Exploring aryl hydrocarbon receptor (AhR) as a target for Bisphenol-A (BPA)-induced pancreatic islet toxicity and impaired glucose homeostasis: Protective efficacy of ethanol extract of Centella asiatica.

The estrogenic impact of Bisphenol-A (BPA), a widely recognized endocrine disruptor, causes disruption of pancreatic ß-cell function through estrogen receptors (ERs). While BPA's binding affinity for ERs is significantly lower than that of its natural counterpart, estrogen, recent observations of BPA's affinity for aryl hydrocarbon receptor (AhR) in specific cellular contexts have sparked a specific question: does AhR play a role in BPA's toxicological effects within the endocrine pancreas? To explore this question, we investigated BPA's (10 and 100 µg/ kg body weight/day for 21 days) potential to activate AhR within pancreatic islets and assessed the protective role of ethanol extract of Centella asiatica (CA) (200 and 400 mg/kg body weight/day for 21 days) against BPA-mediated toxicity in mouse model. Our results indicate that BPA effectively triggers the activation of AhR and modulates its target genes within pancreatic islets. In contrast, CA activates AhR but directs downstream pathways differentially and activates Nrf2. Additionally, CA was observed to counteract the disruption caused by BPA in glucose homeostasis and insulin sensitivity. Furthermore, BPA-induced oxidative stress and exaggerated production of proinflammatory cytokines were effectively counteracted by CA supplementation. In summary, our study suggests that CA influenced AhR signaling to mitigate the disrupted pancreatic endocrine function in BPA exposed mice. By shedding light on how BPA interacts with AhR, our research provides valuable insights into the mechanisms involved in the diabetogenic actions of BPA.

Altered composition of high-lipid diet may generate reactive oxygen species by disturbing the balance of antioxidant and free radicals.

Background In the present era, obesity is increasing rapidly, and high dietary intake of lipid could be a noteworthy risk factor for the occasion of obesity, as well as nonalcoholic fatty liver disease, which is the independent risk factor for type 2 diabetes and cardiovascular disease. For a long time, high-lipid diet (HLD) in "fast food" is turning into part of our everyday life. So, we were interested in fulfilling the paucity of studies by means of preliminary evaluation of these three alternative doses of HLD on a rat model and elucidating the possible mechanism of these effects and divulging the most alarming dose. Methods Thirty-two rats were taken, and of these, 24 were fed with HLD in three distinctive compositions of edible coconut oil and vanaspati ghee in a ratio of 2:3, 3:2 and 1:1 (n = 8), orally through gavage at a dose of 10 mL/kg body weight for a period of 28 days, whereas the other eight were selected to comprise the control group. Results After completion of the experiment, followed by analysis of data it was revealed that hyperlipidemia with increased liver and cardiac marker enzymes, are associated with hepatocellular injury and cardiac damage. The data also supported increased proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). As oxidative stress parameter increased in both liver and heart, there is also an increased in TNF-α due to an increased expression of inducible nitric oxide (NO) synthase, which led to a high production of NO. Moreover, HLD treatment explicitly weakens reasonability of hepatocytes and cardiomyocytes conceivably through G0/G1 or S stage capture or perhaps by means of enlistment of sub-G0/G1 DNA fragmentation and a sign of apoptosis. Conclusions Based on the outcomes, it tends to be inferred that consequences of the present examination uncovered HLD in combination of 2:3 applies most encouraging systemic damage by reactive oxygen species generation and hyperlipidemia and necroapoptosis of the liver and heart. Hence, outcome of this study may help to formulate health care strategy and warns about the food habit in universal population regarding the use of hydrogenated and saturated fats (vanaspati ghee) in diet.

Cold stress modulates redox signalling in murine fresh bone marrow cells and promotes osteoclast transformation.

Context: Alteration of redox signalling and RANK-L expression in FBMCs of mice exposed to different intensities of cold stress (15 °C, 8 °C and 4 °C) were studied.Objective: To understand the effects of varying intensities of cold stress on murine FBMCs and its impact on osteoclastogenesis.Materials and methods: FBMCs were isolated from mice exposed to different intensities of cold stress and used for immunoblotting and biochemical assays. Bone histometry was also done.Results: Different intensities of cold stress perturb redox signalling in FBMCs and alters bone histometry. Higher RANK-L expressions were noted in FBMCs of mice exposed to 8 °C and 4 °C as compared with 15 °C.Discussion and conclusion: Cold stress boosts free radical production in FBMC's, which might enhance RANK-L expression, an indicator of osteoclastogenesis. Thus, we speculate that stronger cold stress (8 °C and 4 °C) contributes to the development of early bone loss.

Protective efficacy of Tinospora sinensis against streptozotocin induced pancreatic islet cell injuries of diabetic rats and its correlation to its phytochemical profiles.

ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora sinensis Lour. (Merr.) belongs to the family Menispermaceae and its stem extract have been used traditionally in broad aspects of therapeutic remedies including debility, dyspepsia, fever, jaundice, ulcer, bronchitis, urinary disease, skin disease, liver disease and diabetes. AIM OF THE STUDY: The aim of the study was to evaluate the protective effects of methanol extract of stem of Tinospora sinensis (METS) on streptozotocin induced pancreatic islet cell injuries of diabetic rats and its correlation to its phytochemical profiles. MATERIALS AND METHODS: A high-performance liquid chromatography technique (HPLC) was used to identify and quantify the major phytochemicals present in the METS. Diabetic rats were administered with METS at a dose of (100, 200 and 400 mg/kg respectively orally) and standard drug Metformin (300 mg/kg) was given orally to group serving positive control. Effect of the METS on glucose homeostasis, oxidative stress, antioxidant status, histopathology of pancreas and also on intracellular reactive oxygen species (ROS), mitochondrial membrane potential, apoptosis, cell cycle of pancreatic islet cells were studied in diabetic rats. RESULTS: The major phytochemicals identified and quantified by HPLC in the extract were berberine, caffeic acid, myricetin and ferulic acid. This result showed that methanol extract exhibited good antioxidant effect. The methanol extract of the plant prevented the diabetogenic effect of STZ and significantly lowered the fasting blood glucose level, glycated haemoglobin and increased insulin and C-peptide level in treated rats. METS reduced apoptosis of STZ treated islet cells by significantly decreasing pro-inflammatory cytokines (TNFα, IL6), intracellular ROS generation, lipid peroxidation, nitric oxide (NO) production and increasing mitochondrial membrane potential and sub-G0 peak area, enzymatic and nonenzymatic antioxidants. CONCLUSION: The results revealed that the methanol extract of the stem of the plant possesses protective effects against diabetes and associated complications.

Inhibition of catalase activity with 3-amino-1,2,4-triazole intensifies bisphenol A (BPA)-induced toxicity in granulosa cells of female albino rats.

Exposure to bisphenol A (BPA), an endocrine disruptor and environmental toxicant, is associated with adverse estrogenic effects in both humans and wildlife species. Because the effects of BPA on the ovary at the cellular level are incompletely understood, the present study was designed to investigate the underlying mechanism of granulosa cell injury following BPA exposure. Eight-week-old female Wistar rats were treated with BPA (25 mg/kg BW/day for 9 days, intraperitonially) with or without pretreatment of the catalase-specific blocker 3-amino-1,2,4-triazole (ATZ; 1 g/kg BW/day for 5 days, intraperitonially). Different oxidative and antioxidant stress parameters, pro-inflammatory cytokines, and hormonal levels were measured. Catalase expression in isolated granulosa cells was analyzed by Western blot. There were noticeable increases in both nitric oxide and lipid peroxidation levels in the granulosa cells of the BPA-treated group with or without pretreatment with ATZ. Compared with the controls, BPA exposure resulted in a significant increase in pro-inflammatory cytokine levels that was further increased following pretreatment with ATZ. Results of the hormonal assays clearly showed a significant decrease in both estrogen and progesterone levels. In contrast, there was a significant increase in both serum follicle-stimulating hormone and luteinizing hormone levels following BPA exposure, with or without ATZ pretreatment. Results of Western blot analysis demonstrated decreased expression of catalase in the BPA-treated group and a further decrease in expression in the group treated with both BPA and ATZ. Our data suggest that catalase plays a role in mediating reproductive damage to granulosa cells exposed to BPA.

Targeting mitochondria with folic acid and vitamin B12 ameliorates nicotine mediated islet cell dysfunction.

Nicotine, one of the well-known highly toxic components of cigarette smoke, causes a number of adverse health effects and diseases. Our previous study has shown that nicotine induces reactive oxygen species (ROS) in islet cell and disrupts islet cell mitochondrial membrane potential (ΔΨm). However, supplementation with folic acid and vitamin B12 were found effective against nicotine induced changes in pancreatic islet cells. But the toxicological effects and underlying mechanisms of nicotine-induced mitochondrial dysfunction is still unknown. In this study, nicotine exposure decreases mitochondrial enzymes (pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, aconitase, malate dehydrogenase) activities by increasing cytosolic Ca2+ level which may contribute to increased mitochondrial ROS production by raising its flow to mitochondria. This in turn produces malondialdehyde and nitric oxide (NO) with a concomitant decrease in the activities of antioxidative enzymes and glutathione levels leading to loss of ΔΨm. Simultaneously, nicotine induces pancreatic islet cell apoptosis by modulating ΔΨm via increased cytosolic Ca2+ level, altered Bcl-2, Bax, cytochrome c, caspase-9, PARP expressions which were prevented by the supplementation of folic acid and vitamin B12 . In conclusion, nicotine alters islet cell mitochondrial redox status, apoptotic machinery, and enzymes to cause disruption in the ΔΨm and supplementation of folic acid and vitamin B12 possibly blunted all these mitochondrial alterations. Therefore, this study may help to determine the pathophysiology of nicotine-mediated islet cell mitochondrial dysfunction.

Possible involvement of iNOS and TNF-α in nutritional intervention against nicotine-induced pancreatic islet cell damage.

Nicotine is the more abundant and most significant components of cigarette smoke. Epidemiological evidence strongly suggests an association between cigarette smoking and pancreatic injury. Although effects of smoking on endocrine pancreas are still controversial Here, we examined the impact and underlying mechanisms of action of folic acid and vitamin B12 on nicotine induced damage in pancreatic islets of rats. Male Wistar rats were treated with nicotine (3mg/kg body weight/day, intraperitonealy) with or without folic acid (36µg/kg body weight/day, orally) and vitamin B12 (0.63µg/kg body weight/day, orally) for 21days. Supplementation with folic acid and vitamin B12 suppressed the nicotine induced changes in HbA1c, insulin, TNF-α, IL-6, generation of reactive oxygen species, and attenuated the changes in markers of oxidative stress. Moreover, folic acid and vitamin B12 also counteracted the increased expression of protein and mRNA contents of TNF-α and iNOS produced by nicotine. Further, folic acid and vitamin B12 in combination limits the nicotine induced changes in cell cycle and excessive apoptosis of the pancreatic ß-cells and also successfully blunted the nicotine induced alteration in loss of mitochondrial membrane potential. In conclusion, data demonstrate that folic acid and vitamin B12 may be possible nutritional intervention against cellular oxidative stress, which is a critical step in nicotine-mediated islet injury, and improves islet cell functional status by scavenging free radicals and by inhibiting the generation of pro-inflammatory mediators.

Protective efficacy of folic acid and vitamin B12 against nicotine-induced toxicity in pancreatic islets of the rat.

Although cigarette smoking is associated with insulin resistance and an increased risk for type 2 diabetes, few studies have examined the effect of nicotine on the adult endocrine pancreas. In this study, male Wister rats were treated with nicotine (3 mg/kg body weight/ day) with or without supplementation of folic acid (36 µg/kg body weight/day) or vitamin B12 (0.63 µg/kg body weight/day) alone or in combination. Fasting blood glucose, insulin and HBA1C level and different oxidative and anti-oxidative stress parameters were measured and pancreatic tissue sections were stained with eosin-haematoxylene. Data were analysed by nonparametric statistics. The results revealed that nicotine induced prediabetes condition with subsequent damage to pancreatic islets in rats. Nicotine also caused oxidative stress in pancreatic tissue as evidenced by increased nitric oxide and malondialdehyde level and decreased superoxide dismutase, catalase and reduced glutathione level. Compared to vitamin B12 supplementation, folic acid blunted the nicotine-induced toxicity in pancreatic islets with higher efficacy. Further, folic acid and vitamin B12 in combination were able to confer significant protection on pancreatic islets against nicotine induced toxicity. These results suggest that supplementation of folic acid and vitamin B12 in combination may be a possible strategy of detoxification against nicotine-induced toxicity in pancreatic islets of the rat.