Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis

Dai, Jianye; Liang, Kai; Zhao, S. J.; Jia, Wentong; Yuan, Lamei; Wu, Hong-Kun; Lu, Jia; Cao, Chen; Chen, Tao; Zhuang, Shentian; Hou, Xiaomeng; Zhou, Shijie; Zhang, Xiannian; Chen, Xiaowei; Huang, Yanyi; Xiao, Rui‐Ping; Wang, Yanling; Luo, Tuoping; Xiao, Junyu; Chu, Wenhui

doi:10.1073/pnas.1801745115

Cited by 236 publications

(199 citation statements)

References 49 publications

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“…Baicalin is a major flavonoid component from the herbal medicine Scutellaria baicalensis . Dai et al . have discovered that baicalin can directly bind to CPT‐1 and activate its activity to accelerate fatty acid degradation, which consequently ameliorates symptoms associated with hepatic steatosis and reduces diet‐induced obesity.…”

Section: Nafld Therapeutics From a Mitochondria‐centric Perspectivementioning

confidence: 99%

Mitochondria‐Mediated Pathogenesis and Therapeutics for Non‐Alcoholic Fatty Liver Disease

Zhang

et al. 2019

Molecular Nutrition Food Res

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Non‐alcoholic fatty liver disease (NAFLD) has become a worldwide epidemic over the last decade. Remarkable progress has been made in understanding the pathogenesis of NAFLD and, subsequently, in developing medications to treat this disease. Although the mechanisms of NAFLD are complex and multifactorial, accumulating and emerging evidence indicates that mitochondria play a critical role in the pathogenesis and progression of NAFLD. Pharmacologic therapies acting on mitochondria may therefore pave the way to novel strategies for the prevention and protection against NAFLD. This review focuses on new insights into the role of hepatic mitochondrial dysfunction in NAFLD, and summarizes recent studies on mitochondria‐centric therapies for NAFLD utilizing new medications or repurposing of currently available drugs. Although some studies presented may feature controversial results or are still in lack of clinical verification, it is undoubted that medications that may spare the mitochondria from multiple levels of damage are highly promising, and have begun to be used with some degree of success.

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Section: Nafld Therapeutics From a Mitochondria‐centric Perspectivementioning

confidence: 99%

Mitochondria‐Mediated Pathogenesis and Therapeutics for Non‐Alcoholic Fatty Liver Disease

Zhang

et al. 2019

Molecular Nutrition Food Res

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“…Cellular Thermal Shift Assay. Cellular thermal shift assay (CETSA) was conducted using cell lysates as previously described (Dai et al, 2018). For the temperature-dependent thermal shift assay, 50 ml of lysates (3 mg/ml) from A549 cells were incubated with 20 mM of Mel at each temperature point from 36°C to 80°C for 4 minutes.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer

Tang¹,

Liu²,

Wang³

et al. 2018

J Pharmacol Exp Ther

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Checkpoint blockade therapy has been proven efficacious in lung cancer patients. However, primary/acquired resistance hampers its efficacy. Therefore, there is an urgent need to develop novel strategies to improve checkpoint blockade therapy. Here we tested whether dual inhibition of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) by flavonoid melafolone improves program death 1 (PD-1) checkpoint blockade therapy through normalizing tumor vasculature and PD-1 ligand (PD-L1) downregulation. Virtual screening assay, cellular thermal shift assay, and enzyme inhibition assay identified melafolone as a potential inhibitor of COX-2 and EGFR. In Lewis lung carcinoma (LLC) and CMT167 models, dual inhibition of COX-2 and EGFR by melafolone promoted survival, tumor growth inhibition, and vascular normalization, and ameliorated CD8 1 T-cell suppression, accompanied by the downregulation of transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), and PD-L1 in the tumor cells. Mechanistically, dual inhibition of COX-2 and EGFR in lung cancer cells by melafolone increased the migration of pericyte, decreased the proliferation and migration of endothelial cells, and enhanced the proliferation and effector function of CD8 1 T cells through VEGF, TGF-b, or PD-L1 downregulation and PI3K/AKT inactivation. Notably, melafolone improved PD-1 immunotherapy against LLC and CMT167 tumors. Together, dual inhibition of COX-2 and EGFR by melafolone improves checkpoint blockade therapy through vascular normalization and PD-L1 downregulation and, by affecting vessels and immune cells, may be a promising combination strategy for the treatment of human lung cancer.

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“…Thus, FP intervention upregulated Acsl1, Acsl4, Acsl6 and Cpt1c, which promoted the conversion of FA to acyl-CoA and the start of mitochondrial fatty acid β-oxidation. Besides, SCFAs and MCFAs permeate the inner mitochondrial membrane in the non-esteri ed form, which are activated into their CoA-derivatives in the mitochondrial matrix [25]. Afterwards, these FAs participate in β-oxidation and the TCA cycle.…”

Section: Fp Intervention Promoted Lipid Metabolism Of the Colonic Epimentioning

confidence: 99%

Flaxseed Polysaccharide Altering Colonic Gene Expression of Lipid Metabolism and Energy Metabolism in Obese Rat

Lin¹,

Qi²,

Zhang³

et al. 2020

Preprint

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BackgroundObesity is one of the most serious public health challenges. Recently, we found that flaxseed polysaccharide (FP) had an anti-obesity effect through promoting lipid metabolism, inducing satiety and regulating gut microbiota, but how FP promote lipid metabolism through altering the colonic epithelial cells remains to be elucidated. In this study, a transcriptome study was performed to investigate the effect of FP altering the gene expression of colonic epithelial cells in an obese rat model. ResultsThe transcriptome analysis showed that 3,785 genes were differentially expressed after FP intervention in colonic epithelial cells, including 374 down-regulated and 3,411 up-regulated genes. Through KEGG analysis, we found out three classical pathways related to lipid metabolism and energy metabolism, including PPAR signaling pathway, nitrogen metabolism and oxidative phosphorylation (OXPHOS). Moreover, qRT-PCR results showed consistent expression trends of differential genes with transcriptome analysis. ConclusionsThe anti-obesity effect of FP may be achieved by regulating the expression of lipid metabolism- and energy metabolism-related proteins acting on the PPAR (peroxisome proliferator-activated receptor) signaling pathway, nitrogen metabolism and OXPHOS pathway in vivo.

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Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis

Cited by 236 publications

References 49 publications

Mitochondria‐Mediated Pathogenesis and Therapeutics for Non‐Alcoholic Fatty Liver Disease

Mitochondria‐Mediated Pathogenesis and Therapeutics for Non‐Alcoholic Fatty Liver Disease

Inhibition of COX-2 and EGFR by Melafolone Improves Anti-PD-1 Therapy through Vascular Normalization and PD-L1 Downregulation in Lung Cancer

Flaxseed Polysaccharide Altering Colonic Gene Expression of Lipid Metabolism and Energy Metabolism in Obese Rat

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