mRNA Expression Of Phosphatidylinositol 3-kinase Research Articles

The effect of Artemisia annua L. aqueous and methanolic extracts on insulin signaling in liver of HFD/STZ diabetic mice.

Many studies have shown the anti-diabetic effects of medicinal plants. But their molecular mechanism has been less studied. Understanding of these mechanisms can help to better manage the treatment of diabetes by using these plants. So, this research examined the effect of Artemisia annua extract on PI3K (phosphatidylinositol 3-kinase)/AKt (serine/threonine kinase protein B) signaling pathway in liver of high-fat diet (HFD)/Streptozotocin (STZ)-induced type 2 diabetic mice. Groups of mice were control, untreated diabetic mice, diabetic mice treated with various doses (400, 200, 100 mg/kg) of methanolic and aqueous extract of A. annua and metformin for four weeks. Type 2 diabetes was produced by feeding high-fat diet following injection of low dose of STZ. After experiment duration all mice were sacrificed and blood glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), index of insulin sensitivity index (ISI) were detected and liver tissues were isolated for to detect m-RNA expression of PI3K and Akt. Extracts of aqueous and methanolic this plant markedly reduced hyperglycemia, hyperinsulinemia, HOMA-IR and elevated ISI in diabetic group in comparison with un-treated diabetic mice. In addition, they could enhance the expression of AKt and PI3K m-RNA in liver tissues in diabetic mice. Artemisia annua extract ameliorated insulin resistance and improved insulin action in liver via the high activity of PI3K/AKt signaling pathway. So, it can be a suitable alternative treatment to synthetic antidiabetic drugs to improve insulin action in condition of type 2 diabetes.

Taraxasterol alleviates aflatoxin B1-induced liver damage in broiler chickens via regulation of oxidative stress, apoptosis and autophagy

Aflatoxin B1 (AFB1) is the most dangerous and abundant mycotoxin, which is toxic to almost all animals, and poultry is more sensitive to AFB1 toxicity. Ingesting AFB1-contaminated feed can cause significant liver damage and brings serious harm to poultry, which greatly restricts the development of the poultry industry. The present research was implemented to explore the intervention effect and its mechanism of taraxasterol on liver damage induced by AFB1 in broiler chickens. The liver damage model in broiler chickens was established by feeding 0.5 mg/kg AFB1 feed, and taraxasterol (25, 50 and 100 mg/kg BW, respectively) was given in the drinking water for 21 days. The growth performance, liver function, oxidative stress, apoptosis and autophagy were evaluated. The results showed that taraxasterol increased BW and reduced feed-to-gain ratio of broiler chickens induced by AFB1. Taraxasterol improved the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), total bilirubin (TBIL) and alkaline phosphatase (ALP), and attenuated hepatic histopathological changes induced by AFB1. Meantime, taraxasterol down-regulated cytochrome P450 (CYP450) enzyme system CYP1A1 and CYP2A6 mRNA expression, inhibited the overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA), and enhanced the activities of antioxidant enzymes glutathione (GSH) and catalase (CAT) and the content of antioxidant superoxide dismutase (SOD) of the liver in broiler chickens induced by AFB1. Furthermore, taraxasterol up-regulated the mRNA and protein expression of hepatic nuclear factor E2 related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), and down-regulated the expression of hepatic kelch like ECH associated protein 1 (Keap1) induced by AFB1 in Keap1/Nrf2 signaling pathway. The ultrastructural observation and RT-qPCR results found that taraxasterol inhibited apoptosis of hepatocytes, up-regulated the expression of B-cell lymphoma-2 (Bcl-2) mRNA and down-regulated the expression of Bax and caspase3 mRNA. Further, taraxasterol restored the autophagy of hepatocytes and down-regulated the mRNA expression of phosphatidylinositol 3-kinase K (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in AFB1-induced liver of broiler chickens. The above results indicate that taraxasterol alleviates liver damage induced by AFB1 in broiler chickens through regulation of Keap1/Nrf2 signaling pathway to exert its antioxidant effect, mitochondrial apoptosis pathway to improve anti-apoptotic ability and PI3K/AKT/mTOR pathway to restore autophagy.

Effects of quercetin on ovarian function and regulation of the ovarian PI3K/Akt/FoxO3a signalling pathway and oxidative stress in a rat model of cyclophosphamide-induced premature ovarian failure.

To investigate the ability of quercetin to improve ovarian function and inhibit ovarian oxidative stress through the PI3K/Akt/FoxO3a signalling pathway in a rat model of premature ovarian failure (POF), we constructed a POF rat model with cyclophosphamide (CTX) and treated it with quercetin. Haematoxylin and eosin staining (H&E staining) was used to observe the morphological changes of the ovaries. The serum levels of AMH, E2, FSH, SOD, GSH-Px and MDA were determined by enzyme-linked immunosorbent assays. The expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), forkhead box O3a (FoxO3a) and their phosphorylated forms AMH, FSH and their receptors in the ovary were detected by western blots. The mRNA expression of PI3K, Akt, FOXO3a, AMH, FSH and their receptors was detected by qRT-PCR. Our results showed that quercetin could significantly increase the expression of AMH, E2, SOD and GSH-Px, upregulate the protein expression of AMH, FSH and its receptor and decrease the expression ratio of phosphorylated PI3K, Akt, FOXO3a and the unphosphorylated forms. Moreover, quercetin inhibited the mRNA expression of PI3K, Akt and FOXO3a. These results suggest that quercetin can restore ovarian function and inhibit oxidative stress by regulating the PI3K/Akt/FoxO3a signalling pathway.

Palm leaf catechins improved insulin-related pathways in diabetic rats

Catechin-rich oil-palm leaf extract (OPLE) (Elaeis guineensis) was previously demonstrated to possess benefits for diabetes and cardio metabolic health (vasodilation, antioxidant, cardiovascular, anti-hypertensive, anti-inflammatory, hepatoprotective and nephroprotective properties) in animal models. For insights into OPLE anti-diabetic mode-of-action and possible toxicity, the effects of dietary OPLE on insulin-signaling pathways mRNA expressions in the liver, kidney, pancreas, and spleen of normal and diabetic rats were examined. Type-2-Diabetes Mellitus (T2DM) were induced by chronic high-fat diet and streptozotocin (35 mg/kg) intraperitoneal injection. The OPLE (100 mg/kg body weight) were fed daily to normal and T2DM-induced rats. The OPLE suppressed hyperglycaemia and excessive weight gain in the T2DM rats, and appeared harmless to normal rats. The OPLE supplementation significantly (p<0.05) modulated the mRNA expressions of phosphatidylinositol-3 kinase (PIK3R1); insulin signaling receptor (INSR); insulin-receptor substrates 1 and 2; and ectonucleotide pyrophosphatase-1 (ENPP1) especially in the livers of normal rats and the spleen of diabetic rats. Results suggested the OPLE probably help prevent diabetes in healthy mammals and ameliorate the immune functions of diabetic mammals. The OPLE improved the antioxidant defence responses, insulin-pathways mRNA expressions in the normal and diabetic rats; suppressed hyperglycaemia and excessive weight gain in T2DM rodents without observable liver or kidney toxicity at the dose used.

Quercetin mitigates ethanol-induced hepatic steatosis in zebrafish via P2X7R-mediated PI3K/ Keap1/Nrf2 signaling pathway

Ethnopharmacological relevanceQuercetin is the active component of the higher content in PCP, which exerts various biological activities such as anti-obesity effect, anti-inflammatory and anti-oxidant activities in alcoholic liver disease (ALD). Aim of the studyP2X7 receptor (P2X7R) plays an important role in health and disease, which can be activated by extracellular ATP to induce a variety of downstream events, including lipid metabolism, inflammatory molecule release, oxidative stress. However, whether the mechanism of quercetin on ethanol-induced hepatic steatosis via P2X7R-mediated haven't been elucidated. Material and methodsZebrafish transgenic (fabp10: EGFP) larvae were treated with 100 μM, 50 μM, 25 μM quercetin for 48 h at 3 days post fertilization (dpf), then soaked in 350 mmol/L ethanol for 32 h, treated with 1 mM ATP (P2X7R activator) for 30min. Serum lipids, liver steatosis, oxidative stress factors were respectively detected. The mRNA levels in the related pathways were measured by quantitative Real-Time PCR (RT-qPCR) to investigate the mechanisms. ResultsQuercetin improved the liver function via decreasing ALT, AST and γ-GT level of zebrafish with acute ethanol-induced hepatic steatosis and attenuated hepatic TG, TC accumulation. Additionally, quercetin significantly reduced the MDA content and suppressed the ethanol-induced reduction of hepatic oxidative stress biomarkers GSH, CAT and SOD and significantly down-regulated the expression of P2X7R, and up-regulated the expression of phosphatidylinositol 3-kinase (PI3K), Kelch like ECH associated protein1 (Keap1), Nuclear Factor E2 related factor 2 (Nrf2). Moreover, ATP stimulation activated P2X7R, which further mediated the mRNA expressions of PI3K, Keap1 and Nrf2. ConclusionQuercetin exhibited hepatoprotective capacity in zebrafish model, via regulating P2X7R-mediated PI3K/Keap1/Nrf2 oxidative stress signaling pathway.

Propranolol inhibits the activity of PI3K, AKT, and HIF-1α in infantile hemangiomas.

We sought to evaluate effect of propranolol in the treatment of infantile hemangiomas by quantifying the amount of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and hypoxia-inducible factor-1α (HIF-1α). Hemangioma tissue was isolated from an infant patient and implanted into nude mice to establish a hemangioma model. Twenty-four hemangioma-model nude mice were divided into two groups including a control group (saline, by gastrogavage) and an experimental group (propranolol, by gastrogavage). The hemangioma-model nude mice were euthanized and tumors were removed at 30 and 50days (before and after treatment). HE staining was used to observe the histopathological changes, and western blot and quantitative real-time PCR were used to describe levels of protein and mRNA expression of PI3K, AKT, and HIF-1α. Propranolol treatment decreased tumor size as compared to the control group. Protein and mRNA expression levels of PI3K, AKT, and HIF-1α were lower in the experimental group at day 50 compared to the control group at day 50 and the experimental group at day 30 (p < 0.05). Propranolol can promote regression of infantile hemangiomas, which may be related to the inhibition of PI3K, AKT, and HIF-1α activity.

The administration of Fructus Schisandrae attenuates dexamethasone-induced muscle atrophy in mice.

In the present study, we aimed to determine whether ethanol extracts of Fructus Schisandrae (FS), the dried fruit of Schizandra chinensis Baillon, mitigates the development of dexamethasone-induced muscle atrophy. Adult SPF/VAT outbred CrljOri:CD1 (ICR) mice were either treated with dexamethasone to induce muscle atrophy. Some mice were treated with various concentrations of FS or oxymetholone, a 17α-alkylated anabolic-androgenic steroid. Muscle thickness and weight, calf muscle strength, and serum creatine and creatine kinase (CK) levels were then measured. The administration of FS attenuated the decrease in calf thickness, gastrocnemius muscle thickness, muscle strength and weight, fiber diameter and serum lactate dehydrogenase levels in the gastrocnemius muscle bundles which was induced by dexamethasone in a dose-dependent manner. Treatment with FS also prevented the dexamethasone-induced increase in serum creatine and creatine kinase levels, histopathological muscle fiber microvacuolation and fibrosis, and the immunoreactivity of muscle fibers for nitrotyrosine, 4-hydroxynonenal, inducible nitric oxide synthase and myostatin. In addition, the destruction of the gastrocnemius antioxidant defense system was also inhibited by the administration of FS in a dose-dependent manner. FS downregulated the mRNA expression of atrogin-1 and muscle RING-finger protein-1 (involved in muscle protein degradation), myostatin (a potent negative regulator of muscle growth) and sirtuin 1 (a representative inhibitor of muscle regeneration), but upregulated the mRNA expression of phosphatidylinositol 3-kinase, Akt1, adenosine A1 receptor and transient receptor potential cation channel subfamily V member 4, involved in muscle growth and the activation of protein synthesis. The overall effects of treatment with 500 mg/kg FS were comparable to those observed following treatment with 50 mg/kg oxymetholone. The results from the present study support the hypothesis that FS has a favorable ameliorating effect on muscle atrophy induced by dexamethasone, by exerting anti-inflammatory and antioxidant effects on muscle fibers, which may be due to an increase in protein synthesis and a decrease in protein degradation.

Effects of Astragalus membranaceus and Potentilla discolor mixture on insulin resistance and its related mRNA expressions in KKAy mice with type 2 diabetes

To investigate the effects of Astragalus membranaceus and Potentilla discolor mixture (APM) on insulin resistance (IR) and mRNA expressions of IR-related genes, including phosphatidylinositol 3-kinase (PI3-K), phosphoenolpyruvate carboxykinase (PEPCK) and peroxisome proliferator-activated receptor γ coactivator 1 (PGC1) in KKAy mice with early type 2 diabetes and to explore the gene regulation mechanisms of AMP. After giving short-term high-fat and high-calorie diet to induce type 2 diabetes, male KKAy mice were randomly divided into model and APM groups. Nine C57BL/6J mice were used as normal control in addition. The mice in the APM group were treated with 830 g/L of the APM liquid by gastric infusion while the mice in the model group and the normal control group were given 0.05% sodium carboxymethyl cellulose at a dose of 0.1 mL/g body weight once per day. After four weeks, fasting plasma glucose (FPG) was tested using tail vein blood. Fasting serum insulin (FINS) was tested by radioimmunoassay. Insulin sensitivity index (ISI) was calculated as the natural logarithm of the product of FPG and FINS. The mRNA expressions of PI3-K, PEPCK and PGC1 in liver tissues were tested by real-time fluorescence quantitative polymerase chain reaction assay. Both the levels of FPG and FINS in the model group and the APM group were increased, while the ISI values were decreased when compared to those of the normal control group (P<0.01). The level of FPG in the APM group was decreased, while ISI was increased when compared to those of the model group (P<0.05). All of the mRNA expressions of PI3-K, PEPCK, and PGC1 in liver tissue of the model group were decreased compared with the normal control group (P<0.01). The mRNA expressions of PI3-K and PGC1 in the liver tissue of the APM group were higher than those in the model group (P<0.05). APM can improve the insulin resistance of mice with type 2 diabetes. The mechanism may be related to increasing the mRNA expressions of PI3-K and PGC1 in the liver tissue.