Low-dose spironolactone combats dyslipidemia and hepatic inflammation by modulating PCSK9 in rat model of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder among women and it is associated with overt metabolic derangement. Circulating lipids are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) which blocks low density lipoprotein (LDL) receptors especially in the liver. The liver is highly vulnerable in dyslipidemia as lipid accumulation leads to progression of non-alcoholic fatty liver disease (NAFLD). An array of scientific endeavours hold that low-dose spironolactone (LDS) is beneficial as intervention for PCOS traits, but this claim is yet to be fully elucidated. The aim of this study was to investigate the effect of LDS on dyslipidemia and hepatic inflammation in rats with letrozole (LET)-induced PCOS and to assess the possible involvement of PCSK9 in these effects. Eighteen female Wistar rats were randomly assigned into 3 groups. The control group received vehicle (distilled water; p.o.), LET-treated group received letrozole (1 mg/kg; p.o.), LET+LDS-treated group received LET plus LDS (0.25 mg/kg, p.o.) for 21 days. Exposure to LET increased body and hepatic weights, plasma and hepatic total cholesterol (TC), TC/HDL, LDL, interleukin-6, MDA, PCSK9, ovarian degenerated follicles and hepatic NLRP3 intensity, reduced GSH and normal ovarian follicles. Interestingly, LDS averted dyslipidemia, NLRP3-dependent hepatic inflammation and ovarian PCOS traits. It is evident herein that LDS ameliorates PCOS traits and combats dyslipidemia and hepatic inflammation in PCOS by a PCSK9-dependent mechanism.

Short chain fatty acid, acetate restores ovarian function in experimentally induced PCOS rat model.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is pathogenically characterized with hyperandrogenism and metabolic alterations, which often result in ovarian changes and infertility in women of reproductive age. Epigenetic changes have been linked to the development of PCOS. However, the involvement of epigenetic regulator, histone deacetylase (HDAC) in PCOS-driven ovarian dysfunction is not clear. Howbeit, the present study hypothesized that acetate, an HDAC inhibitor (HDACi) would protect against ovarian dysfunction in experimentally induced PCOS. MATERIALS AND METHODS: Female Wistar rats weighing 120-150 g were randomly divided into four groups (n = 6). The groups received vehicle, sodium acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole with acetate by oral gavage respectively. The administrations were done daily for 21 days. RESULTS: The rat model of PCOS had increased body weight and ovarian weight, 1-hr postload glucose and plasma insulin, testosterone and LH/FSH ratio as well as reduced insulin sensitivity and plasma 17-ß estradiol and sex hormone binding globulin. This model of PCOS in addition showed a significant increase in plasma and ovarian triglyceride, total cholesterol, TNF-α and HDAC, and ovarian malondialdehyde as well as a significant reduction in ovarian glutathione peroxidase/reduced glutathione and NrF2 with the histology of ovarian tissues showing disrupted morphology with significant increase in the number of degenerated follicles compared with control group. These alterations were however attenuated when treated with HDACi, acetate. CONCLUSION: Altogether, the present results suggest that acetate protects ovarian function with evidence of normal growing follicles and enhanced circulating 17-ß estradiol by inhibition of HDAC.

Melatonin supplementation preserves testicular function by attenuating lactate production and oxidative stress in high fat diet-induced obese rat model.

Metabolic syndrome, including obesity has been documented as a critical factor in male reproductive dysfunction with subsequent reduction in male fertility. The therapeutic potential of melatonin has been demonstrated against oxidative stress-induced pathologies. Therefore, the present study investigated the effects of melatonin on testicular dysfunction associated with high fat diet (FD)-induced obese rat model, and the possible involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ). Adult male Wistar rats (n = 6/group) were used: control group received vehicle (normal saline), obese group received 40% FD, melatonin-treated group received melatonin (4 mg/kg), and obese plus melatonin group received melatonin and 40% FD and the treatment lasted for 12 weeks. High fat diet caused increased body weight and testicular triglyceride, total cholesterol, malondialdehyde, γ-glutamyl transferase, lactate production and lactate/pyruvate ratio as well as decreased glutathione/glutathione peroxidase, nitric oxide and PPAR-γ and circulating testosterone. Nevertheless, all these alterations were attenuated when supplemented with melatonin. Taken together, these results demonstrates that FD-induced obesity causes testicular dysfunction. In addition, the results suggest that melatonin supplementation protects against obesity-associated testicular dysfunction and this effect is accompanied by upregulation of PPAR-γ.

Acetate-mediated-obestatin modulation attenuates adipose-hepatic dysmetabolism in high fat diet-induced obese rat model.

PURPOSE: Approximately 650 million of world adult population is affected by obesity, which is characterized by adipose and hepatic metabolic dysfunction. Short chain fatty acids (SCFAs) have been linked to improved metabolic profile. However, the effect of SCFAs, particularly acetate on adipose-hepatic dysfunction is unclear. Therefore, the present study investigated the role of acetate on adipose-hepatic metabolic dysfunction and the possible involvement of obestatin in high fat diet-induced obese Wistar rats. METHODS: Adult male Wistar rats (160-190 g) were allotted into groups (n = 6/group): Control, acetate-treated, obese and obese + acetate-treated groups received vehicle (distilled water), sodium acetate (200 mg/kg), 40% HFD and 40% HFD plus sodium acetate respectively. The administration lasted for 12 weeks. RESULTS: HFD caused increased body weight gain and visceral adiposity, insulin resistance, hyperinsulinemia and increased pancreatic-ß cell function and plasma/hepatic triglyceride and total cholesterol as well as decreased adipose triglyceride and total cholesterol, increased plasma, adipose, and hepatic malondialdehyde, TNF-α, uric acid, lactate production and plasma/adipose but not gamma-glutamyl transferase and decreased plasma, adipose, and hepatic nitric oxide, glucose-6-phosphate dehydrogenase (G6PD), glutathione (GSH) and obestatin concentration compared to the control group. Notwithstanding, treatment with acetate attenuated the alterations. CONCLUSIONS: The results demonstrate that high fat diet-induced obesity is characterized with adipose and hepatic lipid dysmetabolism, which is associated with obestatin suppression. Findings also suggest that acetate provide protection against adipose and hepatic metabolic perturbations by restoring obestatin as well as G6PD/GSH-dependent antioxidant system.

Dexamethasone increases renal free fatty acids and xanthine oxidase activity in female rats: could there be any gestational impact?

Dexamethasone (DEX) is used for various conditions in female and even during pregnancy. We tested the hypothesis that DEX exposure in female rats would lead to renal free fatty acid (FFA) accumulation with elevated xanthine oxidase (XO) activity that would be aggravated by pregnancy. Twenty-four female rats (n = 6/group) were randomly assigned to non-pregnant (NPR), DEX-exposed non-pregnant (NPR + DEX), pregnant (PRE) and DEX-exposed pregnant (PRE + DEX), respectively. NPR and PRE rats received vehicle (po) while NPR + DEX and PRE + DEX groups received DEX (0.2 mg/kg; po), between gestational days 14 and 19. Data showed that DEX exposure caused increased plasma creatinine, urea, renal FFA accumulation, lipid peroxidation, aminotranferases, depressed glutathione, increased activity of XO, and elevated uric acid in both pregnant and non-pregnant rats. The findings of this study indicate that DEX exposure would cause renal FFA accumulation and glutathione depletion that are accompanied by increased activity of XO/uric acid independently of gestation. The study also implies that DEX-induced renal damage could be worsened by gestation.

Aqueous Extract of Cola nitida and Garcinia kola Synergistically Enhances Hippocampal-hypothalamic Glutamate and Na+ /K+ -ATPase Activity in Male Wistar Rats.

BACKGROUND: The incidence of cognitive decline has been proposed to rise exponentially in the coming years. Therapies targeting molecular pathways involved in the enhancement of memory and energy regulation could be a major breakthrough in the prevention or management of dementia in susceptible populations. OBJECTIVES: This study investigated the effects of aqueous extracts of Cola nitida (AECONS) and Garcinia kola (AEGAK) on glutamate level and Na+/K+-ATPase activity in the hippocampus and hypothalamus of male Wistar rats. METHODS: Adult male Wistar rats (170-200) were randomly allotted into groups (n=5/group); control (distilled water p.o.), AECONS1 (200 mg/kg), AECONS2 (400 mg/kg), AEGAK1 (200 mg/kg), AEGAK2 (400 mg/kg), AECONS1+AEGAK1 and AECONS2+AEGAK2. The extract was prepared and the administration was done daily for 6 weeks. RESULTS AND DISCUSSION: Administration of AECONS or AEGAK increased plasma, hippocampal and hypothalamic glutamate, Na+/K+-ATPase activity, NO, SOD except hippocampal glutamate in AECONS1/AEGAK1, Na+/K+-ATPase activity and SOD in AEGAK1, hypothalamic glutamate and SOD in AECONS1 when compared with control. Besides, MDA level decreased in AEGAK2 and hippocampal but not hypothalamic MDA decreased in AEGAK1 compared with control. However, concomitant administration of AECONS and AEGAK enhanced plasma, hippocampal and hypothalamic biomarkers except hypothalamic MDA level. The present study demonstrates that AECONS and AEGAK synergistically enhance hippocampal and hypothalamic glutamate and Na+/K+- ATPase activity, which are accompanied by NO and SOD-dependent antioxidant enrichment. CONCLUSION: These findings, therefore, suggest that AECONS+AEGAK could be a better therapeutic candidate in hippocampal-hypothalamic-related neurodegenerative diseases.