Autophagy
·
2025
·
IF 14.3
Zizheng Gao,Jiaqi Zhang,Huangxi Fu,Shaoyin Zhang,Jian Chen,Haiyang Zhou,Xueqin Chen,Xiaochen Zhang,Hao Yan,Bo Yang,Qiaojun He,Zhifei Xu,Peihua Luo
Entrectinib stands unparalleled as the sole neurotrophic tyrosine receptor kinase (NTRK) inhibitor that has demonstrated clinical efficacy in treating brain metastases across various cancer types. However, its potential to induce severe cardiotoxicity, compounded by the current lack of effective intervention strategies, poses a substantial risk of treatment failure, underscoring the critical need for in-depth research on the molecular mechanism. Here, we utilized proteomics analysis and a murine model with cardiomyocyte-specific atg7 deletion to reveal that entrectinib activated autophagy in cardiomyocytes, subsequently triggering apoptosis and leading to cardiac dysfunction. Mechanistically, entrectinib directly bound to the HMGB1 protein at the 103rd phenylalanine residue, enhancing its nuclear localization. In the nucleus, HMGB1 suppressed the transcription of the deubiquitinating enzyme OTUD5, a vital regulator of the MTORC1 pathway, which subsequently inhibited the MTORC1 pathway, culminating in the activation of macroautophagy/autophagy. Furthermore, our research demonstrated that HMGB1 inhibition could prevent the cardiotoxicity induced by entrectinib in both in vivo and in vitro models. Specifically, we found that tanshinone IIA could mitigate the cardiotoxic effects of entrectinib by reducing HMGB1 protein levels. Taken together, our findings elucidated the mechanism underlying entrectinib-induced cardiotoxicity, offering a theoretical foundation for the safer clinical application of this targeted therapy.Abbreviations and Acronyms: ATG7: autophagy related 7; CHX: cycloheximide; CKMB: creatine kinase myocardial band; CQ: chloroquine; c-PARP: cleaved poly (ADP-ribose) polymerase family; DAPI: 4‘6-diamidino-2-phenylindole; EF: ejection fraction; FS: fractional shortening; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HW:TL: ratio of heart weight to tibia length; KEGG: Kyoto Encyclopedia of Genes and Genomes; MYH6: myosin heavy polypeptide 6, cardiac muscle, alpha; MYH7: myosin, heavy polypeptide 7, cardiac muscle, beta; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; PI: propidium iodide; qPCR: quantitative real-time PCR; SD: standard deviation; SRB: sulforhodamine B; WGA: wheat germ agglutinin.
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PubMed
高影响因子
Food Bioscience
·
2026
·
IF 6.2
Shiqin Gong,Ziqi Li,Fang Liu,Yi Xiao
High-sugar diets are associated with multiple health risks, such as obesity, metabolic disorders, and cardiovascular diseases. To mitigate the adverse effects of high sugar intake on biological health, aspartame (ASP) is widely used as one of the sugar substitutes. In this study, we used Caenorhabditis elegans ( C. elegans ) as the model to reveal the specific mechanism by which ASP affects healthy lifespan. Our results showed that ASP (1, 10, 100 μmol/L) significantly extended the lifespan of C. elegans and improved health indicators in dose dependent manner, including reduced lipofuscin accumulation and enhanced motility, but did not influence the fertility of worms. Furthermore, by screening the classic signaling pathways, we discovered ASP extended healthspan via mechanistic target of rapamycin complex 1 (mTORC1) pathway. In addition, we found that ASP inhibited mTORC1 activity to promote the nuclear translocation of helix-loop-helix protein 30 (HLH-30), the nematode homolog of transcription factor EB (TFEB), and subsequently upregulated autophagy-related genes such as autophagy-related gene 5 ( atg-5 ), beclin 1 ( bec-1 ), LC3, GABARAP, GATE-16 family member 1 ( lgg-1 ) and LC3, GABARAP, GATE-16 family member 2 ( Lgg-2 ). This ultimately activated the autophagy process, thereby delaying aging. This finding elucidates that ASP induces autophagy to enhance healthspan in C. elegans dependent on the mTORC1/TFEB pathway, offering a novel approach for anti-aging research.
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高影响因子
Frontiers in Medicine
·
2025
·
IF 3
Ping Wang,Cunbo Yu,Yibing Li,Xiaoxiao Zhang,Xueli Yao,Yingjian Zhang
Introduction: This study aims to systematically explore the regulatory effects of ghrelin on hindlimb skeletal muscle function and gastrointestinal smooth muscle in mice. The objective is to elucidate the improvement effects of ghrelin on functional constipation through regulating skeletal muscle function and gastrointestinal motility, providing new theoretical support for the prevention and treatment of functional constipation.Methods: Dexamethasone-induced in vitro cell models and tail suspension-induced in vivo mouse models were employed to analyze the regulatory effect of ghrelin on the PI3K-Akt-mTORC1 signaling pathway. Additionally, a loperamide-induced constipation mouse model was used to evaluate the effects of ghrelin on fecal output, gastric motility, and smooth muscle activity. Experimental techniques included Western blotting, enzyme-linked immunosorbent assay (ELISA), histopathological staining, phenol red assay, and quantitative analyses of Ca2+ and ATP to comprehensively assess the impact of ghrelin on muscle atrophy and gastrointestinal function.Results: The results showed that, in vitro, ghrelin significantly upregulated the expression of p-AKT and reduced the levels of p-Foxo3a, effectively alleviating muscle atrophy. In vivo, the muscle condition of mice was improved and the expression of atrophy-related proteins (MAFbx and MuRF1) decreased, promoting the functional recovery of hindlimb muscles. In constipated mice, ghrelin increased fecal water content and defecation frequency, and accelerated gastric emptying, findings consistent with elevated ghrelin levels in serum and tissue. Moreover, ghrelin promoted calcium ion influx and ATP production in gastric smooth muscle cells, thereby enhancing gastrointestinal motility.Discussion: In conclusion, ghrelin effectively alleviates muscle atrophy by activating the PI3K-Akt-mTORC1 signaling pathway, and improves gastrointestinal motility by enhancing smooth muscle activity. These findings highlight ghrelin’s potential as an effective therapy for functional constipation.
研究领域:
生理学
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药理学
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胃肠病学
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内分泌学
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分子生物学
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PubMed
高影响因子
Cell Reports
·
2022
·
IF 9.995
Na Li,Beilei Hua,Qing Chen,Fukang Teng,Meiyu Ruan,Mengnan Zhu,Li Zhang,Yinbo Huo,Hongqin Liu,Min Zhuang,Huali Shen,Huanhu Zhu
Summary The mTOR-dependent nutrient-sensing and response machinery is the central hub for animals to regulate their cellular and developmental programs. However, equivalently pivotal nutrient and metabolite signals upstream of mTOR and developmental-regulatory signals downstream of mTOR are not clear, especially at the organism level. We previously showed glucosylceramide (GlcCer) acts as a critical nutrient and metabolite signal for overall amino acid levels to promote development by activating the intestinal mTORC1 signaling pathway. Here, through a large-scale genetic screen, we find that the intestinal peroxisome is critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, GlcCer deficiency, inactive mTORC1, or prolonged starvation relocates intestinal peroxisomes closer to the apical region in a kinesin- and microtubule-dependent manner. Those apical accumulated peroxisomes further release peroxisomal-β-oxidation-derived glycolipid hormones that target chemosensory neurons and downstream nuclear hormone receptor DAF-12 to arrest the animal development. Our data illustrate a sophisticated gut-brain axis that predominantly orchestrates nutrient-sensing-dependent development in animals.
研究领域:
生物学
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发育生物学
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营养学
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神经科学
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DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
·
2026
·
IF 3.7
Na Mi,Lili Ma,Jing Zhao,Xinxin Bu,Jing Xu,Jia Fu,Chao Zhang,Yali Zhang,Lifen Yao
Discovery of the "Gut Microbiota-BCAA" metabolic dysregulation in PD. • BCAA supplementation promotes propionate production via microbiota remodeling. • Propionate alleviates neurodegeneration via anti-inflammatory and anti-apoptotic mechanisms. • Identification of the PI3K/Akt/mTORC1 axis as the mediator of propionate’s protection. Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and systemic inflammation, with increasing evidence implicating the gut–brain axis in its pathogenesis. Altered gut microbiota composition and reduced levels of neuroprotective microbial metabolites, such as short-chain fatty acids (SCFAs), have been reported in patients with PD. Branched-chain amino acids (BCAAs), essential nutrients influenced by microbial metabolism, may contribute to neuroimmune regulation through SCFA production, particularly propionate, and modulation of PI3K/Akt/mTORC1 signaling. In this study, we investigated whether dietary BCAA supplementation influences neurodegenerative processes in PD through gut microbiota remodeling and microbial propionate production, and examined the potential involvement of the PI3K/Akt/mTORC1 signaling pathway. We combined human clinical observations with mechanistic studies in MPTP-induced PD mouse models and MPP⁺-treated SH-SY5Y neuronal cells. Gut microbiota composition was profiled using 16S rRNA sequencing, and fecal and serum metabolites were analyzed by GC–MS. Neurobehavioral performance, dopaminergic neuron integrity, apoptosis-related markers, and PI3K/Akt/mTORC1 pathway activation were evaluated using immunohistochemistry, Western blotting, and cellular assays with or without pharmacological inhibition. PD patients exhibited gut dysbiosis, reduced BCAA levels, and depletion of SCFA-producing taxa. In mice, BCAA supplementation partially restored microbial composition and enhanced predicted propionate biosynthesis pathways. Propionate administration improved motor performance, preserved dopaminergic neurons, mitigated neuroinflammatory responses, and reduced apoptosis in vivo and in vitro. Mechanistically, propionate restored PI3K, Akt, and mTORC1 phosphorylation, upregulated Bcl-2, and suppressed cleaved caspase-3, effects that were abolished by PI3K inhibition. Collectively, these findings identify a gut microbiota–BCAA–propionate axis that may influence neurodegenerative processes through modulation of PI3K/Akt/mTORC1 signaling, highlighting microbial metabolites as potential modulators of gut–brain communication in PD.
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PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2024
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IF 4.6
Jiazhen Huang,Ying Tang,Yibing Li,Wei Wei,Fuli Kang,Shuang Tan,Lin Lin,Xiaohang Lu,Heng Wei,Ning Wang
High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer that causes great threats to women's health. Therefore, we performed RNA-sequencing technology in clinical samples to explore the molecular mechanisms underlying the progression of HGSOC. We then noticed BBOX1, a kind of 2-oxoglutarate-dependent enzyme that is highly expressed in HGSOC tumor tissues. Functional studies showed that BBOX1 promotes cell survival and growth of HGSOC cells in vitro and in vivo. Overexpression of the wild-type BBOX1 promoted cell proliferation, but the Asn191 and Asn292 mutation (key amino acid for the enzymatic activity of BBOX1) counteracted this effect ( P < 0.05), which indicated that the promotion effect of BBOX1 on HGSOC cell proliferation was related to its catalytic activity. Downregulation of BBOX1 reduced the activity of the mTORC1 pathway, and decreased protein expression of IP3R3 and phosphorylation level of S6K Thr389 . Metabolomics analysis revealed that BBOX1 is implicated in the glucose metabolism, amino acid metabolism, and nucleotide metabolism of HGSOC cells. In addition, inhibition of BBOX1 suppressed HGSOC cell glycolysis and decreased glucose consumption, lactate production, and the expression of key factors in glycolysis. Finally, we found hypoxia induced the expression of BBOX1 in HGSOC cells and confirmed that BBOX1 could be transcriptionally activated by hypoxia-inducible factor-1α, which could directly bind to the BBOX1 promoter. In summary, BBOX1 mediated the metabolic reprogramming driven by hypoxia, and affected cell metabolism through the mTORC1 pathway, thus acting as an oncogene during HGSOC development.
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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代谢学
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PubMed
高影响因子
Frontiers in Physiology
·
2021
·
IF 4.566
Lin Jinyan,Fan Lele,Han Yuming,Guo Juanjuan,Hao Zhiqiang,Cao Lingna,Kang Jiamin,Wang Xiaoqin,He Jianping,Li Jingang
The Gansu zokor (Eospalax cansus) is a subterranean rodent species that is unique to China. These creatures inhabit underground burrows with a hypoxia environment. Metabolic energy patterns in subterranean rodents have become a recent focus of research; however, little is known about brain energy metabolism under conditions of hypoxia in this species. The mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) coordinates eukaryotic cell growth and metabolism, and its downstream targets regulate hypoxia inducible factor-1α (HIF-1α) under conditions of hypoxia to induce glycolysis. In this study, we compared the metabolic characteristics of hypoxia-tolerant subterranean Gansu zokors under hypoxic conditions with those of hypoxia-intolerant Sprague-Dawley rats with a similar-sized surface area. We exposed Gansu zokors and rats to hypoxia I (44 h at 10.5% O2) or hypoxia II (6 h at 6.5% O2) and then measured the transcriptional levels of mTORC1 downstream targets, the transcriptional and translational levels of glycolysis-related genes, glucose and fructose levels in plasma and brain, and the activity of key glycolysis-associated enzymes. Under hypoxia, we found that hif-1α transcription was upregulated via the mTORC1/eIF4E pathway to drive glycolysis. Furthermore, Gansu zokor brain exhibited enhanced fructose-driven glycolysis under hypoxia through increased expression of the GLUT5 fructose transporter and ketohexokinase (KHK), in addition to increased KHK enzymatic activity, and utilization of fructose; these changes did not occur in rat. However, glucose-driven glycolysis was enhanced in both Gansu zokor and rat under hypoxia II of 6.5% O2 for 6 h. Overall, our results indicate that on the basis of glucose as the main metabolic substrate, fructose is used to accelerate the supply of energy in Gansu zokor, which mirrors the metabolic responses to hypoxia in this species.
研究领域:
生理学
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分子生物学
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代谢学
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神经科学
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PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-17
·
IF 14.7
Jiang Xiaoxue,liu Kan,Luo Peixiang,Li Zi,Xiao Fei,Jiang Haizhou,Wu Shangming,Tang Min,Yuan Feixiang,Li Xiaoying,Shu Yousheng,Peng Bo,Chen Shanghai,Ni Shihong,Guo Feifan
The central nervous system has been implicated in the age-induced reduction in adipose tissue lipolysis. However, the underlying mechanisms remain unclear. Here, we show the expression of SLC7A14 is reduced in proopiomelanocortin (POMC) neurons of aged mice. Overexpression of SLC7A14 in POMC neurons alleviates the aging-reduced lipolysis, whereas SLC7A14 deletion mimics the age-induced lipolysis impairment. Metabolomics analysis reveals that POMC SLC7A14 increased taurochenodeoxycholic acid (TCDCA) content, which mediates the SLC7A14 knockout- or age-induced WAT lipolysis impairment. Furthermore, SLC7A14-increased TCDCA content is dependent on intestinal apical sodium-dependent bile acid transporter (ASBT), which is regulated by intestinal sympathetic afferent nerves. Finally, SLC7A14 regulates the intestinal sympathetic afferent nerves by inhibiting mTORC1 signaling through inhibiting TSC1 phosphorylation. Collectively, our study suggests the function for central SLC7A14 and an upstream mechanism for the mTORC1 signaling pathway. Moreover, our data provides insights into the brain–gut–adipose tissue crosstalk in age-induced lipolysis impairment.
研究领域:
神经科学
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内分泌学
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代谢学
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衰老研究
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DOI
PubMed
高影响因子
CELL RESEARCH
·
2024
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IF 28.1
Feng Ran,Liu Feng,Li Ruofei,Zhou Zhifen,Lin Zhuoheng,Lin Song,Deng Shengcheng,Li Yingying,Nong Baoting,Xia Ying,Li Zhiyi,Zhong Xiaoqin,Yang Shuhan,Wan Gang,Ma Wenbin,Wu Su,Songyang Zhou
Rheb is a small G protein that functions as the direct activator of the mechanistic target of rapamycin complex 1 (mTORC1) to coordinate signaling cascades in response to nutrients and growth factors. Despite extensive studies, the guanine nucleotide exchange factor (GEF) that directly activates Rheb remains unclear, at least in part due to the dynamic and transient nature of protein–protein interactions (PPIs) that are the hallmarks of signal transduction. Here, we report the development of a rapid and robust proximity labeling system named Pyrococcus horikoshii biotin protein ligase ( Ph BPL)-assisted biotin identification (PhastID) and detail the insulin-stimulated changes in Rheb-proximity protein networks that were identified using PhastID. In particular, we found that the lysosomal V-ATPase subunit ATP6AP1 could dynamically interact with Rheb. ATP6AP1 could directly bind to Rheb through its last 12 amino acids and utilizes a tri-aspartate motif in its highly conserved C-tail to enhance Rheb GTP loading. In fact, targeting the ATP6AP1 C-tail could block Rheb activation and inhibit cancer cell proliferation and migration. Our findings highlight the versatility of PhastID in mapping transient PPIs in live cells, reveal ATP6AP1’s role as an unconventional GEF for Rheb, and underscore the importance of ATP6AP1 in integrating mTORC1 activation signals through Rheb, filling in the missing link in Rheb/mTORC1 activation.
研究领域:
分子生物学
·
细胞信号传导
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癌症生物学
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蛋白质组学
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DOI
高影响因子
Cancer Immunology Research
·
2024
·
IF 8.1
Meng Meng,Zhong Zhaoyang,Song Liang,Zhang Zhaohui,Yin Xiaofeng,Xie Xiqiang,Tian Lei,Wu Wei,Yang Yao,Deng Yafei,Peng Hongyan,Wu Shuting,Ran Guanghe,Lin Yuqing,Lai Qiangqiang,Bi Qinghua,Yan Fulin,Ji Yan,Wang Yang,Li Xiaohui,Yi Ping,Yu Jianhua,Deng Youcai
Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1–SAM signal axis in regulating NK-cell activation and effector functions.
研究领域:
免疫学
·
分子生物学
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癌症研究
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PubMed
高影响因子
FUNCTIONAL & INTEGRATIVE GENOMICS
·
2021
·Vol. 21
·期 5
·557-570
·
IF 3.41
Sun Shouxiang,Cao Xiaojuan,Castro L. Filipe C.,Monroig Óscar,Gao Jian
Obesity is a rapidly growing health pandemic, underlying a wide variety of disease conditions leading to increases in global mortality. It is known that the phosphorylation of various proteins regulates sterol regulatory element-binding transcription factors 1 ( srebf1 ), a key lipogenic transcription factor, to cause the development of obesity. To detect the key protein kinases for regulating srebf1 in lipid deposition, we established the srebf1 knockout model in zebrafish (KO, srebf1 −/− ) by CRISPR/Cas9. The KO zebrafish exhibited a significant reduction of total free fatty acid content (fell 60.5%) and lipid deposition decrease compared with wild-type (WT) zebrafish. Meanwhile, srebf1 deletion in zebrafish eliminated lipid deposition induced by high-fat diet feeding. Compared with WT zebrafish, a total of 697 differentially expressed proteins and 316 differentially expressed phosphoproteins with 439 sites were identified in KO by differential proteomic and phosphoproteomic analyses. A significant number of proteins identified were involved in lipid and glucose metabolism. Moreover, some protein kinases critical for regulating srebf1 in lipid deposition, including Cdk2, Pkc, Prkceb, mTORC1, Mapk12, and Wnk1, were determined by network analyses. An in vitro study was performed to verify the network analysis results. Our findings provide potential targets (kinases) for human obesity treatments.
研究领域:
分子生物学
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遗传学
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蛋白质组学
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代谢
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营养学
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肥胖研究
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产品关联
DOI
PubMed
高影响因子
Communications Biology
·
2023
·Vol. 6
·期 1
·1-12
·
IF 5.9
Wang You-Yuan,Zhen Cheng,Hu Wei,Huang Hui-Huang,Li Yan-Jun,Zhou Ming-Ju,Li Jing,Fu Yu-Long,Zhang Peng,Li Xiao-Yu,Yang Tao,Song Jin-Wen,Fan Xing,Zou Jun,Meng Si-Run,Qin Ya-Qin,Jiao Yan-Mei,Xu Ruonan,Zhang Ji-Yuan,Zhou Chun-Bao,Yuan Jin-Hong,Huang Lei,Shi Ming,Cheng Liang,Wang Fu-Sheng,Zhang Chao
CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.
研究领域:
免疫学
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病毒学
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代谢学
·
HIV/AIDS研究
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DOI
PubMed
高影响因子
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