Outcome reporting across randomized controlled trials evaluating potential treatments for male infertility: a systematic review.

STUDY QUESTION: What are the primary outcomes and outcome measures used in randomized controlled trials (RCTs) evaluating potential treatments for male infertility in the last 10 years? SUMMARY ANSWER: Outcome reporting across male infertility trials is heterogeneous with numerous definitions and measures used to define similar outcomes. WHAT IS KNOWN ALREADY: No core outcome set for male infertility trials has been developed. Male infertility trials are unique in that they have potentially three participants, a man, a female partner and their offspring and this will likely lead to significant variation in outcome reporting in randomized trials. STUDY DESIGN SIZE DURATION: A systematic review of RCTs mapping outcomes and outcome measures evaluating potential treatments for men with infertility registered in the Cochrane Register of Controlled Trials (CENTRAL) between January 2010 and July 2021. PARTICIPANTS/MATERIALS SETTING METHODS: Abstract screening and study selection was undertaken in duplicate using a review protocol that was developed prior to commencing the review. No risk of bias assessment was undertaken as this review aims to report on outcome reporting only. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred and seventy-five RCTs were identified, and given the large number of studies we limited our review to the 100 largest trials. Seventy-nine different treatments were reported across the 100 largest RCTs including vitamin and dietary supplements (18 trials), surgical treatments (18 trials) and sperm selection techniques (22 trials). When considering the largest 100 trials (range: 80-2772 participants), 36 primary and 89 secondary outcomes were reported. Forty-seven trials reported a primary outcome and 36 trials clearly defined their primary outcome. Pregnancy outcomes were inconsistently reported and included pregnancy rate (51 trials), pregnancy loss including miscarriage, ectopic pregnancy, stillbirth (9 trials) and live birth (13 trials). Trials consistently reporting the same outcome frequently used different definitions. For example, semen quality was reported by 75 trials and was defined in 7 different ways, including; the World Health Organization (WHO) 2010 criteria (32 trials), WHO 1999 criteria (18 trials), WHO 1992 criteria (3 trials), WHO 1999 and 1992 criteria (1 trial) and the Kruger strict morphology criteria (1 trial). LIMITATIONS REASONS FOR CAUTION: We only evaluated the 100 largest trials published in the last 10 years and did not report outcomes on the remaining 75. An outcome was included as a primary outcome only if clearly stated in the manuscript and we did not contact authors to clarify this. As our review mapped outcomes and outcome measures, we did not undertake an integrity assessment of the trials included in our review. WIDER IMPLICATIONS OF THE FINDINGS: Most randomized trials evaluating treatments for male infertility report different outcomes. Only half of the RCTs reported pregnancy rate and even fewer reported live birth; furthermore, the definitions of these outcomes varies across trials. Developing, disseminating and implementing a minimum data set, known as a core outcome set, for male infertility research could help to improve outcome selection, collection and reporting. STUDY FUNDING/COMPETING INTERESTS: A.P.-chairman of external scientific advisory committee of Cryos International Denmark ApS, member of the scientific advisory board for Cytoswim LDT and ExSeed Health. Guest lecture at the 'Insights for Fertility Conference', funded by MERK SERONO Limited. M.v.W.-holds a ZON-MW research grant. No external funding was obtained for this study.

Hypothalamic neurokinin signalling and its application in reproductive medicine.

The discovery of the essential requirement for kisspeptin and subsequently neurokinin B signalling for human reproductive function has sparked renewed interest in the neuroendocrinology of reproduction. A key discovery has been a population of cells co-expressing both these neuropeptides and dynorphin in the hypothalamus, directly regulating gonadotropin hormone releasing hormone (GnRH) secretion and thus pituitary secretion of gonadotropins. These neurons also project to the vasomotor centre, and their overactivity in estrogen deficiency results in the common and debilitating hot flushes of the menopause. Several antagonists to the neurokinin 3 receptor, for which neurokinin B is the endogenous ligand, have been developed, and are entering clinical studies in human reproductive function and clinical trials. Even single doses can elicit marked declines in testosterone levels in men, and their use has elicited evidence of the regulation of ovarian follicle growth in women. The most advanced indication is the treatment of menopausal vasomotor symptoms, where these drugs show remarkable results in both the degree and speed of symptom control. A range of other reproductive indications are starting to be explored, notably in polycystic ovary syndrome, the most common endocrinopathy in women.

Exploring the facilitators and barriers to using an online infertility risk prediction tool (FoRECAsT) for young women with breast cancer: a qualitative study protocol.

INTRODUCTION: As cancer treatments may impact on fertility, a high priority for young patients with breast cancer is access to evidence-based, personalised information for them and their healthcare providers to guide treatment and fertility-related decisions prior to cancer treatment. Current tools to predict fertility outcomes after breast cancer treatments are imprecise and do not offer individualised prediction. To address the gap, we are developing a novel personalised infertility risk prediction tool (FoRECAsT) for premenopausal patients with breast cancer that considers current reproductive status, planned chemotherapy and adjuvant endocrine therapy to determine likely post-treatment infertility. The aim of this study is to explore the feasibility of implementing this FoRECAsT tool into clinical practice by exploring the barriers and facilitators of its use among patients and healthcare providers. METHODS AND ANALYSIS: A cross-sectional exploratory study is being conducted using semistructured in-depth telephone interviews with 15-20 participants each from the following groups: (1) premenopausal patients with breast cancer younger than 40, diagnosed within last 5 years, (2) breast surgeons, (3) breast medical oncologists, (4) breast care nurses (5) fertility specialists and (6) fertility preservation nurses. Patients with breast cancer are being recruited from the joint Breast Service of three affiliated institutions of Victorian Comprehensive Cancer Centre in Melbourne, Australia-Peter MacCallum Cancer Centre, Royal Melbourne Hospital and Royal Women's Hospital, and clinicians are being recruited from across Australia. Interviews are being audio recorded, transcribed verbatim and imported into qualitative data analysis software to facilitate data management and analyses. ETHICS AND DISSEMINATION: The study protocol has been approved by Melbourne Health Human Research Ethics Committee, Australia (HREC number: 2017.163). Confidentiality and privacy are maintained at every stage of the study. Findings will be disseminated through peer-reviewed scholarly and scientific journals, national and international conference presentations, social media, broadcast media, print media, internet and various community/stakeholder engagement activities.

Cinnamon Polyphenol Extract and Insulin Regulate Diacylglycerol Acyltransferase Gene Expression in Mouse Adipocytes and Macrophages.

Cinnamon polyphenol extract (CPE) improves people with insulin resistance. The objective was to investigate CPE and insulin on diacylglycerol acyltransferase (DGAT) gene expression important for lipid biosynthesis and compared it to anti-inflammatory tristetraprolin/zinc finger protein 36 (TTP/ZFP36) gene expression known to be regulated by both agents. Mouse 3T3-L1 adipocytes and RAW264.7 macrophages were treated with insulin and CPE followed by qPCR evaluation of DGAT and TTP mRNA levels. Insulin decreased DGAT1 and DGAT2 mRNA levels in adipocytes but had no effect on DGAT1 and increased DGAT2 mRNA levels 3-fold in macrophages. Insulin increased TTP mRNA levels 3-fold in adipocytes but had no effect in macrophages. CPE effect on DGAT1 gene expression was minimal but increased DGAT2 mRNA levels 2-4 fold in adipocytes and macrophages. CPE increased TTP mRNA levels 2-7 fold in adipocytes and macrophages. We conclude that CPE and insulin exhibited overlapping and independent effects on DGAT and TTP gene expression and suggest that CPE and insulin have profound effects on fat biosynthesis and inflammatory responses.

Stress exposure alters brain mRNA expression of the genes involved in insulin signalling, an effect modified by a high fat/high fructose diet and cinnamon supplement.

In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement.

Cinnamon extract reduces VEGF expression via suppressing HIF-1α gene expression and inhibits tumor growth in mice.

Although many anti-VEGF agents are available for cancer treatment, side effects of these agents limit their application for cancer treatment and prevention. Here we studied the potential use of a diet-based agent as an inhibitor for VEGF production. Using a VEGF reporter assay, our data showed that an extract from cinnamon (CE) was a potent inhibitor of VEGF production in human cancer cells and suggested inhibition might be mediated through the suppression of HIF-1α gene expression and protein synthesis. Furthermore, CE treatment was found to inhibit expression and phosphorylation of STAT3 and AKT, which are key factors in the regulation of HIF-1α expression, and significantly reduce angiogenesis potential of cancer cells by migration assay. Consistent with these results, we observed significant suppression of VEGF expression, blood vessel formation, and tumor growth in a human ovarian tumor model in mice treated with CE. Cinnamaldehyde, a major component in cinnamon, was identified as one active component in CE that inhibits VEGF expression. Taken together, our findings provide a novel mechanism underlying anti-angiogenic and anti-tumor actions of CE and support the potential use of CE in cancer prevention and treatment. © 2016 Wiley Periodicals, Inc.

Cinnamon extract lowers glucose, insulin and cholesterol in people with elevated serum glucose.

Cinnamon ( ròu guì) has in vitro insulin potentiating activity, and proanthocyanidins from cinnamon prevent in vitro formation of advanced glycation end products. Some human studies were equivocal, but several have shown beneficial effects of cinnamon supplementation on circulating glucose, lipids, and/or insulin. This placebo-controlled double-blind trial tested the effects of a dried water extract of cinnamon (Cinnamomum cassia) on circulating glucose, lipids, insulin, and insulin resistance. Men and women from Beijing and Dalian, China, were invited to participate if they had fasting serum glucose >6.1 mmol/L or 2-h glucose >7.8 mmol/L. Participants, (173 were enrolled and 137 completed the study) were randomly assigned to receive either a spray-dried, water extract of cinnamon (CinSulin®), 250 mg/capsule, or a placebo, twice a day for two months. Mean ± SEM age of participants was 61.3 ± 0.8 years, BMI was 25.3 ± 0.3 and M/F ratio was 65/72. After 2 mo, fasting glucose decreased (p < 0.001) in the cinnamon extract-supplemented group (8.85 ± 0.36 to 8.19 ± 0.29 mmol/L) compared with the placebo group (8.57 ± 0.32 to 8.44 ± 0.34 mmol/L, p = 0.45). Glucose 2 h after a 75 g carbohydrate load, fasting insulin, and HOMA-IR also decreased with cinnamon extract compared with placebo. Total and LDL-cholesterol decreased with cinnamon extract and HDL-cholesterol decreased in both the cinnamon-extract and placebo groups. In conclusion, supplementation with 500 mg of water-extract of cinnamon for two months reduced fasting insulin, glucose, total cholesterol, and LDL cholesterol and enhanced insulin sensitivity of subjects with elevated blood glucose.

Ischemia-induced endothelial cell swelling and mitochondrial dysfunction are attenuated by cinnamtannin D1, green tea extract, and resveratrol in vitro.

Polyphenols possess antioxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular unit. Endothelial cell swelling may contribute to a leaky blood-brain barrier which may result in vasogenic edema in the continued presence of the existing cytotoxic edema. We investigated the protective effects of polyphenols on cytotoxic cell swelling in bEND3 endothelial cultures subjected to 5 hours oxygen-glucose deprivation (OGD). A polyphenol trimer from cinnamon (cinnamtannin D1), a polyphenol-rich extract from green tea, and resveratrol prevented the OGD-induced rise in mitochondrial free radicals, cell swelling, and the dissipation of the inner mitochondrial membrane potential. Monocyte chemoattractant protein (also called CCL2), a chemokine, but not tumor necrosis factor-α or interleukin-6, augmented the cell swelling. This effect of monochemoattractant protein 1-1 was attenuated by the polyphenols. Cyclosporin A, a blocker of the mitochondrial permeability transition pore, did not attenuate cell swelling but BAPTA-AM, an intracellular calcium chelator did, indicating a role of [Ca(2+)]i but not the mPT in cell swelling. These results indicate that the polyphenols reduce mitochondrial reactive oxygen species and subsequent cell swelling in endothelial cells following ischemic injury and thus may reduce brain edema and associated neural damage in ischemia. One possible mechanism by which the polyphenols may attenuate endothelial cell swelling is through the reduction in [Ca(2+)]i.

A thyroid hormone challenge in hypothyroid rats identifies T3 regulated genes in the hypothalamus and in models with altered energy balance and glucose homeostasis.

BACKGROUND: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms. METHODS: Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA. RESULTS: Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (± 1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic ventricular ependymal layer and differentially expressed in animal models of long- and short-term body weight regulation. CONCLUSION: This study identified genes regulated by T3 in the hypothalamus, a key area of the brain involved in homeostasis and neuroendocrine functions. These include genes hitherto not known to be regulated by thyroid status.

Inhibition of phosphatase and tensin homologue (PTEN) in human ovary in vitro results in increased activation of primordial follicles but compromises development of growing follicles.

In the mammalian ovary a small number of follicles are steadily recruited from the quiescent pool to undergo development. Follicle loss, maintenance and growth are strictly controlled by complex molecular interactions including the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signalling pathway. Stimulation of PI3K promotes phosphorylation of Akt resulting in follicle survival and activation of growth whereas this pathway is suppressed by the actions of the phosphatase and tensin homologue (PTEN). The aim of this study was to determine the effect of dipotassium bisperoxo(5-hydroxypyridine-2-carboxyl)oxovanadate (bpV), a reversible inhibitor of PTEN, on the activation, survival and development of human ovarian follicles in vitro. Biopsied ovarian tissue fragments were obtained from 17 women aged 23-46 years and exposed to 1 µM bpV(HOpic) (n = 146) or control medium (n = 128) for 24 h. Media were then replaced with control medium and all tissue incubated for a further 5 days. Ovarian tissue from each treatment group was fixed after the initial 24 h culture period and phosphorylated Akt was quantified by western blotting. After 6 days incubation all tissue fragments were inspected under light microscopy and any secondary follicles ≥100 µm isolated. Isolated follicles were cultured individually in control medium supplemented with 100 ng/ml recombinant human activin A. Tissue fragments without follicles suitable for isolation were fixed and processed for histological and immunohistochemical analysis. During 6 days culture, follicle activation occurred in tissue samples from both treatment groups but with significantly more follicles progressing to the secondary stage of development in the presence of 1 µM bpV(HOpic) compared with control (31 versus 16%; P < 0.05). Increased activation was associated with increased Akt phosphorylation and increased nuclear export of FOXO3. However isolated and cultured follicles that had been exposed to bpV(HOpic) showed limited growth and reduced survival compared with follicles from control fragments (P < 0.05). This study demonstrates that inhibition of PTEN with bpV(HOpic) affects human ovarian follicle development by promoting the initiation of follicle growth and development to the secondary stage, as in rodent species, but severely compromises the survival of isolated secondary follicles.

Cinnamon polyphenols regulate S100ß, sirtuins, and neuroactive proteins in rat C6 glioma cells.

OBJECTIVE: Increasing evidence suggests that cinnamon has many health benefits when used in herbal medicine and as a dietary ingredient. The aim of this study was to investigate the effects of an aqueous extract of cinnamon, high in type A polyphenols, on molecular targets in rat C6 glioma cells that underlie their protective effects. METHODS: C6 rat glioma cells were seeded in 35-mm culture dishes or six-well plates, then were incubated with cinnamon polyphenols at doses of 10 and 20 µg/mL for 24 h. The targeting protein expression, secretion, and phosphorylation were evaluated by immunoprecitation/immunoblotting and immunofluorescence imaging. RESULTS: Cinnamon polyphenols significantly enhanced secretion of S100ß, a Ca(2+)-binding protein, and increased intracellular S100ß expression after 24 h of incubation, in rat C6 glioma cells. Cinnamon polyphenols also enhanced protein levels of sirtuin 1, 2, and 3, deacetylases important in cell survival, and the tumor suppressor protein, p53, and inhibited the inflammatory factors, tumor necrosis factor alpha, and phospho-p65, a subunit of nuclear factor-κß. Cinnamon polyphenols also up-regulated levels of phospho-p38, extracellular signal-regulated protein and mitogen-activated protein and kinase-activated protein kinases that may be important for prosurvival functions. CONCLUSION: Our results indicate that the effects of cinnamon polyphenols on upregulating prosurvival proteins, activating mitogen-activated protein kinase pathways, and decreasing proinflammatory cytokines may contribute to their neuroprotective effects.

Cinnamon counteracts the negative effects of a high fat/high fructose diet on behavior, brain insulin signaling and Alzheimer-associated changes.

Insulin resistance leads to memory impairment. Cinnamon (CN) improves peripheral insulin resistance but its effects in the brain are not known. Changes in behavior, insulin signaling and Alzheimer-associated mRNA expression in the brain were measured in male Wistar rats fed a high fat/high fructose (HF/HFr) diet to induce insulin resistance, with or without CN, for 12 weeks. There was a decrease in insulin sensitivity associated with the HF/HFr diet that was reversed by CN. The CN fed rats were more active in a Y maze test than rats fed the control and HF/HFr diets. The HF/HFr diet fed rats showed greater anxiety in an elevated plus maze test that was lessened by feeding CN. The HF/HFr diet also led to a down regulation of the mRNA coding for GLUT1 and GLUT3 that was reversed by CN in the hippocampus and cortex. There were increases in Insr, Irs1 and Irs2 mRNA in the hippocampus and cortex due to the HF/HFr diet that were not reversed by CN. Increased peripheral insulin sensitivity was also associated with increased glycogen synthase in both hippocampus and cortex in the control and HF/HFr diet animals fed CN. The HF/HFr diet induced increases in mRNA associated with Alzheimers including PTEN, Tau and amyloid precursor protein (App) were also alleviated by CN. In conclusion, these data suggest that the negative effects of a HF/HFr diet on behavior, brain insulin signaling and Alzheimer-associated changes were alleviated by CN suggesting that neuroprotective effects of CN are associated with improved whole body insulin sensitivity and related changes in the brain.

Cinnamon polyphenols regulate multiple metabolic pathways involved in insulin signaling and intestinal lipoprotein metabolism of small intestinal enterocytes.

OBJECTIVE: Increasing evidence suggests that dietary factors may affect the expression of multiple genes and signaling pathways, which regulate intestinal lipoprotein metabolism. The small intestine is actively involved in the regulation of dietary lipid absorption, intracellular transport, and metabolism and is closely linked to systemic lipid metabolism. Cinnamon polyphenols have been shown to improve glucose, insulin, and lipid metabolism and improve inflammation in cell culture, animal, and human studies. However, little is known of the effects of an aqueous cinnamon extract (CE) on the regulation of genes and signaling pathways related to intestinal metabolism. The aim of the study was to investigate the effects of a CE on the primary enterocytes of chow-fed rats. METHODS: Freshly isolated intestinal enterocytes were used to investigate apolipoprotein-B48 secretion by immunoprecipitation; gene expressions by quantitative reverse transcriptase-polymerase chain reaction and the protein and phosphorylation levels were evaluated by western blot and flow cytometric analyses. RESULTS: Ex vivo, the CE significantly decreased the amount of apolipoprotein-B48 secretion into the media, inhibited the mRNA expression of genes of the inflammatory cytokines, interleukin-1ß, interleukin-6, and tumor necrosis factor-α, and induced the expression of the anti-inflammatory gene, Zfp36. CE also increased the mRNA expression of genes leading to increased insulin sensitivity, including Ir, Irs1, Irs2, Pi3k, and Akt1, and decreased Pten expression. CE also inhibited genes associated with increased cholesterol, triacylglycerols, and apolipoprotein-B48 levels, including Abcg5, Npc1l1, Cd36, Mttp, and Srebp1c, and facilitated Abca1 expression. CE also stimulated the phospho-p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular-signal-regulated kinase expressions determined by flow cytometry, with no changes in protein levels. CONCLUSIONS: These results demonstrate that the CE regulates genes associated with insulin sensitivity, inflammation, and cholesterol/lipogenesis metabolism and the activity of the mitogen-activated protein kinase signal pathway in intestinal lipoprotein metabolism.

An extract of chokeberry attenuates weight gain and modulates insulin, adipogenic and inflammatory signalling pathways in epididymal adipose tissue of rats fed a fructose-rich diet.

Chokeberries are a rich source of anthocyanins, which may contribute to the prevention of obesity and the metabolic syndrome. The aim of the present study was to determine if an extract from chokeberries would reduce weight gain in rats fed a fructose-rich diet (FRD) and to explore the potential mechanisms related to insulin signalling, adipogenesis and inflammatory-related pathways. Wistar rats were fed a FRD for 6 weeks to induce insulin resistance, with or without chokeberry extract (CBE) added to the drinking-water (100 and 200 mg/kg body weight, daily: CBE100 and CBE200). Both doses of CBE consumption lowered epididymal fat, blood glucose, TAG, cholesterol and LDL-cholesterol. CBE consumption also elevated plasma adiponectin levels and inhibited plasma TNF-α and IL6, compared with the control group. There were increases in the mRNA expression for Irs1, Irs2, Pi3k, Glut1, Glut4 and Gys1, and decreases in mRNA levels of Gsk3ß. The protein and gene expression of adiponectin and Pparγ mRNA levels were up-regulated and Fabp4, Fas and Lpl mRNA levels were inhibited. The levels of gene expression of inflammatory cytokines, such as Il1ß, Il6 and Tnfα were lowered, and protein and gene expression of ZFP36 (zinc finger protein) were enhanced in the epididymal adipose tissue of the rats that consumed the CBE200 extract. In summary, these results suggest that the CBE decreased risk factors related to insulin resistance by modulating multiple pathways associated with insulin signalling, adipogenesis and inflammation.

Effect of polyphenols on oxidative stress and mitochondrial dysfunction in neuronal death and brain edema in cerebral ischemia.

Polyphenols are natural substances with variable phenolic structures and are elevated in vegetables, fruits, grains, bark, roots, tea, and wine. There are over 8000 polyphenolic structures identified in plants, but edible plants contain only several hundred polyphenolic structures. In addition to their well-known antioxidant effects, select polyphenols also have insulin-potentiating, anti-inflammatory, anti-carcinogenic, anti-viral, anti-ulcer, and anti-apoptotic properties. One important consequence of ischemia is neuronal death and oxidative stress plays a key role in neuronal viability. In addition, neuronal death may be initiated by the activation of mitochondria-associated cell death pathways. Another consequence of ischemia that is possibly mediated by oxidative stress and mitochondrial dysfunction is glial swelling, a component of cytotoxic brain edema. The purpose of this article is to review the current literature on the contribution of oxidative stress and mitochondrial dysfunction to neuronal death, cell swelling, and brain edema in ischemia. A review of currently known mechanisms underlying neuronal death and edema/cell swelling will be undertaken and the potential of dietary polyphenols to reduce such neural damage will be critically reviewed.

Cinnamon increases liver glycogen in an animal model of insulin resistance.

The objective of this study was to determine the effects of cinnamon on glycogen synthesis, related gene expression, and protein levels in the muscle and liver using an animal model of insulin resistance, the high-fat/high-fructose (HF/HFr) diet-fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with (1) HF/HFr diet to induce insulin resistance, (2) HF/HFr diet containing 20 g cinnamon per kilogram of diet, (3) control diet, and (4) control diet containing 20 g cinnamon per kilogram of diet. In the liver, cinnamon added to the HF/HFr diet led to highly significant increases of liver glycogen. There were no significant changes in animals consuming the control diet plus cinnamon. In the liver, cinnamon also counteracted the decreases of the gene expressions due to the consumption of the HF/HFr diet for the insulin receptor, insulin receptor substrates 1 and 2, glucose transporters 1 and 2, and glycogen synthase 1. In muscle, the decreased expressions of these genes by the HF/HFr diet and glucose transporter 4 were also reversed by cinnamon. In addition, the overexpression of glycogen synthase 3ß messenger RNA levels and protein observed in the muscle of HF/HFr fed rats was decreased in animals consuming cinnamon. These data demonstrate that, in insulin-resistant rats, cinnamon improves insulin sensitivity and enhances liver glycogen via regulating insulin signaling and glycogen synthesis. Changes due to cinnamon in control animals with normal insulin sensitivity were not significant.

Cinnamon polyphenol extract regulates tristetraprolin and related gene expression in mouse adipocytes.

Cinnamon (Cinnamomum verum) has been widely used in spices, flavoring agents, and preservatives. Cinnamon polyphenol extract (CPE) may be important in the alleviation of chronic diseases, but the molecular evidence is not substantial. Tristetraprolin (TTP) family proteins have anti-inflammatory effects through the destabilization of pro-inflammatory mRNAs. TTP expression is reduced in fats of obese people with metabolic syndrome and brains of suicide victims. This study used quantitative real-time PCR to explore the effects of CPE on the regulation of TTP, VEGF, and related gene expression in mouse 3T3-L1 adipocytes. CPE (100 µg/mL) increased TTP mRNA levels by up to 10-fold, and this stimulation was sustained over 16 h. The levels of VEGF mRNA, a putative target of TTP, were decreased 40-50% by CPE. It also affected the expression of other genes coding for ZFP36L1 and ZFP36L3 (TTP homologues), GM-CSF, COX2, IL6, APP, G-CSF, and PAI1. This study demonstrated that CPE rapidly induces TTP mRNA and reduces VEGF mRNA and affects the expression of a number of other genes in the cultured adipocytes.

Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer.

CONTEXT: Administration of chemotherapy to premenopausal women shortens their reproductive lifespan by depleting nonrenewable oocytes. Preservation of fertility is a priority for many such women, and identification of women at risk of infertility is therefore important. However, age is the only patient characteristic currently recognized to be predictive of long-term ovarian function after chemotherapy. OBJECTIVE: Our objective was to assess markers of ovarian reserve and age as long-term predictors of ovarian function after chemotherapy. DESIGN AND SETTING: We conducted a prospective, longitudinal study at a university hospital and research institute. PATIENTS: Patients included women who were premenopausal at the time of diagnosis of early breast cancer. MAIN OUTCOME MEASURES: Ovarian function was assessed at 5 yr follow-up in relation to pretreatment hormonal and ultrasound markers of ovarian reserve. RESULTS: Forty-two women received (neo-)adjuvant chemotherapy. Continuing menses 4-5 yr after diagnosis closely reflected ovarian activity as assessed by a range of serum markers, including estradiol, inhibin B, FSH, and anti-müllerian hormone (AMH). Pretreatment serum AMH, FSH, antral follicle count, and age predicted late ovarian activity by univariate analysis. However, only AMH was predictive in a multivariate logistic regression (odds ratio = 13.0; 95% confidence interval = 2.5-66.7); 0.71 ng/ml gave peak likelihood ratio of 7.0 with 54% sensitivity and 92% specificity. Bone mineral density fell over the 4-5 yr after diagnosis with greater loss in women with lower ovarian activity. Higher pretreatment AMH was associated with lower bone mineral density at both lumbar spine and hip at 5 yr (P < 0.02). CONCLUSION: Measurement of AMH at cancer diagnosis predicts long-term ovarian function after chemotherapy. Use of this in clinical practice may allow better prediction of chemotherapy-related risk to future fertility.

Bone mineral density loss during adjuvant chemotherapy in pre-menopausal women with early breast cancer: is it dependent on oestrogen deficiency?

Pre-menopausal women given adjuvant chemotherapy for breast cancer experience both premature ovarian failure and loss of bone mineral density (BMD), and this study was designed to see if these observations are causally linked. Chemotherapy was administered to 41 pre-menopausal women with early breast cancer enrolled prospectively in a study of ovarian function and BMD in such women given systemic therapy. After giving written informed consent, all patients underwent baseline and regular on-treatment measurements of BMD by dual-energy X-ray absorptiometry (DXA) scan, bone turnover and ovarian function by analysis of serum hormone levels and self-reported menstrual diaries. Baseline lumbar spine BMD in the 41 women given chemotherapy was higher than the normal population (Z score 0.28 ± 0.14 (mean ± SEM), P = 0.047), and fell significantly over the first 6 months from a mean of 1.05-1.01 g/m(2), P < 0.0001, and similar but smaller changes were demonstrated in hip BMD. This fall was independent of age at diagnosis, type of chemotherapy, development of amenorrhoea or either baseline or on-treatment estradiol concentration. During the 6 months after completion of adjuvant chemotherapy, BMD fell further only in those women with low estradiol or experiencing amenorrhoea during the first 6 months, although all groups showed evidence of increased bone turnover. This study demonstrates loss of both spine and hip BMD in pre-menopausal women during 6 months' adjuvant systemic chemotherapy to be independent of changes in ovarian function. Ovarian function was, however, related to BMD changes after chemotherapy ceased.

Cinnamon: potential role in the prevention of insulin resistance, metabolic syndrome, and type 2 diabetes.

Metabolic syndrome is associated with insulin resistance, elevated glucose and lipids, inflammation, decreased antioxidant activity, increased weight gain, and increased glycation of proteins. Cinnamon has been shown to improve all of these variables in in vitro, animal, and/or human studies. In addition, cinnamon has been shown to alleviate factors associated with Alzheimer's disease by blocking and reversing tau formation in vitro and in ischemic stroke by blocking cell swelling. In vitro studies also show that components of cinnamon control angiogenesis associated with the proliferation of cancer cells. Human studies involving control subjects and subjects with metabolic syndrome, type 2 diabetes mellitus, and polycystic ovary syndrome all show beneficial effects of whole cinnamon and/or aqueous extracts of cinnamon on glucose, insulin, insulin sensitivity, lipids, antioxidant status, blood pressure, lean body mass, and gastric emptying. However, not all studies have shown positive effects of cinnamon, and type and amount of cinnamon, as well as the type of subjects and drugs subjects are taking, are likely to affect the response to cinnamon. In summary, components of cinnamon may be important in the alleviation and prevention of the signs and symptoms of metabolic syndrome, type 2 diabetes, and cardiovascular and related diseases.