JOURNAL OF ETHNOPHARMACOLOGY
·
2025
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IF 5.4
Zhaolin Sun,Yuhua Wei,Shuangyi Ma,Yuchen Xu,Yuna Zhang,Changxian Li,Jinghan Zhang,Feifei Duan,Jianwei Jiao,Xiuying Duan
Ethnopharmacological relevance Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease worldwide, primarily caused by poor lifestyle choices and dietary habits. Caulis Bambusae In Taenias , commonly known as Zhuru in Chinese, is a traditional Chinese medicinal material from the Bambusoideae family, frequently used for liver detoxification, liver protection, and lowering lipids. Aim of the study The study aimed to reveal the protective effects and underlying mechanisms of Zhuru extracts (EZR) in treating MASLD. Methods High performance liquid chromatography, liquid chromatography-tandem mass spectrometry, and fourier infrared spectroscopy were used to identify the components of EZR. We utilized oleic acid-treated HepG2/LO2 cells as in vitro models and zebrafish on high-fat diets (HFD) as animal models, and conducted network pharmacology, RNA sequencing, and biological assays, including confocal fluorescence, commercial kits, western blotting, and quantitative PCR, to investigate the lipid-lowering effect of EZR and its underlying mechanisms. Results EZR alleviated lipid accumulation in both in vitro and in vivo models. Analyses through network pharmacology and RNA sequencing revealed that the lipid-lowering properties of EZR were associated with pathways related to lipid biosynthesis, antioxidant functions, and anti-inflammatory mechanisms. Subsequent experimental validation confirmed that EZR decreased the expression levels of FASN, ACC1, HMGCR, ACLY, and LDLR. Additional findings indicated that EZR inhibited mTORC1 activation, leading to the suppression of SREBP1 and SREBP2, thereby mitigating lipid accumulation. Furthermore, EZR was found to downregulate oxidative stress and the levels of inflammatory cytokines. Conclusions EZR demonstrated the ability to lower lipid levels and alleviate HFD-induced MASLD. This is achieved by inhibiting mTORC1/SREBPs-related lipid biosynthesis and reducing oxidative stress and inflammation.
研究领域:
药理学
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肝脏疾病
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DOI
PubMed
高影响因子
AMERICAN JOURNAL OF PATHOLOGY
·
2025
·
IF 3.6
Lin Xu,Yuanyuan Zhao,Yang Yang,Enbo Qi,Boao Liu,Peili Zhuang,Shiyi Song,Tingmin Chang,Zhiguo Chen,Xiaohong Kang,Xiwen Xiong
Alcohol-related liver disease (ALD), a consequence of excessive alcohol use, manifests across a broad spectrum of liver damage, ranging from steatosis to cirrhosis. DEPDC5 is a component of the GATOR1 complex, which functions as a repressor of the amino acid-sensing branch of the mTORC1 pathway. In this study, hepatocyte specific Depdc5 knockout mice (Depdc5 △Hep ) were generated and it was found that aberrant activation of mTORC1 caused by Depdc5 deletion led to exacerbated ER stress and hepatocyte ferroptosis in the livers of ethanol-fed mice. Torin-1, an ATP-competitive mTOR inhibitor, suppressed the mTORC1 activity and reversed the effects of Depdc5 deletion on ER stress and ferroptosis in ethanol-fed mouse livers. Furthermore, pharmacological relief of ER stress using TUDCA or inhibition of ferroptosis with liproxstatin-1 both alleviated the liver abnormalities induced by Depdc5 ablation in ethanol-fed mice. Additionally, the research uncovered that ER stress functions as an upstream signal of ferroptosis in the progression of ALD. These findings provide novel in vivo evidence that sustained mTORC1 activation leads to alcoholic liver injury by inducing ER stress and ferroptosis, suggesting that targeting these pathways may represent a potential therapeutic strategy for ALD.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports
·
2023
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IF 8.8
Pengcheng Cai,Rui Ni,Mengzhu Lv,Huijuan Liu,Jieqiong Zhao,Jianbo He,Lingfei Luo
Summary Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases.
研究领域:
分子生物学
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肝脏病学
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再生医学
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DOI
高影响因子
MOLECULAR CELL
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2023
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IF 16
Chenchen Xu,Xiaoqing Pan,Dong Wang,Yuanyuan Guan,Wenyu Yang,Xing Chen,Ying Liu
The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.
研究领域:
细胞生物学
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分子生物学
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代谢
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信号通路
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2021
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IF 2.63
Fang You,Junyan Cao,Li Cheng,Xiaogu Liu,Li Zeng
Premature ovarian insufficiency (POI) is characterized by the loss of ovarian function before 40 years of age and affects approximately 1% of women worldwide. Caragana sinica is a traditional Miao (a Chinese ethnic minority) medicine that improves ovarian function and follicular development. In the present study, we aimed to investigate the effect of active ingredients of C. sinica on POI and determine underlying mechanisms. Herein, the chemical composition of the C. sinica compound was analyzed using ultra-high-performance liquid chromatography, which identified hyperin (HR) as one of the main ingredients in C. sinica. Then, interaction targets of HR and POI were predicted and analyzed using network pharmacology and bioinformatics. The effect of HR on triptolide (TP)-induced granulosa cell injury was evaluated, and the underlying mechanism was explored based on bioinformatic results. A total of 100 interaction targets for POI and HR were obtained. The protein-protein interaction network of identified interaction targets emphasized the topological importance of AKT1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that HR might regulate POI by modulating the mechanistic target of rapamycin (mTOR) signaling pathway. In addition, the KEGG graph of the mTOR signaling pathway revealed that AKT phosphorylation inhibits the TSC1/2, while TSC1/2 activation inhibits the expression of mTORC1. The fundamental experiment revealed that HR increased proliferation, progesterone receptor levels, and estradiol levels decreased by TP in KGN cells. Additionally, HR alleviated TP-induced apoptosis and G1/G1 phase arrest in KGN cells. Western blotting demonstrated that HR increased the phosphorylation of AKT and mTORC1 and decreased TSC1 expression in TP-induced KGN cells. Collectively, our findings revealed that HR alleviates TP-induced granulosa cell injury by regulating AKT/TSC1/mTORC1 signaling, providing insight into the treatment of POI.
研究领域:
药理学
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细胞生物学
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生殖医学
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传统中药
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-17
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IF 10.6
Lai Xuan,Wang Menglei,Zhang Zhen,Chen Suya,Tan Xiner,Liu Wenjing,Liang Huimin,Li Li,Shao Longquan
Zinc oxide nanoparticles (ZNPs) are widely used in sunscreens and nanomedicines, and it was recently confirmed that ZNPs can penetrate stratum corneum into deep epidermis. Therefore, it is necessary to determine the impact of ZNPs on epidermis. In this study, ZNPs were applied to mouse skin at a relatively low concentration for one week. As a result, desmosomes in epidermal tissues were depolymerized, epidermal mechanical strain resistance was reduced, and the levels of desmosomal cadherins were decreased in cell membrane lysates and increased in cytoplasmic lysates. This finding suggested that ZNPs promote desmosomal cadherin endocytosis, which causes desmosome depolymerization. In further studies, ZNPs were proved to decrease mammalian target of rapamycin complex 1 (mTORC1) activity, activate transcription factor EB (TFEB), upregulate biogenesis of lysosome-related organelle complex 1 subunit 3 (BLOC1S3) and consequently promote desmosomal cadherin endocytosis. In addition, the key role of mTORC1 in ZNP-induced decrease in mechanical strain resistance was determined both in vitro and in vivo. It can be concluded that ZNPs reduce epidermal mechanical strain resistance by promoting desmosomal cadherin endocytosis via the mTORC1-TFEB-BLOC1S3 axis. This study helps elucidate the biological effects of ZNPs and suggests that ZNPs increase the risk of epidermal fragmentation. Graphical abstract
研究领域:
纳米技术
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皮肤病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2024
·Vol. 38
·期 4
·2077-2093
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IF 6.1
Ziwei Yuan,Xuejia Yang,Zujian Hu,Yuanyuan Gao,Mengsi Wang,Lili Xie,Hengyue Zhu,Chaosheng Chen,Hong Lu,Yongheng Bai
Cisplatin-induced kidney injury (CKI) is a common complication of chemotherapy. Fraxetin, derived from Fraxinus bungeana A. DC . bark, has antioxidant, anti-inflammatory, and anti-fibrotic effects. This study aims to investigate fraxetin's effects on CKI and its underlying mechanism in vivo and in vitro. Tubular epithelial cells (TECs) and mice were exposed to cisplatin with and without fraxetin preconditioning assess fraxetin's role in CKI. TECs autophagy was observed using transmission electron microscopy. Apoptosis levels in animal tissues were measured using TUNEL staining. The protective mechanism of fraxetin was explored through pharmacological and genetic regulation of mTORC1. Molecular docking was used to identify potential binding sites between fraxetin and mTORC1. The results indicated that fraxetin pretreatment reduced cisplatin-induced kidney injury in a time- and concentration-dependent way. Fraxetin also decreased autophagy in TECs, as observed through electron microscopy. Tissue staining confirmed that fraxetin pretreatment significantly reduced cisplatin-induced apoptosis. Inhibition of mTORC1 using rapamycin or siRNA reversed the protective effects of fraxetin on apoptosis and autophagy in cisplatin-treated TECs, while activation of mTORC1 enhanced fraxetin's protective effect. Molecular docking analysis revealed that fraxetin can bind to HEAT-repeats binding site on mTORC1 protein. In summary, fraxetin pretreatment alleviates CKI by antagonizing autophagy and apoptosis via mTORC1 activation. This provides evidence for the potential therapeutic application of fraxetin in CKI.
研究领域:
药理学
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肾病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
TOXICOLOGY
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2024
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IF 4.8
Di Ouyang,Yiren Xiong,Zuqing Hu,Jiayi He,Shanshan He,Renyi Liu,Zhenjie Gao,Dalin Hu
The mechanistic target of rapamycin (RAPA) complex 1 (mTORC1) - transcription factor EB (TFEB) pathway plays a crucial role in response to nutritional status, energy and environmental stress for maintaining cellular homeostasis. But there is few reports on its role in the toxic effects of arsenic exposure and the related mechanisms. Here, we show that the exposure of bronchial epithelial cells (BEAS-2B) to sodium arsenite promoted the activation of mTORC1 (p-mTORC1) and the inactivation of TFEB (p-TFEB), the number and activity of lysosomes decreased, the content of reduced glutathione (GSH) and superoxide dismutase (SOD) decreased, the content of malondialdehyde (MDA) increased, the DNA and chromosome damage elevated. Further, when mTORC1 was inhibited with RAPA, p-mTORC1 and p-TFEB down-regulated, GSH and SOD increased, MDA decreased, the DNA and chromosome damage reduced significantly, as compared with the control group. Our data revealed for the first time that mTORC1 - TFEB pathway was involved in sodium arsenite induced lysosomal alteration, oxidative stress and genetic damage in BEAS-2B cells, and it may be a potential intervention target for the toxic effects of arsenic.
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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DOI
PubMed
高影响因子
NATURE CELL BIOLOGY
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2024
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IF 17.3
Son Sung Min,Park So Jung,Breusegem Sophia Y.,Larrieu Delphine,Rubinsztein David C.
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism and autophagy. Multiple pathways modulate mTORC1 in response to nutrients. Here we describe that nucleus–cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300 that decreases acetylation of the mTORC1 component raptor, thereby reducing mTORC1 activity and activating autophagy. This is mediated by AMP-activated protein kinase-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in protein phosphatase 2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. Interestingly, p300 cytoplasm–nucleus shuttling is altered in cells from patients with Hutchinson–Gilford progeria syndrome. p300 mislocalization by the disease-causing protein, progerin, activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in Hutchinson–Gilford progeria syndrome, causing mTORC1 hyperactivation and defective autophagy.
研究领域:
细胞生物学
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分子生物学
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医学遗传学
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DOI
PubMed
高影响因子
Translational Oncology
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2024
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IF 4.5
Wei An,Kai Zhang,Guangbing Li,Shunzhen Zheng,Yukun Cao,Jun Liu
Cholangiocarcinoma remains a challenging primary hepatobiliary malignancy with dismal prognosis. Photodynamic therapy (PDT),a less invasive treatment, has been found to inhibit the proliferation and induce ferroptosis, apoptosis and necrosis in other tumor cells in recent years. Regrettably, the role and exact molecule mechanism of PDT is still incompletely clear in cholangiocarcinoma cells. Ferroptosis is a novel regulated cell death(RCD), which is controlled by glutathione peroxidase4(GPX4) with the characteristics of iron dependent and excessive intracellular accumulation of lipid peroxides. This novel form of RCD has attracted great attention as a potential new target in clinical oncology during recent years. In this study, we observed that hypericin mediated PDT(HY-PDT) could significantly inhibit the proliferation of the cholangiocarcinoma cells and suppress migration and the epithelial mesenchymal transition (EMT) as well. Then, we conducted transcriptome sequencing and bioinformatics analysis and observed that HY-PDT was most likely involved in ferroptosis, apoptosis, the EMT process and AKT/mTORC1 signaling pathways in cholangiocarcinoma cells. Next, a series of in vitro and in vivo experiments were performed to confirm that HY-PDT could trigger cholangiocarcinoma cells ferroptosis through inhibiting the expression of GPX4 protein. In terms of molecular mechanism, we found that HY-PDT induced ferroptosis by decreasing GPX4 expression via suppression of the AKT/mTORC1 signaling pathway. In addition, we also found that HY-PDT inhibit cholangiocarcinoma cells migration and the EMT process by inhibiting the AKT/mTORC1 pathway. Our study illustrated a new mechanism of action for HY-PDT and might throw light on the individualized precision therapy for cholangiocarcinoma patients.
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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药理学
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DOI
高影响因子
EXPERIMENTAL NEUROLOGY
·
2021
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IF 5.33
Chao Gu,Junqing Yang,Ying Luo,Dongzhi Ran,Xiaodan Tan,Pu Xiang,Huizhi Fei,Yi Lu,Wenjia Guo,Yujun Tu,Xia Liu,Hong Wang
Zinc and ring finger 2 (ZNRF2), an E3 ubiquitin ligase , plays a crucial role in many diseases . However, its role in cerebral ischemia/reperfusion injury (CIRI) still remains unknown. In this study, the function and molecular mechanism of ZNRF2 in CIRI in vivo and vitro was studied. ZNRF2 was found to be dramatically downregulated in CIRI. Overexpression of ZNRF2 could significantly reduce the neurological deficit, brain infarct volume and histopathological damage of cortex in middle cerebral artery occlusion/reperfusion. Concomitantly, overexpression of ZNRF2 increased the primary neuronal viability and decreased the neuronal apoptosis induced by oxygen-glucose deprivation and reoxygenation (OGD/R). Mechanistically, overexpression of ZNRF2 inhibited the over-induction of autophagy induced by OGD/R which was abolished by mTORC1 inhibitor rapamycin . It can be concluded that ZNRF2 plays a protective effect in CIRI and the underlying mechanism may be related to the inhibition of mTORC1-mediated autophagy.
研究领域:
神经科学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
CELL AND TISSUE RESEARCH
·
2022
·Vol. 390
·期 2
·293-313
·
IF 4.051
Li Zhen-Fang,Hao Shuang-Li,Wang Lan-Min,Qi Hong-Yu,Wang Jia-Ming,Tan Fu-Qing,Yang Wan-Xi
Spermatogenesis is a finely regulated process of germ cell proliferation and differentiation that leads to the production of sperm in seminiferous tubules. Although the mammalian target of rapamycin (mTOR) signaling pathway is crucial for spermatogenesis in mammals, its functions and molecular mechanisms in spermatogenesis remain largely unknown in nonmammalian species, particularly in Crustacea. In this study, we first identified es-Raptor (the core component of mTOR complex 1) and es-Rictor (the core component of mTOR complex 2) from the testis of Eriocheir sinensis . Dynamic localization of es-Raptor and es-Rictor implied that these proteins were indispensable for the spermatogenesis of E. sinensis. Furthermore, es-Raptor and es-Rictor knockdown results showed that the mature sperm failed to be released, causing almost empty lumens in the testis. We investigated the reasons for these effects and found that the actin-based cytoskeleton was disrupted in the knockdown groups. In addition, the integrity of the testis barrier (similar to the blood-testis barrier in mammals) was impaired and affected the expression of cell junction proteins. Further study revealed that es-Raptor and es-Rictor may regulate spermatogenesis via both mTORC1- and mTORC2-dependent mechanisms that involve es-rpS6 and es-Akt/es-PKC, respectively. Moreover, to explore the testis barrier in E. sinensis , we established a cadmium chloride (CdCl 2 )–induced testis barrier damage model as a positive control. Morphological and immunofluorescence results were similar to those of the es-Raptor and es-Rictor knockdown groups. Altogether, es-Raptor and es-Rictor were important for spermatogenesis through maintenance of the actin filament network and cell junctions in E. sinensis.
研究领域:
分子生物学
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生殖生物学
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甲壳动物学
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产品关联
DOI
PubMed
高影响因子
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