Reduction of ovarian reserves and activation of necroptosis to in vivo air pollution exposures.

We investigated the association between air pollution and changes in ovarian follicles, anti-mullerian hormone (AMH) levels, the occurrence of necroptosis cell death by activation of receptor-interacting protein kinase 3 (RIPK3) and, the activation of mixed lineage kinase domain-like (MLKL) proteins. Forty-two female Wistar rats were divided into three groups of 14 each, which were exposed to real-ambient air, filtered air and purified air (control) in two periods of 3 and 5 months. The results showed that the number of ovarian follicles decreased in the group exposed to real-ambient air versus the control group (P < 0.0001). The trend of age-related AMH changes with respect to exposure to air pollutants was affected and its levels decreased after 3 months of exposure. The MLKL increased in the group exposed to the real-ambient air compared to the control group (P = 0.033). Apparently long-term exposure to air pollution can reduce ovarian reserves.

Investigating the Effects of Maternal Separation on Hypothalamic-Pituitary-Adrenal Axis and Glucose Homeostasis under Chronic Social Defeat Stress in Young Adult Male Rat Offspring.

INTRODUCTION: Given the suggested metabolic regulatory effects of stress-responsive genes and based on the impacts of early-life stress on HPA axis development, this study aimed to characterize the maternal separation (MS) impact on the communication between glucose metabolism and HPA axis dysregulations under chronic social defeat stress (CSDS). METHODS: During the first 2 weeks of life, male Wistar rats were either exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3 weeks. There were four groups (n = 10/group): Std-Con, MS-Con, Std-CSDS, and MS-CSDS. RESULTS: Early and/or adult life adversity reduced ß-cell number, muscular FK506-binding protein 51 (FKBP51) content, and BMI in adulthood. The reduction of ß-cell number and BMI in the MS-CSDS rats were more profound than MS-Con group. CSDS either alone or in combination with MS reduced locomotor activity and increased and decreased corticotropin-releasing factor type 1 receptor (CRFR1) content, respectively, in hypothalamus and pancreas. Although, under CSDS, MS intensified HPA axis overactivity and reduced isolated islets' insulin secretion, it could promote resilience to depression symptoms. No differences were observed in hypothalamic Fkbp5 gene DNA methylation and glucose tolerance among groups. CONCLUSION: MS exacerbated HPA axis overactivity and the endocrine pancreas dysfunctions under CSDS. The intensified corticosterone secretion and the diminished content of pancreatic CRFR1 protein could be involved in the reduced ß-cell number and islets' insulin secretion under CSDS. The decreased muscular FKBP51 content might be a homeostatic response to slow down insulin resistance development under chronic stress.

Sustained feeding of a diet high in fat resulted in a decline in the liver's insulin-degrading enzyme levels in association with the induction of oxidative and endoplasmic reticulum stress in adult male rats: Evaluation of 4-phenylbutyric acid.

The current study explored the impact of high fat diet (HFD) on hepatic oxidative and endoplasmic reticulum (ER) stress and its insulin degrading enzyme (IDE) content with the injection of 4-phenyl butyric acid (4-PBA) in adult male rats. Following the weaning period, male offspring were distributed among six distinct groups. The corresponding diet was used for 20 weeks, subsequently 4-PBA was administered for three consecutive days. Plasma glucose and insulin levels, HOMA-ß (homeostasis model assessment of ß-cell), hepatic ER and oxidative stress biomarkers and IDE protein content were assessed. Long-term ingestion of HFD (31 % cow butter) induced oxidative and ER stress in the liver tissue. Accordingly, a rise in the malondialdehyde (MDA) content and catalase enzyme activity and a decrease in the glutathione (GSH) content were detected within the liver of the HFD and HFD + DMSO groups. Consumption of this diet elevated the liver expression of binding immunoglobulin protein (BIP) and C/enhancer-binding protein homologous protein (CHOP) levels while reduced its IDE content. The HOMA-ß decreased significantly. The injection of the 4-PBA moderated all the induced changes. Findings from this study indicated that prolonged HFD consumption led to a reduction in plasma insulin levels, likely attributed to pancreatic ß cell malfunction, as evidenced by a decline in the HOMA-ß index. Also, the HFD appears to have triggered oxidative and ER stress in the liver, along with a decrease in its IDE content.

Long-term high-fat diet disrupts lipid metabolism and causes inflammation in adult male rats: possible intervention of endoplasmic reticulum stress.

This study investigated the effect of long-term high-fat diet (HFD) on plasma lipid profile and probability of inflammation in adult rats. After weaning, male offspring were divided into six groups based on diet type and medication. After 20 weeks of dietary intake, 4-PBA (endoplasmic reticulum (ER) stress inhibitor) was injected for three days. Then, blood samples were taken to measure plasma concentrations of low-density lipoprotein (LDL), triglyceride (TG), high-density lipoprotein (HDL), cholesterol, leptin and interleukin 1-ß (IL 1-ß). The HFD increased body weight and food intake and intra-abdominal fat and thymus weights, which were associated with elevated plasma leptin level. Moreover, HFD increased plasma concentrations of TG, LDL, cholesterol and IL 1-ß and decreased HDL level. Injection of 4-PBA reversed the plasma parameters changes caused by HFD. It seems that long-term HFD feeding through inducing the ER stress, disrupted the lipid metabolism and resulted in inflammation.

Endoplasmic reticulum stress inhibition ameliorated WFS1 expression alterations and reduced pancreatic islets' insulin secretion induced by high-fat diet in rats.

Endoplasmic reticulum (ER) stress is involved in the development of glucose homeostasis impairment. When ER stress occurs, the unfolded protein response (UPR) is activated to cope with it. One of the UPR components is WFS1 (Wolfram syndrome 1), which plays important roles in ER homeostasis and pancreatic islets glucose-stimulated insulin secretion (GSIS). Accordingly and considering that feeding high-fat food has a major contribution in metabolic disorders, this study aimed to investigate the possible involvement of pancreatic ER stress in glucose metabolism impairment induced by feeding high-fat diet (HFD) in male rats. After weaning, the rats were divided into six groups, and fed on normal diet and HFD for 20 weeks, then 4-phenyl butyric acid (4-PBA, an ER stress inhibitor) was administered. Subsequently, in all groups, after performing glucose tolerance test, the animals were dissected and their pancreases were removed to extract ER, islets isolation and assessment of GSIS. Moreover, the pancreatic ER stress [binding of immunoglobulin protein (BIP) and enhancer-binding protein homologous protein (CHOP)] and oxidative stress [malondialdehyde (MDA), glutathione (GSH) and catalase] biomarkers as well as WFS1 expression level were evaluated. HFD decreased pancreatic WFS1 protein and GSH levels, and enhanced pancreatic catalase activity, MDA content, BIP and CHOP protein and mRNA levels as well as Wfs1 mRNA amount. Accordingly, it increased BIP, CHOP and WFS1 protein levels in the extracted ER of pancreas. In addition, the HFD caused glucose intolerance, and decreased the islets' GSIS and insulin content. However, 4-PBA administration restored the alterations. It seems that, HFD consumption through inducing pancreatic ER stress, altered WFS1 expression levels, reduced the islets' GSIS and insulin content and finally impaired glucose homeostasis.

Maternal stress induced endoplasmic reticulum stress and impaired pancreatic islets' insulin secretion via glucocorticoid receptor upregulation in adult male rat offspring.

Exposure to perinatal (prenatal and/or postnatal) stress is considered as a risk factor for metabolic disorders in later life. Accordingly, this study aimed to investigate the perinatal stress effects on the pancreatic endoplasmic reticulum (ER) stress induction, insulin secretion impairment and WFS1 (wolframin ER transmembrane Glycoprotein, which is involved in ER homeostasis and insulin secretion) expression changes, in rat offspring. According to the dams' period of exposure to variable stress, their male offspring were divided into, control (CTRL); pre-pregnancy, pregnancy, lactation stress (PPPLS); pre-pregnancy stress (PPS); pregnancy stress (PS); lactation stress (LS); pre-pregnancy, pregnancy stress (PPPS); pregnancy, lactation stress (PLS); pre-pregnancy, lactation stress (PPLS) groups. Offspring pancreases were removed for ER extraction and the assessment of ER stress biomarkers, WFS1 gene DNA methylation, and isolated islets' insulin secretion. Glucose tolerance was also tested. In the stressed groups, maternal stress significantly increased plasma corticosterone levels. In PPS, PS, and PPPS groups, maternal stress increased Bip (Hsp70; heat shock protein family A member 4), Chop (Ddit3; DNA- damage inducible transcript3), and WFS1 protein levels in pancreatic extracted ER. Moreover, the islets' insulin secretion and content along with glucose tolerance were impaired in these groups. In PPS, PS, LS and PPPS groups, the pancreatic glucocorticoid receptor (GR) expression increased. Maternal stress did not affect pancreatic WFS1 DNA methylation. Thus, maternal stress, during prenatal period, impaired the islets' insulin secretion and glucose homeostasis in adult male offspring, possibly through the induction of ER stress and GR expression in the pancreas, in this regard the role of WFS1 protein alteration in pancreatic ER should also be considered.

The chemical chaperon 4-phenyl butyric acid restored high-fat diet- induced hippocampal insulin content and insulin receptor level reduction along with spatial learning and memory deficits in male rats.

This study assessed the effect of a chronic high-fat diet (HFD) on plasma and hippocampal insulin and corticosterone levels, the hippocampus insulin receptor amount, and spatial learning and memory with or without receiving 4-phenyl butyric acid (4-PBA) in male rats. Rats were divided into high-fat and normal diet groups, then each group was subdivided into dimethyl sulfoxide (DMSO) and 4-PBA groups. After weaning, the rats were fed with HFD for 20 weeks. Then, 4-PBA or DMSO were injected for 3 days. Subsequently, oral glucose tolerance test was done. On the following day, spatial memory tests were performed. Then the hippocampus Bip, Chop, insulin, corticosterone, and insulin receptor levels were determined. HFD increased plasma glucose, leptin and corticosterone concentrations, hippocampus Bip, Chop and corticosterone levels, food intake, abdominal fat weight and body weight along with impaired glucose tolerance. It decreased plasma insulin, and insulin content, and its receptor amount in hippocampus. HFD lengthened escape latency and shortened the duration spent in target zone. 4-PBA administration improved the HFD- induced adverse changes. Chronic HFD possibly through the induction of endoplasmic reticulum (ER) stress and subsequent changes in the levels of hippocampal corticosterone, insulin and insulin receptor along with possible leptin resistance caused spatial learning and memory deficits.

The risk of life-threatening ventricular arrhythmias in presence of high-intensity endurance exercise along with chronic administration of nandrolone decanoate.

Anabolic steroids used to improve muscular strength and performance in athletics. Its long-term consumption may induce cardiovascular adverse effects. We assessed the risk of ventricular arrhythmias in rats which subjected to chronic nandrolone plus high-intensity endurance exercise. Animals were grouped as; control (CTL), exercise (Ex): 8 weeks under exercise, vehicle group (Arach): received arachis oil, and Nan group: received nandrolone decanoate 5 mg/kg twice a week for 8 weeks, Arach+Ex group, and Nan+Ex. Finally, under anesthesia, arrhythmia was induced by infusion of 1.5 µg/0.1 mL/min of aconitine IV and ventricular arrhythmias were recorded for 15 min. Then, animals' hearts were excised and tissue samples were taken. Nandrolone plus exercise had no significant effect on blood pressure but decreased the heart rate (P<0.01) and increased the RR (P<0.01) and JT intervals (P<0.05) of electrocardiogram. Nandrolone+exercise significantly increased the ventricular fibrillation (VF) frequency and also decreased the VF latency (P<0.05 versus CTL group). Combination of exercise and nandrolone could not recover the decreasing effects of nandrolone on animals weight gain but, it enhanced the heart hypertrophy index (P<0.05). In addition, nandrolone increased the level of hydroxyproline (HYP) and malondialdehyde (MDA) but had not significant effect on glutathione peroxidase of heart. Exercise only prevented the effect of nandrolone on HYP. Nandrolone plus severe exercise increases the risk of VF that cannot be explained only by the changes in redox system. The intensification of cardiac hypertrophy and prolongation of JT interval may be a part of involved mechanisms.

The Effects of Nandrolone Decanoate Along with Prolonged Low-Intensity Exercise on Susceptibility to Ventricular Arrhythmias.

We examined the influence of chronic administration of nandrolone decanoate with low-intensity endurance swimming exercise on susceptibility to lethal ventricular arrhythmias in rat. The animal groups included the control group, exercise group (EX), nandrolone group (Nan), vehicle group (Arach), trained vehicle group (Arach + Ex) and trained nandrolone group (Nan + Ex) that treated for 8 weeks. Then, arrhythmia induction was performed by intravenous infusion of aconitine and electrocardiogram recorded. Then, malondialdehyde (MDA), hydroxyproline (HYP) and glutathione peroxidase of heart tissue were measured. Chronic administration of nandrolone with low-intensity endurance swimming exercise had no significant effect on blood pressure, heart rate and basal ECG parameters except RR interval that showed increase (P < 0.05). Low-intensity exercise could prevent the incremental effect of nandrolone on MDA and HYP significantly. It also increased the heart hypertrophy index (P < 0.05) and reduced the abating effect of nandrolone on animal weighting. Nandrolone along with exercise significantly increased the duration of VF (P < 0.05) and reduced the VF latency (P < 0.05). The findings suggest that chronic co-administration of nandrolone with low-intensity endurance swimming exercise to some extent facilitates the occurrence of ventricular fibrillation in rat. Complementary studies are needed to elucidate the involved mechanisms of this abnormality.