BRITISH JOURNAL OF PHARMACOLOGY
·
2025
·
IF 7.7
Wenxian Chen,Tongzhu Jin,Yilin Xie,Changsheng Zhong,Huiying Gao,Lei Zhang,Jin Ju,Ting Cheng,Mengyang Li,Huifang Wang,Zhenbo Yang,Qin Deng,Zhimin Du,Haihai Liang
Background and Purpose Emerging evidence indicated that the excessive lipid droplets (LDs) accumulation and lipotoxicity play a significant role in the development of diabetic cardiomyopathy (DCM), yet the regulatory mechanisms governing the function of cardiac LDs are still unknown. Lipophagy has been shown to be involved in the maintenance of LDs homeostasis. The objective of this study was to explore the mechanism of lipophagy in cardiomyocytes and investigate whether berberine could mitigate DCM by modulating this pathway. Experimental Approach Bioinformatics analysis identified disorders of lipid metabolism and autophagy in DCM. To carry out further research, db/db mice were utilized. Furthermore, H9C2 cells treated with palmitic acid were employed as a model to explore the molecular mechanisms involved in myocardial lipotoxicity. Key Results The results showed that lipophagy was impaired in DCM. Mechanistically, sirtuin 3 (SIRT3) was demonstrated to regulate lipophagy in cardiomyocytes. SIRT3 was down-regulated in DCM. Conversely, activation of SIRT3 by the activator nicotinamide riboside (NR) could promote lipophagy to alleviate PA-induced lipotoxicity in H9C2 cells. Moreover, berberine administration markedly mitigated diabetes-induced cardiac dysfunction and hypertrophy in db/db mice, which dependent on SIRT3-mediated lipophagy. Conclusion and Implications Collectively, SIRT3 could moderate cardiac lipotoxicity in DCM by promoting lipophagy, suggesting that the regulation of SIRT3-mediated lipophagy may be a promising strategy for treating DCM. The findings indicate that the therapeutic potential of berberine for DCM is associated with lipophagy.
研究领域:
心血管医学
·
代谢生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2021
·
IF 7.46
Sayed Mir Sayed,Xiang-Fei Li,Hao-Ran Jia,Samran Durrani,Fu-Gen Wu,Xiaolin Lu
Lipid droplets (LDs) are spherical dynamic subcellular organelles, and play crucial roles in a number of cellular functions, such as lipid metabolism, protein degradation, membrane formation, energy storage, and signal transduction. It is widely recognized that the dysfunction of LDs can lead to many diseases, and hence it is important to monitor the size, distribution, and movement of LDs in living cells. Herein, we report a dibenzothiopene core-based fluorescent probe named triphenylamine dibenzothiophene-S,S-dioxide (TPA-DBTD), which can exhibit aggregation-induced emission (AIE) characteristic and realize selective and wash-free imaging of LDs in live cells. Most importantly, this probe can efficaciously track the dynamic changes of LDs including lipophagy (an autophagic process that is responsible for the degradation of lipids) in live mammalian cells and stain LDs in fungi. Hence, we believe that TPA-DBTD with high photostability, good biocompatibility, AIE characteristic, and LD staining ability in diverse biological systems (mammalian cells and microorganisms) can find practical applications in the fields of biomedical science, cell biology, and diagnosis of LDs-associated diseases.
研究领域:
生物医学
·
细胞生物学
·
诊断学
✓ 已验证
产品关联
DOI
高影响因子
Autophagy
·
2024
·
IF 14.6
Na Kang,Jinling Tan,Sisi Yan,Leiying Lin,Qiang Gao
Lipophagy in the yeast Saccharomyces cerevisiae is a microautophagic process in which lipid droplets (LDs) are directly engulfed into the vacuole, despite the fact that multiple core ATG (autophagy related) genes related to general autophagy have been reported to be essential for this process for unknown reasons. In this study, we report new findings about the regulation of lipophagy by analyzing, under different culture conditions, both the engulfment of LDs into the vacuole and the degradation of LD surface proteins. We find that the degradation of LD surface proteins relies on autophagy and can occur independently of lipophagy. Furthermore, glucose restriction can trigger an ATG1-independent lipophagic process, depending on the glucose concentration in the mediums. In summary, we describe an ATG-independent lipophagic process in yeast, such that the overall level of lipophagy in cells is governed by a dynamic balance between the ATG-dependent and -independent lipophagic processes.Abbreviation AP: autophagosome; ATG: autophagy related; CMA: chaperone-mediated autophagy; ESCRT: endosomal sorting complex required for transport; FA: fatty acid; LD: lipid droplet; Ld microdomains: liquid-disordered microdomains; NL: neutral lipid.
研究领域:
细胞生物学
·
分子生物学
·
酵母遗传学
✓ 已验证
DOI
PubMed
高影响因子
Lipids in Health and Disease
·
2024
·Vol. 23
·期 1
·1-12
·
IF 3.9
Fan Yibao,Zhang Wei,Iqbal Zoya,Li Xinxin,Lin Zhiyin,Wu Zhuolin,Li Qianyou,Dong Hongxia,Zhang Xianbin,Gong Peng,Liu Peng
Background Bufalin (BA) is a potent traditional Chinese medicine derived from toad venom. It has shown significant antitumor activity, but its use is limited by cardiotoxicity, which necessitates innovative delivery methods, such as rod-shaped mesoporous silica nanoparticles (rMSNs). rMSNs have been extensively employed for reducing drug toxicity and for controlled or targeted drug delivery in tumor therapy. However, their potential in delivering BA has not been completely elucidated. Therefore, in this study, BA-loaded rMSNs (BA-rMSNs) were developed to investigate their potential and mechanism in impairing colon cancer cells.Methods rMSNs were developed via the sol‒gel method. Drug encapsulation efficiency and loading capacity were determined to investigate the advantages of the rMSN in loading BA. The antiproliferative activities of the BA-rMSNs were investigated via 5-ethynyl-2’-deoxyuridine and CCK-8. To evaluate cell death, Annexin V-APC/PI apoptotic and calcein-AM/PI double staining were performed. Western blotting, oil red O staining, and Nile red solution were employed to determine the ability of BA-rMSNs to regulate lipophagy.Results The diameter of the BA-rMSNs was approximately 60 nm. In vitro studies demonstrated that BA-rMSNs markedly inhibited HCT 116 and HT-29 cell proliferation and induced cell death. In vivo studies revealed that BA-rMSNs reduced BA-mediated cardiotoxicity and enhanced BA tumor targeting. Mechanistic studies revealed that BA-rMSNs blocked lipophagy.Conclusion srMSNs reduced BA-mediated cardiotoxicity and impaired the growth of colon cancer cells. Mechanistically, antitumor activity depends on lipophagy.
研究领域:
药学
·
纳米技术
·
肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Yu Zhu,Xiang-Yu Ma,Ling-Ge Cui,Ya-Ru Xu,Chen-Xi Li,Milton Talukder,Xue-Nan Li,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical applied as a plasticizer. As an environmental toxicant, DEHP poses a serious health threat. Many studies have revealed that DEHP can cause lead to various degrees of damage to the kidney. However, the evidence of DEHP-induced renal ferroptosis has not been reported. The purpose of this work was to probe the specific role of lipophagy in DEHP-induced renal injury and to investigate the relationship between lipophagy and ferroptosis. Quail were treated with DEHP (250 mg/kg BW/day, 500 mg/kg BW/day and 750 mg/kg BW/day) for 45 days. Microstructural and ultrastructural observations showed that DEHP caused damage to glomerular and tubular cells, and autophagy with multilayer structures were observed, suggesting that DEHP can induce lipophagy. The results indicated that the iron homeostasis was abnormal and the lipid peroxidation was increased. SLC7A11 and SLC3A2 were down-regulated. PTGS2, ACSL4 and LPCAT3 were elevated. In conclusion, DEHP could induce lipid peroxidation, lead to ferroptosis, and damage renal cells. Therefore, the relationship between lipophagy and ferroptosis was elucidated, which provided a new basis for intervention and prevention of DEHP increased diseases.
研究领域:
毒理学
·
环境科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-29
·
IF 12.6
Li Yang,Xue Xiaoxia,Yu Liuchunyang,Qian Jinxiu,Li Xiaoyu,Tian Meng,Yang Jue,Deng Rongjun,Lu Cheng,Xiao Cheng,Liu Yuanyan
Introduction Atherosclerosis serving as the main underlying factor of cardiovascular disease (CVD) remains the primary cause of mortality and morbidity globally, while the deposition of massive cholesterol in macrophage-derived foam cells exerts pivotal roles in the occurrence and progression of atherosclerosis. Celastrol (CEL) is a bioactive ingredient owning potent capability to modulate lipid metabolism, whereas the poor bioavailability and potential toxicity limit its clinical application. Objectives This study aims to design a CEL-loaded recombinant high-density lipoprotein (rHDL) delivery platform for active targeting, which may effectively promote lipid degradation in foam cells and reversely transport excessive cholesterol to the liver for metabolism in time. Methods The rHDL loaded with CEL (CEL-rHDL) was prepared by the thin film dispersion method. Then the anti-atherosclerotic efficacy and targeted delivery to foam cells of atherosclerotic lesions were verified both in vitro and in vivo. RNA-sequence was applied to reveal the potential mechanism against early atherosclerosis, which was further validated through several molecular biology experiments. Results The prepared CEL-rHDL increased the targeting efficiency to foam cells of atherosclerotic lesions, mitigated its off-target toxicity, and improved anti-atherosclerotic efficacy. Importantly, CEL-rHDL decreased lipid storage in foam cells by triggering lipophagy via the activation of Ca 2+ /CaMKKβ/AMPK/mTOR signaling pathway and reverse cholesterol transport (RCT). Conclusion A combination of hypolipidemic chemo-intervention with rHDL participated specific and reverse delivery may offer a promising strategy for biocompatible treatment of early atherosclerosis. Graphical abstract
研究领域:
心血管疾病
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Cong Zhang,Yingying Song,Ming Yuan,Liang Chen,Qianyu Zhang,Junjie Hu,Yan Meng,Shan Li,Guohua Zheng,Zhenpeng Qiu
Excessive fructose consumption exacerbates the progression of nonalcoholic fatty liver disease (NAFLD) by disrupting hepatic lipid homeostasis. This study sought to evaluate the efficacy of urolithin A (UroA) in a fructose-induced NAFLD mouse model. UroA was administered in the high-fructose-fed mice to investigate the antisteatotic effects in vivo. Fructose-stimulated HepG2 cells and primary hepatocytes were established for in vitro mechanistic assessment. The results suggested that UroA ameliorated fructose-induced hepatic steatosis in mice. Mechanistically, UroA impaired lipogenesis and enhanced β-oxidation in the livers of fructose-fed mice. Notably, UroA facilitated hepatic lipophagy through the AMPK/ULK1 pathway both in vivo and in vitro, degrading lipid droplets for fueling β-oxidation. This study indicates that UroA alleviates excessive lipid accumulation and restores lipid homeostasis in the livers of fructose-fed mice by suppressing lipid metabolic reprogramming and triggering lipophagy. Therefore, dietary supplementation of UroA or ellagitannins-rich foods may be beneficial for NAFLD individuals with high fructose intake.
研究领域:
肝病学
·
代谢紊乱
·
营养科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Hepatology Communications
·
2023
·
IF 5.1
Qian Du,Tingting Zhu,Guorong Wen,Hai Jin,Jiaxing An,Jingyu Xu,Rui Xie,Jiaxing Zhu,Xiaoxu Yang,Ting Zhang,Qi Liu,Shun Yao,Xingyue Yang,Biguang Tuo,Xiong Ma
Background: S100 calcium-binding protein A6 (S100A6) is a calcium-binding protein that is involved in a variety of cellular processes, such as proliferation, apoptosis, and the cellular response to various stress stimuli. However, its role in NAFLD and associated metabolic diseases remains uncertain. Methods and Results: In this study, we revealed a new function and mechanism of S100A6 in NAFLD. S100A6 expression was upregulated in human and mouse livers with hepatic steatosis, and the depletion of hepatic S100A6 remarkably inhibited lipid accumulation, insulin resistance, inflammation, and obesity in a high-fat, high-cholesterol (HFHC) diet-induced murine hepatic steatosis model. In vitro mechanistic investigations showed that the depletion of S100A6 in hepatocytes restored lipophagy, suggesting S100A6 inhibition could alleviate HFHC-induced NAFLD. Moreover, S100A6 liver-specific ablation mediated by AAV9 alleviated NAFLD in obese mice. Conclusions: Our study demonstrates that S100A6 functions as a positive regulator of NAFLD, targeting the S100A6-lipophagy axis may be a promising treatment option for NAFLD and associated metabolic diseases.
研究领域:
肝病学
·
代谢疾病
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Yangfei Zhao,Mingyue Guo,Ting Pei,Chenqi Shang,Yirong Chen,Liying Zhao,Yiguang Lu,Chen Liang,Jundong Wang,Jianhai Zhang
Liver disease poses a significant threat to global public health, with arsenic (As) recognized as a major environmental toxin contributing to liver injury. However, the specific mechanisms and the protective effects of α-lipoic acid (LA) remain unclear. Therefore, this study employs network toxicology and network pharmacology to comprehensively analyze the hepatotoxic mechanism of As and the hepatoprotective mechanism of LA, and further verifies the mechanisms of peroxisomal β-oxidation and lipophagy in the process. The network analysis results show that As induces liver damage mainly through autophagy, apoptosis, lipid metabolism, and oxidative stress, whereas LA exerts its hepatoprotective properties mainly by regulating lipid metabolism. Further verifications find that As inhibits SIRT1 expression, activates the P53 and Notch pathways, damages mitochondria, inhibits peroxisomal β-oxidation, increases lipid accumulation, and enhances lipophagy in the liver, while LA intervention alleviates As-induced lipid accumulation and enhances lipophagy by targeting SIRT1, ameliorating mitochondrial damage, enhancing peroxisomal β-oxidation, thereby alleviating As-induced liver damage. This study further clarifies the mechanism of As hepatotoxicity and provides a theoretical basis for LA as a potential hepatoprotective agent.
研究领域:
毒理学
·
药理学
·
分子生物学
·
细胞生物学
·
环境健康
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Jiahan Ke,Jianan Pan,Hao Lin,Shuying Huang,Junfeng Zhang,Changqian Wang,Alex Chia Yu Chang,Jun Gu
Diabetic cardiomyopathy (DbCM) is characterized by diastolic dysfunction, which progresses into heart failure and aberrant electrophysiology in diabetic patients. Dyslipidemia in type 2 diabetic patients leads to the accumulation of lipid droplets (LDs) in cardiomyocytes and results in lipid toxicity which has been suggested to drive DbCM. It is aimed to explore potential pathways that may boost LDs degradation in DbCM and restore cardiac function. LDs accumulation resulted in an increase in lipid toxicity in DbCM hearts is confirmed. Microlipophagy pathway, rather than traditional macrolipophagy, is activated in DbCM hearts. RNA-Seq data and Rab7-CKO mice implicate that Rab7 is a major modulator of the microlipophagy pathway. Mechanistically, Rab7 is phosphorylated at Tyrosine 183, which allows the recruitment of Rab-interacting lysosome protein (Rilp) to proceed LDs degradation by lysosome. Treating DbCM mice with Rab7 activator ML-098 enhanced Rilp level and rescued the observed cardiac dysfunction. Overall, Rab7-Rilp-mediated microlipophagy may be a promising target in the treatment of lipid toxicity in DbCM is suggested.
研究领域:
心脏病学
·
细胞生物学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
CURRENT PHARMACEUTICAL DESIGN
·
2025
·Vol. 31
·期 25
·2025-2037
·
IF 2.8
Linhong Jiang,Dandan Bai,Yunjun Yang,Yingying Wu,Yanran Chen,Mengyuan Wang,Wenxin Wang,Haixia Wang,Yanzhe Xiong,Siqi Zhu,Xinyu He,Jun Long,Dongping Yuan,Jingwei Chen
ObjectiveNaringenin (NAR) is a naturally occurring tiny molecule that has a significant role in lipid metabolism. However, the molecular mechanism by which NAR is involved in lipid metabolism to protect ECs is not clear. This study aims to investigate the effect of NAR on autophagy in oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs) and its potential molecular mechanisms.MethodsOxidized LDL-induced HUVECs injury in vitro was treated with NAR. Chloroquine was used as an autophagy inhibitor. Ionomycin (Iono) and 2-aminoethoxydiphenylborate (2-APB) were used as an SOCE pathway agonist and an inhibitor, respectively. The autophagy levels in HUVECs were determined by quantitative real-time PCR, Western blot, and immunofluorescence methods. The concentration of calcium ions in HUVECs was measured by flow cytometry.ResultsThe findings revealed that NAR increased the viability of ox-LDL-impaired HUVECs. NAR increased the level of autophagy and decreased lipid accumulation in ox-LDL-treated HUVECs, which could interfere with chloroquine. Moreover, NAR significantly downregulated the expression of STIM1 and ORAI1 proteins and Ca2+ levels in the SOCE, which could be interfered with Iono or 2-APB, respectively.ConclusionIn summary, NAR can increase autophagy levels and decrease lipid accumulation in HUVECs, eventually protecting against ox-LDL-induced injury in HUVECs, which is associated with inhibition of the SOCE pathway.
研究领域:
药理学
·
细胞生物学
·
分子生物学
·
心血管研究
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2018
·
IF 3.977
Chunxue Zhao,Yiwei Zhou,Liangliang Liu,Jimin Long,Hongwen Liu,Juan Li,Yi Cao
Nanoparticle (NP) exposure might promote hepatic steatosis , but relatively few studies investigated the influence of multi-walled carbon nanotubes (MWCNTs) on lipid accumulation in hepatocytes in vitro . This study investigated lipid accumulation and the possible role of lipophagy (autophagic degradation of lipid droplets) in MWCNT-exposed HepG2 cells. Pristine (XFM19) and carboxylated MWCNTs (XFM21) were internalized, accompanying cytotoxicity, lysosomal destabilization , and intracellular reactive oxygen species (ROS) production. Compared with XFM21, XFM19 promoted lipid accumulation in HepG2 cells more effectively, which was further enhanced by pre-incubation with autophagy inhibitor NH 4 Cl. In addition, MWCNTs increased the expression of lipophagy genes PLIN2 and BECN1 but decreased that of ATG7 . The expression of endoplasmic reticulum (ER) stress regulators, namely DDIT3 , HSPA5 , and XBP- 1s, was also altered in MWCNT exposed HepG2 cells. Combined, these results suggested that MWCNT exposure might promote lipid accumulation in hepatocytes probably through the modulation of lipophagy pathway.
研究领域:
毒理学
·
细胞生物学
·
纳米技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）