Drug Design Development and Therapy
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2019
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IF 3.208
Xiaohong Xu,Vinothkumar Rajamanickam,Sheng Shu,Zhoudi Liu,Tao Yan,Jinxin He,Zhiguo Liu,Guilong Guo,Guang Liang,Yi Wang
Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer which is associated with poor patient outcome and lack of targeted therapy. Our laboratory has synthesized a series of indole-2-carboxamide derivatives. Among this series, compound LG25 showed a favorable pharmacological profile against sepsis and inflammatory diseases. In the present study, we investigated the chemotherapeutic potential of LG25 against TNBC utilizing in vitro and in vivo models. Methods Changes in cell viability, cell cycle phases and apoptosis were analyzed using MTT, clonogenic assay, FACS and Western blotting assays. The anti-cancer effects of LG25 were further determined in a xenograft mouse model. Results Our findings reveal that LG25 reduced TNBC viability in a dose-dependent manner. Flow cytometric and Western blot analyses showed that LG25 enhances G2/M cell cycle arrest and induced cell apoptosis. In addition, LG25 treatment significantly inhibited Akt/mTOR phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB). These inhibitory activities of LG25 were confirmed in mice implanted MDA-MB-231 TNBC cells. Conclusion Our studies provide experimental evidence that indole-2-carboxamide derivative LG25 effectively targeted TNBC in preclinical models by inducing cell cycle arrest and apoptosis, through suppressing Akt/mTOR/NF-κB signaling pathway.
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Materials Today Bio
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2024
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IF 8.7
Linquan Zhou,Chengcheng Zhang,Tengbin Shi,Dingwei Wu,Huina Chen,Jiaxin Han,Dehui Chen,Jinxin Lin,Wenge Liu
The migration and differentiation of bone marrow mesenchymal stem cells (BMSCs) play crucial roles in bone repair processes. However, conventional scaffolds often lack of effectively inducing and recruiting BMSCs. In our study, we present a novel approach by introducing a 3D-bioprinted scaffold composed of hydrogels, with the addition of laponite to the GelMA solution, aimed at enhancing scaffold performance. Both in vivo and in vitro experiments have confirmed the outstanding biocompatibility of the scaffold. Furthermore, for the first time, Apt19s has been chemically modified onto the surface of the hydrogel scaffold, resulting in a remarkable enhancement in the migration and adhesion of BMSCs. Moreover, the scaffold has demonstrated robust osteogenic differentiation capability in both in vivo and in vitro environments. Additionally, the hydrogel scaffold has shown the ability to induce the polarization of macrophages from M1 to M2, thereby facilitating the osteogenic differentiation of BMSCs via the bone immune pathway. Through RNA-seq analysis, it has been revealed that macrophages regulate the osteogenic differentiation of BMSCs through the AMPK/mTOR signaling pathway. In summary, the functionalized GelMA/Laponite scaffold offers a cost-effective approach for tailored in situ bone regeneration.
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ACS Omega
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2024
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IF 3.7
Hong Duan,Han Li,Tianyi Liu,Yuan Chen,Mengmeng Luo,Ying Shi,Jing Zhou,Marwan M. A. Rashed,Kefeng Zhai,Lili Li,Zhaojun Wei
Atherosclerosis (AS) is a common cardiovascular disease that poses a major threat to health. Schisandra chinensis is a medicinal and edible plant that is commonly used to treat cardiovascular diseases. In this paper, HPLC was used to detect and analyze 5 different components in Schisandra chinensis. Network pharmacological predictions highlight the PI3K/AKT/mTOR pathway as an important pharmacological pathway. The effective ingredient Schisandrin C was screened by the molecular docking technique. ox-LDL-induced HUVECs were used to construct the atherosclerosis model for further experimental verification. The results showed that Schisandrin C interfered with the PI3K/AKT/mTOR autophagy pathway. This study lays a foundation for the further application of Schisandrin C in the prevention and treatment of atherosclerosis in the future.
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INFLAMMATION RESEARCH
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2024
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IF 4.8
Tan Min,Mao Jing,Zheng Jianxiong,Meng Yu,Li Jun,Hao Jiayao,Shen Haili
Background Mammalian STE20-like kinase 1 (MST1) is involved in the occurrence of cancer and autoimmune diseases by regulating cell proliferation, differentiation, apoptosis and other functions. However, its role and downstream targets in rheumatoid arthritis (RA) remain unclear. Methods The model of RA fibroblast-like synoviocytes (RA-FLSs) overexpressing MST1 was constructed by lentiviral transfection in vitro and analyzed the effects of MST1 on apoptosis, migration, invasion, and inflammation of RA-FLSs. The effect of MST1 on joint synovial membrane inflammation and bone destruction was observed in vivo by establishing a rat model of arthritis with complete Freund’s adjuvant. Results MST1 is down-regulated in RA-FLSs, and up-regulation of MST1 inhibits the survival, migration, invasion and inflammation of RA-FLSs. Mechanistically, MST1 inhibits SIRT3/mTOR-signaling pathway, inducing decreased mitochondrial autophagy and increased mitochondrial fission, resulting in mitochondrial morphological abnormalities and dysfunction, and ultimately increased apoptosis. We have observed that activation of MST1 alleviates synovial inflammation and bone erosion in vivo. Conclusions MST1 reduces the survival, migration, invasion and inflammation of FLSs by inhibiting the SIRT3/mTOR axis to reduce mitochondrial autophagy and promote mitochondrial division, thereby achieving the potential role of relieving rheumatoid arthritis.
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BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
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2024
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IF 1.9
Zheng Delu,Cui Chenli,Ye Chengsong,Shao Chen,Zha Xiujing,Xu Ying,Liu Xu,Wang Can
Coenzyme Q10 (CoQ10) is a potent antioxidant that is implicated in the inhibition of osteoclastogenesis, but the underlying mechanism has not been determined. We explored the underlying molecular mechanisms involved in this process. RAW264.7 cells received receptor activator of NF-κB ligand (RANKL) and CoQ10, after which the differentiation and viability of osteoclasts were assessed. After the cells were treated with CoQ10 and/or H2O2 and RANKL, the levels of reactive oxygen species (ROS) and proteins involved in the PI3K/AKT/mTOR and MAPK pathways and autophagy were tested. Moreover, after the cells were pretreated with or without inhibitors of the two pathways or with the mitophagy agonist, the levels of autophagy-related proteins and osteoclast markers were measured. CoQ10 significantly decreased the number of TRAP-positive cells and the level of ROS but had no significant impact on cell viability. The relative phosphorylation levels of PI3K, AKT, mTOR, ERK, and p38 were significantly reduced, but the levels of FOXO3/LC3/Beclin1 were significantly augmented. Moreover, the levels of FOXO3/LC3/Beclin1 were significantly increased by the inhibitors and mitophagy agonist, while the levels of osteoclast markers showed the opposite results. Our data showed that CoQ10 prevented RANKL-induced osteoclastogenesis by promoting autophagy via inactivation of the PI3K/AKT/mTOR and MAPK pathways in RAW264.7 cells.
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MICROBIOLOGICAL RESEARCH
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2025
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IF 6.9
Zheng Jia,Lingdi Niu,Junjie Guo,Jiaqing Wang,Hai Li,Runhang Liu,Ning Liu,Shuhe Zhang,Fang Wang,Junwei Ge
Regulation of the innate immune response may be an effective strategy to enhance Staphylococcus aureus vaccines. Based on our previous findings that the Listeria peptidoglycan skeleton (pBLP) enhances the immune response through an unknown mechanism, we hypothesized that pBLP provides protection by modulating the innate immune response via trained immunity. In vitro, pBLP increased phagocytosis and inflammatory cytokine levels and elevated the anti-inflammatory cytokine TGF-β following secondary stimulation. In an in vivo model, our findings indicate that pBLP, when administered with a vaccine, protects mice from methicillin-resistant S. aureus challenge and also provides protection against S. aureus CMCC26003 in the absence of antigens. Using an ex vivo model, we demonstrated that pBLP increases markers of trained immunity in peritoneal macrophages. Transcriptome analysis of differentially expressed genes and inhibitor experiments revealed that the trained immunity process induced by pBLP depends on mTOR-HIF-1α and hexokinase 2. This study is the first to demonstrate that pBLP can induce trained immunity. Furthermore, we show that the peptidoglycan skeleton induces a distinct trained immunity phenotype compared to β-glucan, enhancing vaccine protection. Our study provides valuable insights for the design of novel vaccines that integrate both specific and innate immune responses.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Ying Ren,Xiangka Hu,Mushuang Qi,Wanjun Zhu,Jin Li,Shuyu Yang,Chunmei Dai
Background Diabetes is a metabolic disease characterized by hyperglycaemia. Tangningtongluo Tablet (TNTL) is an inpatient formula extensively utilized to treat diabetes mellitus (DM), but the protective mechanism is not clear. This study aimed to investigate the relevant mechanisms by which TNTL affects pancreatic damage in diabetic mice and autophagy. Methods The impact of TNTL on pancreatic damage in diabetic mice in vitro and in vivo was investigated via glucose and lipid metabolism analyses, HE staining, CCK-8, TUNEL staining, Annexin V/PI, and Western blotting. Molecular docking and Western blotting were used to verify the results of network pharmacological analysis, which was carried out to explore the mechanism by which TNTL affects DM. The autophagosome levels were visualized via RFP-GFP-LC3 and transmission electron microscopy, and lysosomal function was evaluated via Lysotracker red staining. Western blot, immunohistochemistry and immunofluorescence staining were used to detect the expression of the autophagy proteins LC3, p62 and LAMP2. Results Compared with the model group, TNTL protected pancreas from oxidative stress, decreased the level of MDA, increased the levels of SOD and GSH-px, induced the occurrence of autophagy and decreased the levels of apoptotic factors. Moreover, TNTL inhibited the protein expression of p-PI3K, p-Akt and p-mTOR, increased the levels of LC3 and LAMP2 and decreased the level of p62, and the autophagy inhibitor CQ blocked the protective effect of TNTL on pancreatic damage in diabetic mice. Conclusion These results demonstrated that TNTL ameliorated pancreatic damage in diabetic mice by inhibiting the PI3K/Akt/mTOR signaling and regulating autophagy.
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Frontiers in Pharmacology
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2022
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IF 5.988
Xujun You,Yongrong Wu,Qixin Li,Wen Sheng,Qing Zhou,Wei Fu
Objective: Prostate cancer (PCa) is an epithelial malignancy of the prostate that currently lacks effective treatment. Traditional Chinese medicine (TCM) can play an anticancer role through regulating the immune system, anti-tumor angiogenesis, regulating tumor cell apoptosis, autophagy dysfunction, and other mechanisms. This study attempted to explore the active ingredients and potential mechanism of action of the Astragalus–Scorpion (A–S) drug pair in PCa, in order to provide new insights into the treatment of PCa. Methods: Network pharmacology was used to analyze the A–S drug pair and PCa targets. Bioinformatics analysis was used to analyze the LncRNAs with significant differences in PCa. The expression of LC3 protein was detected by immunofluorescence. CCK8 was used to detect cell proliferation. The expressions of GDPD4-2, {"type":"entrez-nucleotide","attrs":{"text":"AC144450.1","term_id":"29893803","term_text":"AC144450.1"}} AC144450.1 , LINC01513, AC004009.2, {"type":"entrez-nucleotide","attrs":{"text":"AL096869.1","term_id":"5565922","term_text":"AL096869.1"}} AL096869.1 , {"type":"entrez-nucleotide","attrs":{"text":"AP005210.1","term_id":"21039028","term_text":"AP005210.1"}} AP005210.1 , and {"type":"entrez-nucleotide","attrs":{"text":"BX119924.1","term_id":"27884222","term_text":"BX119924.1"}} BX119924.1 were detected by RT-qPCR. The expression of the PI3K/AKT/mTOR pathway and autophagy-related proteins were detected by western blot. LC-MS/MS was used to identify the active components of Astragalus and Scorpion. Results: A–S drug pair and PCa have a total of 163 targets, which were mainly related to the prostate cancer and PI3K/AKT pathways. A–S drug pair inhibited the formation of PCa, promoted the expression of LC3Ⅱ and Beclin1 proteins, and inhibited the expression of P62 and PI3K–AKT pathway proteins in PCa mice. Astragaloside IV and polypeptide extract from scorpion venom (PESV) were identified as the main active components of the A–S drug pair. GDPD4-2 was involved in the treatment of PCa by Astragaloside IV-PESV. Silencing GDPD4-2 reversed the therapeutic effects of Astragaloside IV-PESV by regulating the PI3K/AKT/mTOR pathway. Conclusion: Astragaloside IV-PESV is the main active components of A–S drug pair treated PCa by regulating the GDPD4-2/PI3K–AKT/mTOR pathway and autophagy.
研究领域:
肿瘤学
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药理学
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中医
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分子生物学
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生物化学
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PubMed
高影响因子
European Review for Medical and Pharmacological Sciences
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2018
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IF 2.387
X. Lv,C.-Y. Li,P. Han,X.-Y. Xu
OBJECTIVE: MicroRNAs are a class of small non-coding RNAs that be involved in the pathogenesis of non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the effects of miR-520a-3p in cell growth and metastasis.MATERIALS AND METHODS: The mimics and inhibitor of miR-520a-3p were used to identify the effects of miR-520a-3p on cell proliferation and apoptosis using methylthiazol tetrazolium (MTT) assay and flow-cytometric method, respectively. Transwell assay was used to evaluate the cell migration and invasion. The protein expression levels related PI3K/AKT/mTOR signaling pathways were measured by Western blot.RESULTS: The results showed that miR-520a-3p overexpression could significantly inhibit cell proliferation and induce apoptosis, suppress cell migration and invasion. MiR-520a-3p overexpression could markedly reduce the ratio of p-AKT/AKT, p-PI3K/PI3K and Bcl-2/Bax, the levels of mTOR, matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) compared with control. However, miR-520a-3p overexpression could increase caspase-3 expression compared with control group. After inhibited the expression of miR-520a-3p, the capacity of cell proliferation, migration and invasion were increased, cell apoptosis was inhibited compared with control group. The ratio of p-AKT/AKT, p-PI3K/PI3K and Bcl-2/Bax, the levels of mTOR, MMP-2 and MMP-9 were increased compared with control group.CONCLUSIONS: Our study suggested that miR-520a-3p could suppress the NSCLC proliferation, migration and invasion through PI3K/AKT/mTOR signaling pathway.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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BIOCHEMICAL PHARMACOLOGY
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2019
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IF 4.825
Wensong Yao,Zhen Lin,Peiying Shi,Bing Chen,Gang Wang,Jianyong Huang,Yuxia Sui,Qicai Liu,Shaoguang Li,Xinhua Lin,Qicai Liu,Hong Yao
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron , showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo . It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis , the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca 2+ in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo . In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.
研究领域:
肿瘤学
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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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IMMUNOLOGY
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2026
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IF 5.4
Sisi Zhang,Zhou Jingxiang,Caixia Tan,Yuanyuan Xiao,Ju Zou,Biyue Tian,Anhua Wu,Chunhui Li
Clostridioides difficile infection (CDI) remains a major cause of antibiotic-associated colitis and is characterized by excessive intestinal inflammation, epithelial barrier disruption and impaired mucosal repair. Although sodium butyrate (NaB), a microbiota-derived short-chain fatty acid, has demonstrated anti-inflammatory and barrier-protective properties, the immunological mechanisms underlying its protective effects during CDI remain incompletely understood. In this study, we investigated the role of NaB in regulating macrophage polarization and epithelial repair using murine CDI models, primary bone marrow-derived macrophages, THP-1-derived macrophages, Caco-2 epithelial cells and macrophage–epithelial co-culture systems. NaB treatment significantly alleviated CDI-associated weight loss, colonic shortening, histopathological injury and inflammatory cytokine production while restoring epithelial barrier integrity and tight junction protein expression. Mechanistically, NaB promoted macrophage polarization towards an anti-inflammatory M2 phenotype, characterized by increased CD206 and IL-10 expression and reduced CD86 and IL-1β expression. These immunomodulatory effects were accompanied by suppression of PI3K/Akt/mTOR signalling in both colonic tissues and macrophages. Pharmacological inhibition and activation studies further supported the involvement of this pathway in NaB-mediated macrophage reprogramming. Importantly, conditioned medium from NaB-treated macrophages enhanced epithelial viability, migration and barrier-associated protein expression, whereas IL-10 neutralization partially abolished these protective effects, highlighting a critical role for macrophage–epithelial crosstalk. Collectively, our findings demonstrate that low-dose NaB protects against CDI-induced intestinal injury through coordinated regulation of macrophage polarization and epithelial barrier repair, at least in part via modulation of PI3K/Akt/mTOR signalling. These results identify NaB as a promising host-directed therapeutic strategy for CDI and provide new insights into microbiota-derived metabolite–immune interactions during intestinal inflammation.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Shenghui Zhang,Qin Liu,Bo Chen,Hui Chang,Ying Pan,Yanli Liu,Xin Zhao,Juntang Lin
MenSC-EVs alleviate STZ-induced ovarian dysfunction in diabetic mice. • MenSC-EVs suppress high-glucose-induced ferroptosis in granulosa cells. • EV-associated HSPA5 mediates protection via AKT/mTOR–BECN1/SLC7A11 signaling. Type 1 diabetes mellitus (T1DM) is associated with ovarian dysfunction, including menstrual irregularities, impaired ovarian reserve, and premature reproductive aging, yet effective therapeutic strategies to safeguard ovarian function against metabolic stress remain limited. Mesenchymal stem cells (MSCs) have emerged as pivotal regulators of tissue homeostasis, with their paracrine effects largely mediated by extracellular vesicles (EVs). Here, we demonstrate that menstrual blood-derived endometrial stem cell-EVs (MenSC-EVs) alleviate streptozotocin (STZ)-induced ovarian dysfunction and inhibit granulosa cells (GCs) ferroptosis by delivering HSPA5. Mechanistically, EV-associated HSPA5 restored AKT/mTOR signaling and was accompanied by reduced BECN1 phosphorylation, thereby preserving the SLC7A11/GPX4-associated antioxidant pathway. We further show that BECN1 directly interacts with SLC7A11, linking BECN1 signaling to regulation of the system Xc−/GPX4 antioxidant axis. MenSC-EVs preserved this antioxidant pathway and reduced lipid peroxidation in injured GCs. Collectively, these findings identify an HSPA5-dependent anti-ferroptotic mechanism through which MenSC-EVs ameliorate T1DM-associated ovarian dysfunction, supporting their potential as an ovarian-protective strategy under diabetic conditions. Download: Download high-res image (241KB) Download: Download full-size image
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