Lactobacillus rhamnosus supplementation ameliorates high fat diet-induced epigenetic alterations and prevents its intergenerational inheritance.

AIM: Multiple studies have reported the epigenetic inheritance of parental metabolic traits could increase the risk of developing metabolic disorders in offsprings. L. rhamnosus (LR) as a probiotic has been found to be beneficial in metabolic diseases. Current study was aimed to explore the effects of LR on high-fat diet induced epigenetic alterations and their transgenerational inheritance. METHODS: Prediabetes was induced in SD rats by feeding HFD for 16 weeks, followed by LR supplementation for 12 weeks, and were put on mating. Biochemical parameters and histopathological changes were assessed in both F0 and F1 generations. Epigenetic alterations were assessed in liver and paternal sperms using Western blotting and qRT-PCR. RESULTS: HFD fed animals displayed alterations in metabolic indices and histopathological features in liver and pancreas which were more prominent in males. These alterations were also inherited to male offsprings. LR supplementation reversed these metabolic and histological alterations in F0 animals and also prevented their intergenerational inheritance. At molecular level, LR supplementation reversed the alterations in miRNA (miR-155-5p, miR-26a-5p, miR-21-5p, miR-200c-3p, and miR-let7a-5p) expression, DNMT1 expression and the histone modification landscape within liver involving H3K36me2, H3K79me2 and H3K27me3 histone marks. Furthermore, expression of the mentioned miRNAs was found to be altered in the sperms of F0 males which was partly restored by LR supplementation. SIGNIFICANCE: Present study indicates that parental HFD-induced prediabetes can transfer the altered epigenetic memory to offspring. Parental LR supplementation can erase this memory and protect the offspring from intergenerational transfer of pathological traits.

Selenium nanoparticles stimulate osteoblast differentiation via BMP-2/MAPKs/ß-catenin pathway in diabetic osteoporosis.

Aim: To evaluate whether selenium nanoparticles (SeNPs) can stimulate bone formation and inhibit the bone loss involved in hyperglycemia-induced osteoporosis. Methods: Rat osteoblastic UMR-106 cells were used for in vitro studies and female Sprague-Dawley rats were used for type 2 diabetes-associated osteoporosis in vivo study. Results:In vitro studies show that SeNPs promote osteoblast differentiation via modulating alkaline phosphatase (ALP) activity, and promoting calcium nodule formation and collagen content. The authors also provide evidence regarding the involvement of the BMP-2/MAPKs/ß-catenin pathway in preventing diabetic osteoporosis. Further, in vivo and ex vivo studies suggested that SeNPs can preserve mechanical and microstructural properties of bone. Conclusion: To the best of our knowledge, this study provides the first evidence regarding the therapeutic benefits of SeNPs in preventing diabetes-associated bone fragility.

Osteoporosis is a common complication for people with diabetes. High glucose causes oxidative stress, and the antioxidant and anti-inflammatory properties of selenium nanoparticles (SeNPs) make them useful in the treatment of metabolic disorders associated with high glucose levels. The results of this paper report the protective effects of SeNPs in diabetic osteoporosis using rat osteoblastic UMR-106 cells and female Sprague­Dawley rats with type-2 diabetes-induced osteoporosis. SeNPs promote osteoblast differentiation and mineralization in osteoblasts, preserve bone microstructure and improve biomechanical stability, which suggests that SeNPs could be used therapeutically in the maintenance of diabetic osteoporosis.

L-Methionine supplementation attenuates high-fat fructose diet-induced non-alcoholic steatohepatitis by modulating lipid metabolism, fibrosis, and inflammation in rats.

Recently, the protective effects of a methionine-rich diet on hepatic oxidative stress and fibrosis have been suggested but not adequately studied. We, therefore, hypothesized that L-methionine supplementation would ameliorate the progression of hepatic injury in a diet-induced non-alcoholic steatohepatitis (NASH) model and aimed to investigate the underlying mechanism. NASH was developed in male Sprague Dawley rats by feeding them with a high-fat-fructose diet (HFFrD) for 10 weeks. The results demonstrated that L-methionine supplementation to NASH rats for 16 weeks improved the glycemic, lipid, and liver function profiles in NASH rats. Histological analysis of liver tissue revealed a remarkable improvement in the three classical lesions of NASH: steatosis, inflammation, and ballooning. Besides, L-methionine supplementation ameliorated the HFFrD-induced enhanced lipogenesis and lipid peroxidation. An anti-inflammatory effect of L-methionine was also observed through the inhibition of the release of proinflammatory cytokines. Furthermore, the hepatic SIRT1/AMPK signaling pathway was associated with the beneficial effects of L-methionine. This study demonstrates that L-methionine supplementation in HFFrD-fed rats improves their liver pathology via regulation of lipogenesis, inflammation, and the SIRT1/AMPK pathway, thus encouraging its clinical evaluation for the treatment of NASH.

Methionine as a double-edged sword in health and disease: Current perspective and future challenges.

Methionine is one of the essential amino acids and plays a vital role in various cellular processes. Reports advocate that methionine restriction and supplementation provide promising outcomes, and its regulation is critical for maintaining a healthy life. Dietary methionine restriction in houseflies and rodents has been proven to extend lifespan. Contrary to these findings, long-term dietary restriction of methionine leads to adverse events such as bone-related disorders, stunted growth, and hyperhomocysteinemia. Conversely, dietary supplementation of methionine improves hepatic steatosis, insulin resistance, inflammation, fibrosis, and bone health. However, a high level of methionine intake shows adverse effects such as hyperhomocysteinemia, reduced body weight, and increased cholesterol levels. Therefore, dietary methionine in a safe dose could have medicinal values. Hence, this review is aimed to provide a snapshot of the dietary role and regulation of methionine in the modulation of health and age-related diseases.

Dietary Supplementation of Methyl Donor l-Methionine Alters Epigenetic Modification in Type 2 Diabetes.

SCOPE: The aim of the current study is to evaluate whether l-methionine supplementation (l-Met-S) improves type 2 diabetes-induced alterations in glucose and lipid metabolism by modulating one-carbon metabolism and methylation status. METHODS AND RESULTS: Diabetes is induced in male Sprague-Dawley rats using high-fat diet and low dose streptozotocin. At the end of study, various biochemical parameters, immunoblotting, qRT-PCR and ChIP-qPCR are performed. The first evidence that l-Met-S activates p-AMPK and SIRT1, very similar to "metformin," is provided. l-Met-S improves the altered key one-carbon metabolites in diabetic rats by modulating methionine adenosyl transferase 1A and cystathione ß synthase expression. qRT-PCR shows that l-Met-S alleviates diabetes-induced increase in Forkhead transcription factor 1 expression and thereby regulating genes involved in glucose (G6pc, Pdk4, Pklr) and lipid metabolism (Fasn). Interestingly, l-Met-S inhibits the increased expression of DNMT1 and also prevents methylation of histone H3K36me2 under diabetic condition. ChIP assay shows that persistent increase in abundance of histone H3K36me2 on the promoter region of FOXO1 in diabetic rats and it is recovered by l-Met-S. CONCLUSION: The first evidence that dietary supplementation of l-Met prevents diabetes-induced epigenetic alterations and regulating methionine levels can be therapeutically exploited for the treatment of metabolic diseases is provided.

Effect of diethyldithiocarbamate in cyclophosphamide-induced nephrotoxicity: Immunohistochemical study of superoxide dismutase 1 in rat.

OBJECTIVES: To investigate the role of diethyldithiocarbamate (DEDTC) in cyclophosphamide (CP)-induced nephrotoxicity in Sprague-Dawley rat. DEDTC is a known chelating agent for copper and zinc. It is also used as a thiol protecting agent, as nuclear factor kappa-light-chain-enhancer of activated B-cells inhibitor and nitric oxide synthase inhibitor. It is also reported to inhibit superoxide dismutase (SOD) both in vitro and in vivo conditions. Considering this wide range of actions, current study investigated the role of DEDTC in CP-induced nephrotoxicity in experimental rat model. MATERIALS AND METHODS: Thirty-two male rats were randomized into four groups. Group 1, control received only saline ip; Group 2 and 4, received CP at the dose of 150 mg/kg body weight ip on the 4th day, while Group 3 and 4, received DEDTC at the dose of 250 mg/kg alternatively (fractionated dose of 1000 mg/kg). All the experimental animals were sacrificed on the 7th day and organs of interest were collected for biochemical, histopathological, DNA damage, and immunohistochemical assessments. RESULTS: DEDTC administration was found to further exacerbate the condition of CP-induced kidney damage as assessed by several biochemical and histological parameters. Further, the damage was also significantly reflected in the bladder in DEDTC-treated animals as compared to controls. SOD1 (Cu/Zn- dependent enzyme) expression was found to be decreased and this might be due to the action of DEDTC on SOD and other antioxidants. CONCLUSION: The present study indicates that DEDTC administration further exacerbated the CP-induced kidney damage in rat.