ENVIRONMENT INTERNATIONAL
·
2020
·
IF 7.577
Miaoling Lin,Rui Hua,Jing Ma,Yao Zhou,Pei Li,Xiya Xu,Zhiqiang Yu,Song Quan
Background Bisphenol A (BPA) is a widespread endocrine-disrupting chemical with estrogen like effects, which could interfere with the human reproductive system by disrupting the normal function of granulosa cells (GCs) leading to abnormal ovarian function. However, the mechanism of its toxicity on human GCs has not been clearly described thus far. Methods 106 normogonadotropic infertile women undergoing their first in-vitro fertilization-embryo transfer (IVF-ET) cycle were recruited. Urinary BPA level and the early outcomes of IVF-ET were analysed. Patients were divided to low and high BPA exposure groups using the median urinary BPA concentration as the cut-off value. In-vivo and in-vitro studies were conducted using mice and human granulosa cell line (KGN cells). Female Kunming mice approximately 6–8 weeks of age were poisoned with BPA at different dosages (1, 10 or 100 μg/kg) by oral gavage once daily for 2 weeks, while KGN cells were exposed to BPA at the concentration of 1, 10 or 100 nM for 24 h, 48 h or 72 h. BPA-induced ovarian morphologic changes were analysed by histopathology investigation. Cell viability and apoptosis were evaluated using CCK-8, TUNEL and flowcytometric, respectively. Hormone levels were determined using ELISA and the molecular mechanism studies were conducted using immunofluorescence, RT-PCR and western blots. Results The oocyte retrieval rate, maturation rate and embryo implantation rate significantly decreased with the higher level of urinary BPA concentration. Peak E2 level was lower in high BPA group, but no statistical significance could be observed. In BPA treated mice, cystic dilation of the follicles with a decreased number of GCs could be observed histopathologically. Decreased E2, P4 and AMH level and GCs autophagy could be detected both in-vivo and in-vitro with the activation of AMPK/mTOR/ULK1 signalling pathway. As being confirmed in KGN cells, phosphorylated AMPK and ULK1 increased while phosphorylated mTOR decreased, and by inhibition autophagy using knockdown of AMPK or 3-MA, adverse effects of BPA exposure in-vitro could be reversed. Conclusion BPA exposure might abnormally influence human ovarian functions leading to abnormal folliculogenesis by activation of autophagy in GCs through AMPK/mTOR/ULK1 pathway.
研究领域:
内分泌学
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生殖生物学
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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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产品关联
DOI
PubMed
高影响因子
Autophagy
·
2022
·
IF 13.391
Jie Yao,Shuming Tang,Chenyan Shi,Yunzhi Lin,Lanlan Ge,Qinghua Chen,Baoru Ou,Dongyu Liu,Yuyang Miao,Qiujie Xie,Xudong Tang,Jia Fei,Guangyi Yang,Jun Tian,Xiaobin Zeng
Isoginkgetin (ISO), a natural biflavonoid, exhibited cytotoxic activity against several types of cancer cells. However, its effects on hepatocellular carcinoma (HCC) cells and mechanism remain unclear. Here, we revealed that ISO effectively inhibited HCC cell proliferation and migration in vitro. LC3-II expression and autophagosomes were increased under ISO treatment. In addition, ISO-induced cell death was attenuated by treatment with chloroquine or knockdown of autophagy-related genes (ATG5 or ULK1). ISO significantly suppressed SLC2A1/GLUT1 (solute carrier family 2 member 1) expression and glucose uptake, leading to activation of the AMPK-ULK1 axis in HepG2 cells. Overexpression of SLC2A1/GLUT1 abrogated ISO-induced autophagy. Combining molecular docking with thermal shift analysis, we confirmed that ISO directly bound to the N terminus of CDK6 (cyclin-dependent kinase 6) and promoted its degradation. Overexpression of CDK6 abrogated ISO-induced inhibition of SLC2A1/GLUT1 transcription and induction of autophagy. Furthermore, ISO treatment significantly decreased the H3K27ac, H4K8ac and H3K4me1 levels on the SLC2A1/GLUT1 enhancer in HepG2 cells. Finally, ISO suppressed the hepatocarcinogenesis in the HepG2 xenograft mice and the diethylnitrosamine+carbon tetrachloride (DEN+CCl4)-induced primary HCC mice and we confirmed SLC2A1/GLUT1 and CDK6 as promising oncogenes in HCC by analysis of TCGA data and human HCC tissues. Our results provide a new molecular mechanism by which ISO treatment or CDK6 deletion promotes autophagy; that is, ISO targeting the N terminus of CDK6 for degradation inhibits the expression of SLC2A1/GLUT1 by decreasing the enhancer activity of SLC2A1/GLUT1, resulting in decreased glucose levels and inducing the AMPK-ULK1 pathway.
研究领域:
肿瘤学
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分子生物学
·
细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2022
·
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
Biology Direct
·
2026
·Vol. 21
·期 1
·30
·
IF 5.5
Liu Shan,Yu Shangmin
Background Depression is a prevalent mental disorder, and its pathogenesis has not yet been fully elucidated. Circular RNAs (CircRNAs) have exhibit critical regulatory role in depression, while Unc-51-like kinase 1 (ULK1)-mediated autophagy participates in the pathophysiology of the disorder. Nevertheless, the potential involvement of circRNAs in modulating ULK1-mediated autophagy in depression remains unclear. Objectives This study aimed to identify depression-associated circRNAs regulating ULK1-medaited autophagy, and uncover the underlying mechanisms. Methods The depression model was established in mice using chronic unpredictable mild stress (CUMS) procedure. RNA sequencing and bioinformatics analysis were carried out to screen signaling pathways, circRNAs and microRNAs (miRNAs) related to depression. Overexpression and knockdown of circRNAs or miRNAs were conducted by lentivirus microinjection and cell transfection. The depression-like phenotypes were assessed through behavioral tests. Western blot, immunofluorescence and transmission electron microscopy (TEM) were employed to evaluated ULK1-mediated autophagy. RNA pull-down and dual-luciferase reporter assay was executed to explore the underlying mechanisms. Results CircADAM9 exhibited the most significant downregulation in CUMS mice among the differentially expressed circRNAs. Overexpression of circADAM9 relieved depressive-like behaviors, and promoted ULK1-mediated autophagy in vivo and in vitro. Importantly, circADAM9 sponged miR-302b-3p to regulate Ulk1 gene expression, and miR-302b-3p mimics diminished the behavioral improvements and pro-autophagic effect modulated by circADAM9. Conclusion We identified circADAM9 as a novel regulator in depression, which activated autophagy via miR-302b-3p/ULK1 axis to improve depressive-like behaviors. Our findings would provide a new potential therapeutic target for the treatment of depression.
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DOI
高影响因子
Frontiers in Bioscience-Landmark
·
2023
·Vol. 28
·期 12
·324
·
IF 3.1
Chao Tian,Yuchao Feng,Tianhua Chen,Zuyang Zhang,Xiaojie He,Liangdong Jiang,Mingjiang Liu
Background: Delayed wound healing, a common problem in patients with diabetes mellitus (DM), is associated with impaired keratinocyte autophagy. Epigallocatechin gallate (EGCG), a catechin, has been proven to promote diabetic wound healing. This study aims to explore the therapeutic mechanism of EGCG on diabetic wound healing. Methods: High glucose (HG)-induced keratinocytes and streptozotocin (STZ)-induced DM rats were prepared and intervened with EGCG to examine its therapeutic effects in in vivo and in vitro settings. The AMPK inhibitor, Compound C, was utilized to determine whether EGCG exerted its therapeutic effects through the AMPK/ULK1 pathway. Results: In vitro, EGCG improved HG-induced autophagy impairment in keratinocytes by increasing LC3II/LC3I, Becline1, and ATG5 levels and decreasing p62 level. Mechanically, EGCG activated the AMPK/ULK1 pathway, thereby promoting keratinocyte autophagy through the phosphorylation of AMPK and ULK1. Notably, EGCG promoted the proliferation, migration, synthesis and release of C-C motif chemokine ligand 2 (CCL2) in HG-treated keratinocytes. Furthermore, EGCG indirectly promoted the activation of fibroblasts, as evidenced by increased alpha-smooth muscle actin (α-SMA) and Collagen I levels. In vivo, EGCG promoted wound healing in DM rats, primarily by reducing inflammatory infiltration and increasing granulation tissue to promote wound epithelialization. Besides, EGCG promoted ATG5, KRT10, KRT14, TGF-β1, Collagen I, and α-SMA expressions in the neonatal epithelial tissues of DM rats. However, the use of Compound C reversed the effects of EGCG. Conclusions: These findings indicated that EGCG restored keratinocyte autophagy to promote diabetic wound healing through the AMPK/ULK1 pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DEVELOPMENTAL CELL
·
2021
·
IF 12.27
Cansu Karabiyik,Mariella Vicinanza,Sung Min Son,David C. Rubinsztein
Summary Autophagy is an essential catabolic process induced to provide cellular energy sources in response to nutrient limitation through the activation of kinases, like AMP-activated protein kinase (AMPK) and ULK1. Although glucose starvation induces autophagy, the exact mechanism underlying this signaling has yet to be elucidated. Here, we reveal a role for ULK1 in non-canonical autophagy signaling using diverse cell lines. ULK1 activated by AMPK during glucose starvation phosphorylates the lipid kinase PIKfyve on S1548, thereby increasing its activity and the synthesis of the phospholipid PI(5)P without changing the levels of PI(3,5)P 2 . ULK1-mediated activation of PIKfyve enhances the formation of PI(5)P-containing autophagosomes upon glucose starvation, resulting in an increase in autophagy flux. Phospho-mimic PIKfyve S1548D drives autophagy upregulation and lowers autophagy substrate levels. Our study has identified how ULK1 upregulates autophagy upon glucose starvation and induces the formation of PI(5)P-containing autophagosomes by activating PIKfyve.
研究领域:
细胞生物学
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分子生物学
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生物化学
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DOI
PubMed
高影响因子
VETERINARY RESEARCH
·
2023
·Vol. 54
·期 1
·1-12
·
IF 4.4
Fu Shaodong,Wang Zhenglei,Han Xiangan,Xu Yuanyuan,Miao Jinfeng
Macrophages play a pivotal role in the inflammatory response to the zoonotic pathogen E. coli, responsible for causing enteric infections. While considerable research has been conducted to comprehend the pathogenesis of this disease, scant attention devoted to host-derived H2S. Herein, we reported that E. coli infection enhanced the expression of CSE in macrophages, accompanied by a significantly increased inflammatory response. This process may be mediated by the involvement of excessive autophagy. Inhibition of AMPK or autophagy with pharmacological inhibitors could alleviate the inflammation. Additionally, cell model showed that the mRNA expression of classic inflammatory factors (Il-1β, Il-6), macrophage polarization markers (iNOS, Arg1) and ROS production was significantly down-regulated after employing CSE specific inhibitor PAG. And PAG is capable of inhibiting excessive autophagy through the LKB1-AMPK-ULK1 axis. Interestingly, exogenous H2S could suppress inflammation response. Our study emphasizes the importance of CSE in regulating the macrophage-mediated response to E. coli. Increased CSE in macrophages leads to excessive inflammation, which should be considered a new target for drug development to treat intestinal infection.
研究领域:
免疫学
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微生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Da Binlin,Guo Lei,Li Liming,Zhu Feng,Zhang Juanjuan,Wang Zhiming,Guo Feilong
Hyperammonemia is frequently encountered in cirrhosis; nevertheless, its direct hepatotoxic effects remain poorly characterized. In this study, we aimed to delineate the hepatotoxic effects of chronic hyperammonemia and and explore the related mechanisms of liver injury. Thirty male C57BL/6 mice were randomly divided into three groups ( n = 10 per group): a control group, a hyperammonemia group, and a rifaximin-treated group. Starting on day 0, the hyperammonemia and rifaximin-treated groups were fed a diet supplemented with an amino acid (AA) mixture at a 1:2 ratio to normal powdered (NP) diet for 14 consecutive days to establish chronic hyperammonemia, while the control group received NP diet. From day 8 onward, mice in the rifaximin-treated group received rifaximin by gavage at 100 mg/kg once daily for 7 days; the control and hyperammonemia groups received an equivalent volume of 0.9% saline. Twenty-four hours after the final administration, blood was collected; serum was separated by centrifugation and analyzed on an automatic biochemical analyzer for blood ammonia, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Immediately after blood sampling, mice were euthanized; whole brain and liver were rapidly excised, blotted dry, weighed, and used to calculate brain weight and liver index values. Tissue specimens were fixed for hematoxylin–eosin (H&E) staining to evaluate histopathological damage. Commercial kits were used to measure superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, urea content and glutamine synthetase (GS) activity in the liver tissue. Take paraffin sections of liver tissue and use Terminal Deoxynucleotide Transferase dUTP Nick End Labeling (TUNEL) method to detect the apoptosis level of liver cells. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were performed on liver samples to measure the mRNA and protein expression levels, respectively. Hyperammonemia significantly increased brain weight index, liver index, blood ammonia, serum ALT and AST ( p < 0.001); rifaximin reversed these changes ( p < 0.001). Liver urea content was significantly lower in the hyperammonemia group (0.245 ± 0.008 mmol/g, p < 0.01) than in the control group (0.281 ± 0.004 mmol/g), and rifaximin obviously rescued this reduction and raised hepatic urea to 0.300 ± 0.014 mmol/g ( p < 0.01). Hepatic GS activity declined remarkably in the hyperammonemia group (8.37 ± 0.50, p < 0.05) compared with the control group (8.87 ± 0.41), and rifaximin treatment effectively increased GS activity (9.42 ± 0.27, p < 0.05). Histologically, H&E-stained brain sections from hyperammonemia mice displayed pronounced cytotoxic edema, while liver sections showed disordered hepatocellular cords, and marked inflammatory infiltration, both of which were mitigated by rifaximin. Compared with the control group, the liver tissue SOD activity in the hyperammonemia model group was significantly reduced, and the MDA content was significantly increased ( p < 0.01); After intervention with rifaximin, SOD activity increased and MDA content decreased ( p < 0.01). TUNEL staining further showed that the apoptosis level of liver cells in the model group mice was significantly increased compared to the control group, while treatment with rifaximin significantly reduced the number of apoptotic cells ( p < 0.0001). Mechanically, hyperammonemia-induced hepatic injury are underpinned by its ability to upregulate MAPK/mTOR signaling and downregulate ULK1 activity, thereby impairing autophagic flux. Hyperammonemia may negatively regulate ULK1 activity through the MAPK/mTOR pathway, impair autophagic flux, promote liver oxidative stress and hepatocyte apoptosis, and lead to liver injury.
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DOI
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Bingqing Liang,Fengxian Shi,Can Jin,Min Chen,Yuxiao Niu,Anhong Li,Weihua Xu,Zhongping Ning,Fengfeng Xue,Xinming Li,Yuzhong Yan
Curcumin, a highly hydrophobic phenolic compound, has demonstrated potent anticancer activity. However, poor water solubility and a short biological half-life hinder its clinical application. We developed Curcumin-loaded Pluronic F-127 nanoparticles to enhance the bioavailability of Curcumin. It has been reported that excessive autophagy is considered to be the main mechanism of death of various cancer cells. The aim of this study is to investigate whether the Curcumin-loaded Pluronic F-127 nanoparticles exert anti-colon cancer effects by modulating autophagy and explore the specific regulatory mechanism. The proliferative, migratory and apoptotic activity of CT26 cells was assessed by CCK-8 assay, wound healing assay and flow cytometry, respectively. In addition, levels of reactive oxygen species (ROS) were examined by DCFH-DA assay in vitro. ATP levels were detected by the ELISA. The expression levels of autophagy-related proteins and apoptosis-related proteins were visualized by western blotting. Curcumin-loaded Pluronic F-127 nanoparticle inhibited the proliferation of CT26 cells and the growth of colon tumours by promoting cellular autophagy. In addition, Curcumin-loaded Pluronic F-127 nanoparticle reduced mitochondrial membrane potential and impaired mitochondrial function by increasing ROS levels, disrupting ATP biosynthesis. Then the decreased ATP/AMP ratio activated the AMPK/mTOR/ULK1 autophagy signalling pathway and induced autophagy-dependent apoptosis in CT26 cells. Intriguingly, the apoptosis and excessive autophagy induced by Curcumin-loaded Pluronic F-127 nanoparticle were reversed after pretreatment with the antioxidant N-acetyl-L-cysteine. Curcumin-loaded Pluronic F-127 nanoparticle induced autophagy-dependent apoptosis through ROS-AMPK/mTOR/ULK1 signalling in colon cancer cells. Our study offers new insights for colon cancer treatment advancement.
研究领域:
肿瘤学
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纳米医学
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分子生物学
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药理学
·
细胞信号转导
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Linghui Song,Panpan Chen,Baimei Shi,Aihua Qu,Chuanlai Xu,Hua Kuang,Maozhong Sun
Autophagy is a key regulator in a diverse range of human diseases. Here, chiral copper sulfide (CuS) nanoparticles (NPs) modified with penicillamine are fabricated, which exhibited a circular dichroism (CD) spectrum between 300 and 1000 nm and a fluorescence peak at 680 nm. The experimental data showed that D -CuS NPs exhibited chirality-dependent autophagy induction, outperforming L -CuS NPs, and targeted breast cancer cells with 228.4 times higher affinity for CD81 receptor. The mechanism is revealed that chiral NPs specifically bound to CD81 receptor to open mechanosensitive calcium channels and motivated the calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK pathway, which enhanced Atg1/Unc-51-like autophagy activating kinase 1 (ULK1) activity to promote autophagy. In vivo experiments confirmed the selective accumulation of D -CuS NPs in tumors, induction of autophagy, and successful treatment of the tumor. Therefore, chiral CuS NPs show great potential for modulating biological processes and improving tumor treatment.
研究领域:
纳米医学
·
肿瘤学
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分子生物学
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细胞自噬
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生物材料
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转化医学
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产品关联
DOI
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
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营养科学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2024
·
IF 3.9
Xin Gao,Huan He,Qi Zheng,Siju Chen,Yu Wei,Taifa Zhang,Yi Wang,Bo Wang,Dake Huang,Shengquan Zhang,Sumei Zhang,Jinxia Zhai
BDE-209 exposure induced male reproductive toxicity with sperm quality decline. However, the role of autophagy in this was unclear. The purpose was to evaluate the protective effect and its potential mechanism of trehalose (Tre, autophagy inducer) on reproductive damage during spermiogenesis induced by BDE-209. We used 2% w/v Tre and 75 mg/kg/d BDE-209 cotreated mice for 42 days. GC-2 spd cells were cotreated with Tre, chloroquine (CQ, inhibition of autophagic flux), compound C (CC, AMPK inhibitor), and BDE-209. Tre intake significantly recovered decrease in sexual organ ratio and poor sperm quality in BDE-209-exposed mice. Supplementation with Tre rescued sperm head malformation by improving aberrant histone-protamine exchange in BDE-209-exposed mice. However, Tre intake couldn't restore the acrosome biogenesis. In addition, Tre supplementation improved testicular damage induced by BDE-209. BDE-209 blocked autophagic flux with increased P62 and LC3BⅡ/Ⅰ levels. Mechanistically, CQ treatment aggravated elevation of P62 and LC3BⅡ/Ⅰ levels induced by BDE-209, otherwise, CC and Tre treatments inhibited the rise in p-AMPK, p-ULK1, P62 and LC3BⅡ/Ⅰ levels induced by BDE-209. Tre supplementation improved reproductive injury in BDE-209-exposed mice by regulating autophagic flow via AMPK-ULK1 signaling pathways, which providing a new theoretical basis and possible therapeutic targets for male reproductive toxicity.
研究领域:
生殖毒理学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）