查找使用阿拉丁产品的科研文献

Gastrodin ameliorates oxidative stress-induced RPE damage by facilitating autophagy and phagocytosis through PPARα-TFEB/CD36 signal pathway

Chaojuan Wen,Xinyue Yu,Jingya Zhu,Jingshu Zeng,Xielan Kuang,Youao Zhang,Shiyu Tang,Qingjiong Zhang,Jianhua Yan,Huangxuan Shen

Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly, is primarily characterized by the degeneration of the retinal pigment epithelium (RPE). However, effective therapeutic options for dry AMD are currently lacking, necessitating further exploration into preventive and pharmaceutical interventions. This study aimed to investigate the protective effects of gastrodin on RPE cells exposed to oxidative stress. We constructed an in vitro oxidative stress model of 4-hydroxynonenal (4-HNE) and performed RNA-seq, and demonstrated the protective effect of gastrodin through mouse experiments. Our findings reveal that gastrodin can inhibit 4-HNE-induced oxidative stress, effectively improving the mitochondrial and lysosomal dysfunction of RPE cells. We further elucidated that gastrodin promotes autophagy and phagocytosis through activating the PPARα-TFEB/CD36 signaling pathway. Interestingly, these outcomes were corroborated in a mouse model, in which gastrodin maintained retinal integrity and reduced RPE disorganization and degeneration under oxidative stress. The accumulation of LC3B and SQSTM1 in mouse RPE-choroid was also reduced. Moreover, activating PPARα and downstream pathways to restore autophagy and phagocytosis, thereby countering RPE injury from oxidative stress. In conclusion, this study demonstrated that gastrodin maintains the normal function of RPE cells by reducing oxidative stress, enhancing their phagocytic function, and restoring the level of autophagic flow. These findings suggest that gastrodin is a novel formulation with potential applications in the development of AMD disease.

Paeoniflorin recued hepatotoxicity under zinc oxide nanoparticles exposure via regulation on gut-liver axis and reversal of pyroptosis

Xingyao Pei,Shusheng Tang,Haiyang Jiang,Wenjuan Zhang,Gang Xu,Zonghui Zuo,Zhenhui Ren,Chun Chen,Yao Shen,Cun Li,Daowen Li

The risks of Zinc oxide nanoparticles (ZnO NPs) applications in biological medicine, food processing industry, agricultural production and the biotoxicity brought by environmental invasion of ZnO NPs both gradually troubled the public due to the lack of research on detoxification strategies. TFEB-regulated autophagy-pyroptosis pathways were found as the crux of the hepatotoxicity induced by ZnO NPs in our latest study. Here, our study served as a connecting link between preceding toxic target and the following protection mechanism of Paeoniflorin (PF). According to a combined analysis of network pharmacology/molecular docking-intestinal microbiota-metabolomics first developed in our study, PF alleviated the hepatotoxicity of ZnO NPs from multiple aspects. The hepatic inflammatory injury and hepatocyte pyroptosis in mice liver exposed to ZnO NPs was significantly inhibited by PF. And the intestinal microbiota disorder and liver metabolic disturbance were rescued. The targets predicted by bioinformatics and the signal trend in subacute toxicological model exhibited the protectiveness of PF related to the SIRT1-mTOR-TFEB pathway. These evidences clarified multiple protective mechanisms of PF which provided a novel detoxification approach against ZnO NPs, and further provided a strategy for the medicinal value development of PF.

Osimertinib activates TFEB to trigger hepatocyte cytoplasmic vacuolation-associated cell death

Qiu Yueping,Liu Yijie,Ding Haiying,Xin Wenxiu,Lu Shuanghui,Hu Yan,Chen Jing,Weng Qinjie,Wang Jiajia,Fang Luo

Osimertinib is a first-line treatment for advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR)-sensitive mutations; however, the severe hepatotoxicity of osimertinib is a challenge that has attracted attention. In this study, we found that osimertinib directly caused hepatocyte damage, with cells showing morphological features of vacuolization after treatment. Using transmission electron microscopy and other analytical techniques, we found that excessive activation of the autophagy-lysosome pathway was the main cause of cell vacuolation. Mechanistically, osimertinib causes dephosphorylation of transcription factor EB (TFEB), leading to its translocation into the nucleus to exert transcriptional regulatory functions. TFEB in the nucleus induces autophagy and lysosome biogenesis, thereby causing excessive activation of the autophagy-lysosome pathway subsequently leading to vacuolation-associated cell death. Through this study, we have identified S-adenosyl-L-methionine as a clinical hepatoprotective agent that could mitigate osimertinib-induced hepatocyte damage by inhibiting TFEB activation. Collectively, our findings not only lay the groundwork for addressing the clinical challenges posed by osimertinib hepatotoxicity but also broaden our understanding of drug-induced hepatocyte injury, thereby offering a novel research pathway for the study of drug-induced liver injury.

10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC

Siying Li,Kaihua Shi,Lei Huang,Ziqing Li,Zhuo Qin,Yanan Sun,Caifang Qin,Chunmei Wang,He Li,Jinghui Sun,Wei Liu,Jiping Wu,Zhihong Zhang

10-Gingerol (10-G) exhibits antitumor activity, yet its mechanism in non-small cell lung cancer (NSCLC) remains unclear. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. This study investigated the antitumor mechanism of 10-G in NSCLC, emphasizing its dual role in activating lysosomes and inducing ferroptosis. In this study, we found 10-G induced ferroptosis in NSCLC by increasing iron accumulation, lipid peroxidation, intracellular ROS levels, and malondialdehyde (MDA) production, while depleting glutathione (GSH) and rising Fe 2+ levels. Mechanistically, 10-G induced the dephosphorylation of Transcription Factor EB (TFEB) and TFEB dissociation from the 14–3-3 protein, thereby promoting the nuclear translocation of TFEB and the activation of lysosomal gene expression. Subsequently, the activation of lysosomes promoted the degradation of Nuclear factor erythroid 2-related factor 2 (NRF2), thereby affecting the expression levels of downstream targets Glutathione Peroxidase 4 (GPX4) and cystine/glutamate antiporter SLC7A11 (xCT), ultimately leading to ferroptosis. In vivo , 10-G suppressed tumor growth by inhibiting the TFEB-mediated NRF2/xCT/GPX4 axis and promoting ferroptosis. These findings demonstrated that 10-G suppressed the progression of NSCLC by promoting TFEB-mediated lysosomal degradation of NRF2, thereby inducing ferroptosis, which provides a rationale for a novel potential therapeutic strategy.

STING-IRG1 inhibits liver metastasis of colorectal cancer by regulating the polarization of tumor-associated macrophages

Yixuan Liu,Qi Sun,Chengfei Zhang,Min Ding,Cheng Wang,Qian Zheng,Zhijie Ma,Haojun Xu,Guoren Zhou,Xiaoming Wang,Zhangjun Cheng,Hongping Xia

Summary The liver is the main site of colorectal cancer (CRC) metastasis. Tumor-associated macrophages (TAMs) play a key role in tumor metastasis. Therefore, modulating the function of tumor-associated macrophages is a potential therapeutic strategy to control tumor metastasis. We found in vivo experiments that the activation of STING inhibited CRC liver metastasis in model mice and affected the macrophage phenotype in the tumor microenvironment. Mechanistically, STING affects TAM polarization and regulates macrophage function through IRG1. And STING activates IRG1 to promote the nuclear translocation of TFEB, affecting the ability of macrophages to suppress tumor metastasis.Therefore, this study highlights the critical role of the STING-IRG1 axis on TAM reprogramming and its role in the process of tumor liver metastasis, which may provide a promising therapeutic strategy for CRC liver metastasis.

Resveratrol promotes lysosomal function via ER calcium-dependent TFEB activation to ameliorate lipid accumulation

Shao Rong,Shi Jiahui,Du Kaili,Wang Na,Cai Weijie,Liu Siyu,Ding Zongxian,Wang Yihan,Li Dan

Abnormal lipid accumulation is associated to the development of metabolic diseases such as hepatic steatosis and lipid storage diseases. Pharmacological agents that can attenuate lipid accumulation therefore have therapeutic potentials for these diseases. Resveratrol (RSV), a natural active substance found in fruits and nuts, has been reported to effectively reduce the intracellular lipid accumulation, but the underlying mechanisms of RSV remain elusive. Here, we show that RSV triggers an endoplasmic reticulum (ER)- Ca2+ signaling that activates transcriptional factor EB (TFEB), a master transcriptional regulator of autophagic and lysosomal biogenesis. Moreover, RSV activates protein phosphatase 2A (PP2A), which binds and dephosphorylates TFEB, promoting its nuclear translocation and the expression of TFEB target genes required for autophagosome and lysosomal biogenesis. Notably, genetic inhibition of TFEB significantly ameliorates RSV-mediated lipid clearance. Taken together, these data link RSV-induced ER calcium signaling, PP2A and TFEB activation to promote autophagy and lysosomal function, by which RSV may trigger a cellular self-defense mechanism that effectively mitigate lipid accumulation commonly associated with many metabolic diseases.

TFEB Activator Curcumin Analog C1 Downregulates PKM2 and Alleviates Inflammatory Injury in Endotoxemic Mice

Yanliuying Zhu,Xinyan Zan,Kerui Fan,Jiao Wang,Ying Zhi,Jinlin Liu,Yongqiang Yang,Li Zhang

Objective Autophagy dysfunction results in the accumulation of pro-inflammatory components and drives inflammatory injury. Transcription factor EB (TFEB) is a master regulator of autophagy and a novel target for controlling inflammatory injury. Curcumin analog C1 directly binds to and activates TFEB, but its anti-inflammatory effects remain unclear.Methods The anti-inflammatory and protective effects of curcumin analog C1 were investigated in lipopolysaccharide (LPS)-induced endotoxemia mice.Results Curcumin analog C1 reversed LPS-induced autophagy dysfunction, downregulated pyruvate kinase M2 (PKM2), and reduced pro-inflammatory cytokines including TNF–α, IL–6, and MCP–1. It also attenuated systemic abnormalities, alleviated lung injury, and decreased blood urea nitrogen (BUN), brain-type natriuretic peptide (BNP), and extracellular DNA levels.Conclusions Curcumin analog C1 exhibits potential pharmacological value in the control of inflammatory injury.Thank you for your assistance.

SMURF1 controls the PPP3/calcineurin complex and TFEB at a regulatory node for lysosomal biogenesis

Qin Xia,Hanfei Zheng,Yang Li,Wanting Xu,Chengwei Wu,Jiachen Xu,Shanhu Li,Lingqiang Zhang,Lei Dong

Gigantol Ameliorates Metabolic Dysfunction-Associated Steatohepatitis by Promoting TFEB-Mediated Lipophagy and Fatty Acid Oxidation

Cong Zhang,Yingxi Luo,Yangkun Xiong,Liang Chen,Haixia Zhao,Zhenpeng Qiu,Yuan Yang

Gigantol, a naturally active molecule derived from the edible plant Dendrobium, has been demonstrated to have hepatoprotective potential, but its effect in the treatment of metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. Here, we found that gigantol treatment greatly corrected dyslipidemia, hepatic dysfunction, and hepatic histological changes that arrested MASH occurrence in high-fat and high-fructose-diet (HFFD)-fed mice. Mechanistically, gigantol promoted the nuclear translocation of the transcription factor EB (TFEB) to regulate the key factors of lipophagy and fatty acid oxidation to maintain hepatic lipid metabolism homeostasis. Consistent results were observed in palmitic acid-induced cell models. Notably, silencing TFEB reversed the effect of gigantol in enhancing lipophagy and fatty acid oxidation in vivo and in vitro. In summary, this study provides strong evidence to demonstrate that gigantol attenuates HFFD-induced MASH by promoting TFEB-dependent lipophagy and fatty acid oxidation, suggesting that gigantol, an edible plant-derived compound, is promising to be developed as a therapeutic drug for MASH in the future.

Putrescine promotes maturation of oocytes from reproductively old mice via mitochondrial autophagy

Siyuan Xie,Yuyi Wang,Chenxi Zhao,Yugui Cui,Chunyan Gu,Wei Wu

ABSTRACT Research question: Does putrescine improve oocytes from reproductively old mice by promoting mitochondrial autophagy༟ Design: Germinal vesicle (GV) stage cumulus-oocyte complexes (COCs) were obtained from 9-month-old female C57B6L/N mice and divided into three groups: NC (control group), PUT (putrescine group), and DFMO (difluoromethylornithine, inhibitor group). These GV-COCs underwent mouse in vitro maturation (IVM) culture to observe the extrusion of the first polar body in each group. Using JC-1 and DCFH-DA fluorescent probes and a confocal microscope to measure the mitochondrial membrane potential integrity and ROS levels in MII stage oocytes. The expression and cellular localization of the p53 protein were examined by immunofluorescence. RT-qPCR was used to detect the activation of mitochondrial autophagy pathways. The potential mechanisms through which putrescine improves oocytes from reproductively old mice were explored by single-cell transcriptomic analysis. Autophagosomes, autolysosomes, and mitochondria in different groups were directly observed using transmission electron microscopy. Results: The study found that adding exogenous putrescine can promote the in vitro maturation of oocytes from reproductively old mice. Putrescine reduces oxidative stress in oocytes from reproductively old mice by promoting the autophagy of damaged mitochondria, decreasing the levels of reactive oxygen species, and increasing mitochondrial membrane potential. Putrescine affects the expression and subcellular localization of the p53 protein, and increases the expression of TFEB, which may be the potential mechanism behind its promotion of autophagy. Conclusion: This study clarified the target and regulatory pathway of putrescine in oocytes, suggesting that putrescine is an effective small molecule compound with significant potential for non-invasively improving the fertility of elderly women.

CB2R Activation Regulates TFEB-Mediated Autophagy and Affects Lipid Metabolism and Inflammation of Astrocytes in POCD

Lieliang Zhang,Xifeng Wang,Wen Yu,Jun Ying,Pu Fang,Qingcui Zheng,Xiaojin Feng,Jialing Hu,Fan Xiao,Shoulin Chen,Gen Wei,Yue Lin,Xing Liu,Danying Yang,Yang Fang,Guohai Xu,Fuzhou Hua

Evidence suggests that the accumulation of lipid drots (LDs) accelerates damage to mitochondria and increases the release of inflammatory factors. These have been implicated as a mechanism underlying neurodegenerative diseases or tumors and aging-related diseases such as postoperative cognitive dysfunction (POCD), nevertheless, accumulation of lipid droplets has not been extensively studied in the central nervous system (CNS). Here, we found that after surgery, there was activation of astrocytes and lipid accumulation in the hippocampus. However, cannabinoid receptor type II (CB2R) activation significantly reduced lipid accumulation in astrocytes and change the expression of genes related to lipid metabolism. CB2R reduces the release of the inflammatory factors interleukin-1 beta (IL-1β) and interleukin 6 (IL-6) in peripheral serum and simultaneously improves cognitive ability in mice with POCD. Further research on mechanisms indicates that CB2R activation promotes the nuclear entry of the bHLH-leucine zipper transcription factor, the transcription factor EB (TFEB), and which is a master transcription factor of the autophagy–lysosomal pathway, also reduces TFEB-S211 phosphorylation. When CB2R promotes TFEB into the nucleus, TFEB binds at two sites within promoter region of PGC1α, promoting PGC1α transcription and accelerating downstream lipid metabolism. The aforementioned process leads to autophagy activation and decreases cellular lipid content. This study uncovers a new mechanism allowing CB2R to regulate lipid metabolism and inflammation in POCD.

ZNPs reduce epidermal mechanical strain resistance by promoting desmosomal cadherin endocytosis via mTORC1-TFEB-BLOC1S3 axis

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