查找使用阿拉丁产品的科研文献

Taurine suppresses ROS-dependent autophagy via activating Akt/mTOR signaling pathway in calcium oxalate crystals-induced renal tubular epithelial cell injury

Yan Sun,Shiting Dai,Jin Tao,Yunlong Li,Ziqi He,Quan Liu,Jiawen Zhao,Yaoliang Deng,Juening Kang,Xuepei Zhang,Sixing Yang,Yunlong Liu

Oxidative stress and autophagy are the key promoters of calcium oxalate (CaOx) nephrolithiasis. Taurine is an antioxidant that plays a protective role in the pathogenesis of kidney disease. Previous studies found that taurine suppressed cellular oxidative stress, and inhibited autophagy activation. However, the effect of taurine on CaOx kidney stone formation remains unknown. In the present work, we explored the regulatory effects of taurine on CaOx crystals-induced HK-2 cell injury. Results showed that pretreatment with taurine significantly enhanced the viability of HK-2 cells and ameliorated kidney tissue injury induced by CaOx crystals. Taurine also markedly reduced the levels of inflammatory cytokines, apoptosis, and CaOx crystals deposition. Furthermore, we observed that taurine supplementation alleviated CaOx crystals-induced autophagy. Mechanism studies showed that taurine reduced oxidative stress via increasing SOD activity, reducing MDA concentration, alleviating mitochondrial oxidative injury, and decreasing the production of intracellular ROS. Taurine treatment also effectively activated Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cells both in vitro and in vivo . In summary, the current study shows that taurine inhibits ROS-dependent autophagy via activating Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cell and kidney injury, suggesting that taurine may serve as an effective therapeutic agent for the treatment of CaOx nephrolithiasis.

Transcriptome analysis of induced pluripotent stem cells’ osteogenic differentiation reveals NPY1R activating PI3K/AKT/mTOR in alveolar bone loss during periodontitis

Xiaowen Li,Ruikang Guo,Lingling Liang,Hao Liang,Guangqi Zhou,Qinglan Lu,Yonghui Huang,Zhen Qi,Xiaojie Li

Objective: Periodontitis, a prevalent oral disease leading to alveolar bone defects, remains a primary cause of tooth loss in adults. The biologic mechanisms driving bone loss in periodontitis are still poorly understood, limiting the development of genetic treatment. This study investigates potential therapeutic targets for alveolar bone loss by analyzing transcriptomic data related to the osteogenic differentiation of induced pluripotent stem cells (iPSCs). Methods: Using in vitro and in vivo models, we examined the role of neuropeptide Y receptor Y1 (NPY1R) and the PI3K-AKT-mTOR (PAM) signaling pathway in osteogenic differentiation and bone loss. A combination of bioinformatics, molecular biology, and histologic techniques was employed to pinpoint key signaling events that influence bone remodeling in periodontitis and to identify potential intervention points. Results: Transcriptomic profiling during iPSC osteogenic differentiation revealed significant upregulation of neuropeptide Y (NPY) and NPY1R. Suppression of NPY1R reduced the osteogenic capacity of iPSCs. Activation of the PAM pathway was observed during osteogenesis, and treatment with LY294002, a PAM pathway inhibitor, led to decreased osteogenic activity. In vivo experiments using a rat periodontitis model confirmed increased expression of NPY1R and activation of the PAM pathway, suggesting a role in bone repair processes. Conclusion: The NPY/NPY1R axis and the PAM signaling pathway appear to regulate bone regeneration and may be involved in preventing alveolar bone loss in periodontitis. These findings provide a new direction for therapy targeting bone defects associated with periodontal disease.

EPHA2 Promotes the Invasion and Migration of Human Tongue Squamous Cell Carcinoma Cal-27 Cells by Enhancing AKT/mTOR Signaling Pathway

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.

Flavonoids from Apios americana Medikus Leaves Protect RAW264.7 Cells against Inflammation via Inhibition of MAPKs, Akt-mTOR Pathways, and Nfr2 Activation

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.

Tumor-secreted IFI35 promotes proliferation and cytotoxic activity of CD8+ T cells through PI3K/AKT/mTOR signaling pathway in colorectal cancer

Li Peisi,Zhou Dawang,Chen Dongwen,Cheng Yikan,Chen Yuan,Lin Zhensen,Zhang Xi,Huang Zhihong,Cai Jiawei,Huang Wenfeng,Lin Yanyun,Ke Haoxian,Long Jiahui,Zou Yifeng,Ye Shubiao,Lan Ping

Background A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8 + T cells, and to investigate its effect on CAR-T cells against colorectal cancer. Methods Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8 + T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. Results The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8 + T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8 + T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8 + T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8 + T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. Conclusion Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8 + T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells. Graphical Abstract

Apigenin Suppresses the Warburg Effect and Stem-like Properties in SOSP-9607 Cells by Inactivating the PI3K/Akt/mTOR Signaling Pathway

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.

ROS-induced autophagy regulates porcine trophectoderm cell apoptosis, proliferation, and differentiation

Zhen Luo,Xue Xu,Takami Sho,Jing Zhang,Weina Xu,Jianbo Yao,Jianxiong Xu

Significant embryo loss remains a serious problem in pig production. Reactive oxygen species (ROS) play a critical role in embryonic implantation and placentation. However, the potential mechanism of ROS on porcine trophectoderm (pTr) cell fate during the peri-implantation period has not been investigated. This study aimed to elucidate the effects of ROS on pTr cell phenotypes and the regulatory role in cell attachment and differentiation. Herein, results showed that exogenous H2O2 inhibited pTr cell viability, arrested the cell cycle at S and G2/M phases, and increased cell apoptosis and autophagy protein light chain 3B and Beclin-1, whereas these effects were reversed by different concentrations of N-acetyl-l-cysteine (NAC) posttreatment. In addition, NAC abolished H2O2-induced autophagic flux, inhibited intracellular and mitochondrial ROS, and restored expression of genes important for mitochondrial DNA and biogenesis, cell attachment, and differentiation. NAC reversed H2O2-activated MAPK and Akt/mammalian target of rapamycin pathways in dose-dependent manners. Furthermore, analyses with pharmacological and RNA interference approaches suggested that autophagy regulated cell apoptosis and gene expression of caudal-related homeobox 2 and IL-1β. Collectively, these results provide new insights into the role of the ROS-induced autophagy in pTr cell apoptosis, attachment, and differentiation, indicating a promising target for decreasing porcine conceptus loss during the peri-implantation period.

Therapeutic effects of Ainsliaea fragrans champ. and its active compounds on cervicitis: An integrated approach combining metabolomics, network pharmacology, and experimental validation

Zhengwen Zhang,Zhaojun Wang,Yushun Cui,Min Yao,Jiajian Lu,Mingzhen He,Yulin Feng,JunMao Li

Ethnopharmacological relevance Ainsliaea fragrans Champ. (AFC) , a traditional Chinese medicinal herb with a well-documented history in the management of gynecological disorders, serves as the principal component of several Chinese patent medicines that have demonstrated significant clinical efficacy against cervicitis, endometritis, and pelvic inflammatory disease. However, its specific mechanism of action against cervicitis has not been fully elucidated. Purpose This study aims to determine the therapeutic efficacy and underlying mechanisms of AFC in treating cervicitis, and identifying its key active components. Materials and methods First, an in vivo model of cervicitis was established using a phenolic mucilage solution, while an in vitro LPS induced RAW264.7 cell inflammation model was employed. The therapeutic effects of AFC were evaluated through HE staining, uterine index measurements, RT-qPCR and ELISA. The chemical constituents of AFC were identified using ultra-performance liquid chromatography coupled with UPLC-Q-TOF/MS. Subsequently, cellular metabolomics and network pharmacology were utilized to predict the potential targets, mechanisms, and active components of AFC in treating cervicitis. Finally, the underlying mechanisms and active ingredients were validated using methods such as RT-qPCR, Western blot, and molecular docking. Results Both in vivo and in vitro experiments demonstrated that AFC ameliorated phenol mucilage-induced cervicitis in rats and significantly suppressed the expression of inflammatory factors including IL-6, TNF-α, and IL-1β. UPLC-Q-TOF-MS/MS analysis identified 93 chemical constituents in AFC. Cellular metabolomics revealed 79 differential metabolites, including PGE2 and COX-2, among others. Integrated network pharmacology analysis identified potential targets including IDO1 and COX-2, and enriched signaling pathways such as TLR4 and PI3K/AKT-mTOR. Among the nine candidate compounds screened, luteolin, apigenin, and isorhamnetin ranked as the top three by degree value were hypothesized to be the primary active constituents of AFC against cervicitis. Subsequent experimental validation through RT-qPCR, Western blot, and molecular docking demonstrated that AFC treats cervicitis by modulating the PGE2/COX-2/IDO1-FLG in coordination with the TLR4 and PI3K/AKT-mTOR pathways, with luteolin, apigenin, and isorhamnetin confirmed as the key active compounds. Conclusion AFC exerts its therapeutic effects against cervicitis through coordinated regulation of the PGE2/COX-2/IDO1-FLG in conjunction with the TLR4 and PI3K/AKT-mTOR signaling pathways.

Hydrogen sulfide improves depression-like behaviors in CUMS-induced mice by regulating autophagy

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.

Salvianolic Acid B Enhances Motor Function Recovery after Spinal Cord Injury in Association with AKT/mTOR/HIF-1α Pathway Activation and Angiogenesis

Jiange Yao,Yingfeng Chen,Fengjun Pan,Susu Zhang

Synergistic Induction of Apoptosis by Apocytochrome C and Sodium Aescinate Is Mediated by Excessive Autophagy via the AKT-mTOR-TFEB Signaling Axis

Jia-Wei Sun,Yin-Kang Chen,Liang Ji,Jian Zhao,Fu-Jun Wang

Cytochrome C (Cyt C) is a central mediator of intrinsic apoptosis, whereas its heme-free precursor, apocytochrome C (APO-Cyt C), competitively inhibits this process. Sodium aescinate (SA), a natural triterpene saponin, is known to facilitate the endosomal escape of protein drugs. We initially aimed to investigate the effects of enhancing endosomal escape efficiency on protein activity through the combination of SA and Cyt C. However, this study investigates an cytotoxicity observed when APO-Cyt C is combined with SA and aims to elucidate the underlying molecular mechanism. Contrary to its established anti-apoptotic function, APO-Cyt C, when co-administered with a non-toxic concentration of SA, induced potent, caspase-dependent mitochondrial apoptosis in cancer cells. This pro-apoptotic switch was not primarily triggered by BCL-2 family protein modulation, ROS generation, or calcium overload. Instead, the primary mechanism is the induction of excessive and lethal autophagy. SA was found to induce lysosomal membrane damage, evidenced by Galectin-9 recruitment, which initiates lysophagy. The addition of APO-Cyt C significantly amplified the autophagic flux, leading to decreased p62 levels and enhanced LC3-II turnover. Mechanistically, this synergy is driven by a dual impact on the AKT-mTOR-TFEB pathway: APO-Cyt C treatment decreased mTOR phosphorylation, while the combination promoted the nuclear translocation of the autophagy regulator, TFEB. Inhibition of autophagic flux using Bafilomycin A1 or Tetrandrine rescued cells from apoptosis, confirming that excessive autophagy is the direct cause of cell death. This study reveals a novel therapeutic strategy wherein an anti-apoptotic protein is converted into a potent pro-apoptotic agent. The combination of APO-Cyt C and SA triggers apoptosis by overwhelming the cell with excessive autophagic flux, driven by synergistic inhibition of the mTOR-TFEB axis. These findings highlight the therapeutic potential of modulating autophagy and suggest that combining mTOR inhibitors with lysosome-targeting agents like SA could be an effective anti-cancer strategy. Summary This study reveals a novel strategy to combat cancer by repurposing an endogenous anti-apoptotic protein into a potent therapeutic agent. We demonstrate that apocytochrome C (APO-Cyt C), when combined with the natural compound sodium aescinate (SA), triggers cancer cell death through excessive autophagy rather than conventional apoptotic pathways. The discovery that this combination induces lethal autophagy by synergistically targeting both mTOR signaling and lysosomal function provides important insights for overcoming drug resistance. These findings highlight the promising therapeutic potential of combining mTOR inhibitors with lysosome-targeting saponins, establishing a new paradigm for cancer treatment through coordinated regulation of autophagic processes.

Salidroside alleviates senile osteoporosis in SAMP8 mice by inhibiting the ferroptosis of bone marrow stromal cells via PI3K/AKT/mTOR signaling pathway

Zhun Li,Sixia Yang,Wei Liu,Long Ling,Hailan Hu,Yanming Cao,Shouyu Xiang

Salidroside, one of the main active compounds extracted from Rhodiola, has shown promising potential for the treatment of osteoporosis. Our previous study demonstrated that salidroside alleviated cognitive dysfunction in senescence-accelerated mouse prone 8(SAMP8) mice. In this study, we further investigated the effect of salidroside on osteoporosis in SAMP8 mice and explored the mechanism. The results of micro-computed tomography(micro-CT) and histology showed that salidroside significantly increased trabecular bone formation and improved bone microstructure in senile osteoporotic SAMP8 mice, and upregulated the protein expression levels of phosphatidylinositol-3-kinase(PI3K), glutathione peroxidase 4(GPX4), and Runt-related transcription factor 2(RUNX2) in the distal femur. Cell-based assays, including the Cell Counting Kit-8(CCK-8) assay, senescence-associated β-galactosidase (SA-β-galactosidase) staining, alkaline phosphatase (ALP) staining, Alizarin Red staining, and lipid peroxide detection, demonstrated that salidroside significantly promoted the proliferation and osteogenic differentiation of senile osteoporotic bone marrow stromal cells (BMSCs) and decreased lipid peroxide levels. Furthermore, real-time polymerase chain reaction (RT-PCR) and Western blotting analysis showed that salidroside increased protein and gene expression levels of solute carrier family 7 member 11(SLC7A11), GPX4, and ferroptosis suppressor protein 1(FSP1). Additionally, salidroside also increased the phosphorylation of PI3K, AKT, and mTOR, an effect reversed by LY294002.In conclusion, our investigation showed that salidroside could prevent ferroptosis, promote proliferation, and enhance osteogenic differentiation in senile osteoporotic BMSCs, thereby alleviating senile osteoporosis in SAMP8 mice. The PI3K/AKT/mTOR signaling pathway might play a crucial role in this mechanism. These findings suggest that salidroside has the potential to prevent senile osteoporosis and may serve as a candidate for therapeutic development.