ABSTRACT
Intrahepatic cholestasis is a common clinical form of hepatobiliary injury characterized by the intrahepatic accumulation of toxic bile acids. Besides its antidiabetic activity, the dipeptidyl peptidase IV inhibitor sitagliptin (SG) has been recently assigned diverse pharmacological activities and therapeutic potential against different disorders owing to its emerging antioxidant and anti-inflammatory properties. The current study explored the potential hepatoprotective effect of SG on α-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury (CLI) in mice and investigate its possible targeted signaling pathways. Mice received SG (10 and 20â¯mg/kg) for four consecutive days, two days before and after a single oral administration of ANIT (75â¯mg/kg). Our results revealed that SG administration remarkably prevented ANIT-induced histopathological lesions in the liver and maintained hepatic functions and oxidative/antioxidant balance. Ultimately, SG counteracted the inflammatory response in the liver, as indicated by the marked suppression of hepatic expression of NF-κB, TNF-α, and IL-6. Moreover, it inhibited the endoplasmic reticulum (ER) stress response in the liver. These beneï¬cial effects of SG were accompanied by upregulation of SIRT1, p-AMPK, and Nrf2 expressions while downregulating keap1 expression in the liver. In conclusion, this study is the first to demonstrate the ability of SG to protect against ANIT-induced CLI through modulating multiple signaling cascades, including SIRT1/AMPK, Nrf2/keap1, and NF-кB, which resulted in enhanced antioxidant capacity and repressed inflammatory and ER stress responses in the liver.
Subject(s)
1-Naphthylisothiocyanate , AMP-Activated Protein Kinases , Endoplasmic Reticulum Stress , NF-E2-Related Factor 2 , NF-kappa B , Oxidative Stress , Sirtuin 1 , Sitagliptin Phosphate , Animals , Sirtuin 1/metabolism , Oxidative Stress/drug effects , NF-E2-Related Factor 2/metabolism , Sitagliptin Phosphate/pharmacology , Endoplasmic Reticulum Stress/drug effects , Male , Mice , AMP-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , 1-Naphthylisothiocyanate/toxicity , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/drug therapy , Signal Transduction/drug effects , Inflammation/prevention & control , Inflammation/metabolism , Cholestasis, Intrahepatic/chemically induced , Cholestasis, Intrahepatic/drug therapy , Cholestasis, Intrahepatic/prevention & control , Liver/drug effects , Liver/metabolism , Liver/pathologyABSTRACT
Evidence showed that herbal medicine could be beneficial for protection against diseases that may be exist in consequence of exposure to environmental toxicants. Propylparaben (PrP) is used as preservative in food, pharmaceuticals, and cosmetics. It is classified as one of endocrine disruptive chemicals (EDCs). This study evaluated the protective effect of Rhus tripartita methanolic extract (RTME) against reproductive toxicity induced by PrP in male rats. A total of 60 Wister albino rats were divided into four groups (15 rats for each group). Group I (control): rats received the vehicle (DMSO), group II: normal rats received RTME (10 mg/kg/day), group III: rats received PrP (10 mg/kg/day), and group IV: rats received PrP (10 mg/kg/day) and RTME (10 mg/kg/day) for 4 weeks. At the end of experiment, levels of testosterone, dihydrotestosterone (DHT), and 5α-reductase were analyzed in sera. Data obtained showed a significant reduction in the levels of testosterone, dihydrotestosterone (DHT), and 5α- reductase in rats given PrP versus control (p < 0.001) and RTME treatment improved these parameters but not returned to normal. Data obtained showed a significant elevation in levels of IL-6 and TNF-α in the testis of rats given PrP versus control (p < 0.001), these inflammatory mediators were significant reduced in rats treated with RTME compared with untreated rats (p < 0.001). There was a positive correlation between level of DHT and antioxidant enzymes activities (r = 0.56). A significant elevation in the levels of MDA with reduction in the activities of GST, GSPx, SOD, and catalase (p < 0.001) in rat testicular tissues of PrP group versus control (p < 0.001) was found. Treatment with RTME significantly reduced the levels of MDA and enhanced activities of GST, GSPx, SOD, and catalase (p < 0.001) compared to untreated group (p < 0.001). In conclusion, the active ingredient components of RTME abrogate the toxicity of PrP by exhibiting antioxidative and anti-inflammatory effects, enhancing 5-α reductase with improved hormonal status against PrP- induced testicular damage. Toxicity of propylparaben, and effect of Rhus tripartita methanolic extract.
Subject(s)
Antioxidants , Rhus , Rats , Male , Animals , Antioxidants/pharmacology , Antioxidants/metabolism , Catalase/metabolism , Cholestenone 5 alpha-Reductase/metabolism , Cholestenone 5 alpha-Reductase/pharmacology , Dihydrotestosterone/metabolism , Dihydrotestosterone/pharmacology , Methanol , Rats, Wistar , Testis , Testosterone , Plant Extracts/pharmacology , Plant Extracts/metabolism , Superoxide Dismutase/metabolism , Anti-Inflammatory Agents/pharmacology , Oxidative StressABSTRACT
Bioactive natural products are essential components for drug development. Protein glycation in diabetic subjects leads to diabetic complications as nephropathy and neuropathy. We investigated the impact of pomegranate hexane extract (PHE) as antioxidant, anti-inflammatory, and antiglycation in diabetic rats. Gas chromatography/mass spectrum (GC/MS) analysis of PHE revealed presence of resorcinol, catechol, tau-cadinol, metacetamol, scopoletin, phytol, and phenol, 3-pentadecyl as the most active ingredients that related to biological activity. Results obtained showed that, PHE increased serum aldose reductase and total antioxidant activity compared with untreated diabetic rats (p < 0.001). In addition, PHE exert antioxidant by enhancing, catalase and SOD (p < 0.001) and decreased MDA (p < 0.001), anti-inflammatory by inhibition production of 1 ß (IL-1ß), tumor necrosis factor (TNF-α) (p < 0.001), and AGEs (p < 0.001) against nephropathy in diabetic rats compared with untreated group. It was concluded that, pomegranate is promising in development a functional biomolecule in treatment and protection against diabetic complications as nephropathy. More study required to investigate the molecular action of these molecules.
Subject(s)
Diabetes Complications , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Lythraceae , Pomegranate , Rats , Animals , Diabetic Nephropathies/chemically induced , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/complications , Antioxidants/metabolism , Flavonoids/pharmacology , Pomegranate/metabolism , Streptozocin/pharmacology , Streptozocin/therapeutic use , Oxygen , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Diabetes Complications/drug therapy , Lythraceae/metabolism , Anti-Inflammatory Agents/pharmacology , Oxidative StressABSTRACT
OBJECTIVE: This study aimed to analyze the agricultural soils from different regions in Saudi Arabia for cobalt and related metals as Cu(2+), Ni(2+), Cr(3+), Zn(2+) and Pb(2+). MATERIALS AND METHODS: Liver and muscle tissues of livestock grazing on the selected areas were analyzed for the content of Co and vitamin B12. RESULTS: Our results indicated that the levels of Co in surface soil (0-15 cm) were higher than in sub-surface soil (>15 cm-45 cm). In contrast, Pb and Zn were higher in sub-surface soil than in surface soil. A significant positive correlation existed between the levels of Co and vitamin B12 in the liver of livestock. However, Co was not detected in muscle tissues while vitamin B12 was present at very low levels in comparison with the levels found in the liver. The results indicated that Zn(2+), Pb(2+) compete with Co in soil, which eventually affected the levels of vitamin B12 in liver. CONCLUSION: It was recommended that survey of heavy metals in grazing fields of cattle should consider inclusion of multiple elements that compete with the bioavailability of essential elements in plants and animals for the prevention of deficiency of essential elements such as Co.