Molecular Medicine Reports
·
2019
·Vol. 20
·期 1
·529-538
·
IF 1.851
Shasha Chen,Feng Cai,Jirong Wang,Zhouxin Yang,Chi Gu,Guofu Wang,Genxiang Mao,Jing Yan
The abnormal aggregation of α‑synuclein (α‑syn), which is an important pathological feature of Parkinson's disease (PD), is cytotoxic to dopaminergic neurons and causes cellular damage and apoptosis. Salidroside (SAL) is the main active component of the traditional Chinese medicine Rhodiola rosea. Previous research has demonstrated that SAL exerts cellular protection against cell senescence and neurodegeneration. However, the role and mechanism of action of SAL in PD remain unclear. The present study used overexpression of the wild‑type and the A53T mutation of α‑syn to induce a neuronal model of PD in SH‑SY5Y cells, which led to neuronal toxicity and a reduced cell proliferation index. SAL increased the cell proliferation index of both PD model groups in a dose‑dependent manner. Additionally, SAL alleviated pathogenic phosphorylated (Ser129) α‑syn expression as well as the ratio of microtubule‑associated proteins 1A/1B light chain 3 (LC3)‑I to LC3‑II expression, which is related to autophagic function. Furthermore, the results suggested that the underlying mechanism for the SAL‑induced protection of PD model neurons may involve the preservation of autophagy, which attenuates the phosphorylation of α‑syn in neurons predominantly via mTOR/p70S6K, and is independent of the PI3K/Akt signaling pathway.
研究领域:
神经科学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2020
·
IF 4.225
Sun Xiaowei,Wang Dongyan,Zhang Tingting,Lu Xuejian,Duan Fangfang,Ju Lili,Zhuang Xiaotong,Jiang Xicheng
Eugenol, as an active compound isolated from Acorus gramineus, has been shown to protect against cerebral ischemia-reperfusion (I/R) injury. Nonetheless, the detailed neuroprotective mechanisms of eugenol in cerebral I/R injury have not been elaborated. In the present study, cerebral I/R injury model was established by middle cerebral artery occlusion (MCAO) in rats. HT22 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic cerebral I/R injury in vitro. The results showed that eugenol pre-treatment relieved cerebral I/R injury as evidenced by improving neurological deficits and reducing infarct volume. Autophagy was induced by MCAO, which was further promoted by eugenol administration. Moreover, rapamycin, an activator of autophagy, promoted eugenol-induced decreases in neurological score, infarct volume, brain water content, and apoptosis. However, pretreatment with 3-MA, an inhibitor of autophagy, led to the opposite results. Similarly, eugenol pretreatment increased the viability and restrained apoptosis of OGD/R-challenged HT22 cells. OGD/R-induced autophagy was strengthened by eugenol. Mechanically, eugenol promoted autophagy through regulating AMPK/mTOR/P70S6K signaling pathway in vivo and in vitro. In conclusion, pretreatment with eugenol attenuated cerebral I/R injury by inducing autophagy via AMPK/mTOR/P70S6K signaling pathway.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Bioengineered
·
2021
·
IF 3.269
Yingnan Dai,Yeping Chen,Guoqian Wei,Li Zha,Xueqi Li
Ivabradine (Iva), a heart rate reducing agent that specifically inhibits the pacemaker I(f) ionic current, has been demonstrated to be cardioprotective in many cardiovascular diseases. Autophagy is an evolutionarily conserved metabolic process that regulates cardiac homeostasis. This study is aimed to explore whether autophagy is functionally involved in the cardioprotective effect of Iva in a rat model of myocardial infarction (MI). We observed that Iva treatment (po, 10 mg/kg/day) showed significant recovery on the hemodynamics parameters in MI rats, including left ventricular systolic pressure, left ventricular end diastolic pressure, and maximal ascending/descending rate of left ventricular pressure. Also, Iva treatment dramatically decreased infarct size, inhibited myocardial apoptosis, and reduced the levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in MI rats. Moreover, Iva treatment enhanced autophagy and inhibited PI3K/AKT/mTOR/p70S6K pathway in MI rats. Simultaneously, we observed that autophagy enhancer rapamycin (ip, 10 mg/kg/day) showed similar cardioprotective effects with Iva. Furthermore, we observed that addition of autophagy inhibitor 3-methyladenine (ip, 10 mg/kg/day) counteracted the therapeutic effect of Iva, addressing that Iva attenuated post-MI cardiac injury by enhancing autophagy. In summary, these findings demonstrated that Iva attenuated MI in rats by enhancing autophagy, and PI3K/AKT/mTOR/p70S6K pathway might be involved in the process. Autophagy activation by Iva may be a potential therapeutic strategy for the treatment of MI.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND BIOPHYSICS
·
2025
·
IF 2.5
Zhao Wenxin,Gong Zelin,Wang Benjie,Wu Zhiyu,Guo Yiyuan,Wang Shurong,Zhai Hao,Zheng Xiaomei,Yang Lu
Autophagy dysfunction plays an influential role in fluoride-induced neurotoxicity, but the mechanism has not yet been clarified. The aim of this study was to investigate the effects of grape seed proanthocyanidin extract (GSPE) on sodium fluoride (NaF)-treated offspring SD rats and SH-SY5Y cells, and to elucidate the mechanism of mTOR/p70s6k-mediated autophagy signaling pathway action. The results of in vivo experiments showed that different doses of GSPE treatment could alleviate NaF-induced neurological damage, centering on the improvement of learning and memory ability, recovery of autonomous exploration ability, reduction of anxiety-like behaviors, restoration of neuronal structure in hippocampal tissues, and reduction of the expression of apoptotic protein cleaved-PARP. Meanwhile, GSPE significantly promoted autophagy in hippocampal tissues, as evidenced by the blockage of mTOR/p70s6k phosphorylation and the upregulation of LC3-II and downregulation of p62 expression. To further explore the mechanistic issues, we conducted cellular experiments, which suggested that GSPE pretreatment significantly increased cell viability and strengthened autophagy compared with the NaF group. These results were evidenced by the inhibition of mTOR/p70s6k phosphorylation and the upregulation of LC3-II protein. To further investigate the effect of GSPE on the mTOR/p70s6k pathway, the mTOR inhibitor rapamycin (RAPA) and activator MHY1485 were incorporated. The results indicated that GSPE inhibited the enhancement of mTOR phosphorylation in combination with MHY1485, and further inhibited the phosphorylation of mTOR in combination with RAPA, and the levels of LC3-II and p62 and immunofluorescence results also confirmed that the pretreatment of GSPE promoted cellular autophagy. Similarly, Hoechst33342 fluorescence intensity and apoptotic protein cleaved-PARP expression were further reduced after GSPE combined with RAPA or MHY1485. In addition, downstream of the mTOR/p70s6k pathway, brain-derived neurotrophic factor (BDNF), which has been widely used in studies of mood disorders, was significantly reduced by GSPE pretreatment, suggesting that GSPE may not only have a role in attenuating neurotoxicity, but also potentially in improving mood. In conclusion, the present study reveals that GSPE may alleviate fluoride-induced neurotoxicity by inhibiting the activation of the mTOR/p70s6k signaling pathway and thereby enhancing cellular autophagy and antagonizing apoptosis.
研究领域:
神经毒理学
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分子生物学
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药理学
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发育神经科学
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细胞自噬
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环境健康
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2017
·
IF 2.466
Menglu Zhou,Shuying Shen,Xin Zhao,Xingguo Gong
Autophagy has attracted a great deal of interest in tumour therapy research in recent years. However, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, on autophagy remains poorly understood in human lung cells. In the present study, we have investigated the anticancer effects of luteoloside on non-small cell lung cancer (NSCLC) cells and demonstrated that luteoloside effectively inhibited cancer cell proliferation , inducing G 0 /G 1 phase arrest associated with reduced expression of CyclinE, CyclinD1 and CDK4; we further found that treatment with luteoloside did not strongly result in apoptotic cell death in NSCLC (A549 and H292) cells. Interestingly, luteoloside induced autophagy in lung cancer cells, which was correlated with the formation of autophagic vacuoles, breakdown of p62, and the overexpression of Beclin-1 and LC3-II, but not in a human bronchial epithelial cell line (BEAS-2B). Notably, pretreatment of cancer cells with 3-MA, an autophagy inhibitor, protected against autophagy and promoted cell viability but not apoptosis. To further clarify whether luteoloside-induced autophagy depended on the PI3K/AKT/mTOR/p70S6K signalling pathway , a major autophagy-suppressive cascade, cells were treated with a combination of AKT inhibitor (LY294002) and mTOR inhibitor (Rap). These results demonstrated that luteoloside induced autophagy in lung cancer cell lines by inhibiting the pathway at p -Akt (Ser473), p -mTOR and p-p70S6K (Thr389). Moreover, we observed that luteoloside-induced cell autophagy was correlated with production of reactive oxygen species (ROS). NAC-mediated protection against ROS clearly implicated ROS in the activation of autophagy and cell death. In addition, the results showed that ROS served as an upstream effector of the PI3K/AKT/mTOR/p70S6K pathway. Taken together, the present study provides new insights into the molecular mechanisms underlying luteoloside-mediated cell death in NSCLC cells and supports luteoloside as a potential anti-cancer agent for targeting NSCLC through the induction of autophagy, inhibition of proliferation and PI3K/AKT/mTOR/p70S6K signalling.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2021
·
IF 11.614
Ping-Ting Xiao,Zhi-Shen Xie,Yu-Jia Kuang,Shi-Yu Liu,Chun Zeng,Ping Li,E-Hu Liu
The mammalian target of rapamycin (mTOR)-sterol regulatory element-binding proteins (SREBPs) signaling promotes lipogenesis. However, mTOR inhibitors also displayed a significant side effect of hyperlipidemia. Thus, it is essential to develop mTOR-specific inhibitors to inhibit lipogenesis. Here, we screened the endogenous inhibitors of mTOR, and identified that FKBP38 as a vital regulator of lipid metabolism. FKBP38 decreased the lipid content in vitro and in vivo via suppression of the mTOR/P70S6K/SREBPs pathway. 3,5,6,7,8,3ʹ,4ʹ-Heptamethoxyflavone (HMF), a citrus flavonoid, was found to target FKBP38 to suppress the mTOR/P70S6K/SREBPs pathway, reduce lipid level, and potently ameliorate hyperlipidemia and insulin resistance in high fat diet (HFD)-fed mice. Our findings suggest that pharmacological intervention by targeting FKBP38 to suppress mTOR/P70S6K/SREBPs pathway is a potential therapeutic strategy for hyperlipidemia, and HMF could be a leading compound for development of anti-hyperlipidemia drugs.
研究领域:
药理学
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代谢学
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脂质生物学
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药物发现
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
·
2022
·Vol. 78
·期 1
·213-227
·
IF 5.08
Zhang Haihua,Lang Wuying,Liu Xin,Bai Jiangsong,Jia Qinghui,Shi Qiumei
Ulcerative colitis (UC) is a recurrent chronic inflammatory disease. The symptom of UC is mainly diarrhea including bloody stools. Increasing evidence has suggested that procyanidin A1 (PCA1) exerts an anti-inflammatory effect in several diseases. However, the role of PCA1 in UC is still a mystery. In our study, we explored the effect of PCA1 in dextran sulfate sodium (DSS)–induced UC mice and lipopolysaccharide (LPS)-stimulated HT-29 and IEC-6 cells. Then, cell proliferation, apoptosis, the production of proinflammatory cytokines, and autophagy-related markers were determined. Furthermore, the AMPK/mTOR/p70S6K signaling pathway was assayed by Western blot assay. In in vivo study, we found that PCA1 administration alleviated DSS-induced UC, as evidenced by reducing weight loss, clinical scores, colon weight/length ratio, histological damage, proinflammatory cytokines, and apoptosis. Moreover, we showed that the expression of Beclin-1 and LC3II/I ratio was increased, whereas the level of p62 was decreased after PCA1 treatment in vivo . Meanwhile, the reduced AMP/ATP ratio, enhanced expression of p-AMPK, and decreased p-p70S6K and p-mTOR levels indicate the activation of AMPK/mTOR/p70S6K signaling pathway. In in vitro study, PCA1 promoted cell proliferation and inhibited cell apoptosis in LPS-stimulated HT-29 and IEC-6 cells. Pro-inflammatory cytokines and autophagy-related factors exhibited the same trend as in in vivo results. Mechanically, PCA1 activated the AMPK/mTOR/p70S6K signaling pathway. The treatment with an AMPK inhibitor compound C significantly reversed the anti-inflammatory effect of PCA1 in LPS-stimulated cells. Taken together, these data indicated that PCA1 alleviated UC through induction of AMPK/mTOR/p70S6K-mediated autophagy.
研究领域:
胃肠病学
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药理学
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免疫学
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细胞生物学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2021
·
IF 5.194
Liang Pei,Linxi He
Sepsis triggers liver dysfunction with high morbidity and mortality. Here, we elucidated the effect of anemoside B4 on sepsis in cecal ligation and puncture (CLP)-induced mouse model and LPS-induced primary hepatocytes. Following CLP surgery, septic mice were intraperitoneally injected with anemoside B4 (50 or 100 mg/kg). Anemoside B4 improved septic mouse survival rate, decreased serum AST and ALT levels and attenuated liver histopathologic damages. Western blot analysis showed that anemoside B4 elevated the expression of Beclin-1, LC3II/LC3I, Atg3, Atg5, and Atg7, and reduced p62, suggesting the restoration of autophagy flux in liver. More autophagic vesicles were observed in liver after anemoside B4 treatment using transmission electron microscopy . Using ELISA and commercial enzyme kits, we found that anemoside B4 decreased serum TNF-α, IL-6, and IL-1β levels and increased CAT , SOD and GSH activities. TUNEL staining and western blot revealed that anemoside B4 suppressed cell apoptosis, along with decreased Bax, leaved caspase-3, cleaved PARP, but increased Bcl-2. Consistent with in vivo findings, anemoside B4 inhibited apoptosis, inflammatory response, and oxidative stress and enhanced autophagy in LPS-induced primary hepatocytes. Importantly, these cellular processes were possibly mediated by mTOR/p70S6K signaling, as reflected by the offset of 3-MA in the immunosuppression of anemoside B4.
研究领域:
药理学
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免疫学
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病理学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2026
·Vol. 24
·期 1
·893
·
IF 9.7
Hao Zhihua,Su Xin,Li Jiantao,Jin Jing,Li Zheng,Yan Zhiqiang,Jiao Wenpeng,Jiao Wenjing,Wang Yingying,Ji Chenguang,Wang Xuan,He Yutong
Background Metabolic reprogramming underpins the acquisition of radioresistance in esophageal squamous cell carcinoma (ESCC); however, the specific bioenergetic vulnerabilities and direct pharmacological targets remain to be fully elucidated. This study defines a distinct metabolic phenotype conferring radioresistance and evaluates the natural alkaloid Cepharanthine (CEP) as a mechanism-driven radiosensitizer. Methods Matched clinical cohorts of radiosensitive and radioresistant ESCC patients were analyzed using widely-targeted and targeted metabolomics. Bioenergetic profiling (ECAR/OCR) was performed on established isogenic radioresistant cells. The mechanistic interactions between CEP and its target were mapped via network pharmacology, surface plasmon resonance (SPR), cellular thermal shift assays (CETSA), ubiquitin-proteasomal degradation assays, and Q347A site-directed mutagenesis. In vivo efficacy was validated across human cell-derived xenografts (CDX) and immunocompetent syngeneic (AKR/C57BL/6) mouse models. Results Clinical multi-omics revealed a "metabolic duality" in radioresistant ESCC, characterized by the concurrent hyperactivation of glycolysis and oxidative phosphorylation (OXPHOS). CEP administration disrupted this metabolic network, significantly sensitizing ESCC cells to irradiation [Dose-modifying factor at 37% survival (DMF 37 ) > 1]. Mechanistically, CEP directly engages the kinase domain of p70S6K—a structural interaction dependent on the Q347 residue—and triggers its ubiquitin-proteasomal degradation. This targeted clearance disrupts the upstream PI3K/Akt/mTOR survival axis. Genetic overexpression of wild-type p70S6K, but not the Q347A mutant, rescued the dual hypermetabolic phenotype and reinstated radioresistance. Clinically, elevated p70S6K expression correlated with poor disease-free survival and therapeutic failure. In vivo, CEP synergized with radiotherapy to suppress tumor kinetics in both CDX and syngeneic models, while concurrently enhancing CD8 + T cell infiltration in the immunocompetent microenvironment, with no observable systemic toxicity. Conclusions Radioresistant ESCC relies on a dual hypermetabolic state driven by the PI3K/Akt/mTOR/p70S6K cascade. CEP overcomes this radioresistance by physically binding to and degrading p70S6K, thereby inducing bioenergetic exhaustion and reshaping the anti-tumor microenvironment. These findings provide a solid mechanistic rationale for translating CEP into clinical radiotherapeutic regimens.
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PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 8
·期 1
·201-211
·
IF 5.251
Shuli Man,Miao Li,Jin Zhou,Haiyue Wang,Jinyan Zhang,Long Ma
Fe3O4 magnetic nanoparticles (MNPs), as one of the most intensively researched NPs, have a range of applications in cancer treatments. In current research, we have focused on the influences of MNPs on cancer cells. We chose polyethyleneimine (PEI) coated MNPs (PEI-MNPs) as a model and they are colloidally stable in biological media. It can be proved that PEI-MNPs result in autophagy induction via mTOR-Akt-p70S6 K and ATG7 signaling pathways. For the first time, we have reported that PEI-MNPs activate both NF-κB and TGF-β signaling, two key pro-inflammatory pathways, in cancer cells. More significantly, we have found that autophagy induction and NF-κB and TGF-β activation can be efficiently suppressed through the inhibition of PEI-MNP dependent reactive oxygen species (ROS) over-production. ROS are deemed as a ‘double edge sword’ for cancer cells, owing to the cancer-suppressing and cancer-promoting actions. Our findings would be useful for designing MNPs induced ROS anti-cancer strategies or diminishing long-term toxic effects.
研究领域:
纳米技术
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癌症生物学
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细胞信号传导
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药理学
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产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
·
2022
·Vol. 322
·期 5
·C1022
·
IF 5.282
Mingfa Sun,Hongchao Jiao,Xiaojuan Wang,Haifang Li,Yunlei Zhou,Jingpeng Zhao,Hai Lin
Creatine (Cr) is beneficial for increasing muscle mass and preventing muscle atrophy via involving in energy metabolism through the Cr and phosphocreatine (PCr) system. This study aimed to evaluate the supplemental effect of Cr on protein metabolism under normal and starvation conditions. The primary myoblasts were obtained from the breast muscle of chicks. The mammalian target of rapamycin (mTOR)/P70S6 kinase (P70S6K), ubiquitin-proteasome (UP) pathways, and mitochondrial function of myotubes were evaluated at normal or starvation state and with or without glucose supplementation. Under normal condition, Cr supplementation enhanced protein synthesis rate as well as upregulated the total and phosphorylated P70S6K expressions. Cr had little influence on protein catabolism and mitochondrial function. In a starvation state, however, Cr alleviated myotube atrophy and enhanced protein accretion by inhibiting Atrogin1 and myostatin (MSTN) expression. Furthermore, Cr treatment upregulated the transcriptional coactivators peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression and decreased reactive oxygen species (ROS) accumulation under starvation condition. In the presence of glucose, however, the favorable effect of Cr on protein content and myotube diameter did not occur under starvation condition. The present result indicates that at a normal state, Cr stimulated protein synthesis via the mTOR/P70S6K pathway. In a starvation state, Cr mainly takes a favorable effect on protein accumulation via suppression of the UP pathway and mediated mitochondrial function mainly by serving as an energy supplier. The result highlights the potential clinical application for the modulation of muscle mass under different nutritional conditions.
研究领域:
肌肉生物学
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营养学
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细胞代谢
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蛋白质合成
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能量代谢
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DOI
PubMed
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-13
·
IF 4.259
Hu Dongfang,Cao Shengliang,Zhang Guihua,Xiao Yihong,Liu Sidang,Shang Yingli
Florfenicol (FLO) is one of the most popular antibiotics used in veterinary clinic and aquaculture. FLO can inhibit both bacterial and mitochondrial protein synthesis. However, the effects of FLO on mitochondrial function and cellular homeostasis remain unclear. Here we show that FLO inhibits expression of mitochondrial DNA-encoded proteins, decreases mitochondrial membrane potential, and promotes generation of reactive oxygen species (ROS) in vitro . As a result, activities of mitochondrial respiratory chain complex I and IV and the cellular ATP level are decreased and mitochondrial morphology is damaged. FLO represses cell growth and proliferation by suppression of phosphorylation of p70S6K through AMPK/mTOR/p70S6K pathway. Furthermore, FLO also induces G0/G1 cell cycle arrest via increase of p21 levels through activating ROS/p53/p21 pathway. Moreover, the clearance of damaged mitochondria by autophagy is impaired, leading to cell proliferation inhibition and promotes cell senescence. In addition, FLO-induced upregulation of cytosolic p53 may contribute to mitophagy deficiency via regulation of Parkin recruitment. In summary, our data suggest that florfenicol is an inhibitor of mitochondrial protein synthesis that can induce noticeable cytotoxicity. Thus, these findings can be useful for guiding the proper use of FLO and the development of safe drugs.
研究领域:
兽医学
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细胞生物学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）