Cancer Communications
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2022
·Vol. 43
·期 1
·100-122
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IF 15.283
Yufei Yang,Dakui Luo,Yang Shao,Zezhi Shan,Qi Liu,Junyong Weng,Weijing He,Ruoxin Zhang,Qingguo Li,Ziliang Wang,Xinxiang Li
Background Circular RNAs (circRNAs) generated by back-splicing of precursor mRNAs (pre-mRNAs) are often aberrantly expressed in cancer cells. Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers, including colorectal cancer (CRC). However, the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited. Here, we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis. Methods circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients. The expression of circRNAs were determined by quantitative PCR (qPCR) and in situ hybridization (ISH). The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs. The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array, RNA pull-down/mass spectrometry, RNA immunoprecipitation assay, luciferase reporter assay, chromatin immunoprecipitation analysis, and fluorescence in situ hybridization (FISH). Results Among circRNAs, circCAPRIN1 was most significantly upregulated in CRC tissue specimens. circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients. Downregulation of circCAPRIN1 suppressed proliferation, migration, and epithelial-mesenchymal transition of CRC cells, while circCAPRIN1 overexpression had opposite effects. RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism. Moreover, circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1 (ACC1) expression. Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2 (STAT2) to activate ACC1 transcription, thus regulating lipid metabolism and facilitating CRC tumorigenesis. Conclusions These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC. circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1. circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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肿瘤学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Jia-Lin Yu,Zhen-Yang Zhang,Sheng-Ping Liu,Hong-Ping Long,Ting-Ting Wang,Feng-Qing Huang,Jia Guo,Wei-Long Xu,Fei Li
Ethnopharmacological relevance Type 2 diabetes mellitus (T2DM) poses significant threats to public health. In Traditional Chinese Medicine (TCM), the Phellodendri Chinensis Cortex-Anemarrhenae Rhizoma (PCC/AR) herb pair has long been used for T2DM treatment, although its specific anti-diabetic mechanisms remain unclear. Aim of the study This study aimed to elucidate the relationship between metabolomics of T2DM patients and the anti-diabetic effects of PCC/AR herb pair in mice through clinical metabolomics and both in vitro and in vivo experiments. Materials and methods In this study, a T2DM mouse model was established via high-fat feeding (HFD) and streptozotocin (STZ) injection. The effects of PCC/AR on blood glucose, lipid metabolism, and inflammatory markers were evaluated. High-performance liquid chromatography-mass spectrometry (HPLC-MS) was performed for metabolomics analysis of T2DM patients. Results Serum metabolomics analysis identified significant alterations in metabolites linked to the biosynthesis of unsaturated fatty acids and purine metabolism in T2DM patients, with elevated 2-hydroxyvaleric acid (2HB) levels. In T2DM mice, PCC/AR intervention normalized FBG, GHbA1c, TC, TG, LDL-C, HDL-C, TNF-α and IL-1β levels, while improving insulin sensitivity and pancreatic β-cell function in T2DM mice. Notably, PCC/AR reduced key enzymes in gluconeogenesis and fatty acid synthesis, PEPCK and ACC1. Conclusion PCC/AR herb pair exerts an anti-diabetes effect in T2DM mice by regulating 2HB through ACC1 inhibition, thereby reducing FFA and TG synthesis. Additionally, PCC/AR may also exert its effects by modulating glucose and lipid metabolism and reducing inflammation. These results support further investigation into the PCC/AR herb pair as a complementary therapy for T2DM.
研究领域:
中药学
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代谢组学
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糖尿病研究
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PubMed
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Zhi-Hua Deng,Liang-Jun He,Shanshan Wei,Chang-Sheng Li,Ya Chen,Xin-Yi Ai,Chatchai Chaotham,Supat Jiranusornkul,Pei-Cheng Zhang,Zhuo Luo,Shang-Ping Xing,Jie Yang
Background Targeting tumor metabolic reprogramming, particularly de novo lipogenesis (DNL) regulated by acetyl-CoA carboxylase 1 (ACC1), constitutes a promising therapeutic strategy. Non-small cell lung cancer (NSCLC) is a predominant subtype of lung cancer, characterized by limited treatment options and poor prognosis. Plumbagin (PLB), a natural naphthoquinone, exhibits broad antitumor activity. However, its direct targets and mechanisms in NSCLC remain unclear. Purpose This study aims to identify the molecular targets of PLB and elucidate its antitumor mechanism in NSCLC. Methods High-resolution mass spectrometry, in conjunction with a biotin-labeled PLB probe, was utilized to identify the direct targets of PLB. Surface plasmon resonance (SPR), streptavidin-based immunoprecipitation, and molecular dynamics simulation were employed to confirm the direct interaction between PLB and ACC1. ACC1 knockdown NSCLC cells were generated using siRNAs, followed by colony formation, wound-healing, and transwell assays. Tissue microarray analysis of clinical NSCLC samples was conducted to assess ACC1 expression and its clinical relevance. Lipid metabolites in NSCLC cells and tissues were quantified using an ELISA, and lipid droplet formation was observed via BODIPY staining. The in vivo therapeutic efficacy of PLB was evaluated using NSCLC xenograft models. Results Proteomic analysis identified ACC1 as a direct PLB target. Binding assays and SPR analyses confirmed the specific interaction between PLB and ACC1, and structural simulations revealed that PLB binds to the carboxyltransferase domain of ACC1 with high affinity. Importantly, tissue microarray analysis revealed that ACC1 was significantly overexpressed in tumor tissues of patients with NSCLC, and high expression of ACC1 was positively correlated with poor prognosis. Mechanistically, PLB inhibited the ACC1/FASN/SCD1 lipogenic axis, resulting in a substantial reduction in lipid metabolites and lipid droplet accumulation. Furthermore, exogenous palmitic acid supplementation partially reversed the antitumor effects of PLB, whereas ACC1 knockdown synergistically enhanced PLB’s antitumor efficacy. In NSCLC xenograft models, PLB significantly inhibited tumor growth by targeting the ACC1/FASN/SCD1 pathway and reducing key lipid metabolites. Conclusion Our findings identify PLB as a novel ACC1 inhibitor that suppresses NSCLC by targeting the ACC1/FASN/SCD1 axis-mediated DNL pathway, highlighting its potential as a metabolic modulator for NSCLC therapy.
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高影响因子
PHYTOTHERAPY RESEARCH
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2026
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IF 8.1
Wen Jiang,Chen Ye,Ting Hu,Jichao Liang,Yong Chen
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over a quarter of the global adult population and is the primary cause of liver diseases worldwide. Costunolide (COS) is a sesquiterpene lactone that exhibits a range of biological activities and has significant hepatoprotective effects. However, the regulatory effects of COS on hepatic lipid metabolism and its potential molecular mechanisms remain poorly understood. This study aimed to examine the effects of COS on MASLD and to elucidate the underlying molecular mechanisms. The therapeutic effects of COS were assessed using a mouse model, fed a high-fat/high-fructose/high-cholesterol diet (HFHFrC) and primary hepatocytes treated with palmitic acid (PA) and oleic acid (OA). RNA sequencing (RNA-seq), quantitative PCR and western blotting were performed to explore the molecular mechanisms by which COS modulates hepatic lipid metabolism. Our findings indicated that COS effectively reduced lipid accumulation in the livers of mice fed a HFHFrC diet and lowered triglyceride (TG) content in hepatocytes induced by PA/OA. RNA-seq analysis, along with in vitro and in vivo experiments, demonstrated that COS activated ACC1 phosphorylation by promoting AMPK phosphorylation and inhibiting the expression of genes related to lipid synthesis. Co-treatment with the AMPK inhibitor, compound C abolished the lipid-lowering effect of COS. COS reduced the expression of genes related to lipid synthesis through the AMPK/ACC1 signalling pathway, thereby improving liver function, alleviating excessive lipid accumulation and ameliorating MASLD in both in vitro and in vivo models.
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ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
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2019
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IF 3.061
Jianying Bai,Zhen He,Yaofu Li,Xuexia Jiang,Hongmei Yu,Qing Tan
Mono-2-ethylhexyl phthalate (MEHP) is a major bioactive metabolite in the widely used industrial plasticizer diethylhexyl phthalate (DEHP) that has been found to be toxic to the liver. The aim of this study is to determine whether MEHP exposure can change the expression of fatty acid metabolism-related genes in HepG2 cells, which might be related to non-alcoholic fatty liver disease (NAFLD). The results revealed that exposure to MEHP promoted lipid accumulation in HepG2 cells. The levels of intracellular triglycerides in the hepatocytes increased after exposure to 0.8–100 μM MEHP for 24 h and 48 h. The genetic expressions of SREBP-1c, ChREBP, ACC1, FASN, and SCD significantly increased at 6 h after exposure to MEHP. At 24 h, the expression of the SREBP-1c and ChREBP genes remained increased, while the expression of the FASN and SCD genes decreased. At 48 h, the expression of SREBP-1c, ChREBP, ACC1, FASN, and SCD decreased. Furthermore, the levels of proteins including ACC1, FASN, SCD, and ChREBP (except SREBP-1c) increased at 24 h. These findings suggest that MEHP exposure can promote fatty acid synthesis in hepatocytes by regulating the expression of relevant genes and proteins, contributing to NAFLD.
研究领域:
毒理学
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细胞生物学
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分子生物学
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肝病学
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PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Wang Yang-Yang,Sun Yan-Ping,Yang Bing-You,Wang Qiu-Hong,Kuang Hai-Xue
Herbs with a “hot” properties are frequently used to treat cold symptoms in TCM. However, the underlying mechanisms of the herbs with “hot” properties on hypothyroidism have not been investigated. This study aimed to explore four typical “hot” and “cold” property herb on hypothyroidism. Firstly, the difference efficacy between the four typical “hot” property herbs and the four typical “cold” property herbs was assessed by physical signs, thyroid function, and the metabolic profile using multivariate statistical analysis. The influence of the four typical “hot” property herbs on hypothyroidism was validated pathologically. The impact mechanism of the four typical “hot” property herbs on hypothyroidism was investigated through a metabolomics method combined with network analysis. Na+/K+-ATP, ACC1 enzyme, UCP-1, and the PI3K-Akt pathway were used to confirm the metabolite pathways and target-associated metabolites. The results showed that the four typical “hot” property herbs could significantly improve physical signs, thyroid function, and the metabolic profile in hypothyroidism rats, the four typical “cold” property herbs did not show any benefit. Moreover, the four typical “hot” property herbs could improve lipid metabolism, energy metabolism, and thyroid hormone levels by the PI3K-Akt signaling pathway, Ca2+- AMPK signaling pathways, purine metabolism, and tryptophan metabolism. Additionally, the levels of UCP-1, Na+/K + -ATP enzyme, and ACC1 were ameliorated by the four typical “hot” property herbs in hypothyroidism rats. Therefore, a metabolomics strategy combined with network analysis was successfully performed and interpreted the mechanism of the four typical “hot” property herbs on hypothyroidism based on the theory of “cold and hot” properties of TCM well.
研究领域:
中医中药
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药理学
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代谢组学
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内分泌学
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PubMed
高影响因子
Cell Reports
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2023
·Vol. 42
·期 11
·113453-113453
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IF 8.8
Lin Y,Yang M,Huang L,Yang F,Fan J,Qiang Y,Chang Y,Zhou W,Yan L,Xiong J,Ping J,Chen S,Men D,Li F
Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drugs targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, have been approved by the FDA. Whether cytosolic ACC1 can be regulated spatially remains to be explored. Herein, we find that streptavidin (SA), which is a bacterium-derived tetrameric protein, forms cytosolic condensates and efficiently induces a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensate formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase. Notably, AAV-mediated delivery of SA partially blocks mouse liver DNL and ameliorates NASH without eliciting hypertriglyceridemia. In summary, our study shows that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.
研究领域:
分子生物学
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肝病学
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药理学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
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IF 5.895
Bei Yan,Lei Chen,Yanhui Wang,Jiacheng Zhang,Hui Zhao,Qinglian Hua,Shengjie Pei,Zihang Yue,Hui Liang,Huaqi Zhang
In this work, the protective effect of apple polyphenol extract (APE) on hepatic steatosis was investigated. Thirty-two C57BL/6J mice were assigned randomly to control group, hepatic steatosis group, lovastatin group, and APE group. After 8 weeks of intervention, APE supplementation markedly decreased the body weight gain, liver weight, liver index, epididymal adipose weight, epididymal adipose index, serum, and hepatic lipid levels. Hematoxylin and eosin staining revealed that APE supplementation alleviated histopathological changes of hepatic steatosis. Western blot revealed that APE downregulated the protein levels of GRP78, IRE1α, p-IRE1α, XBP1, PERK, p-PERK, p-eIF2α, ATF6, PPAR-γ, SREBP-1c, FAS, and ACC1. In conclusion, this study found that APE inhibited IRE1α-XBP1, PERK-eIF2α, and ATF6 signaling pathways to alleviate endoplasmic reticulum stress, thereby improving HFD-induced hepatic steatosis.
研究领域:
药理学
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营养学
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分子生物学
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病理学
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PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Sa Yang,Shijie Cao,Congyu Li,Jichao Zhang,Chang Liu,Feng Qiu,Ning Kang
Non-alcoholic fatty liver disease (NAFLD) is a major public health problem in many countries. Berberine (BBR) is an effective therapeutic agent in alleviating NAFLD. Berberrubine (BRB) is one of the main active metabolites of BBR, which shows significant anti-obesity and antihypoglycemic effects. However, whether BRB is responsible for the in vivo therapeutic effect and the underlying mechanism of BRB on NAFLD have not been elucidated. In this study, the ability of BRB to ameliorate NAFLD, together with its molecular mechanism, was investigated. The results showed that BRB treatments could significantly improve hepatic steatosis and insulin resistance in high-fat diet (HFD)-fed mice and oleic acid (OA)-treated HepG2 cells. Meanwhile, BBR and BRB treatment similarly prevented lipid accumulation by regulating the protein expression of ATGL, GK, PPARα, CPT-1, ACC1, FAS, and CD36. In addition, compared with BBR, BRB could maintain glucose homeostasis via GLUT2, GSK3β, and G6Pase in HFD-fed mice. Furthermore, the components of the gut microbiota in mice were analyzed by 16S rRNA gene sequencing. BBR and BRB treatment could greatly modify the structure and composition of gut microbiota. At the genus level, BBR and BRB treatment decreased Lactobacillus and Romboutsia , while BBR increased beneficial bacteria, such as Akkermansia and Bacteroides , and BRB increased beneficial bacteria, such as Ileibacterium and Mucispirillum . Altogether, both BRB and BBR were active in alleviating NAFLD in vivo and BRB might be used as a functional material to treat NAFLD clinically.
研究领域:
药理学
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代谢学
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胃肠病学
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微生物学
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PubMed
高影响因子
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