Repression of HDAC5 by acetate restores hypothalamic-pituitary-ovarian function in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) accounts for 90-95 % of worldwide diabetes cases and is primarily characterized by insulin resistance. Its progression as a chronic metabolic disease has been largely associated with female reproductive abnormalities, including ovarian dysfunction with consequent infertility. Epigenetic modifications have been suggested as a possible link to metabolic comorbidities. We therefore hypothesized that short chain fatty acids, acetate (ACA), a potential histone deacetylase inhibitor (HDAC) ameliorates hypothalamic-pituitary-ovarian (HPO) dysfunction in T2DM. Female Wistar rats weighing 160-190 g were allotted into three groups (n = 6/group): Control (vehicle; po), T2D and T2D + ACA (200 mg/kg; po). T2DM was induced by fructose administration (10 %; w/v) for 6 weeks and single dose of streptozotocin (35 mg/kg; ip). The present data showed that in addition to insulin resistance, increased fasting blood glucose and insulin, T2DM induced elevated plasma, hypothalamic and ovarian triglyceride, lipid peroxidation, TNF-α and glutathione depletion. Aside, T2DM also led to increased plasma lactate production and γ-Glutamyl transferase as well as decreased gonadotropins/17ß-estradiol. Histologically, hypothalamus, pituitary and ovaries revealed disrupted neuronal cells/moderate hemorrhage, altered morphology/vascular congestions, and degenerated antral follicle/graafian follicle with mild fibrosis and infiltrated inflammatory cells respectively in T2D animals. Interestingly, these alterations were accompanied by elevated plasma/hypothalamic HDAC5 and attenuated when treated with acetate. The present results demonstrate that T2DM induces HPO dysfunction, which is accompanied by elevated circulating/hypothalamic HDAC5. The results in addition suggest that acetate restores HPO function in T2DM by suppression of HDAC5 and enhancement of insulin sensitivity.

Acetate ameliorates nephrotoxicity in streptozotocin-nicotinamide-induced diabetic rats: Involvement of xanthine oxidase activity.

Impaired renal function is a common complication of diabetes mellitus (DM) that often degenerates to cardiovascular disease, contributing to high morbidity and reduced survival worldwide. Short chain fatty acids (SCFAs), including acetate has shown potential benefits in glycemic or metabolic regulation but its effect on diabetes-associated renal toxicity/impairment is not clear. Herein, we investigated the hypothesis that acetate would ameliorate renal toxicity, accompanying DM, possibly by suppression of xanthine oxidase (XO) activity. Adult male Wistar rats (230-260 g) were allotted into groups (n = 6/group) namely: control (vehicle; po), sodium acetate (NaAc)-treated (200 mg/kg), diabetic with or without NaAc groups. DM was induced by intraperitoneal injection of streptozotocin 65 mg/kg after a dose of nicotinamide (110 mg/kg). Diabetic animals showed increased fasting glucose and insulin, renal triglyceride, total cholesterol, atherogenic lipid, malondialdehyde, XO, tissue necrosis factor-α, uric acid, interleukin-6, aspartate transaminase/alanine aminotransferase ratio, gamma-glutamyl transferase and decreased glutathione and nitric oxide concentration. The renal tissue was characterized with disrupted tissue architecture, enlarged Bowman's space, congested glomeruli and adherence of abnormal segments of tuft to Bowman's capsule with consequent elevated serum creatinine and urea concentration. However, these alterations were attenuated by NaAc. The study demonstrates that acetate ameliorates diabetes-induced nephrotoxicity, which is associated with suppressed XO and its accompanied pro-inflammatory mediators. Therefore, SCFAs, acetate would be a promising dietary-derived therapeutic agent for the prevention and management of diabetes-associated renal disturbances.

Hibiscus sabdariffa extract protects against cadmium-induced ovarian toxicity in adult Wistar rats.

Hibiscus sabdariffa (HS) is native to tropical and subtropical regions, and its enrichment as a source of antioxidants and phytoestrogen has been documented. The present study investigated effects of HS on ovarian toxicity induced by cadmium. Adult female Wistar rats were grouped into 4 (n=5/group): Group A received HS (100 mg/kg), group B received cadmium sulphate (5 mg/kg), group C received cadmium sulphate and HS, and group D (control) received 1 ml of distilled water. Cadmium sulphate was administered for five days (i.p) followed by oral administration of HS for 28 days. Results showed distortion in the cytoarchitecture of the follicular cells in the ovary of cadmium-treated rats while there was mild or no distortion recorded for the ovary of the rats treated with cadmium and HS. There was also a significant reduction in the serum level of Luteinizing and follicle stimulating hormone of the rats treated with cadmium (group B) when compared with control rats. However, these alterations were attenuated when treated with HS. We concluded that HS has an ovarian protective effect in cadmium-treated adult female rats. Hence the present results suggest that HS extract would be a potential therapeutic agent in ovarian dysfunction.

Sodium acetate-mediated inhibition of histone deacetylase alleviates hepatic lipid dysregulation and its accompanied injury in streptozotocin-nicotinamide-induced diabetic rats.

OBJECTIVE: Hepatic lipid dysregulation with consequent lipotoxicity remains critical in the progression of non-alcoholic fatty liver disease, a rising prevalent complication of diabetes mellitus particularly type 2 diabetes. Diabetes-associated hepatic complications are among the leading causes of liver-related morbidity and mortality worldwide. Short chain fatty acids (SCFAs) have been demonstrated to regulate glycemic metabolism but its effect on diabetes-driven hepatic perturbation is unknown. This study is therefore designed to investigate the effect of SCFAs, acetate on diabetes-characterised hepatic lipotoxicity, and plausible involvement of histone deacetylase (HDAC) activity. METHODS: Adult male Wistar rats (230-260 g) were allotted into groups (n = 6/group) namely: control (vehicle; p.o.), sodium acetate (SAT)-treated (200 mg/kg), diabetic with/without SAT groups. Diabetes was induced by intraperitoneal injection of streptozotocin 65 mg/kg after a dose of nicotinamide 110 mg/kg. RESULTS: Data from diabetic animals showed increased fasting glycemia and insulinemia, decreased insulin sensitivity and body weight with increased relative hepatic mass. It also revealed increased hepatic lipid, serum/hepatic malondialdehyde, tissue necrosis factor-α, uric acid, aspartate transaminase, alanine aminotransferase and decreased glutathione content with elevated hepatic HDAC. Histologically, the hepatic tissue was characterised with disrupted architecture, inflammation of central vein and foci of periportal and sinusoidal cellular infiltration. However, these alterations were attenuated by sodium acetate. CONCLUSION: The study demonstrates that diabetes mellitus drives hepatic lipotoxicity, characterised with lipid accumulation, excessive lipid peroxidation, pro-inflammation, depleted glutathione content and accompanied by increased HDAC activity. Besides, the study suggests that acetate ameliorates diabetes-associated hepatic lipotoxicity through HDAC suppression and enhancement of insulin sensitivity.

Protective role of glutamine against cadmium-induced testicular dysfunction in Wistar rats: Involvement of G6PD activity.

BACKGROUND: Endocrine disruptor such as cadmium has been widely reported to cause testicular toxicity, which contributes to recent decline in male fertility worldwide. Glutamine, the most abundant amino acid in the body has been demonstrated to exert protective effects in cellular toxicity. However, its role in testicular toxicity is unknown. The present study is therefore aimed at investigating the effects of glutamine supplementation on cadmium-induced testicular toxicity, and the possible involvement of glucose-6-phosphate dehydrogenase (G6PD) activity. MATERIALS AND METHOD: Male Wistar rats weighing 160-190 g were allotted into 4 groups (n = 5/group): The groups received vehicle (distilled water; p.o.), glutamine (1gkg-1; p.o.), cadmium chloride (5mgkg-1p.o.) and Cadmium chloride plus glutamine respectively, daily for 30 days. Biochemical and histological analyses were performed with appropriate method. RESULTS: Administration of cadmium significantly decreased body weight, sperm count, motility and viability, as well as altered sperm morphology and progressivity. Cadmium also caused atrophy of the seminiferous tubule in addition to disrupted testicular architecture, lumen, Sertoli cells and spermatogonia. Similarly, serum and testicular aspartate transaminase, and malondialdehyde significantly increased, and G6PD, glutathione, nicotinamide adenine dinucleotide phosphate and nitric oxide significantly decreased with corresponding decrease in follicle stimulating hormone, luteinizing hormone and testosterone in cadmium-treated animals compared with control groups. However, supplementation with glutamine attenuated these alterations. CONCLUSION: The present study demonstrates that cadmium induces testicular dysfunction that is attributable to defective G6PD and accompanied by increased lipid peroxidation and impaired NO-dependent endothelial function. Interestingly, glutamine supplementation ameliorates cadmium-induced testicular dysfunction through enhancement of G6PD activity.

Methanolic extract of Cola nitida elicits dose-dependent diuretic, natriuretic and kaliuretic activities without causing electrolyte impairment, hepatotoxicity and nephrotoxicity in rats.

Cola nitida (Kolanut) is conventionally used in tropical Africa for the treatment of all kinds of ailments such as migraine, morning sickness, metabolic disorders etc. However, this study was designed to investigate the diuretic, natriuretic and kaliuretic activities of methanolic extract of Cola nitida (MECN) in male Wistar rats. Adult male Wistar rats were randomly allotted into control (25 ml/kg b.w.), furosemide (20 mg/kg b.w; standard), MECN1 (100 mg/kg), MECN2 (200 mg/kg), MECN3 (300 mg/kg), MECN4 (400 mg/kg), MECN5 (500 mg/kg), MECN6 (600 mg/kg) groups with n=6. The extract was prepared as previously described and the treatment lasted for 14 days. Urine volume and diuretic indices were estimated. Urine electrolytes, plasma electrolytes, plasma/renal AST/ALT, plasma creatinine and urea were assayed using flame photometry and standard colorimetric method respectively.Administration of different doses of C. nitida significantly altered body weight gain and water intake but not food intake compared with control group. There were significant increases in urine volume and urine electrolytes (Na+, K+ and Cl-), a decrease in plasma/renal ALT and AST activities, a decrease in plasma creatinine and urea concentration and no alteration in plasma electrolytes when compared with control and furosemide-treated groups. Our study suggests that MECN elicits diuretic, natriuretic, and kaliuretic activities without causing electrolyte impairment, hepatotoxicity and nephrotoxicity. These effects are dose-dependent.