PMC:4277126 / 82656-86012
Annnotations
2_test
{"project":"2_test","denotations":[{"id":"25552899-17184177-26094351","span":{"begin":377,"end":380},"obj":"17184177"},{"id":"25552899-25045414-26094352","span":{"begin":548,"end":551},"obj":"25045414"},{"id":"25552899-25045414-26094353","span":{"begin":1505,"end":1508},"obj":"25045414"},{"id":"25552899-25045414-26094354","span":{"begin":2681,"end":2684},"obj":"25045414"},{"id":"25552899-25045414-26094355","span":{"begin":2946,"end":2949},"obj":"25045414"},{"id":"25552899-25045414-26094356","span":{"begin":3077,"end":3080},"obj":"25045414"}],"text":"HD-induced insulin resistance\nNrf2 is a master regulator for the expression of Phase II detoxifying enzymes such as HO-1, SOD, and CAT.113 Upon stimulation by oxidative stress, Nrf2 is translocated into the nucleus and induces the expression of antioxidant enzymes by binding antioxidant response element. JNK activation is a crucial mediator of ROS-induced insulin resistance.114 Suppression of JNK activation prevents insulin receptor substrate-1 (IRS-1) degradation and promotes insulin signaling and insulin-dependent glucose uptake.\nYang et al110 investigated the mechanisms involved in LBP-mediated phosphatidylinositol 3-kinase (PI3K)/Akt/Nrf2 pathway against high-fat-induced insulin resistance in human hepatoma HepG2 cells and male C57BL/6J mice. HepG2 cells were incubated with LBPs for 12 hours in the presence of palmitate. C57BL/6J mice were fed an HD together with 100 mg/kg LBPs for 24 weeks. Liver glucokinase (GCK) and pyruvate kinase (PK) activities were monitored. The mRNA levels of GCK, PK, phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), IL-6, TNF-α, and monocyte chemotactic protein 1 (MCP-1) were determined using quantitative real-time PCR. The protein expression levels of Nrf2 and phosphorylated (p)-Nrf2 at Ser40; HO-1, SOD, CAT, JNK, glycogen synthase kinase 3β (GSK3β), and p-GSK3β at Ser9; IRS-1, p-IRS-1 at Ser307; PI3K and p-PI3K at Tyr458/199; Akt and p-Akt at Ser473; and JNK and p-JNK at Thr183/Tyr were determined by Western blotting assay.110 The results showed that oral treatment with 100 mg/kg LBPs for 24 weeks lowered blood glucose and insulin concentrations and increased pyruvate concentration compared with high fat-fed mice. In the liver, LBPs increased hepatic GCK and PK mRNA levels but decreased liver PEPCK and G6Pase mRNA levels. LBPs treatment of mice significantly enhanced the phosphorylation of IRS-1, PI3K, and Akt in liver. In HepG2 cells, incubation of 100–600 µg/mL LBPs for 12 hours significantly promoted the phosphorylation of IRS-1, PI3K, and Akt. In in vivo experiment, administration of LBPs effectively inhibited the phosphorylation of JNK but increased the phosphorylation of GSK3β in the liver of high-fat diet-fed mice. LBPs also lowered the mRNA levels of liver MCP-1, IL-6, and TNF-α. In HepG2 cells, LBPs significantly increased the phosphorylation of GSK3β but reduced the phosphorylation of JNK. When HepG2 cells were pretreated with 10 µM LY294002 and 2 µM wortmannin (both PI3K/Akt inhibitors) for 2 hours, and then treated with 300 µg/mL LBPs for 12 hours, the inhibitor-induced p-JNK level was suppressed by LBPs, and inhibitor-suppressed p-GSK3β level was reversed by LBPs.110 LBPs regulated phosphorylation levels of GSK3β and JNK through PI3K/Akt signaling. In HepG2 cells, 300 µg/mL LBPs caused the nuclear translocation of p-Nrf2. LBPs significantly induced the phosphorylation of Nrf2 through PI3K/Akt signaling in vitro and in vivo.110 LBPs increased the expression of hepatic HO-1, SOD, and CAT and reduced intracellular ROS level via PI3K/Akt/Nrf2 axis in mice.110 These data indicate that LBPs significantly reversed glycolytic and gluconeogenic gene expression via the activation of Nrf2-mediated cytoprotective effects and that LBPs reverse insulin resistance induced by HD via activation of PI3K/Akt/Nrf2-mediated antioxidative pathway."}
NEUROSES
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insulin resistance\nNrf2 is a master regulator for the expression of Phase II detoxifying enzymes such as HO-1, SOD, and CAT.113 Upon stimulation by oxidative stress, Nrf2 is translocated into the nucleus and induces the expression of antioxidant enzymes by binding antioxidant response element. JNK activation is a crucial mediator of ROS-induced insulin resistance.114 Suppression of JNK activation prevents insulin receptor substrate-1 (IRS-1) degradation and promotes insulin signaling and insulin-dependent glucose uptake.\nYang et al110 investigated the mechanisms involved in LBP-mediated phosphatidylinositol 3-kinase (PI3K)/Akt/Nrf2 pathway against high-fat-induced insulin resistance in human hepatoma HepG2 cells and male C57BL/6J mice. HepG2 cells were incubated with LBPs for 12 hours in the presence of palmitate. C57BL/6J mice were fed an HD together with 100 mg/kg LBPs for 24 weeks. Liver glucokinase (GCK) and pyruvate kinase (PK) activities were monitored. The mRNA levels of GCK, PK, phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), IL-6, TNF-α, and monocyte chemotactic protein 1 (MCP-1) were determined using quantitative real-time PCR. The protein expression levels of Nrf2 and phosphorylated (p)-Nrf2 at Ser40; HO-1, SOD, CAT, JNK, glycogen synthase kinase 3β (GSK3β), and p-GSK3β at Ser9; IRS-1, p-IRS-1 at Ser307; PI3K and p-PI3K at Tyr458/199; Akt and p-Akt at Ser473; and JNK and p-JNK at Thr183/Tyr were determined by Western blotting assay.110 The results showed that oral treatment with 100 mg/kg LBPs for 24 weeks lowered blood glucose and insulin concentrations and increased pyruvate concentration compared with high fat-fed mice. In the liver, LBPs increased hepatic GCK and PK mRNA levels but decreased liver PEPCK and G6Pase mRNA levels. LBPs treatment of mice significantly enhanced the phosphorylation of IRS-1, PI3K, and Akt in liver. In HepG2 cells, incubation of 100–600 µg/mL LBPs for 12 hours significantly promoted the phosphorylation of IRS-1, PI3K, and Akt. In in vivo experiment, administration of LBPs effectively inhibited the phosphorylation of JNK but increased the phosphorylation of GSK3β in the liver of high-fat diet-fed mice. LBPs also lowered the mRNA levels of liver MCP-1, IL-6, and TNF-α. In HepG2 cells, LBPs significantly increased the phosphorylation of GSK3β but reduced the phosphorylation of JNK. When HepG2 cells were pretreated with 10 µM LY294002 and 2 µM wortmannin (both PI3K/Akt inhibitors) for 2 hours, and then treated with 300 µg/mL LBPs for 12 hours, the inhibitor-induced p-JNK level was suppressed by LBPs, and inhibitor-suppressed p-GSK3β level was reversed by LBPs.110 LBPs regulated phosphorylation levels of GSK3β and JNK through PI3K/Akt signaling. In HepG2 cells, 300 µg/mL LBPs caused the nuclear translocation of p-Nrf2. LBPs significantly induced the phosphorylation of Nrf2 through PI3K/Akt signaling in vitro and in vivo.110 LBPs increased the expression of hepatic HO-1, SOD, and CAT and reduced intracellular ROS level via PI3K/Akt/Nrf2 axis in mice.110 These data indicate that LBPs significantly reversed glycolytic and gluconeogenic gene expression via the activation of Nrf2-mediated cytoprotective effects and that LBPs reverse insulin resistance induced by HD via activation of PI3K/Akt/Nrf2-mediated antioxidative pathway."}