Activation Of AMPK Signaling Pathway Research Articles

Metformin and gefitinib cooperate to inhibit bladder cancer growth via both AMPK and EGFR pathways joining at Akt and Erk

EGFR is a potential therapeutic target for treating bladder cancer, but has not been approved for clinical use yet. Metformin is a widely used antidiabetic drug and has demonstrated interesting anticancer effects on various cancer models, alone or in combination with chemotherapeutic drugs. The efficacy of gefitinib, a well-known EGFR tyrosine kinase inhibitor, combined with metformin was assessed on bladder cancer and underlying mechanisms were explored. This drug combination induced a strong anti-proliferative and anti-colony forming effect and apoptosis in bladder cancer cell lines. Gefitinib suppressed EGFR signaling and inhibited phosphorylation of ERK and Akt. Metformin amplified this inhibitory effect and enhanced gefitinib-induced activation of AMPK signaling pathway. In vivo intravesical treatment of metformin and gefitinib on syngeneic orthotopic mice confirmed the significant inhibitory effect on bladder tumor growth. These two drugs may be an excellent combination for the treatment of bladder cancer through intravesical instillation.

Hispidulin enhances the anti-tumor effects of temozolomide in glioblastoma by activating AMPK.

Glioblastoma is an aggressive malignancy, which is notorious for its poor prognosis. Although Temozolomide (TMZ) has been showed to be an effective chemotherapeutic agent for glioblastoma treatment, the response rate is far from satisfactory. As a natural compound with anti-cancer activity against a variety of cancers, Hispidulin is a good candidate drug for combination therapy. This study is designed to determine whether Hispidulin could potentiate the anti-tumor activity of TMZ in glioblastoma. Cell proliferation and apoptosis were determined by MTT assay and Hoechst staining, respectively. Expression of proteins relevant to apoptosis and proliferation was detected by Western blotting. Our in vitro assays showed that Hispidulin enhanced the anti-tumor activity of TMZ in glioblastoma by both inhibiting cell proliferation and inducing cell apoptosis. The anti-tumor activity of Hispidulin and the enhanced TMZ anti-tumor activity by Hispidulin induced the activation of AMPK signaling pathway. Our results showed that Hispidulin, by activating AMPK, exhibited anti-tumor activity and potentiated the anti-tumor activity of TMZ in glioblastoma. Although further preclinical and clinical studies are needed, this study provides insight for using Hispidulin as a chemosensitizing agent in clinic settings.

Sophocarpine alleviates hepatocyte steatosis through activating AMPK signaling pathway

Sophocarpine, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200μmol/L oleic acid for 24h to induce steatotic model, then treated with sophocarpine for 72h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While sophocarpine treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, sophocarpine could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that sophocarpine could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK.

EGCG inhibits Tat-induced LTR transactivation: Role of Nrf2, AKT, AMPK signaling pathway

AimsTranscription is a crucial step for human immunodeficiency virus 1 (HIV-1) gene expression in infected host cells. The HIV-1 Tat activates the nuclear factor-kappa B (NF-κB) signaling transduction pathway, which is necessary for viral replication. Epigallocatechin-3-gallate (EGCG) has antioxidant, anti-inflammatory, and anti-viral properties. In this study, we investigated the effects of EGCG on Tat-induced HIV-1 transactivation and potential mechanisms by which EGCG inhibited activation of NF-κB pathway. Main methodsHeLa-CD4-long terminal repeat (LTR)-β-gal (MAGI) cells were transfected with Tat plasmid. Tat-induced HIV-1 LTR transactivation was determined by MAGI cell assay. The reactive oxygen species (ROS) levels and glutathione (GSH) levels were measured. In addition, the protein expressions were assayed by western blotting. Key findingsTat caused a significant decrease in the intracellular glutathione (GSH) levels, a mild increase in the expression of nuclear levels of NF-E2-related factor-2 (Nrf2), a significant increase in the levels of NF-κB (phosphorylation of p65 and IKK) and a significant increase in ROS production. EGCG supplementation significantly improved the changes associated with Tat-induced oxidative stress by increasing nuclear levels of Nrf2, decreasing levels of NF-κB and ROS production. EGCG reversed Tat-mediated AKT activation and AMPK inhibition in MAGI cells. EGCG inhibited Tat-induced LTR transactivation in a dose-dependent manner. SignificanceThe results suggest that Nrf2 signaling pathway may be the primary target for prevention of Tat-induced HIV-1 transactivation by EGCG, and EGCG also reduce NF-κB activation by inhibiting AKT signaling pathway and activating AMPK signaling pathway.

Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3T3-L1 adipocyte

Metabolic disorders such as obesity are major obstacles in improving the average life span. Therefore, a therapeutic approach using natural compounds has been proposed as a novel strategy for preventing metabolic disorders. Ginsenoside Rh2 is one of the ginsenosides that exert anti-diabetes, anti-inflammatory, and anti-cancer effects. However, the anti-obesity effects of Ginsenoside Rh2 remain unclear. Here, we investigated the anti-obesity ability of ginsenoside Rh2 using cell culture systems. Ginsenoside Rh2 effectively inhibited adipocyte differentiation via PPAR-γ inhibition. Next, to find specific target molecules based on this result, we used cell culture systems to examine whether AMPK activation was involved in the anti-obesity ability of ginsenoside Rh2 since several published papers have indicated that AMPK signaling is involved in the regulation of metabolic disorders. Ginsenoside Rh2 significantly activated AMPK in 3T3-L1 adipocytes. In addition, we also examined the effect of AMPK on lipolysis molecules such as CPT-1 and UCP-2 by using an AMPK inhibitor. Ginsenoside Rh2 effectively induced CPT-1 and UCP-2 and this induction was abolished by AMPK inhibitor treatment. Moreover, we observed that ROS is an important upstream signal for AMPK activation during ginsenoside Rh2 treatment. Taken together, these results indicate that ginsenoside Rh2 is the most effective candidate for preventing metabolic disorders such as obesity and that it acts via the AMPK signaling pathway. Thus, AMPK signaling might contribute toward improving human health.