Risperidone Exacerbates Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Renal Impairment in Obese Mice.

Risperidone, a second-generation antipsychotic drug used for schizophrenia treatment with less-severe side effects, has recently been applied in major depressive disorder treatment. The mechanism underlying risperidone-associated metabolic disturbances and liver and renal adverse effects warrants further exploration. This research explores how risperidone influences weight, glucose homeostasis, fatty liver scores, liver damage, and renal impairment in high-fat diet (HFD)-administered C57BL6/J mice. Compared with HFD control mice, risperidone-treated obese mice exhibited increases in body, liver, kidney, and retroperitoneal and epididymal fat pad weights, daily food efficiency, serum triglyceride, blood urea nitrogen, creatinine, hepatic triglyceride, and aspartate aminotransferase, and alanine aminotransferase levels, and hepatic fatty acid regulation marker expression. They also exhibited increased insulin resistance and glucose intolerance but decreased serum insulin levels, Akt phosphorylation, and glucose transporter 4 expression. Moreover, their fatty liver score and liver damage demonstrated considerable increases, corresponding to increases in sterol regulatory element-binding protein 1 mRNA, fatty acid-binding protein 4 mRNA, and patatin-like phospholipid domain containing protein 3 expression. Finally, these mice demonstrated renal impairment, associated with decreases in glutathione peroxidase, superoxide dismutase, and catalase levels. In conclusion, long-term administration of risperidone may exacerbate diabetes syndrome, nonalcoholic fatty liver disease, and kidney injury.

Exercise Affects Blood Glucose Levels and Tissue Chromium Distribution in High-Fat Diet-Fed C57BL6 Mice.

Obesity is commonly associated with hyperglycemia and type 2 diabetes and negatively affects chromium accumulation in tissues. Exercise prevents and controls obesity and type 2 diabetes. However, little information is available regarding chromium changes for regulating glucose homeostasis in high-fat diet (HFD)-fed animals/humans who exercise. Therefore, this study explored the effects of exercise and whether it alters chromium distribution in obese mice. Male C57BL6/J mice aged 4 weeks were randomly divided into two groups and fed either an HFD or standard diet (SD). Each group was subgrouped into two additional groups in which one subgroup was exposed to treadmill exercise for 12 weeks and the other comprised control mice. HFD-fed mice that exercised exhibited significant lower body weight gain, food/energy intake, daily food efficiency, and serum leptin and insulin levels than did HFD-fed control mice. Moreover, exercise reduced fasting glucose and enhanced insulin sensitivity and pancreatic ß-cell function, as determined by homeostasis model assessment (HOMA)-insulin resistance and HOMA-ß indices, respectively. Exercise also resulted in markedly higher chromium levels within the muscle, liver, fat tissues, and kidney but lower chromium levels in the bone and bloodstream in obese mice than in control mice. However, these changes were not noteworthy in SD-fed mice that exercised. Thus, exercise prevents and controls HFD-induced obesity and may modulate chromium distribution in insulin target tissues.

Newly Diagnosed Bipolar Disorder and the Subsequent Risk of Erectile Dysfunction: A Nationwide Cohort Study.

BACKGROUND: Although erectile dysfunction (ED) is a common problem in men with mental disorders, there are few reports in the literature on the relation between bipolar disorder (BD) and ED. AIMS: To establish the incidence rate of ED in men with BD and assess the risk of ED in patients with BD according to type of treatment offered or no active treatment with medication during the 1st year of onset. METHODS: We identified 5,150 men with newly diagnosed BD using Taiwan's National Health Insurance Research Database. 2 matched controls per case were selected using the propensity score and a greedy matching method to obtain a balanced control group. Multivariate Cox regression analysis was used to examine the independent risk factors for ED, including obesity and comorbidities. Hazard ratios (HRs) for ED risk were calculated for the different psychotropic therapy groups, including antidepressants, antipsychotics, and mood stabilizers. OUTCOME: HRs for ED risk were calculated for the different psychotropic therapy groups, including antidepressants, antipsychotics, and mood stabilizers. Patients with BD had a significantly higher HR for an ED diagnosis than controls. RESULTS: Patients with BD had a higher HR for an ED diagnosis than controls. Although some psychotropic medications can increase the risk of ED, patients with BD not actively treated with medication still showed a higher risk of ED than controls. CLINICAL IMPLICATIONS: Because ED might be more prevalent in patients with BD than in the general population, clinicians should assess erectile function when selecting appropriate treatment for patients with BD to minimize the risk of ED as an annoying side effect and improve treatment compliance. STRENGTHS AND LIMITATIONS: This is the first large-scale population-based study to explore the association between BD and ED. A particular strength of this study is its nationwide, population-based study design, which afforded substantial statistical power for detecting subtle differences between the 2 cohorts, thereby minimizing selection bias. There are some limitations to the present study. (i) Data on other potential risk factors is lacking. (ii) Patient compliance and dose effect between psychotropic medication and ED could not be established. (iii) We could not assess the relation between ED and the severity and phases of BD. CONCLUSION: This cohort study found a temporal association between BD and subsequent ED in a large national sample of men. Clinicians should consider the risk of ED when choosing treatment for patients with BD. Hou P-H, Mao FC, Chang G-R, et al. Newly Diagnosed Bipolar Disorder and the Subsequent Risk of Erectile Dysfunction: A Nationwide Cohort Study. J Sex Med 2018;15:183-191.

Steroidogenic enzymes of adipose tissue in modulation of trivalent chromium in a mouse model of PCOS.

Polycystic ovary syndrome (PCOS) is a type of endocrine metabolic disorder with many different consequences to health, most commonly infertility, obesity and insulin resistance. Trivalent chromium (Cr3+) was previously found to improve the metabolic profiles of patients with PCOS. The aim of this study was to explore the effect of Cr on regulating steroidogenic enzymes in adipose tissue. Female BALB/c mice were divided into three groups (n = 6 per group): the control group, PCOS + placebo milk group and PCOS + Cr-containing milk group. The dietary intake of Cr significantly decreased fasting blood sugar (FBS) and homeostasis model assessment of insulin resistance levels in the murine model of PCOS. Importantly, we found significant correlations among the levels of Cr, insulin and dehydroepiandrosterone (DHEA). In adipose tissue, decreases in the enzyme expressions of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and 17ß-hydroxysteroid dehydrogenase, but not of aromatase, were observed. By understanding the role of steroidogenic enzymes in PCOS in normal and pathological states, trace elements may be used as a form of adjunctive therapy in the management of patients with PCOS.

Association of anticardiolipin, antiphosphatidylserine, anti-ß2 glycoprotein I, and antiphosphatidylcholine autoantibodies with canine immune thrombocytopenia.

BACKGROUND: In humans, the presence of antiphospholipid antibodies (aPL) is frequently found in immune thrombocytopenia. The present study investigated whether aPL and any aPL subtypes are associated with canine thrombocytopenia, in particular, immune-mediated thrombocytopenia (immune thrombocytopenia) that usually manifests with severe thrombocytopenia. RESULTS: Sera were collected from 64 outpatient dogs with thrombocytopenia (Group I, platelet count 0 - 80 × 10(3)/uL), and 38 of which having severe thrombocytopenia (platelet count < 30 × 10(3)/uL) were further divided into subgroups based on the presence of positive antiplatelet antibodies (aPLT) (subgroup IA, immune thrombocytopenia, n =20) or the absence of aPLT (subgroup IB, severe thrombocytopenia negative for aPLT, n =18). In addition, sera of 30 outpatient dogs without thrombocytopenia (Group II), and 80 healthy dogs (Group III) were analyzed for comparison. Indirect ELISAs were performed to compare serum levels of aPL subtypes, including anticardiolipin antibodies (aCL), antiphosphatidylserine antibodies (aPS), antiphosphatidylcholine (aPC), and anti-ß2 glycoprotein I antibodies (aß2GPI), and antiphosphatidylinositol antibodies (aPI), among different groups or subgroups of dogs. Among outpatient dogs, aCL, being highly prevalent in outpatient dogs with thrombocytopenia (63/64, 98 %), is an important risk factor for thrombocytopenia (with a high relative risk of 8.3), immune thrombocytopenia (relative risk 5.3), or severe thrombocytopenia negative for aPLT (relative risk ∞, odds ratio 19). In addition, aPS is a risk factor for immune thrombocytopenia or severe thrombocytopenia negative for aPLT (moderate relative risks around 2), whereas aPC and aß2GPI are risk factors for immune thrombocytopenia (relative risks around 2). CONCLUSIONS: Of all the aPL subtypes tested here, aCL is highly associated with canine thrombocytopenia, including immune thrombocytopenia, severe thrombocytopenia negative for aPLT, and less severe thrombocytopenia. Furthermore, aPS is moderately associated with both canine immune thrombocytopenia and severe thrombocytopenia negative for aPLT, whereas aß2GPI, and aPC are moderately relevant to canine immune thrombocytopenia. In contrast, aPI is not significantly associated with canine immune thrombocytopenia.

Chromium supplementation improved post-stroke brain infarction and hyperglycemia.

Hyperglycemia is common after acute stroke and is associated with a worse outcome of stroke. Thus, a better understanding of stress hyperglycemia is helpful to the prevention and therapeutic treatment of stroke. Chromium is an essential nutrient required for optimal insulin activity and normal carbohydrate and lipid metabolism. Beyond its nutritional effects, dietary supplement of chromium causes beneficial outcomes against several diseases, in particular diabetes-associated complications. In this study, we investigated whether post-stroke hyperglycemia involved chromium dynamic mobilization in a rat model of permanent focal cerebral ischemia and whether dietary supplement of chromium improved post-stroke injury and alterations. Stroke rats developed brain infarction, hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Post-stroke hyperglycemia was accompanied by elevated secretion of counter-regulatory hormones including glucagon, corticosterone, and norepinephrine, decreased insulin signaling in skeletal muscles, and increased hepatic gluconeogenesis. Correlation studies revealed that counter-regulatory hormone secretion showed a positive correlation with chromium loss and blood glucose increased together with chromium loss. Daily chromium supplementation increased tissue chromium levels, attenuated brain infarction, improved hyperglycemia, and decreased plasma levels of glucagon and corticosterone in stroke rats. Our findings suggest that stroke rats show disturbance of tissue chromium homeostasis with a net loss through urinary excretion and chromium mobilization and loss might be an alternative mechanism responsible for post-stroke hyperglycemia.

The effect of chromium on inflammatory markers, 1st and 2nd phase insulin secretion in type 2 diabetes.

OBJECTIVE: Impaired insulin sensitivity (SI) and ß-cell function are the two main causes of type 2 diabetes (T2D) and are related to low-grade inflammation status. Trivalent chromium has shown to improve SI in our previous study. This might be due to the ability of decreasing interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) shown in animal studies. In the current study, we measured SI, ß-cell function, and plasma levels of IL-6 and TNF-α after treatment of chromium chloride (GaCr) in T2D. RESEARCH DESIGN AND METHODS: Sixty-six patients were randomly assigned to the 20 g of GaCr milk powder studying group or the milk powder placebo group. Oral glucose tolerance test was performed before and after the treatment. The SI and the ß-cell function were measured as well. RESULTS: The SI was significantly improved. At the same time, the static insulin responsivity index (Φs) was significantly higher after the treatment (p = 0.003). On the other hand, the dynamic insulin responsivity index (Φd) remained unchanged. Interestingly, a significant decrease in the IL-6 level after the treatment (p = 0.015) was noted. Although there was a trend of decreasing in TNF-α, it was not statistically significant. Finally, there was no significant correlation between the δ-IL-6, SI, and Φd after GaCr treatment. CONCLUSIONS: In conclusion, other than the improvement of SI, GaCr could also improve the second phase of insulin responsivity (Φs) and IL-6. However, δ-IL-6 was correlated with neither δ-SI nor δ-Φs which indicated that the improvement of SI and Φs might involve mechanisms other than lower inflammatory effect.

Supplementation of Vitis thunbergii root extract alleviated high-fat diet-induced obesity in C57BL/6J mice.

Vitis thunbergii root, widely used as folk medicine in Taiwan, has been found to contain polyphenolic compounds and resveratrol derivatives, which have been implicated in the prevention and treatment of obesity. Thus, we hypothesized it might show beneficial effects against obesity. C57BL/6JNarl mice fed with a high fat diet for 14 weeks increased body weight and epididymal fat pad weight, and accompanied by fatty liver, hyperglycemia, hyperinsulinemia, insulin resistance, hyperleptinemia, hypercholesterolemia, hyper-LDL-cholesterol, and high level of serum GPT, GOT, creatinine, and BUN. Supplementation of VTE in the last 7 weeks remarkably decreased body weight and epididymal fat pad weight, implying a potential anti-obesity effect. Mechanistic study showed that VTE supplementation increased energy expenditure-related CPT1 mRNA expression and AMPK phosphorylation, and decreased lipogenesis-related SREBP-1 expression in liver. In conclusion, Vitis thunbergii roots could alleviate high fat diet-induced obesity and its related complications by enhancing hepatic fatty acid oxidation and inhibitng lipogenesis.

Chromium levels in insulin-sensitive tissues and the thigh bone are modulated by prednisolone and high-fat diets in mice.

Glucocorticoids (GCs) are often prescribed in clinics but many adverse effects are also attributed to GCs. It is important to determine the role of GCs in the development of those adverse effects. Here, we investigated the impact of GCs on trivalent chromium (Cr) distribution in animals. Cr has been proposed to be important for proper insulin sensitivity, and deficits may lead to disruption of metabolism. For comparison, the effect of a high-fat diet on Cr modulation was also evaluated. C57BL/6JNarl mice were fed regular or high-fat diets for 12 weeks and further grouped for treatment with prednisolone or saline. Cr levels in tissues were determined 12 h after the treatments. Interestingly, prednisolone treatment led to significantly reduced Cr levels in fat tissue in mice fed regular diets; compared to the high-fat diet alone, prednisolone plus the high-fat diet led to a further reduction in Cr levels in the liver, muscle, and fat. Notably, a single dose of prednisolone was linked with elevated Cr levels in the thigh bones of mice fed by either regular or high-fat diets. In conclusion, this report has provided evidence that prednisolone in combination with a high-fat diet effects modulation of Cr levels in selected tissues.

Antimicrobial Peptide Mastoparan-AF Kills Multi-Antibiotic Resistant Escherichia coli O157:H7 via Multiple Membrane Disruption Patterns and Likely by Adopting 3-11 Amphipathic Helices to Favor Membrane Interaction.

We investigated the antimicrobial activity and membrane disruption modes of the antimicrobial peptide mastoparan-AF against hemolytic Escherichia coli O157:H7. Based on the physicochemical properties, mastoparan-AF may potentially adopt a 3-11 amphipathic helix-type structure, with five to seven nonpolar or hydrophobic amino acid residues forming the hydrophobic face. E. coli O157:H7 and two diarrheagenic E. coli veterinary clinical isolates, which are highly resistant to multiple antibiotics, are sensitive to mastoparan-AF, with minimum inhibitory and bactericidal concentrations (MIC and MBC) ranging from 16 to 32 µg mL-1 for E. coli O157:H7 and four to eight µg mL-1 for the latter two isolates. Mastoparan-AF treatment, which correlates proportionally with membrane permeabilization of the bacteria, may lead to abnormal dents, large perforations or full opening at apical ends (hollow tubes), vesicle budding, and membrane corrugation and invagination forming irregular pits or pores on E. coli O157:H7 surface. In addition, mRNAs of prepromastoparan-AF and prepromastoparan-B share a 5'-poly(A) leader sequence at the 5'-UTR known for the advantage in cap-independent translation. This is the first report about the 3-11 amphipathic helix structure of mastoparans to facilitate membrane interaction. Mastoparan-AF could potentially be employed to combat multiple antibiotic-resistant hemolytic E. coli O157:H7 and other pathogenic E. coli.

Chromium attenuates high-fat diet-induced nonalcoholic fatty liver disease in KK/HlJ mice.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with insulin resistance, oxidative stress, and inflammation. Evidence indicates that chromium has a role in the regulation of glucose and lipid metabolism and may improve insulin sensitivity. In this study, we report that chromium supplementation has a beneficial effect against NAFLD. We found that KK/HlJ mice developed obesity and progressed to NAFLD after feeding with high-fat diet for 8weeks. High-fat-fed KK/HlJ mice showed hepatocyte injury and hepatic triglyceride accumulation, which was accompanied by insulin resistance, oxidative stress, and inflammation. Chromium supplementation prevented progression of NAFLD and the beneficial effects were accompanied by reduction of hepatic triglyceride accumulation, elevation of hepatic lipid catabolic enzyme, improvement of glucose and lipid metabolism, suppression of inflammation as well as resolution of oxidative stress, probably through enhancement of insulin signaling. Our findings suggest that chromium could serve as a hepatoprotective agent against NAFLD.

Mirtazapine Reduces Adipocyte Hypertrophy and Increases Glucose Transporter Expression in Obese Mice.

Metabolic syndrome is known to engender type 2 diabetes as well as some cardiac, cerebrovascular, and kidney diseases. Mirtazapine-an atypical second-generation antipsychotic drug with less severe side effects than atypical first-generation antipsychotics-may have positive effects on blood glucose levels and obesity. In our executed study, we treated male high-fat diet (HFD)-fed C57BL/6J mice with mirtazapine (10 mg/kg/day mirtazapine) for 4 weeks to understand its antiobesity effects. We noted these mice to exhibit lower insulin levels, daily food efficiency, body weight, serum triglyceride levels, aspartate aminotransferase levels, liver and epididymal fat pad weight, and fatty acid regulation marker expression when compared with their counterparts (i.e., HFD-fed control mice). Furthermore, we determined a considerable drop in fatty liver scores and mean fat cell size in the epididymal white adipose tissue in the treated mice, corresponding to AMP-activated protein kinase expression activation. Notably, the treated mice showed lower glucose tolerance and blood glucose levels, but higher glucose transporter 4 expression. Overall, the aforementioned findings signify that mirtazapine could reduce lipid accumulation and thus prevent HFD-induced increase in body weight. In conclusion, mirtazapine may be useful in body weight control and antihyperglycemia therapy.

Long-term administration of olanzapine induces adiposity and increases hepatic fatty acid desaturation protein in female C57BL/6J mice.

OBJECTIVES: Weight gain and metabolic disturbances such as dyslipidemia, are frequent side effects of second-generation antipsychotics, including olanzapine. This study examined the metabolic effects of chronic olanzapine exposure. In addition, we investigated the hepatic fatty acid effects of olanzapine in female C57BL/6J mice fed a normal diet. MATERIALS AND METHODS: Female C57BL/6J mice orally received olanzapine or normal saline for 7 weeks. The effects of long-term olanzapine exposure on body weight changes, food efficiency, blood glucose, triglyceride (TG), insulin, and leptin levels were observed. Hepatic TG and abdominal fat mass were investigated, and fat cell morphology was analyzed through histopathological methods. The levels of protein markers of fatty acid regulation in the liver, namely fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1), were measured. RESULTS: Olanzapine treatment increased the food intake of the mice as well as their body weight. Biochemical analyses showed that olanzapine increased blood TG, insulin, leptin, and hepatic TG. The olanzapine group exhibited increased abdominal fat mass and fat cell enlargement in abdominal fat tissue. Western blotting of the mouse liver revealed significantly higher (1.6-fold) levels of SCD-1 in the olanzapine group relative to the control group; by contrast, FAS levels in the two groups did not differ significantly. CONCLUSION: Enhanced lipogenesis triggered by increased hepatic SCD-1 activity might be a probable peripheral mechanism of olanzapine-induced dyslipidemia. Some adverse metabolic effects of olanzapine may be related to the disturbance of lipid homeostasis in the liver.

Isoproterenol exacerbates hyperglycemia and modulates chromium distribution in mice fed with a high fat diet.

BACKGROUND AND PURPOSE: Isoproterenol (ISO), a nonselective ß-adrenoceptor agonist for treating bradycardia and asthma, has been proposed to raise blood glucose level. Little is known regarding the relationship between ISO treatment, the induced chromium (Cr) redistribution, and changes in glucose metabolism. We aimed to characterize the effects of a single dose of ISO on glucose homeostasis and Cr level changes in an obesity mouse model. METHODS: Mice (C57BL6/j strain) were first fed for a continuous period of 12 weeks with either a high fat diet (HFD), to develop an obesity animal model, or a standard diet (SD), to develop a lean animal model as controls. These groups were each separated into two subgroups to receive either a single dose of ISO or saline (control). We measured in vivo their metabolic parameters, fasting glucose level, area under the curve (AUC) for glucose level time profile, insulin level time profile, insulin sensitivity index, and chromium distribution. RESULTS: After a single dose of ISO, the SD-fed mice had slightly higher blood glucose levels compared with the SD controls, when the level was measured 30 and 60min after injection. By contrast, the ISO-treated HFD-fed mice had significantly higher blood glucose levels and AUC during the entire 120min following one administration compared with the HFD control group. Additionally, they had a substantially lower HOMA-IR index, whereas insulin levels remained unchanged. The Cr level in their bones and liver was decreased, and loss of Cr through urinary excretion was elevated. CONCLUSION: The results demonstrated that ISO exacerbated hyperglycemic syndrome in the obesity animal model. ISO induced a net negative Cr balance as a result of increased urinary excretion, leading to Cr mobilization that was not desirable to overcome the hyperglycemia.

Resveratrol protects against diet-induced atherosclerosis by reducing low-density lipoprotein cholesterol and inhibiting inflammation in apolipoprotein E-deficient mice.

OBJECTIVES: Resveratrol (RES) is a polyphenol compound that has been shown a promising cardioprotective effect. However, some reports have yielded conflicting findings. Herein, we investigated the anti-atherosclerotic effects of RES in apolipoprotein E (apo E)-deficient mice on a high cholesterol diet. MATERIALS AND METHODS: Firstly, atherosclerosis was induced by feeding a high cholesterol diet to apo E-deficient mice. Then, we examined its effects on weight control, and serum interleukin-6 (IL-6) levels and used histopathological methods to analyze morphology and inflammatory marker of atherosclerotic lesions in mice orally supplemented with high (25 mg/kg/day) and low (5 mg/kg/day) doses of RES for 8 weeks. RESULTS: Mice with high dose of RES had reduced epididymal fat pads, and lower serum IL-6 levels compared with those of control mice. Moreover, RES in high doses also decreased the low-density lipoprotein cholesterol (LDL-C) levels and atherogenic index (LDL-C/HDL-C) in the mice. Dissection of high-dose RES-treated mice revealed a marked reduction in fat deposition, percentage of mice with atherosclerotic lesion, and intima/media ratio in the aortic areas. The expressions of macrophage-specific marker F4/80 and cardiovascular inflammatory marker NF-κB in atherosclerotic vessels were both diminished in the atherosclerotic vessels of high-dose RES-supplementated apo E-deficient mice. CONCLUSION: These results suggest that RES prevented the effects of a high cholesterol diet on the rate of accretion in atherosclerosis progression by reducing the LDL-C levels and suppressing atherosclerotic inflammation. RES can therefore be valuable in the development of new anti-atherosclerotic agents.

Effect of Chromium Supplementation on Element Distribution in a Mouse Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder and one of the most common causes of anovulatory infertility. In addition, insulin resistance is commonly associated with PCOS and contributed to pathophysiology connected to dietary minerals including chromium (Cr), copper (Cu), iron (Fe), and zinc (Zn). The aims of this study were to explore whether PCOS in mice alters levels of these elements and determine if Cr supplementation resolves changes. Twenty-four female BALB/c mice were divided into three groups of eight mice [normal control (NC), PCOS+placebo milk (PP), and PCOS+Cr-containing milk (PCr)]. Each group received a high-fat diet for 4 weeks. Our results show significantly higher levels of dehydroepiandrosterone (DHEA) (p<0.001), fasting glucose (p<0.05), and fasting insulin (p<0.05) in the PP group compared with both NC and PCr group. However, Cr levels were significantly lower in muscle, bone, and serum in the PP group (p<0.05) compared with NC and PCr groups. In liver, bone, and serum, Fe levels were significantly higher in the PP group compared with the NC group (p<0.05). In addition, we found significant correlations between Cu/Zn ratio and fasting insulin in all mice (r=0.61; p=0.002). Given that significant research shows that Cr supplementation improves fasting glucose, fasting insulin, and metal metabolism disorders for PCOS mice, our data suggest that trace element levels can serve as biomarkers to prescribe therapeutic supplementation to maintain a healthy metabolic balance and treat disease conditions.

Rapamycin impairs HPD-induced beneficial effects on glucose homeostasis.

BACKGROUND AND PURPOSE: Rapamycin, which is used clinically to treat graft rejection, has also been proposed to have an effect on metabolic syndrome; however, very little information is available on its effects in lean animals/humans. The purpose of this study was to characterize further the effects of the continuous use of rapamycin on glucose homeostasis in lean C57BL6/J mice. EXPERIMENTAL APPROACH: Mice were fed a high-protein diet (HPD) for 12 weeks to develop a lean model and then were treated daily with rapamycin for 5 weeks while remaining on a HPD. Metabolic parameters, endocrine profiles, glucose tolerance tests, insulin sensitivity index, the expression of the glucose transporter GLUT4 and chromium distribution were measured in vivo. KEY RESULTS: Lower body weight gain as well as a decreased caloric intake, fat pads, fatty liver scores, adipocyte size and glucose tolerance test values were observed in HPD-fed mice compared with mice fed a high-fat or standard diet. Despite these beneficial effects, rapamycin-treated lean mice showed greater glucose intolerance, reduced insulin sensitivity, lower muscle GLUT4 expression and changes in chromium levels in tissues even with high insulin levels. CONCLUSION AND IMPLICATIONS: Our findings demonstrate that continuous rapamycin administration may lead to the development of diabetes syndrome, as it was found to induce hyperglycaemia and glucose intolerance in a lean animal model.

The synergistic effect of rapamycin combined with 5-fluorouracil in BALB/cByJNarl mice bearing CT-26 tumor cells.

BACKGROUND: The aim of this study was to investigate the antitumor effect of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) signaling, combined with 5-fluorouracil treatment on CT-26 colorectal adenocarcinoma cells implanted into BALB/c mice. MATERIALS AND METHODS: Two experiments were carried out: treatment from day 1 after CT-26 cell implantation; and treatment from day 7 after CT-26 cell implantation after the detection of a tumor mass. There were four groups in each experiment: control; treatment with 5-fluorouracil; with rapamycin; and with rapamycin with 5-fluorouracil. RESULTS: Rapamycin combined with 5-fluorouracil significantly reduced tumor size, suppressed expression of B-cell lymphoma 2, increased tumor apoptosis, and inhibited mTOR signaling activity by de-phosphorylation of S6K. CONCLUSION: The results strongly suggest that rapamycin might increase the chemosensitization of tumor cells. Rapamycin combined with 5-fluorouracil treatment had a synergistic tumor-inhibition effect. Future research on rapamycin is required to develop new therapeutic strategies.

Synergistic antibacterial efficacies of the combination of bovine lactoferrin or its hydrolysate with probiotic secretion in curbing the growth of meticillin-resistant Staphylococcus aureus.

The occurrence of multidrug-resistant or meticillin-resistant Staphylococcus aureus (MRSA) has become an important issue in clinics. This study evaluated a combinatorial treatment approach by using the well-documented antibacterial protein apo-bovine lactoferrin (apo-bLf) or its hydrolysate and specific probiotic supernatants for controlling MRSA infection. Clinical MRSA strains were isolated from different patient specimens. Apo-bLf-hydrolysate possessed stronger anti-MRSA activity than complete bLf in that it inhibited the growth of most MRSA strains tested in vitro. Otherwise, the supernatants produced by Lactobacillus fermentum (ATCC 11739), Bifidobacterium longum subsp. longum (ATCC 15707) and Bifidobacterium animalis subsp. lactis (BCRC 17394) inhibited the growth of various MRSA strains. Further, L. fermentum or B. animalis subsp. lactis supernatant plus apo-bLf or bLf-hydrolysate led to partially synergistic to synergistic growth-inhibitory activity against MRSA strains. However, L. fermentum and not B. animalis subsp. lactis or B. longum subsp. longum was observed to resist the antibacterial activity of both apo-Lf and bLf-hydrolysate. Therefore, it is suggested that L. fermentum could be the best candidate to be used with apo-bLf or bLf-hydrolysate as a live supplement against MRSA infections.

Glucagon and insulin have opposite effects on tissue chromium distribution in an obese mouse model.

AIMS/INTRODUCTION: Previous studies have suggested that chromium (Cr) is an essential cofactor for normal carbohydrate metabolism and affects insulin sensitivity, especially in rodent models. Several factors, such as insulin challenge, high carbohydrate intake, and response to stress (e.g., in obesity), alter Cr excretion or distribution. Glucagon is known to regulate carbohydrate metabolism and hyperglucagonemia plays a role in the development of hyperglycemia in diabetic subjects. MATERIALS AND METHODS: In the present study we investigated possible modulation of Cr levels by glucagon using an obese mouse model. Mice were kept on a high-fat diet and then used as an obesity model. These obese mice were injected with one dose of glucagon or insulin and Cr levels in their tissues were determined. RESULTS: In obese mice, glucagon challenge significantly increased Cr levels in bone but decreased them in the fat and liver. In contrast, insulin challenge significantly decreased Cr levels in bone but increased them in the fat, liver and muscle. CONCLUSIONS: The results show that glucagon and insulin have opposite effects on Cr levels in bone, fat, liver, and muscle.