.

Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone.

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 ß-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.

Effect of cardiometabolic risk factors on the relationship between adiposity and bone mass in girls.

BACKGROUND/OBJECTIVE: Childhood obesity has been separately associated with cardiometabolic risk factors (CMRs) and increased risk of fracture. However, both augmented and compromised bone mass have been reported among overweight/obese children. Metabolic dysfunction, often co-existing with obesity, may explain the discrepancy in previous studies. The aim of this study was to examine whether the relationship between adiposity and dual-energy X-ray absorptiometry (DXA) derived bone mass differed in young girls with and without CMR(s). SUBJECTS/METHODS: Whole-body bone and body composition measures by DXA and measures of CMR (fasting glucose, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), systolic and diastolic blood pressure, waist circumference (WC)) were obtained from 307, 9- to 12-year-old girls. Girls with 1 or ≥ 2 CMR(s) were considered to be at risk (vs. no CMR). Multiple linear regression was used to test the relationship of total fat mass with total body bone mineral content (BMC) after controlling for height, lean mass, CMR risk, and other potential confounders. RESULTS: There was a significant interaction between CMR risk and total body fat mass. When girls were stratified by CMR group, all groups had a significant positive relationship between fat mass and BMC (p < 0.05), however, girls with ≥ 2 CMRs had a lower BMC for a given level of body fat. Total body fat was not significantly related to bone mineral density (p > 0.05). CONCLUSION: Fat mass has a positive relationship with BMC even after controlling for lean mass. However, the positive relationship of fat mass with BMC may be attenuated if multiple CMRs are present.

Relationship between fat distribution and cardiometabolic risk in Hispanic girls.

OBJECTIVE: 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. METHODS: Measures of total percent body fat, percent of total fat within the android, gynoid, leg, and trunk regions, and cardiometabolic biomarkers (insulin, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), triglycerides (TG), low and high lipoprotein cholesterol (LDL-C, HDL-C)) were obtained from 232 Hispanic girls (age 10.7 ±1.1 years). Regression models for each metabolic parameter were run against adiposity measures. Partial correlations of the adiposity measures were used to compare associations between adiposity measures and the cardiometabolic risk factors, controlling for somatic maturation. RESULTS: Total and regional adiposity were significantly related with cardiometabolic risk factors (P < 0.05) except fasting glucose. The partial correlations of total and regional adiposity measures with each cardiometabolic biomarker were similar. More variance was explained for insulin and the HOMA-IR (33%-43%) than other risk factors. Partial correlations for the percentage of total fat in the gynoid and leg regions with insulin, HOMA-IR, TG, and LDL-C were negative, and positive with HDL-C. CONCLUSION: Measures of total and regional fat perform similarly in predicting cardiometabolic risk in Hispanic girls. A higher proportion of fat distributed in the gynoid or leg region is associated with lower cardiometabolic risk.

Interrogating Estrogen Signaling Pathways in Human ER-Positive Breast Cancer Cells Forming Bone Metastases in Mice.

Breast cancer bone metastases (BMET) are incurable, primarily osteolytic, and occur most commonly in estrogen receptor-α positive (ER+) breast cancer. ER+ human breast cancer BMET modeling in mice has demonstrated an estrogen (E2)-dependent increase in tumor-associated osteolysis and bone-resorbing osteoclasts, independent of estrogenic effects on tumor proliferation or bone turnover, suggesting a possible mechanistic link between tumoral ERα-driven osteolysis and ER+ bone progression. To explore this question, inducible secretion of the osteolytic factor, parathyroid hormone-related protein (PTHrP), was utilized as an in vitro screening bioassay to query the osteolytic potential of estrogen receptor- and signaling pathway-specific ligands in BMET-forming ER+ human breast cancer cells expressing ERα, ERß, and G protein-coupled ER. After identifying genomic ERα signaling, also responsibility for estrogen's proliferative effects, as necessary and sufficient for osteolytic PTHrP secretion, in vivo effects of a genomic-only ER agonist, estetrol (E4), on osteolytic ER+ BMET progression were examined. Surprisingly, while pharmacologic effects of E4 on estrogen-dependent tissues, including bone, were evident, E4 did not support osteolytic BMET progression (vs robust E2 effects), suggesting an important role for nongenomic ER signaling in ER+ metastatic progression at this site. Because bone effects of E4 did not completely recapitulate those of E2, the relative importance of nongenomic ER signaling in tumor vs bone cannot be ascertained here. Nonetheless, these intriguing findings suggest that targeted manipulation of estrogen signaling to mitigate ER+ metastatic progression in bone may require a nuanced approach, considering genomic and nongenomic effects of ER signaling on both sides of the tumor/bone interface.

Curcuminoids limit neutrophil-mediated reperfusion injury in experimental stroke by targeting the endothelium.

OBJECTIVE: 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. METHODS: Male Sprague Dawley rats subjected to MCAO/R were treated with turmeric-derived curcuminoids (vs. vehicle) 1 hour prior to reperfusion (300 mg/kg ip). Neutrophil adhesion to the cerebral microcirculation and measures of neutrophil and endothelial activation were assayed during early reperfusion (0-4 hours); cerebral infarct size, edema, and neurological function were assessed at 24 hours. Curcuminoid effects on TNFα-stimulated human brain microvascular endothelial cell (HBMVEC) were assessed. RESULTS: Early during reperfusion following MCAO, curcuminoid treatment decreased neutrophil rolling and adhesion to the cerebrovascular endothelium by 76% and 67% and prevented >50% of the fall in shear rate. The increased number and activation state (CD11b and ROS) of neutrophils were unchanged by curcuminoid treatment, while increased cerebral expression of TNFα and ICAM-1, a marker of endothelial activation, were blocked by >30%. Curcuminoids inhibited NF-κB activation and subsequent ICAM-1 gene expression in HBMVEC. CONCLUSION: Turmeric-derived curcuminoids limit reperfusion injury in stroke by preventing neutrophil adhesion to the cerebrovascular microcirculation and improving shear rate by targeting the endothelium.

Curcuminoids block TGF-ß signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis.

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)-ß-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-ß signaling revealed decreases in phospho-Smad2/3 and Ets-1 protein levels with no effect on p-38 MAPK-mediated TGF-ß 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-ß induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells.

Nonequilibrium thermodynamics and mitochondrial protein content predict insulin sensitivity and fuel selection during exercise in human skeletal muscle.

Introduction: Many investigators have attempted to define the molecular nature of changes responsible for insulin resistance in muscle, but a molecular approach may not consider the overall physiological context of muscle. Because the energetic state of ATP (ΔGATP) could affect the rate of insulin-stimulated, energy-consuming processes, the present study was undertaken to determine whether the thermodynamic state of skeletal muscle can partially explain insulin sensitivity and fuel selection independently of molecular changes. Methods: 31P-MRS was used with glucose clamps, exercise studies, muscle biopsies and proteomics to measure insulin sensitivity, thermodynamic variables, mitochondrial protein content, and aerobic capacity in 16 volunteers. Results: After showing calibrated 31P-MRS measurements conformed to a linear electrical circuit model of muscle nonequilibrium thermodynamics, we used these measurements in multiple stepwise regression against rates of insulin-stimulated glucose disposal and fuel oxidation. Multiple linear regression analyses showed 53% of the variance in insulin sensitivity was explained by 1) VO2max (p = 0.001) and the 2) slope of the relationship of ΔGATP with the rate of oxidative phosphorylation (p = 0.007). This slope represents conductance in the linear model (functional content of mitochondria). Mitochondrial protein content from proteomics was an independent predictor of fractional fat oxidation during mild exercise (R2 = 0.55, p = 0.001). Conclusion: Higher mitochondrial functional content is related to the ability of skeletal muscle to maintain a greater ΔGATP, which may lead to faster rates of insulin-stimulated processes. Mitochondrial protein content per se can explain fractional fat oxidation during mild exercise.

Metabolically favorable adiposity and bone mineral density: a Mendelian randomization analysis.

OBJECTIVE: 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. METHODS: 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. RESULTS: In all MR analyses, genetically predicted MFA was inversely associated with aBMD for the whole body (ß = -0.053, p = 0.0002), lumbar spine (ß = -0.075; p = 0.0001), femoral neck (ß = -0.045; p = 0.008), and forearm (ß = -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. CONCLUSIONS: 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.

Association of ß-glucuronidase activity with menopausal status, ethnicity, adiposity, and inflammation in women.

OBJECTIVES: 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. METHODS: ß-Glucuronidase activity and C-reactive protein (CRP) were assayed in stored serum from the Women's Breast and Bone Density Study, and dual-energy x-ray absorptiometry and anthropometry assessed body composition. Participants were premenopausal (n = 133) or postmenopausal (n = 89), and Hispanic (37%) or non-Hispanic White (63%). Multivariate linear regression models tested associations between ß-glucuronidase and menopausal status, ethnicity, CRP, and body composition metrics, overall and stratified by menopausal status. RESULTS: Postmenopausal (vs premenopausal) women were older (60.4 ± 3.7 vs 44.8 ± 2.4 y) with a lower Hispanic ethnicity prevalence (27% vs 44%), and higher serum ß-glucuronidase activity (1.5 ± 0.8 vs 1.3 ± 0.5 U/L) and CRP (4.2 ± 4.4 vs 3.3 ± 4.7 mg/L). Adjusting for confounders, ß-glucuronidase was positively associated with Hispanic ethnicity, CRP, body mass index, and total fat mass (all, P < 0.01), but not menopausal status nor lean mass. Central adiposity measures were also positively associated with ß-glucuronidase with the same covariates. CONCLUSIONS: ß-Glucuronidase enzyme activity, upon which polyphenol health-related benefits may depend, is not associated with menopausal status. Future studies are required to determine clinical significance and mechanisms driving ß-glucuronidase associations with ethnicity, inflammation, and adiposity in women.

Fuel Selection in Skeletal Muscle Exercising at Low Intensity; Reliance on Carbohydrate in Very Sedentary Individuals.

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.

Curcumin Inhibition of TGFß signaling in bone metastatic breast cancer cells and the possible role of oxidative metabolites.

TGFß 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 TGFß 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 TGFß signaling and the application of this finding across multiple BCa cell lines forming TGFß-dependent BMETs, including a possible role for bioactive curcumin metabolites in mediating these effects. Immunoblot analysis of TGFß signaling proteins in bone tropic human (MDA-SA, MDA-1833, MDA-2287) and murine (4T1) BCa cells revealed uniform curcumin blockade of TGFß-induced Smad activation due to down-regulation of plasma membrane associated TGFßR2 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 TGFßR2, 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 TGFß signaling, curcumin caused early activation of MAPK signaling in all cell lines, including JNK, an effect possibly involving interactions with TGFßR2 within lipid rafts. Treatment with curcumin or oxidizable analogs of curcumin may have clinical relevancy in the management of TGFß-dependent BCa BMETs.

Serum Follicle-Stimulating Hormone and 5-Year Change in Adiposity in Healthy Postmenopausal Women.

CONTEXT: Evidence from animal studies suggests that the gradual rise in follicle-stimulating hormone (FSH) during reproductive senescence may contribute to the change in adiposity distribution characteristic of menopause. The potential independent role the interrelationships of FSH and estradiol (E2) may play in postmenopausal adiposity changes are not well studied. OBJECTIVE: Our objective was to evaluate the associations of FSH and dual x-ray absorptiometry (DXA)-derived adiposity measures, with consideration of estradiol and postmenopausal hormone therapy use. METHODS: In a sample of 667 postmenopausal women from the Women's Health Initiative Buffalo OsteoPerio Ancillary Study, we studied the associations of serum FSH and E2 levels with dual x-ray absorptiometry (DXA)-derived adiposity measures via cross-sectional and longitudinal analyses (5-year follow-up). RESULTS: In cross-sectional analyses, FSH levels were inversely associated with all measures of adiposity in models adjusted for age, years since menopause, smoking status, pack-years, and hormone therapy (HT) use; these associations were not influenced by adjustment for serum E2. In longitudinal analyses, the subset of women who discontinued HT over follow-up (n = 242) experienced the largest increase in FSH (+33.9 mIU/mL) and decrease in E2 (-44.3 pg/mL) and gains in all adiposity measures in unadjusted analyses. In adjusted analyses, an increase in FSH was associated with a gain in percentage of total body fat, total body fat mass, and subcutaneous adipose tissue (SAT). CONCLUSION: While cross-sectional findings suggest that FSH is inversely associated with adiposity, our longitudinal findings suggest that greater increases in FSH were associated with greater increases in percentage of total body fat, total body fat mass, and SAT. Future studies are needed to provide additional insight into FSH-adiposity mechanisms in larger samples.

Exaggerated neutrophil-mediated reperfusion injury after ischemic stroke in a rodent model of type 2 diabetes.

OBJECTIVE: 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. MATERIALS AND METHODS: Twelve- to thirteen-week-old male Zucker Diabetic Fatty (ZDF) rats vs. Zucker Lean Controls (ZLC) rats were tested at baseline and after middle cerebral artery occlusion (ischemia) and reperfusion (I-R). Neutrophil adhesion to the cerebral microcirculation, neutrophil expression of CD11b, infarction size, edema, neurologic function, sICAM, and cerebral expression of neutrophil-endothelial inflammatory genes were measured. RESULTS: At baseline, CD11b and sICAM were significantly increased in ZDF vs. ZLC animals (p < 0.05). After I-R, significantly more neutrophil adhesion and cell aggregates were observed in ZDF vs. ZLC (p < 0.05); infarction size, edema, and neurologic function were significantly worse in ZDF vs. ZLC (p < 0.05). CD11b and sICAM-1 remained significantly increased in ZDFs (p < 0.05), and cerebral expression of IL-1ß, GRO/KC, E-selectin, and sICAM were significantly induced in ZDF, but not ZLC groups (p < 0.05) after 2.5 hours of reperfusion. CONCLUSION: Both sides of the neutrophil-endothelial interface appear to be primed prior to I-R, and remain significantly more activated during I-R in an experimental model of T2DM. Consequently, reperfusion injury appears to play a significant role in poor stroke outcome in T2DM.

Perspective on Improving the Relevance, Rigor, and Reproducibility of Botanical Clinical Trials: Lessons Learned From Turmeric Trials.

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.

Osteolytic effects of tumoral estrogen signaling in an estrogen receptor-positive breast cancer bone metastasis model.

AIM: 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 (E2)-dependent ER+ breast cancer BMET model. METHODS: Female athymic Foxn1nu mice were inoculated with human ER+ MCF-7 breast cancer cells via the left cardiac ventricle post-E2 pellet placement, and age- and dose-dependent E2 effects on osteolytic ER+ BMET progression, as well as direct bone effects of E2, were determined. RESULTS: Osteolytic BMETs, which did not form in the absence of E2 supplementation, occurred with the same frequency in young (5-week-old) vs. skeletally mature (16-week-old) E2 (0.72 mg)-treated mice, but were larger in young mice where anabolic bone effects of E2 were greater. However, in mice of a single age and across a range of E2 doses, anabolic E2 bone effects were constant, while osteolytic ER+ BMET lesion incidence and size increased in an E2-dose-dependent fashion. Osteoclasts in ER+ tumor-bearing (but not tumor-naive) mice increased in an E2-dose dependent fashion at the bone-tumor interface, while histologic tumor size and proliferation did not vary with E2 dose. E2-inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein (PTHrP) was dose-dependent and mediated by ERα, with significantly greater levels of secretion from ER+ BMET-derived tumor cells. CONCLUSION: These results suggest that tumoral ERα signaling may contribute to ER+ BMET-associated osteolysis, potentially explaining the greater predilection for ER+ tumors to form clinically-evident osteolytic BMETs.