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
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Fan Yang,Dongju Zhao,Meng Cheng,Yining Liu,Ziyao Chen,Jin Chang,Yan Dou
Metabolic reprogramming that senses brain homeostasis imbalances is necessary to drive detrimental microglial polarization, and specific targeting of this process contributes to the flexible control of pathological inflammatory responses in Alzheimer’s disease (AD), displaying distinctive therapeutic benefits. Herein, glutathione-functionalized gold nanocages loaded with the immunosuppressant fingolimod hydrochloride are developed as brain-targeted and microglia-located immunometabolic reprogramming nanomodulators (GAF NPs) for AD management. By virtue of glutathione-mediated transport properties, this nanomodulator can cross the blood-brain barrier and localize to microglia in AD lesions. Through blocking Akt/mTOR/HIF-1α signaling pathways, GAF NPs not only promote the dominated metabolic shift from glycolysis to oxidative phosphorylation under immune activation but also inhibit transporter-mediated glucose overconsumption by microglia. Correlation analysis based on real-time bioenergetic assessment and 18F-labeled fluorodeoxyglucose (FDG) PET reveals that brain glucose utilization and metabolism restored by GAF NP treatment can serve as a sensitive and effective indicator for microglial M1 to M2 polarization switching, ultimately alleviating neuroinflammation and its derived neurodegeneration as well as ameliorating cognitive decline in AD mice. This work highlights a potential nanomedicine aimed at modifying mTOR-mediated immunometabolic reprogramming to halt energy deprivation-induced AD progression.
研究领域:
神经科学
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纳米技术
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药理学
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免疫学
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代谢学
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治疗学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
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IF 3.8
Lu Xiu,Rongguang Ge,Siyu Lu,Linwei Li,Wenqi Huang,Guojun Du,Zengli Zhang,Jie Zhang,Zhongxiao Wan,Jie Chang
Diabetes, a ruthless chronic metabolic disorder, is increasingly considered to jeopardize global well-being over the decades. Royal jelly (RJ) is a complex natural product secreted by worker bees containing a unique fatty acid known as 10-hydroxy-2-decenoic acid (10-HDA). This study aimed to verify the protective effect on cognitive function of RJ and 10-HDA in diabetic mice and explore the underlying mechanism. Briefly, our animal experiment results suggested that 10-HDA had a significant hypoglycemic effect and improved cognitive performance. Through western blotting, RJ and 10-HDA intervention notably increased Atg7, Atg16L1, Beclin-1, Atg5, Atg12, Atg3, and LC3-II expression and decreased p62 expression. Meanwhile, decreased mTOR expression and increased ULK1 expression were also observed in the 10-HDA intervention group. In conclusion, 10-HDA can regulate mTOR/ULK1 pathway to activate autophagy to alleviate hippocampal damage, thereby improving cognitive function in mice with diabetes, which may provide a new option for real-world cognitive impairment management.
研究领域:
医学
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生物学
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DOI
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 8
·1080
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IF 4.8
Ruoqing Guan,Zhaoyun Xue,Kaikun Huang,Yanqing Zhao,Gongyun He,Yuxing Dai,Mo Liang,Yanzi Wen,Xueshi Ye,Peiqing Liu,Jianwen Chen
Background/Objectives: Oxidative stress constitutes a principal pathophysiological mechanism driving neurodegeneration and brain aging. α-Ketoglutarate (AKG), a key intermediate of the tricarboxylic acid (TCA) cycle, has shown potential in longevity and oxidative stress resistance. However, the role of AKG in oxidative stress-induced neuronal senescence and its interaction with the mTOR signaling pathway during neuronal aging remain poorly understood, posing a key challenge for developing senescence-targeted therapies.Methods: We investigated the neuroprotective effects of AKG using H2O2-induced senescence in HT22 cells and a D-galactose-induced brain aging mouse model. Assessments encompassed SA-β-gal staining, EdU incorporation, mitochondrial membrane potential (JC-1), and ROS measurement. Antioxidant markers, ATP levels, and the NAD+/NADH ratio were also analyzed. Proteomic profiling (DIA-MS) and KEGG/GSEA enrichment analyses were employed to identify AKG-responsive signaling pathways, and Western blotting validated changes in mTOR signaling and downstream effectors.Results: AKG significantly alleviated H2O2-induced senescence in HT22 cells, evidenced by enhanced cell viability, reduced ROS level, restored mitochondrial function, and downregulated p53/p21 expression. In vivo, AKG administration improved cognitive deficits and vestibulomotor dysfunction while ameliorating brain oxidative damage in aging mice. Proteomics revealed mTOR signaling pathways as key targets for AKG’s anti-aging activity. Mechanistically, AKG suppressed mTOR phosphorylation and activated ULK1, suggesting modulation of autophagy and metabolic homeostasis. These effects were accompanied by enhanced antioxidant enzyme activities and improved redox homeostasis.Conclusions: Our study demonstrates that AKG mitigates oxidative stress-induced neuronal senescence through suppression of the mTOR pathway and enhancement of mitochondrial and antioxidant function. These findings highlight AKG as a metabolic intervention candidate for age-related neurodegenerative diseases.
研究领域:
神经科学
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衰老研究
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生物化学
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药理学
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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
METABOLIC BRAIN DISEASE
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2018
·Vol. 34
·期 1
·93-101
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IF 2.441
Zhu Ji-Xiao,Shan Jia-Ling,Hu Wei-Qiong,Zeng Jin-Xiang,Shu Ji-Cheng
Gallic acid (3,4,5-trihydroxybenzoic acid) is a naturally occurring polyphenolic compound. Previous study has shown that gallic acid possessed significant antidepressant-like activity in mice, which was partly mediated by increasing serotonin and catecholamine levels. The main aim of the present study is to investigate the possible effects of gallic acid on brain-derived neurotrophic factor (BDNF) signaling activation. Mice were exposed to chronic mild stress (CMS) and orally administrated with gallic acid for four weeks. The behavioral results showed that gallic acid not only reversed the decreased sucrose preference, but also attenuated the increased immobility time. In addition, gallic acid promoted both the BDNF and p-TrkB levels in the hippocampus induced by CMS. Moreover, the results also demonstrated that the inactivated Akt-mTOR signaling pathway, as well as its downstream effectors induced by CMS was activated again by gallic acid. Last, immunofluorescence detection indicated that gallic acid reversed the newborn neurons inhibition in the dentate gyrus by CMS. In conclusion, these results show that the activation of the hippocampal BDNF-Akt-mTOR signaling is involved in the antidepressant-like effects of gallic acid.
研究领域:
神经科学
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药理学
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压力研究
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
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2024
·Vol. 32
·期 33
·7357-7376
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IF 3.5
Jinna Di,Wei Bo,Chun Wang,Chunying Liu
IntroductionThe effectiveness of therapy is strongly impacted by the resistance of lung cancer cells to cisplatin. The objective of this research is to characterize the impact of ailanthone on cisplatin resistance in non-small cell lung cancer (NSCLC) and examine any potential in vivo and in vitro molecular pathways.MethodsFollowing treatment of A549/DDP cells with ailanthone and cisplatin, cell survival and apoptosis were measured using flow cytometry and Cell Counting Kit-8 (CCK8) assays, respectively. mRFP-GFP-LC3 adenovirus transfection was used to track autophagy, and protein expression levels were analyzed by western blotting. Hematoxylin and eosin (H&E) staining was used after the organs of the mice were removed for in vivo investigations. In A549/DDP cells, ailanthone and cisplatin together induced autophagy and apoptosis in a dose and time-dependent manner (p< 0.05). After receiving combined treatment with ailanthone and cisplatin, the expression levels of cleaved caspase-3, Bcl-2, cleaved PARP, Beclin 1, LC3B-II were considerably elevated by inhibiting the PI3K/AKT/mTOR signaling pathway.ResultsOur findings show that ailanthone, without causing adverse effects in vivo, greatly suppressed the growth of A549/DDP-grafted tumors and improved the anti-tumor efficaciousness of cisplatin.ConclusionAccording to this study, ailanthone may increase sensitivity to cisplatin and promote autophagy and death in NSCLC A549/DDP cells through the signaling pathway of PI3K/AKT/mTOR.
研究领域:
肿瘤学
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分子生物学
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药理学
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转化医学
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细胞信号转导
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DOI
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2024
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IF 4.8
Suizhi Cheng,Jin Chen,Qianhui Li,Yuhong Nie,Ting Ni,Caiting Peng,Xi Luo,Yasin Pazilat,Shumin Zhang,Jiancai Tang,Zhenzhong Liu
Recent research has revealed that N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) constitutes a significant risk factor in the development of esophageal cancer. Several investigations have elucidated the beneficial impact of folic acid (FA) in safeguarding esophageal epithelial cells against MNNG-induced damage. Therefore, we hypothesized that FA might prevent MNNG-induced proliferation of esophageal epithelial cells by interfering with the PI3K/AKT/mTOR signaling pathway. In vivo experiments, we found that FA antagonized MNNG-induced proliferation of rat esophageal mucosal epithelial echinocytes and activation of the PI3K/AKT/mTOR signaling pathway. In our in vitro experiments, it was observed that acute exposure to MNNG for 24 h led to a decrease in proliferative capacity and inhibition of the PI3K/AKT/mTOR signaling pathway in an immortalized human normal esophageal epithelial cell line (Het-1A), which was also ameliorated by supplementation with FA. We successfully established a Het-1A-T-cell line by inducing malignant transformation in Het-1A cells through exposure to MNNG. Notably, the PI3K/AKT2/mTOR pathway showed early suppression followed by activation during this transition. Next, we observed that FA inhibited cell proliferation and activation of the PI3K/AKT2/mTOR signaling pathway in Het-1A-T malignantly transformed cells. We further investigated the impact of 740Y-P, a PI3K agonist, and LY294002, a PI3K inhibitor, on Het-1A-T-cell proliferation. Overall, our findings show that FA supplementation may be beneficial in safeguarding normal esophageal epithelial cell proliferation and avoiding the development of esophageal cancer by decreasing the activation of the MNNG-induced PI3K/AKT2/mTOR signaling pathway.
研究领域:
肿瘤学
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细胞生物学
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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
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2019
·Vol. 42
·期 6
·886-891
·
IF 1.54
Yangbiao He,Xujun Lang,Dong Cheng,Zhihao Yang
Previous studies implicated the mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway in renal fibrosis and found that curcumin could suppress the expression of mTOR. Therefore, the aim of the present study was to investigate the therapeutic effects of curcumin against chronic renal failure (CRF) in a rat model induced by 5/6 nephrectomy through inhibition of mTOR/HIF-1α/VEGF signaling. A total of 70 male Sprague–Dawley rats were divided into seven groups: a sham group, a CRF group, and five treatment groups. Except for the sham rats, all rats underwent 5/6 nephrectomy to induce CRF. The 5/6 nephrectomized rats received treatment with curcumin vehicle, everolimus vehicle, curcumin, everolimus, or the combination of curcumin and everolimus. Everolimus, a specific inhibitor of mTOR, was used as a positive control. At the end of treatment, blood biochemical indexes, proteinuria and the kidney index were detected. Moreover, histological change was examined by hematoxylin and eosin staining, and protein expression levels were detected by Western blotting. The blood biochemical indexes, proteinuria, and kidney index were increased in the CRF group as compared to the sham group, which was accompanied by marked activation of the mTOR/HIF-1α/VEGF pathway. However, curcumin, as well as everolimus, restored or ameliorated these changes. These results indicate that activation of the mTOR/HIF-1α/VEGF signaling pathway plays an important role in the occurrence and development of CRF, and that curcumin has renoprotective effects by blocking activation of this pathway.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
·
2020
·Vol. 75
·期 4
·321
·
IF 2.598
Cao Qian,Du Hongjiao,Fu Xi,Duan Na,Liu Changhe,Li Xiaodong
Artemisinin is an endoperoxide sesquiterpene lactone from Artemisia annua L with multiple beneficial effects, including anti-inflammation, antioxidant, and vascular protection. Recent studies have found that inflammation along with autophagy deficiency in macrophages is the possible reason for foam cell accumulation in the intima, which leads to atherosclerotic plaque formation. The primary aims of this study were to explore the inhibiting effect of artemisinin on atherosclerosis in high-fat diet–fed ApoE −/− mice and investigate the probable mechanism. Artemisinin (50 and 100 mg/kg, intragastric administration) treatment effectively inhibited foamy macrophage transformation and decreased atherosclerotic plaque formation in atherosclerotic mice. Moreover, artemisinin promoted AMP-activated protein kinase (AMPK) activation, inhibited mammalian target of rapamycin (mTOR) and uncoordinated-51-like kinase 1 (ULK1) phosphorylation, and increased LC-3II accumulation and P62 degradation, thereby enhancing macrophage autophagy . Besides, the inhibiting effect of artemisinin on mTOR and ULK1 phosphorylation could be abrogated by AMPK knockdown, suggesting AMPK was the essential target of artemisinin on promoting macrophage autophagy . Our study indicated that artemisinin alleviated atherosclerotic lesions by accelerating macrophage autophagy through the AMPK/mTOR/ULK1 pathway.
研究领域:
药理学
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心血管疾病
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分子生物学
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产品关联
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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产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2021
·
IF 4.06
Lingli Huang,Di Xiao,Tianyu Wu,Xin Hu,Jun Deng,Xinjian Yan,Jingtao Wu,Simeng Xu,Xiaoping Yang,Gaofeng Li
Sorafenib is a first-line drug to treat advanced hepatocellular carcinoma (HCC), which can prolong the median overall survival of patients by approximately 3 months. Phenformin is a biguanide derivative that has been shown to exhibit antitumor activity superior to that of metformin. We herein explored the ability of phenformin to enhance the anti-cancer activity of sorafenib against HCC and the mechanisms underlying such synergy. The Hep-G2 and SMMC-7721 HCC cell lines were treated with sorafenib and/or phenformin, after which the proliferation of these cells was evaluated via MTT and colony formation assays, while invasion and apoptotic cell death were evaluated via Transwell and flow cytometry assays, respectively. In addition, protein levels were assessed by Western blotting, drug synergy was assessed with the CompuSyn software, and xenograft models were established by implanting Hep-G2 cells into nude mice and then assessing drug antitumor efficacy. Sorafenib and phenformin exhibited a synergistic ability to suppress HCC cell proliferation, migration, and survival. Phenformin further bolstered the ability of sorafenib to inhibit the CRAF/ERK and PI3K/AKT/mTOR pathways. Strikingly, the combination of these two drugs achieved better in vivo efficacy in a murine model system, without causing significant weight loss or hepatorenal toxicity. Sorafenib and phenformin can synergistically suppress CRAF/ERK and PI3K/AKT/mTOR pathway activation in HCC cells, and may thus represent a promising approach to treating this deadly cancer.
研究领域:
肿瘤学
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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
BEHAVIOURAL NEUROLOGY
·
2023
·
IF 2.8
Lijuan Chen,Jing Li,Xinglian Liu,Zhiwei Zhao,Yan Jin,Yikun Fu,Aiqin Zhou,Chengqun Wang,Yan Zhou
Vitamin B6 (VB6) exhibits therapeutic effects towards autism spectrum disorder (ASD), but its specific mechanism is poorly understood. Rat dams were treated with VB6 standard, VB6 deficiency, or VB6 supplementary diet, and the same treatment was provided to their offspring, with their body weights monitored. Three-chambered social test and open field test were employed to evaluate the effect of VB6 on autism-like behaviors. Gamma-aminobutyric acid (GABA) generation and synaptic inhibition of neurons in the hippocampus of rat were detected via immunofluorescence staining, followed by the measurement of GABA concentration through high-performance liquid chromatography (HPLC). The role of VB6 in the autophagy and apoptosis of cells was determined via Western blot and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). In order to conduct rescue experiments, the inhibition of mammalian target of rapamycin (mTOR) or the activation of GABA was achieved by drug administration to the offspring rats with VB6 deficiency. As a result, no evident difference in weight was observed in the offspring with varied VB6 treatments. VB6 deficiency impaired social interaction; aggravated self-grooming and bowel frequency; decreased GABA concentration, VIAAT, GAD67, vGAT expressions, and LC3 II/LC3 I ratio; increased p62 level and p-mTOR/mTOR ratio; and promoted cell apoptosis. Inhibition of mTOR reversed the effect of VB6 deficiency on cell autophagy. GABA activation or mTOR inhibition offset the role of VB6 deficiency in autism-like behaviors and hippocampal GABA expression. Collectively, VB6 deficiency induces autism-like behaviors in rats by regulating mTOR-mediated autophagy in the hippocampus.
研究领域:
神经科学
·
药理学
·
行为科学
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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）