Preventive effect of andrographolide against ultraviolet-B radiation-induced oxidative stress and apoptotic signaling in human dermal fibroblasts.

Ultraviolet radiation induces oxidative photoaging in the skin cells. In this study, we investigated the ability of andrographolide (ADP) to protect human dermal fibroblasts (HDFa) from UVB radiation-induced oxidative stress and apoptosis. The HDFa cells were exposed to UVB (19.8 mJ/cm2 ) radiation in the presence or absence of ADP (7 µM) and then oxidative stress and apoptotic protein expression were analyzed. UVB exposure resulted in a significant decline in the activity of antioxidant enzymes and altered mitochondrial membrane potential (MMP). Furthermore, UVB-irradiation causes increased intracellular reactive oxygen species (ROS) production, apoptotic morphological changes, and lipid peroxidation levels in the HDFa. Moreover, the pretreatment with ADP reduced the UVB-induced cytotoxicity, ROS production, and increased antioxidant enzymes activity. Further, the ADP pretreatment prevents the UVB-induced loss of MMP and apoptotic signaling in HDFa cells. Therefore, the present results suggest that ADP protects HDFa cells from UVB-induced oxidative stress and apoptotic damage.

Ursolic acid and rosiglitazone combination improves insulin sensitivity by increasing the skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat diet-fed C57BL/6J mice

The aim of this present study was to investigate the effect of ursolic acid (UA) and rosiglitazone (RSG) on insulin sensitivity and proximal insulin signaling pathways in high-fat diet (HFD)-fed C57/BL/6J mice. Male C57BL/6J mice were fed either normal diet or HFD for 10 weeks, after which animals in each dietary group were divided into the following six groups (normal diet, normal diet plus UA and RSG, HFD alone, HFD plus UA, HFD plus RSG, and HFD plus UA and RSG) for the next 5 weeks. UA (5 mg/kg BW) and RSG (4 mg/kg BW) were administered as suspensions directly into the stomach using a gastric tube. The HFD diet elevated fasting plasma glucose, insulin, and homeostasis model assessment index. The expression of insulin receptor substrate (IRS)-1, phosphoinositide 3-kinase (PI3-kinase), Akt, and glucose transporter (GLUT) 4 were determined by Western blot analyses. The results demonstrated that combination treatment (UA/RSG) ameliorated HFD-induced glucose intolerance and insulin resistance by improving the homeostatic model assessment (HOMA) index. Further, combination treatment (UA/RSG) stimulated the IRS-1, PI3-kinase, Akt, and GLUT 4 translocation. These results strongly suggest that combination treatment (UA/RSG) activates IRS-PI3-kinase-Akt-dependent signaling pathways to induce GLUT 4 translocation and increases the expression of insulin receptor to improve glucose intolerance (AU)

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Effect of protocatechuic acid on lipid profile and DNA damage in D-galactosamine-induced hepatotoxic rats.

BACKGROUND: Our aim in this study is to investigate the effect of protocatechuic acid (PCA) on lipid profile and DNA damage in D-galactosamine (D-GalN)-induced hepatotoxic rats. METHODS: Hepatotoxicity was induced by a single intraperitoneal dose of D-GalN in male Wistar rats. The activities of hepatic markers and levels of kidney function markers were determined. The plasma and tissue lipid levels were estimated. DNA damage was determined by COMET assay. Histopathological examination was also performed using portions of the liver and kidney tissues. RESULTS: D-GalN-induced hepatotoxic rats showed increased in the activities of hepatic marker enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and γ-glutamyl transpeptidase (GGT) in serum. The levels of kidney function markers such as urea, uric acid, and creatinine increased in serum. Levels of lipid profile such as total cholesterol (TC), triglycerides (TG), free fatty acid (FFA), and phospholipids (PLs) in the plasma and tissues (liver and kidney) were significantly increased in D-GalN-induced rats. In plasma, levels of very low density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) significantly increased, whereas high-density lipoprotein cholesterol (HDL-C) level decreased in D-GalN-induced rats. Furthermore, D-GalN-induced rats showed increased percentage of tail DNA and tail length and decreased percentage of head DNA. Oral administration of PCA (100 mg/ kg BW) for 20 days improved these levels when compared to D-GalN-induced rats. These biochemical changes were reflected on the attenuation and the structural alteration of the liver and kidney integrity. CONCLUSIONS: The results of the study suggest that PCA has a potent hepatoprotective activity that may be linked to its antihyperlipidemic effect.

Ursolic acid and rosiglitazone combination improves insulin sensitivity by increasing the skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat diet-fed C57BL/6J mice.

The aim of this present study was to investigate the effect of ursolic acid (UA) and rosiglitazone (RSG) on insulin sensitivity and proximal insulin signaling pathways in high-fat diet (HFD)-fed C57/BL/6J mice. Male C57BL/6J mice were fed either normal diet or HFD for 10 weeks, after which animals in each dietary group were divided into the following six groups (normal diet, normal diet plus UA and RSG, HFD alone, HFD plus UA, HFD plus RSG, and HFD plus UA and RSG) for the next 5 weeks. UA (5 mg/kg BW) and RSG (4 mg/kg BW) were administered as suspensions directly into the stomach using a gastric tube. The HFD diet elevated fasting plasma glucose, insulin, and homeostasis model assessment index. The expression of insulin receptor substrate (IRS)-1, phosphoinositide 3-kinase (PI3-kinase), Akt, and glucose transporter (GLUT) 4 were determined by Western blot analyses. The results demonstrated that combination treatment (UA/RSG) ameliorated HFD-induced glucose intolerance and insulin resistance by improving the homeostatic model assessment (HOMA) index. Further, combination treatment (UA/RSG) stimulated the IRS-1, PI3-kinase, Akt, and GLUT 4 translocation. These results strongly suggest that combination treatment (UA/RSG) activates IRS-PI3-kinase-Akt-dependent signaling pathways to induce GLUT 4 translocation and increases the expression of insulin receptor to improve glucose intolerance.

Effect of ursolic acid and Rosiglitazone combination on hepatic lipid accumulation in high fat diet-fed C57BL/6J mice.

This study investigated the combined effect of ursolic acid (UA) and Rosiglitazone (RSG) on lipid regulatory genes in high fat diet (HFD)-fed mice. Male C57BL/6J mice were fed either normal diet or HFD for 10 weeks, after which animals in each dietary group were divided into following six groups, (normal diet, normal diet plus UA and RSG, HFD alone, HFD plus UA, HFD plus RSG, and HFD plus UA and RSG), for the next 5 weeks. UA (5mg/kg BW) and RSG (4mg/kg BW) were administered as suspensions directly into the stomach using a gastric tube. At the end of the study (106th day), their liver was analyzed for lipid content. RT-PCR and western blotting methods were used to analyze lipid regulatory genes. HFD-fed mice showed increased activities of hepatic marker enzymes (aspartate aminotransferase and alanine aminotransferase) in plasma and an increased concentration of total cholesterol, triglyceride and free fatty acid in liver. These results were confirmed by upregulated mRNA expression of lipogenic genes such as sterol-regulatory-element-binding protein-1c, fatty acid synthase and acetyl-CoA carboxylase and downregulated mRNA expression of fatty acid oxidative genes such as carnitine palmitoyltransferase-1, acetyl-CoA carboxylase and peroxisome proliferator activated receptor-α in HFD-fed mice. Combined treatment (UA/RSG) significantly reduced the hepatic marker enzyme activities and decreased the lipid accumulation in liver. Furthermore, combination treatment (UA/RSG) down-regulated lipogenic genes and upregulated fatty acid oxidative genes in HFD-fed mice. This study suggests that UA in combination with RSG reduced lipid accumulation in liver.

Antihyperglycemic effect of carvacrol in combination with rosiglitazone in high-fat diet-induced type 2 diabetic C57BL/6J mice.

Thiazolidinediones constitute a family of antidiabetic drugs, and rosiglitasone (RSG) has an extensive usage in treating the complications of type 2 diabetes mellitus. Carvacrol (CVL), a monoterpenic phenol that occurs in many essential oils of the family Labiatae including Origanum, Satureja, Thymbra, Thymus, and Corydothymus species, possess a wide variety of pharmacological properties including antioxidant potential. We hypothesized that carvacrol in combination with RSG would prove beneficial to ameliorate the dysregulated carbohydrate metabolism in high-fat diet (HFD)-induced type 2 diabetic C57BL/6J mice. Mice were divided into six groups and fed HFD, for 10 weeks. CVL (20 mg/kg BW) and RSG (4 mg/kg BW) were administered post-orally, daily for 35 days. HFD mice showed an elevation in plasma glucose, insulin, glycosylated hemoglobin and a decrease in hemoglobin. The activities of carbohydrate metabolic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase increased whereas glucokinase and glucose-6-phosphate dehydrogenase activities decreased in the liver of HFD mice. The activities of hepatic marker enzymes such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase increased in HFD mice. Combination of CVL and RSG prevented the above changes toward normalcy. Histopathological analysis of H&E stained pancreas was also in agreement with the biochemical findings. These major findings provide evidence that combination of CVL with RSG has better antidiabetic properties.

Effect of ursolic acid on cardiac marker enzymes, lipid profile and macroscopic enzyme mapping assay in isoproterenol-induced myocardial ischemic rats.

This study investigates the antihyperlipidemic effect of ursolic acid (UA) on isoproterenol (ISO) induced male albino Wistar rats. Myocardial ischemia was induced by subcutaneous injection of ISO (85 mg/kg BW) twice at an interval of 24 h, for two consecutive days. A significant increase in the activities of the serum marker enzymes [creatine kinase, creatine kinase-MB and lactate dehydrogenease (LDH)], a prominent expression of LDH 1 and LDH 2 isoenzymes, increased levels of plasma total cholesterol (TC), low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, triglycerides (TG), free fatty acids (FFA), phospholipids (PL) and atherogenic index and decreased level of high density lipoprotein-cholesterol were observed in ISO-induced rats. The levels of TC, TG and FFA increased and the level of PL decreased in the heart tissue of ISO-induced rats. Further, there was an increased DNA damage (Comet assay) and myocardium infarct size as observed by staining with triphenyltetrazolium chloride (TTC). UA was administered subcutaneously for 7 days at a dose of 40 mg/kg BW. UA administration to ischemic rats brought all these parameters to near normality showing the protective effect of UA on ISO-induced rats.

Effect of ursolic acid treatment on apoptosis and DNA damage in isoproterenol-induced myocardial infarction.

The present study was designed to evaluate the protective effect of ursolic acid (UA) against isoproterenol-induced myocardial infarction. Myocardial infarction was induced by subcutaneous injection of isoproterenol hydrochloride (ISO) (85 mg/kg BW), for two consecutive days. ISO-induced rats showed elevated levels of cardiac troponins T (cTn T) and I (cTn I) and increased activity of creatine kinase-MB (CK-MB) in serum. Lipid peroxidative markers (thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lipid hydroperoxides (HP)) elevated in the plasma and heart tissue whereas decreased activities of enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR)) in erythrocytes and heart tissue of ISO-induced rats. Non-enzymatic antioxidants (vitamin C, vitamin E and reduced glutathione (GSH)) levels were decreased significantly in the plasma and heart tissue of ISO-induced rats. Furthermore, ISO-induced rats showed increased DNA fragmentation, upregulations of myocardial pro-apoptotic B-cell lymphoma-2 associated-x (Bax), caspase-3, -8 and -9, cytochrome c, tumor necrosis factor-α (TNF-α), Fas and down-regulated expressions of anti-apoptotic B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL). UA-administered rats showed decreased levels/activity of cardiac markers, DNA fragmentation and the levels of lipid peroxidative markers in the plasma and heart tissue. Activities of enzymatic antioxidants were increased significantly in the erythrocytes and heart tissue and also non-enzymatic antioxidants levels were increased significantly in the plasma and heart tissue in UA-administered rats. UA influenced decreased DNA fragmentation and an apoptosis by upregulation of anti-apoptotic proteins such as Bcl-2, Bcl-xL and down-regulation of Bax, caspase-3, -8 and -9, cytochrome c, TNF-α, Fas through mitochondrial pathway. Histopathological observations were also found in line with biochemical parameters. Thus, results of the present study demonstrated that the UA has anti-apoptotic properties in ISO-induced rats.

Theaflavin, a black tea polyphenol, protects nigral dopaminergic neurons against chronic MPTP/probenecid induced Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by loss of dopominergic neurons in substantia nigra pars compacta, and can be experimentally induced by the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Chronic administration of MPTP/probenecid (MPTP/p) leads to oxidative stress, induction of apoptosis, and loss of dopominergic neurons which results in motor impairments. Epidemiological studies have shown an inverse relationship between tea consumption and susceptibility to PD. Theaflavin is a black tea polyphenol, which possess a wide variety of pharmacological properties including potent anti oxidative, anti apoptotic and anti inflammatory effects. The current study is aimed to assess the effect of theaflavin against MPTP/p induced neurodegenaration in C57BL/6 mice. We found that the theaflavin attenuates MPTP/p induced apoptosis and neurodegeneration as evidenced by increased expression of nigral tyrosine hydroxylase (TH), dopamine transporter (DAT) and reduced apoptotic markers such as caspase-3, 8, 9 accompanied by normalized behavioral characterization. This may be due to anti oxidative and anti apoptotic activity and these data indicate that theaflavin may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases such as PD.