JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
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2018
·Vol. 78
·期 2
·157-171
·
IF 3.49
Yan Bing Chun,Wang Jie,Rui Yanggang,Cao Jianwen,Xu Pei,Jiang Dan,Zhu Xiaolu,Won Moo-Ho,Bo Ping,Su Peiqing
Gabapentin (GBP), an analgesic, adjunct antiepileptic, and migraine prophylactic drug, reduces neuronal injury induced by cerebral ischemia reperfusion (IR). However, the underlying biological molecular mechanism of GBP neuroprotection is not clear. In this study, we confirmed that dose-dependent (75 and 150 mg/kg) GBP treatment could significantly reduce IR-induced neuronal death. IR-induced neuronal death was inhibited by pretreatment with 150 mg/kg GBP in a middle cerebral artery occlusion rat model. In addition, 150 mg/kg GBP treatment remarkably promoted the levels of antioxidants and reduced the autophagy of neurons in the infarct penumbra. Moreover, the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway was activated by pretreatment with 150 mg/kg GBP, as detected by Western blot analyses. In vitro, pretreatment of PC12 cells with 450 µM GBP significantly reduced cell death induced by oxygen-glucose deprivation, increased antioxidant function, and reduced the levels of autophagy and reactive oxygen species via activation of the PI3K/Akt/mTOR pathway. This neuroprotection by GBP was inhibited significantly by 10 µM LY294002. In summary, dose-dependent pretreatment with GBP protected against cerebral IR injury via activation of the PI3K/Akt/mTOR pathway, which provided a neuroprotective function to inhibit oxidative stress-related neuronal autophagy.
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Evidence-based Complementary and Alternative Medicine
·
2022
·
IF 2.65
Yihua Shi,Kai Lian,Jiguang Jia
Osteosarcoma (OS) is a prevalent primary malignant bone tumor that commonly occurs in children and adolescents. Apigenin (4′,5,7-trihydroxyflavone) is one of the most researched phenolic compounds that exhibits antitumor effects in several cancers. The aim of the current study was to investigate the effect and underlying mechanisms of apigenin on OS. To address this, OS cells (SOSP-9607) were treated with different concentrations of apigenin. The proliferation, migration, invasion, stem-like properties, and Warburg effect of apigenin-treated OS cells were evaluated. Apigenin was found to suppress the proliferation of SOSP-9607 cells and inhibit epithelial-mesenchymal transition, as indicated by decreased number of migrated and invaded cells, decreased protein expression of vimentin, and increased protein expression of E-cadherin. Additionally, apigenin suppressed tumorsphere formation and reduced the proportion of SOSP-9607 cells with positive expression of the stem cell-related markers Nanog and OCT-4. Apigenin inhibited the Warburg effect in SOSP-9607 cells, as demonstrated by decreased glucose and lactic acid levels, increased citrate and ATP levels, and downregulation of GLUT1, HK1, and LDHA, which are metabolism-related enzymes related to the Warburg effect. Moreover, apigenin inhibited the phosphorylation of PI3K, Akt, and mTOR in SOSP-9607 cells. Collectively, these results indicate that apigenin suppresses the Warburg effect and stem-like properties in SOSP-9607 cells, which may be mediated by PI3K/Akt/mTOR signaling, thus, providing a novel strategy for OS treatment.
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Biomed Research International
·
2021
·
IF 3.411
Fengqin Wang,Hanzhong Zhang,Zhigang Cheng
EPHA2 is a member of the ephrin receptor tyrosine kinase family and is closely related to the malignant tumor progression. The effect of EPHA2 on OSCC is not clear. This study explored the role of EPHA2 and AKT/mTOR signaling pathways in Cal-27 cell invasion and migration. The expression of EPHA2 and EPHA4 in human OSCC and normal oral tissue was detected by immunohistochemistry. EPHA2-overexpressing and EPHA2-knockdown Cal-27 cells were established, and the cells were treated with an AKT inhibitor (MK2206) and mTOR inhibitor (RAD001). The expression of EPHA2 was detected by qRT-PCR, cell proliferation was evaluated by MTT assay, cell migration and invasion were examined by scratch and Transwell assay, and cell morphology and apoptosis were assessed by Hoechst 33258 staining. Western blot was performed to detect the expression of proteins related to AKT/mTOR signaling, cell cycle, and pseudopod invasion. EPHA2 and EPHA4 were highly expressed in clinical human OSCC. Overexpression of EPHA2 promoted the proliferation, migration, and invasion of Cal-27 cells, inhibited cell cycle blockage and apoptosis, and enhanced the activity of the AKT/mTOR signaling pathway. MK2206 (AKT inhibitor) and RAD001 (mTOR inhibitor) reversed the effect of EPHA2 overexpression on the biological behavior of Cal-27 cells. EPHA2 promotes the invasion and migration of Cal-27 human OSCC cells by enhancing the AKT/mTOR signaling pathway.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Xinrui Li,Peiquan Yu,Yinghua Yu,Ting Xu,Jiao Liu,Yuan Cheng,Xia Yang,Xiaoying Cui,Cui Yin,Yi Liu
Hyperglycemia-induced neuroinflammation promotes the progression of diabetic encephalopathy. Hydrogen sulfide (H 2 S) exerts anti-inflammatory and neuroprotective activities against neurodegenerative diseases. However, the effects of H 2 S on hyperglycemia-induced neuroinflammation has not been investigated in neurons. Herein, by using HT-22 neuronal cells, we found that high glucose decreased the levels of endogenous H 2 S and its catalytic enzyme, cystathionine-β-synthase (CBS). The administration of sodium hydrosulfide (NaHS, a H 2 S donor) or S-adenosylmethionine (SAMe, an allosteric activator of CBS) restored high glucose-induced downregulation of CBS and H 2 S levels. Importantly, H 2 S ameliorated high glucose-induced inflammation in HT-22 cells, evidenced by NaHS or SAMe inhibited the pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) expression in HT-22 cells exposed to high glucose. Furthermore, NaHS or SAMe restored the SIRT1 level and the phosphorylation of mTOR and NF-κB p65 disturbed by high glucose in HT-22 cells, suggesting H 2 S reversed high glucose-induced alteration of SIRT1-mTOR/NF-κB signaling pathway. Our results demonstrated that exogenous H 2 S treatment or enhancing endogenous H 2 S synthesis prevents the inflammatory processes in the neurons with the exposure of high glucose. Therefore, increasing the H 2 S level using NaHS or SAMe might shed light on the prophylactic treatment of diabetic encephalopathy.
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Oxidative Medicine and Cellular Longevity
·
2019
·
IF 4.868
Qiang Chu,Xin Yu,Ruoyi Jia,Yaxuan Wang,Yiru Zhang,Shuang Zhang,Yangyang Liu,Yonglu Li,Wen Chen,Xiang Ye,Xiaodong Zheng
Apios americana Medikus was once widely accepted as staple food in India for a long time, and the tuber of which possesses high nutrients. During the past decades, most of the research has focused on the biological activity in the tubers of Apios americana Medikus whereas the leaves were ignored. In this study, the Apios americana Medikus leaf extract (ALE) was obtained and seven compounds were identified. LPS-induced RAW264.7 cells were used to study the anti-inflammation activity of ALE. As expected, ALE reduced the secretion of nitric oxide (NO) and inflammatory cytokines via inhibition of NF-κB and MAPK signaling together with activation of Nrf2-Keap1 and FOXO pathways, as well as alleviating the oxidative stress and mitochondrial dysfunction. In addition, ALE could activate HMGB1-Beclin1 and Sirt1-FoxO1 pathways and inhibit the Akt-mTOR signaling pathway to activate autophagy, protecting RAW264.7 cells from inflammation. In summary, our results suggested that ALE might help activate the anti-inflammation system, resulting in the prevention of LPS-induced damage in RAW264.7 cells.
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JOURNAL OF FOOD AND DRUG ANALYSIS
·
2024
·Vol. 32
·期 4
·506
·
IF 2.6
Tian-Shuang Xia,Sheng-Yan Xu,Li-Yong Lai,Yi-Ping Jiang,Na-Ni Wang,Hai-Liang Xin
Bitter acids (BA) are main component of Humulus lupulus L. (hops). They are known for beer brewing and have various biological and pharmacological properties, especially the bone-protective effect confirmed by our previous in vivo study. Here we aimed to elucidate the anti-senior osteoporosis (SOP) effect of BA on osteoblasts and explore its underlying mechanism. In vitro SOP model was established by D-galactose (D-gal) injured osteoblasts, and the bone formation markers and apoptosis level were measured. mCherry-EGFP-LC3 adenovirus infection and autophagic markers including beclin1 and LC3 proteins were detected to investigate the autophagy level in osteoblasts. To further verify whether BA play the bone-protective role through regulating autophagy, the autophagy inhibitor 3-MA was used, and the cell proliferation, ALP activity, bone mineralization, apoptosis rate and SA-β-gal staining areas were measured. Finally, the protein expressions of AKT/mTOR signaling pathway were detected by Western blotting, and AKT agonist SC79 and mTOR agonist MHY1485 were used to further study the mechanism of BA on AKT/mTOR-mediated autophagy. The results showed that BA stimulated osteoblastic differentiation and inhibited apoptosis proteins Bcl-2/Bax in D-gal-treated osteoblasts. BA also increased the expression of autophagic markers beclin1 and LC3-II/LC3-I in D-gal-treated osteoblasts. mCherry-EGFP-LC3 autophagic double fluorescent adenovirus showed BA promoted the generation of autolysosomes and autophagosomes in D-gal-injured osteoblasts, indicating that BA might prevent osteoblastic bone loss through activating autophagy. Autophagy inhibitor 3-MA was used to further verify whether BA played the bone-protective role via regulating autophagy. The results revealed the promotion effects of BA on proliferation, ALP activity, and mineralized nodule formation in D-gal-injured osteoblasts were eliminated after autophagy blocking with 3-MA, and the inhibitory effects of BA on apoptosis rate and SA-β-gal staining areas were also eliminated. Moreover, BA reduced the phosphorylation levels of AKT, mTOR, p70S6K, and 4EBP in AKT/mTOR pathway, and the promotion of BA on the autophagic markers was blocked after the activation of AKT and mTOR by SC79 and MHY1485. In conclusion, it was the first time to demonstrate that BA improved cell activities and bone formation in aging osteoblasts, and revealed the mechanism of BA against SOP in osteoblasts was activating AKT/mTOR-mediated autophagy.
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Journal of Functional Foods
·
2024
·
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.
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FASEB JOURNAL
·
2025
·Vol. 39
·期 16
·e70901
·
IF 4.2
Yanping Dai,Xiaoqin Gao
Aging-related decline in male fertility is closely associated with impaired sperm quality and dysregulated autophagy/apoptosis in reproductive tissues. This study elucidates the protective role of the AKT2/mTOR/VEGF axis in mitigating age-induced epididymal dysfunction and sperm deterioration. Utilizing iTRAQ proteomics and transcriptome sequencing in young (6-month) versus aged (18-month) rat models, we identified AKT2 and VEGF as key regulators of reproductive aging. Functional validation revealed that AKT2/mTOR/VEGF activation suppressed oxidative stress, preserved mitochondrial membrane potential, and inhibited autophagy/apoptosis in rat epididymal epithelial cells (REECs, cells lining the epididymis involved in sperm maturation and transport) through downstream targets including Bcl-2, Bax, and LC3-II. Notably, extracellular vesicles (EVs) derived from AKT2-activated REECs enhanced sperm motility and reduced sperm DNA fragmentation through reactive oxygen species (ROS) scavenging and autophagy modulation. Pharmacological inhibition of VEGF or AKT2 exacerbated cellular stress responses, while lentivirus-mediated AKT2 overexpression reversed age-related epididymal damage in vivo. Mechanistically, the pathway crosstalk between mTOR-driven VEGF secretion and EV-mediated intercellular communication emerged as a critical mechanism for maintaining sperm viability. These findings establish AKT2/mTOR/VEGF signaling as a central coordinator of epididymal homeostasis and propose EV-based therapies as promising strategies to counteract male reproductive aging. Graphical The AKT2/mTOR/VEGF axis inhibits oxidative stress in REECs, alleviating autophagy and apoptosis. It promotes sperm activity and motility by secreting EVs, reducing sperm autophagy and apoptosis, and thereby increasing the IVF rate.
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FEBS Open Bio
·
2025
·
IF 2.3
Wenheng Gao,Yunlong Li,Lihua Chen,Wenshuo Yang,Yong He,Ye Yang,Dengke Yin,Song Tan
Hyperlipidemia is a common chronic disease characterized by elevated levels of lipids in the blood. There is some evidence that suggests that berberine (BBR) might be beneficial for the treatment of hyperlipidemia. However, its low intestinal bioavailability limits its potential therapeutic action. In the present study, we explored the effect and the underlying mechanism of berberine–cinnamic acid co-crystal (BBR-CA), which is self-assembled from CA and BBR and displays a high intestinal bioavailability. In mice, BBR-CA showed the ability to decrease body weight gain and hepatic lipid accumulation in animals fed a high-fat diet. To further characterize the molecular basis of this effect, we established a hyperlipidemia cell model by treating human hepatocellular carcinoma cells (HepG2) with free fatty acids. Similarly to our in vivo experiments, lipid accumulation in free fatty acids-induced HepG2 cells was also reduced by BBR-CA. We hypothesized that BBR-CA might act through the regulation of sterol regulatory element-binding proteins-1 (SREBP-1), a key factor regulating lipid synthesis, and, indeed, SREBP-1 protein expression was inhibited by BBR-CA treatment, resulting in the decreased expression of its downstream proteins stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase. Furthermore, the phosphorylation of phosphatidylinositol 3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) was inhibited by BBR-CA, contributing to decreased active SREBP-1 in the nucleus, and was reversed and enhanced by the PI3K agonist recilisib and inhibitor LY294002, respectively. Taken together, our results suggest that BBR-CA could function by modulating the PI3K/AKT/mTOR signaling pathway, resulting in decreased nuclear expression of SREBP-1, as well as reduced expression of stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase, thus alleviating hyperlipidemia. Further experimental validation is required to confirm these results.
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American Journal of Translational Research
·
2021
·
IF 4.06
Zhen Zhang,Dongming Zhu,Xiaobo Zhang,Yun Liu,Jingcheng Wang,Lianqi Yan
Post-surgery arthrofibrosis is one of the most restrictive factors in the development of intra-articular surgery and has presented tremendous obstacles for most orthopaedic surgeons. Tanshinone IIA (Tan IIA), a key active ingredient of Den-shen, has been used to treat fibrosis-related diseases, such as pulmonary, hepatic and myocardial fibrosis. In the present study, we aimed to investigate the effects of Tan IIA on post-surgery arthrofibrosis in vivo and in vitro . Histological analysis indicated that topical application of Tan IIA (10 mg/mL) could significantly alleviate postsurgery arthrofibrosis in rabbits. Immunohistochemistry results showed that proliferating cell nuclear antigen (PCNA) and tubulin protein expression was inhibited, whereas LC3 was activated in vivo . In vitro , EdU and flow cytometry assays demonstrated that Tan IIA could inhibit fibroblast proliferation by arresting cells in G2 phase. Scratch, Transwell and cytoskeleton protein immunofluorescence assays revealed that fibroblast migration was attenuated. Interestingly, LC3 immunofluorescence staining and transmission electron microscopy indicated that autophagy flux could be induced in fibroblasts by Tan IIA. However, the inhibitory effects of Tan IIA against fibroblast proliferation and migration were partially restored when fibroblast autophagy was suppressed after combined treatment with the autophagy inhibitor 3-methyladenine (3-MA). Finally, the expression of p-mTOR was suppressed in a dose-dependent manner after Tan IIA treatment but partially restored when Tan IIA treatment was combined with 3-MA intervention. The inhibitory effect of Tan IIA against fibroblast proliferation and migration may be related to autophagy induction mediated by the PI3K and AMPK-mTOR signaling pathway.
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OncoTargets and Therapy
·
2020
·
IF 3.337
Xia Tian,Meng Liu,Xiaodong Huang,Qingxi Zhu,Weijie Liu,Wei Chen,Yanli Zou,Yishan Cai,Shasha Huang,Aifang Chen,Ting Zhan,Min Huang,Xiaoli Chen,Zheng Han,Jie Tan
Background Noscapine is an opium alkaloid that has recently been shown to potentiate anti-cancer therapeutic effects by inducing apoptosis in various malignant cells without any detectable toxicity. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. Materials and Methods In this study, we explored the anti-cancer activity of noscapine in 5-fluorouracil (5-FU)-resistant human colon cancer cell lines HT29/5-FU and LoVo/5-FU and investigated the possible underlying mechanism. The apoptosis and mitochondrial morphology of cells were detected by TUNEL assay and transmission electron microscopy (TEM). The mitochondrial membrane potential (MMP) was determined using JC-1. The mitochondrial permeability transition pore (mPTP) opening was detected by the calcein-AM/cobalt assay. The levels of glucose, lactic, and ATP in cells were evaluated by ELISA kits. Relative protein expression levels were detected by Western blot. Results We verified that PTEN was involved in noscapine-induced apoptosis in HT29/5-FU and LoVo/5-FU cells. Noscapine greatly increased mitochondrial damage by altering mitochondrial morphology, inducing mitochondrial membrane potential depolarization, and enabling mitochondrial permeability transition pore opening in HT29/5-FU and LoVo/5-FU cells. In addition, noscapine inhibited the Warburg effect by decreasing the levels of glucose, lactic acid, and ATP and inhibiting the protein expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in HT29/5-FU and LoVo/5-FU cells. However, PTEN interference counteracted the effect of noscapine on mitochondrial damage and the Warburg effect in HT29/5-FU and LoVo/5-FU cells by decreasing the activation of PI3K/mTOR signaling. Conclusion These results indicated that noscapine induced the apoptosis of HT29/5-FU and LoVo/5-FU human colon cancer cells by regulating mitochondria damage and the Warburg effect via PTEN, and the process is closely related to the PI3K/mTOR signaling pathway.
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PSYCHONEUROENDOCRINOLOGY
·
2025
·
IF 3.6
Zhaoke Ling,Qingqing Kong,Zhiqiang He,Xin Hao,Ruiyao Liu,Jie Liu,Yushi Wang,Jiao Liu,Wenlong Du,Yi Liu
The pathogenesis of depression is associated with synaptic impairment and dysfunction in autophagy processes. Mendelian randomization (MR) analysis revealed that six GWAS IDs revealed a significant association between Beclin-1 levels and depression risk. Besides, all SNPs had a positive effect on depression risk. Analyzing neurons from depressed individuals using single-cell RNA sequencing (scRNA-seq) uncovered decreased expression of AKT, mTOR, and genes linked to synaptic plasticity. The activation of the PI3K/AKT/mTOR signaling has been demonstrated to control autophagy and have a protective effect on the nervous system. Hydrogen sulfide (H 2 S) is an endogenous gasotransmitter that can potentially treat various neurological disorders by improving neuronal synaptic plasticity. However, whether H 2 S regulates autophagy through PI3K/AKT/mTOR signaling, improves neuronal synaptic plasticity damage, and plays an antidepressant role is unclear. Our current research revealed that the reduction in the expression of p-PI3K, p-AKT, and p-mTOR proteins increase in neuronal autophagy activity and decline synaptic plasticity in mice with depression induced by chronic unpredictable mild stress (CUMS). Treatment with the exogenous hydrogen sulfide donor NaHS for one day and continuous treatment for one week improved the depression-like behaviors in the mice. Compared with those after one day of NaHS treatment, the above protein expression levels were restored and maintained, and the antidepressant effect was more significant after one week of continuous treatment with NaHS. Moreover, the PI3K inhibitor LY294002 was used to demonstrate that NaHS suppresses autophagy through activating the PI3K/AKT/mTOR signaling and ameliorates synaptic plasticity impairments. This study provides novel insights into the antidepressant mechanisms of H 2 S, highlighting its antidepressant therapeutic potential.
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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