EXPERIMENTAL CELL RESEARCH
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2022
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IF 4.145
Wuguang Liu,Xiaolong Liu,Ying Liu,Ting Ling,Di Chen,Wuxiyar Otkur,Hailong Zhao,Ming Ma,Kexin Ma,Bing Dong,Zexuan Yang,Hai-long Piao,Rui Liang,Chengyong Dong
PLIN2 has been found to be dysregulated in several human malignancies, which influences cancer progression. However, the roles of PLIN2 in regulating hepatocellular carcinoma (HCC) progression are still unclear. Here, we revealed that PLIN2 was frequently upregulated in HCC cells and tissues, and increased PLIN2 expression was associated with poor prognosis outcomes in HCC. In HCC cells, overexpressing PLIN2 promoted cell proliferation , PLIN2-deficiency inhibited cell vitality. Mechanistically, silencing of PLIN2 expression downregulated hypoxia inducible factor 1-α (HIF1α) expression and this downregulation in turn inhibited the targeting genes of HIF1α. Furthermore, we found that PLIN2 stabilized and retarded the degradation of the HIF1α through autophagy-lysosomal pathway by inhibiting AMPK/ULK1. Collectively, we clarified the carcinogenic role of PLIN2 in HCC and suggested a prognostic biomarker for diagnosis and clinical therapy in the future.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Hui Luo,Xiaolu She,Yubo Zhang,Bingfan Xie,Shibo Zhang,Qianqian Li,Yangyang Zhou,Shuang Guo,Shushan Zhang,Yanhui Jiang,Yingying Dong,Jianzhong He,Lijie Wang,Qianqian Zhang,Yuan Zhuang,Panxia Deng,Feng Wang,Jihong Liu,Xin Chen,Huilong Nie,Huanhuan He
A major characteristic of ovarian cancer (OC) is its unique route of metastasis via ascites. The immune microenvironment in ascites remains understudied, leaving the mechanism of ascites-mediated abdominal metastasis obscure. Here, a single-cell transcriptomic landscape of CD45 + immune cells across multiple anatomical sites is depicted, including primary tumors, metastatic lesions, and ascites, from patients diagnosed with high-grade serous ovarian carcinoma (HGSOC). A novel subset of perilipin 2 high (PLIN2 hi ) macrophages are identified that are enriched in ascites and positively correlated with OC progression, hence being designated as “ascites-associated macrophages (AAMs)”. AAMs are lipid-loaded with overexpression of the lipid droplet protein PLIN2. Overexpression or suppression of PLIN2 can enhance or inhibit tumor cell migration, invasion, and vascular permeability in vitro, which is also confirmed in vivo. Mechanistically, it is demonstrated that PLIN2 boosts HIF1α/SPP1 signaling in macrophages, thereby exerting pro-tumor functions. Finally, a PLIN2-targeting liposome is designed to efficiently suppress ascites production and tumor metastasis. Taken together, this work provides a comprehensive characterization of the cancer-promoting function and lipid-rich property of ascites-enriched PLIN2 hi macrophages, establishes a link between lipid metabolism and hypoxia within the context of the ascites microenvironment, and elucidates the pivotal role of ascites in trans-coelomic metastasis of OC.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症代谢
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DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2021
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IF 6.922
Shutian Zhang,Li Hu,Chengzhi Han,Renhui Huang,Kokwin Ooi,Xinyi Qian,Xiaorong Ren,Dechang Chu,Haili Zhang,Dongshu Du,Chunmei Xia
Purpose Oxidative/nitrosative stress, neuroinflammation and their intimate interactions mediate sympathetic overactivation in hypertension. An immoderate inflammatory response is characterized not only by elevated proinflammatory cytokines (PICs) but by increases in mitochondrial dysfunction, reactive oxygen species (ROS), and nitric oxide (NO). Recent data pinpoint that both the phospholipid and lipid droplets (LDs) are potent modulators of microglia physiology. Methods Stress rats underwent compound stressors for 15 days with PLIN2-siRNA or scrambled-siRNA (SC-siRNA) administrated into the rostral ventrolateral medulla (RVLM). Lipids were analyzed by mass spectroscopy-based quantitative lipidomics. The phenotypes and proliferation of microglia, LDs, in the RVLM of rats were detected; blood pressure (BP) and myocardial injury in rats were evaluated. The anti-oxidative/nitrosative stress effect of phosphatidylethanolamine (PE) was explored in cultured primary microglia. Results Lipidomics analysis showed that 75 individual lipids in RVLM were significantly dysregulated by stress [PE was the most one], demonstrating that lipid composition changed with stress. In vitro, prorenin stress induced the accumulation of LDs, increased PICs, which could be blocked by siRNA-PLIN2 in microglia. PLIN2 knockdown upregulated the PE synthesis in microglia. Anti-oxidative/nitrosative stress effect of PE delivery was confirmed by the decrease of ROS and decrease in 3-NT and MDA in prorenin-treated microglia. PLIN2 knockdown in the RVLM blocked the number of iNOS + and PCNA + microglia, decreased BP, alleviated cardiac fibrosis and hypertrophy in stressed rats. Conclusion PLIN2 mediates microglial polarization/proliferation via downregulating PE in the RVLM of stressed rats. Delivery of PE is a promising strategy for combating neuroinflammation and oxidative/nitrosative stress in stress-induced hypertension.
研究领域:
神经科学
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药理学
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分子生物学
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心脏病学
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生理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2026
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IF 11.3
Jian Chen,Zhixiang Wei,Zixuan Song,Sitong Meng,Jiaqi An,Zhenqun Zhang,Yaning Biao,Muqing Zhang,Yixin Zhang
Background Obesity prevalence is rising, increasing risks of metabolic associated fatty liver disease, diabetes mellitus, and cardiovascular disease. Atractylodin (ATR), a bioactive compound from Atractylodes lancea , exhibits potential against metabolic disorders, but its mechanisms against obesity-driven hepatic steatosis remain unclear. Purpose This study aimed to investigate the therapeutic effects and underlying mechanisms of ATR in ameliorating obesity-associated hepatic steatosis via lipid droplet (LD)-mitochondria interactions. Methods Mice were fed a high-fat diet (HFD) for 12 weeks, followed by administration of ATR or Orlistat for 6 weeks beginning at week 6. Hepatic steatosis and molecular targets were assessed via serum biochemistry, histology, fluorescent staining, and Western blot. AML-12 and HepG2 cells were induced with free fatty acids (FFA) and treated with ATR, Atglistatin (ATGLi), etomoxir (ETO), subjected to CPT1A knockdown, or subjected to PLIN2 overexpression/knockdown. In addition to analyzing key proteins and lipid content by molecular and biochemical methods, LD-mitochondria contacts were visualized by transmission electron microscope and laser confocal fluorescence microscopy. Results ATR significantly ameliorated obesity-associated hepatic steatosis in mice and reduced lipid accumulation in AML-12 and HepG2 cells. Visual analysis confirmed that ATR promoted LD-mitochondria contacts. Molecular analysis showed that ATR regulated proteins for lipolysis and fatty acid oxidation (FAO) in liver. Genetic approaches validated that ATR downregulated PLIN2. Mechanistically, ATR promoted LD-mitochondria interactions, lipolysis, and FAO. The effects may be mediated through the regulation of the PLIN2-ATGL/CPT1A axis. Conclusions ATR ameliorates obesity-associated hepatic steatosis by enhancing lipolysis and FAO. Promoting LD-mitochondria interactions represents a promising therapeutic strategy, with ATR showing potential as a therapeutic agent for obesity.
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DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
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2024
·Vol. 51
·期 4
·e13845
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IF 2.4
Wen-Cong Gao,Tie-Hua Yang,Bin-Bao Wang,Qian Liu,Qing Li,Xiao-Huan Zhou,Chang-Bo Zheng,Peng Chen
Abnormalities in vascular smooth muscle cells (VSMCs) are pivotal in the pathogenesis of cardiovascular pathologies such as atherosclerosis and hypertension. Scutellarin (Scu), a flavonoid derived from marigold flowers, exhibits a spectrum of biological activities including anti-inflammatory, antioxidant, antitumor, immunomodulatory and antimicrobial effects. Notably, Scu has demonstrated the capacity to mitigate vascular endothelial damage and prevent atherosclerosis via its antioxidative properties. Nevertheless, the influence of Scu on the formation of VSMC-derived foam cells remains underexplored. In this study, Scu was evidenced to efficaciously attenuate oleic acid (OA)-induced lipid accumulation and the upregulation of adipose differentiation-associated protein Plin2 in a dose- and time-responsive manner. We elucidated that Scu effectively diminishes OA-provoked VSMC foam cell formation. Further, it was established that Scu pretreatment augments the protein expression of LC3B-II and the mRNA levels of Map1lc3b and Becn1, concurrently diminishing the protein levels of the NLRP3 inflammasome compared to the OA group. Activation of autophagy through rapamycin attenuated NLRP3 inflammasome protein expression, intracellular lipid droplet content and Plin2 mRNA levels. Scu also counteracted the OA-induced decrement of LC3B-II levels in the presence of bafilomycin-a1, facilitating the genesis of autophagosomes and autolysosomes. Complementarily, in vivo experiments revealed that Scu administration substantially reduced arterial wall thickness, vessel wall cross-sectional area, wall-to-lumen ratio and serum total cholesterol levels in comparison to the high-fat diet model group. Collectively, our findings suggest that Scu attenuates OA-induced VSMC foam cell formation through the induction of autophagy and the suppression of NLRP3 inflammasome activation.
研究领域:
心血管疾病
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药理学
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细胞生物学
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炎症
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DOI
PubMed
高影响因子
JOURNAL OF DAIRY SCIENCE
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2023
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IF 3.5
Shendong Zhou,Mengru Chen,Meijuan Meng,Nana Ma,Wan Xie,Xiangzhen Shen,Zhixin Li,Guangjun Chang
ABSTRACT Ketosis is a metabolic disease that often occurs in dairy cows postpartum and results from disordered lipid metabolism. Acetyl-coenzyme A (CoA) acetyltransferase 2 ( ACAT2 ) is important for balancing cholesterol and triglyceride ( TG ) metabolism; however, its role in subclinical ketotic dairy cows is unclear. This study aimed to explore the potential correlation between ACAT2 and lipid metabolism disorders in subclinical ketotic cows through in vitro and in vivo experiments. In the in vivo experiment, liver tissue and blood samples were collected from healthy cows ( CON , n = 6, β-hydroxybutyric acid [ BHBA ] concentration < 1.0 mM) and subclinical ketotic cows (subclinical ketosis [ SCK] , n = 6, BHBA concentration = 1.2–3.0 mM) to explore the effect of ACAT2 on lipid metabolism disorders in SCK cows. For the in vitro experiment, bovine hepatocytes ( BHEC ) were used as the model. The effects of BHBA on ACAT2 and lipid metabolism were investigated via BHBA concentration gradient experiments. Subsequently, the relation between ACAT2 and lipid metabolism disorder was explored by transfection with siRNA of ACAT2. Transcriptomics showed an upregulation of differentially expression genes ( DEGs ) during lipid metabolism and significantly lower ACAT2 mRNA levels in the SCK group. Compared with the CON group in vivo, the SCK group showed significantly higher expression levels of peroxisome proliferator–activated receptor γ ( PPARγ ) and sterol regulator element binding protein 1c ( SREBP1c ) and significantly lower expression levels of peroxisome proliferator-activated receptor α ( PPARα ), carnitine palmitoyl-transferase 1A ( CPT1A ), sterol regulatory element binding transcription factor 2 ( SREBP2 ), and 3-hydroxy-3-methylglutaryl-CoA reductase ( HMGCR ). Moreover, the SCK group had a significantly higher liver TG content and significantly lower plasma total cholesterol ( TC ) and free cholesterol ( FC ) content. These results were indicative of TG and cholesterol metabolism disorders in the liver of dairy cows with SCK. Additionally, the SCK group showed an increased expression of Perilipin-2 ( PLIN2 ), decreased expression of apolipoprotein B ( APOB ), and decreased plasma concentration of very low-density lipoproteins ( VLDL ) and low-density lipoproteins-cholesterol ( LDL-C ) by downregulating ACAT2, which indicated an accumulation of TG in liver. I n vitro experiments showed that BHBA induced an increase in the TG content of BHEC, decreased content TC, increased expression of PPARγ and SREBP1c, and decreased expression of PPARα, CPT1A, SREBP2, and HMGCR. Additionally, BHBA increased the expression of PLIN2 in BHEC, decreased the expression and fluorescence intensity of ACAT2, and decreased the VLDL and LDL-C contents. Furthermore, silencing ACAT2 expression increased the TG content; decreased the TC, VLDL, and LDL-C contents; decreased the expression of HMGCR and SREBP2; and increased the expression of SREBP1c; but had no effect on the expression of PLIN2. These results suggest that ACAT2 downregulation in BHEC promotes TG accumulation and inhibits cholesterol synthesis, leading to TG and cholesterol metabolic disorders. In conclusion, ACAT2 downregulation in the SCK group inhibited cholesterol synthesis, increased TG synthesis, and reduced the contents of VLDL and LDL-C, eventually leading to disordered TG and cholesterol metabolism.
研究领域:
兽医学
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分子生物学
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生物化学
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动物生理学
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产品关联
DOI
PubMed
高影响因子
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