Bawei Chenxiang Wan ameliorates right ventricular hypertrophy in rats with high altitude heart disease by SIRT3-HIF1α-PDK/PDH signaling pathway improving fatty acid and glucose metabolism.

BACKGROUND: Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, whether it confers protection through a right-ventricle (RV) myocardial metabolic mechanism is unknown. METHODS: Male Sprague-Dawley rats were orally administrated with BCW, which was injected concurrently with a bolus of Sugen5416, and subjected to hypoxia exposure (SuHx; 5000 m altitude) for 4 weeks. Right ventricular hypertrophy (RVH) in high-altitude heart disease (HAHD) was assessed using Fulton's index (FI; ratio of RV to left ventricle + septum weights) and heart-weight-to-body-weight ratio (HW/BW). The effect of therapeutic administration of BCW on the RVH hemodynamics was assessed through catheterization (mean right ventricular pressure and mean pulmonary artery pressure (mRVP and mPAP, respectively)). Tissue samples were used to perform histological staining, and confirmatory analyses of mRNA and protein levels were conducted to detect alterations in the mechanisms of RVH in HAHD. The protective mechanism of BCW was further verified via cell culture. RESULTS: BCW considerably reduced SuHx-associated RVH, as indicated by macro morphology, HW/BW ratio, FI, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and myocardial enzymes. Moreover, BCW can alleviate the disorder of glucose and fatty acid metabolism through upregulation of carnitine palmitoyltransferase1ɑ, citrate synthase, and acetyl-CoA and downregulation of glucose transport-4, phosphofructokinase, and pyruvate, which resulted in the reduced levels of free fatty acid and lactic acid and increased aerobic oxidation. This process may be mediated via the regulation of sirtuin 3 (SIRT3)-hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) signaling pathway. Subsequently, the inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) can reverse substantially the anti-RVH effect of BCW in HAHD, as indicated by hypertrophy marker and serum myocardial enzyme levels. CONCLUSIONS: BCW prevented SuHx-induced RVH in HAHD via the SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD.

Astragaloside regulates lncRNA LOC100912373 and the miR­17­5p/PDK1 axis to inhibit the proliferation of fibroblast­like synoviocytes in rats with rheumatoid arthritis.

Previous studies have confirmed that astragaloside (AST) exerts a positive effect on alleviating synovial and joint injury in rheumatoid arthritis (RA). However, the precise mechanisms through which AST acts in the treatment of RA remain unclear. Long non­coding RNA (lncRNA) LOC100912373 was identified as a key gene related to RA and has been proven to interact with miR­17­5p, in order to regulate the pyruvate dehydrogenase kinase 1 and protein kinase B axis (PDK1/AKT axis). The present study aimed to determine whether AST may treat RA through the interaction between lncRNA LOC100912373 and the miR­17­5p/PDK1 axis. MTT assays and flow cytometry were used to detect the proliferation and cell cycle progression of AST­treated fibroblast­like synoviocytes (FLSs). The expression of lncRNA LOC100912373 and miR­17­5p, as well as relative the mRNA expression of the PDK1 and AKT genes following AST intervention was detected by reverse transcription­quantitative PCR (RT­qPCR), immunofluorescence and western blot analysis. The results revealed that AST inhibited FLS proliferation, reduced lncRNA LOC100912373 expression levels, increased miR­17­5p expression levels, and decreased the PDK1 and p­AKT expression levels. Additionally, consecutive rescue experiments revealed that AST counteracted the effects of lncRNA LOC100912373 overexpression on FLS proliferation and cell cycle progression. On the whole, the present study demonstrates that AST inhibits FLS proliferation by regulating the expression of lncRNA LOC100912373 and the miR­17­5p/PDK1 axis.

Benzyl butyl phthalate (BBP) triggers the malignancy of acute myeloid leukemia cells via upregulation of PDK4.

Acute Myeloid Leukemia (AML) is a cancer of hematopoietic stem cells with a rapid progression. Recent studies indicated that endocrine disruptor chemicals (EDCs) are potential risk factors for AML progression. Our present data showed that an industrial endocrine disrupting chemical, Benzyl butyl phthalate (BBP), can promote the proliferation of AML cells and decrease their sensitivity to daunorubicin (DNR) and cytarabine (Ara-C) treatments. Further, BBP can increase the glucose consumption, lactate generation, and ATP levels of AML cells. Among the measured glycolysis-related genes, BBP can increase the expression of pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4), a mitochondrial protein that regulates the tricarboxylic acid cycle (TCA) cycle. The inhibitor of PDK4 or its specific siRNA can attenuate BBP-induced cell proliferation and ATP generation, which suggested the essential roles of PDK4 in BBP-induced glycolysis and proliferation. Further, BBP can increase the mRNA stability of PDK4, while had no effect on its transcription and protein stability. miR-15b-5p can bind with the 3'UTR of PDK4 to decrease its mRNA stability, while BBP can decrease the expression of miR-15b-5p in AML cells. Collectively, our data showed that BBP can trigger the malignancy of AML cells via regulation of miR-15b-5p/PDK4 signals.

Repurposing Eukaryotic Kinase Inhibitors as Colistin Adjuvants in Gram-Negative Bacteria.

Kinase inhibitors comprise a diverse cohort of chemical scaffolds that are active in multiple biological systems. Currently, thousands of eukaryotic kinase inhibitors are commercially available, have well-characterized targets, and often carry pharmaceutically favorable toxicity profiles. Recently, our group disclosed that derivatives of the natural product meridianin D, a known inhibitor of eukaryotic kinases, modulated behaviors of both Gram-positive and Gram-negative bacteria. Herein, we expand our exploration of kinase inhibitors in Gram-negative bacilli utilizing three commercially available kinase inhibitor libraries and, ultimately, identify two chemical structures that potentiate colistin (polymyxin E) in multiple strains. We report IMD-0354, an inhibitor of IKK-ß, as a markedly effective adjuvant in colistin-resistant bacteria and also describe AR-12 (OSU-03012), an inhibitor of pyruvate dehydrogenase kinase-1 (PDK-1), as a potentiator in colistin-sensitive strains. This report comprises the first description of the novel cross-reactivity of these molecules.

Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma.

Cetuximab, an EGFR-blocking antibody, is currently approved for treatment of metastatic head and neck squamous cell carcinoma (HNSCC), but its response rate is limited. In addition to blocking EGFR-stimulated cell signaling, cetuximab can induce endocytosis of ASCT2, a glutamine transporter associated with EGFR in a complex, leading to glutathione biosynthesis inhibition and cellular sensitization to ROS. Pyruvate dehydrogenase kinase-1 (PDK1), a key mitochondrial enzyme overexpressed in cancer cells, redirects glucose metabolism from oxidative phosphorylation toward aerobic glycolysis. In this study, we tested the hypothesis that targeting PDK1 is a rational approach to synergize with cetuximab through ROS overproduction. We found that combination of PDK1 knockdown or inhibition by dichloroacetic acid (DCA) with ASCT2 knockdown or with cetuximab treatment induced ROS overproduction and apoptosis in HNSCC cells, and this effect was independent of effective inhibition of EGFR downstream pathways but could be lessened by N-acetyl cysteine, an anti-oxidative agent. In several cetuximab-resistant HNSCC xenograft models, DCA plus cetuximab induced marked tumor regression, whereas either agent alone failed to induce tumor regression. Our findings call for potentially novel clinical trials of combining cetuximab and DCA in patients with cetuximab-sensitive EGFR-overexpressing tumors and patients with cetuximab-resistant EGFR-overexpressing tumors.