NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2026
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IF 4
Liu Hengxu,Xiong Rui,Zhang Shipeng,Zheng Quanyou,Lai Xiaodan
Fatigue is a widespread health problem, and abnormal autophagy in skeletal muscle cells is a key mechanism driving fatigue progression. The purpose of this study was to evaluate the effect of ginsenoside Rg3 (Rg3) on fatigue in ammonium chloride (NH 4 Cl)-induced C2C12 myoblasts cells and to elucidate its potential molecular mechanism. The potential anti-fatigue mechanism of Rg3 was predicted by network pharmacology and molecular dynamics simulations. C2C12 cells were treated with NH 4 Cl to construct an in vitro fatigue model and then treated with Rg3. CCK-8, live/dead staining, Giemsa staining, autolysosome staining, and Western blot were used to evaluate cell viability, myotube morphology, autophagic flow, and key protein expression. Network pharmacology analysis indicated that the anti-fatigue effect of Rg3 was associated with the PI3K/AKT/mTOR pathway-regulated autophagy. Molecular docking and molecular dynamics simulations confirmed that Rg3 binds strongly to PI3K. Cell experiments showed that Rg3 significantly attenuated cell death, myotube injury and abnormal autophagy in NH 4 Cl-induced C2C12 cells. Moreover, Rg3 effectively activated the PI3K/AKT/mTOR pathway. Our results indicated that the anti-fatigue effect of Rg3 may be associated with the attenuation of autophagy through activation of the PI3K/AKT/mTOR pathway. This provides a potential therapeutic candidate for fatigue intervention.
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高影响因子
Journal of Inflammation Research
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2025
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IF 4.1
Jing Ma,Lu Ding,Xiaoyu Zang,Yingying Yang,Wei Zhang,Xiangyan Li,Daqing Zhao,Zepeng Zhang,Zeyu Wang,Linhua Zhao,Xiaolin Tong
Purpose Pulmonary Fibrosis (PF) is a severe interstitial lung disease currently lacking effective prevention strategies. Endothelial mesenchymal transition (EndMT), a novel mechanism for fibroblast production, is closely associated with PF. The precise mechanisms underlying the contribution of EndMT-derived fibroblasts to PF, however, remain unclear.Methods Using network pharmacology, molecular docking, and molecular dynamics, we identified the key targets and pathways through which Qimai Feiluoping decoction (QM) combats PF. EndMT and autophagy proteins were quantified in bleomycin (BLM) -induced C57BL/6 mice, human umbilical vein endothelial cells (HUVECs), and zebrafish using Western blotting (WB), quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), immunofluorescence (IF), Transwell migration assays, and transmission electron microscopy (TEM), revealing the targets and pathways through which QM mitigates PF.Results Network pharmacology, molecular docking, and molecular dynamics suggest that QM combats PF by modulating the PI3K/AKT/mTOR pathway. Observations from the study indicated that QM was found to alleviate EndMT by restoring autophagy, primarily through inhibition of the PI3K/AKT/mTOR signaling pathway in both BLM-induced C57 mice and HUVECs. Supporting evidence from zebrafish models demonstrated that QM not only counteracts EndMT but also improves a range of vascular functional disorders and remodeling issues following EndMT.Conclusion Our research validates the active compounds, core targets, and signaling pathways through which QM counters PF, providing valuable insights for its therapeutic application in PF management.
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MATERIALS & DESIGN
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2026
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IF 8.2
Jiali Deng,Xiaoqiong Huang,Yang Yang,Linjuan Li,Jiaqi Shen,Wenyi Zeng,Xiaolin Yu,Feilong Deng,Ruogu Xu,Zhengchuan Zhang
Ti‑preconditioned exosomes suppress macrophage inflammation via autophagy activation. • Lyophilized exosome–loaded biomimetic periosteum was successfully constructed. • The delivery system promotes M2 macrophage polarization to facilitate angiogenic osteogenesis. Critical-sized bone defects remain a clinical challenge due to dysregulated inflammation that impairs angiogenesis. Here, we developed a cell-free biomaterial system consisting of a decellularized biomimetic periosteum (DBP) loaded with engineered exosomes derived from nanoporous titanium–preconditioned mesenchymal stem cells (Ti–Exos). We further demonstrated that Ti-Exos significantly attenuated LPS-induced macrophage inflammation by enhancing autophagy through the inhibition of the PI3K/AKT/mTOR pathway, thereby promoting M1-to-M2 macrophage polarization and anti‑inflammatory cytokine secretion. The bilayer DBP scaffold enabled sustained release of Ti-Exos and mimicked key functions of natural periosteum. In a rat critical-sized calvarial defect model, DBP/Ti-Exos facilitated the early macrophage transition from the M1 to M2 phenotype, reduced inflammatory infiltration, stimulated angiogenesis, and ultimately enhanced the formation of mature and mineralized bone. Collectively, this study demonstrates that the engineered exosomes integrated within a biomimetic periosteum can synergistically orchestrate immunomodulation and angiogenesis, offering a promising cell–free therapeutic strategy for vascularized bone regeneration of critical-sized bone defects. This study introduces an engineered exosome–based cell–free strategy that orchestrates the local immune microenvironment to accelerate vascularized bone repair. Specifically, nanoporous Ti-preconditioned exosomes (Ti-Exos) were fabricated and proven to attenuate LPS-induced macrophage inflammation by inhibiting PI3K/AKT/mTOR to activate autophagy. Lyophilized Ti-Exos-loaded decellularized biomimetic periosteum (DBP/Ti-Exos) was constructed and exhibited uniform distribution of Ti-Exos. DBP/Ti-Exos was demonstrated to drive M1-to-M2 macrophage polarization, and promote angiogenic osteogenesis in rat calvarial defects. Download: Download high-res image (182KB) Download: Download full-size image
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JOURNAL OF CLINICAL LABORATORY ANALYSIS
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2022
·Vol. 36
·期 7
·e24406
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IF 3.124
Zhihai Li,Qiaozhi Jin,Yana Sun
Background LINC00941 has been proved to be related to various tumors, but its relationship with laryngocarcinoma remains vague. Methods LINC00941 expression in laryngocarcinoma tumor and laryngocarcinoma cells was determined by real time-quantitative polymerase chain reaction (RT-qPCR). Besides, the five-year survival of laryngocarcinoma patients with different LINC00941 expression was analyzed with Kaplan–Meier survival analysis, and the clinical characteristics of laryngocarcinoma patients were also recorded. After transfection, cell viability, cell proliferation, apoptosis, cell cycle, migration, and invasion were detected by cell counting kit-8 (CCK-8), colony formation, flow cytometry, cell scratch, and Transwell assays, respectively. Glycolysis was assessed by the colorimetric method. Expressions of proliferation-associated proteins, migration-associated proteins, glycolysis-associated proteins, and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signal pathway-associated proteins were detected by Western blot. Results In laryngocarcinoma tumor tissues and cells, LINC00941 was highly expressed. High expression of LINC00941 decreased the 5-year survival of laryngocarcinoma patients, and it was positively related to lymph node metastasis and clinical stages. LINC00941 overexpression decreased apoptosis but promoted cell viability, proliferation, cell-cycle progression, migration, and invasion, and glucose consumption and lactate production in laryngocarcinoma cells. Moreover, LINC00941 overexpression elevated expressions of Ki-67, PCNA, MMP2, N-Cadherin, HK2, PFKFB4, and PKM, activated the PI3K/AKT/mTOR signal pathway but reduced E-Cadherin expression, while LINC00941 silencing had the opposite effects. PKM overexpression reversed the effects of LINC00941 silencing on cellular and glycolytic phenotypes. Conclusion LINC00941 promoted in vitro progression and glycolysis of laryngocarcinoma cells by upregulating PKM via activating the PI3K/AKT/mTOR signaling pathway.
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BURNS
·
2024
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IF 3.2
Meiyue Yang,Zhibo Yang,Xiangjun Huang,Xiaoping Li,Fangqin Chou,Shuiqing Zeng
The aim of this study was to explore the effect and mechanism of formononetin (FMNT) in thermal-injured fibroblast proliferation, apoptosis, and oxidative stress. After the thermal injury, HSF cells showed inhibited proliferation, migration, and ECM synthesis, whereas increased apoptosis, ROS production, and inflammation. Specifically, after thermal injury, cell viability, migration distance, and protein levels of Collage I, Collage III, α-SMA, MMP1, and MMP3 were reduced; cell apoptosis rate and TUNEL-positive cell numbers were increased; the levels of Bax and Cleaved caspase-3 showed to be elevated, while Bcl-2 level showed to be reduced. Moreover, the thermal injured-HSF cells showed increased levels of ROS, MDA, LDH, TNF-α, and IL-1β, and decreased GSH, SOD, GSH-Px, and CAT. FMNT levels can partially eliminate the effects of thermal injury on HSF cells, as shown by promoting thermal injured-HSF cell proliferation and migration, and inhibiting cell apoptosis, ROS production, and inflammation. FMNT exerted no significant effect on normal HSF cells. Additionally, the level of the P13K/AKT/mTOR signaling-related proteins (p-P13K, p-AKT, and p-mTOR) was reduced in thermal injured-HSF cells, whereas FMNT could promote p-P13K, p-AKT, and p-mTOR levels. FMNT can partially alleviate the thermal injury-induced inhibition of fibroblast proliferation and migration; FMNT also inhibited the apoptosis, ROS level, and inflammation in thermal-injured cells. The effects of FMNT may be mediated by regulating the P13K/AKT/mTOR pathway.
研究领域:
药理学
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细胞生物学
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伤口愈合
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FITOTERAPIA
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2025
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IF 2.6
Ren-Fen Ma,Xin-Cheng Zhuang,Qian Wu,Hua Zhang
An intensive phytochemical study on the aerial parts of Euphorbia wallichii afforded ten lathyrane-type diterpenoids, including six formerly unreported ones ( 1 – 4 , 6 and 8 ). Their structures were determined via comprehensive spectroscopic analyses, and the absolute stereochemistries were assigned on the basis of electronic circular dichroism technique. Among these diterpenoids, compound 2 exhibited the best inhibitory activity on NO production and its potential anti-inflammatory mechanism was then explored by network pharmacology analysis. Further experimental validation demonstrated that diterpenoid 2 could exert its anti-inflammatory effect by suppressing pro-inflammatory factors and modulating PI3K/Akt/mTOR signaling pathway. In short, the present work confirms the promising potential of E. wallichii as a source of natural anti-inflammatory agents.
研究领域:
植物化学
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药理学
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药物化学
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天然产物研究
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ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2023
·Vol. 30
·期 19
·55200-55213
·
IF 5.8
Feng Huimiao,Zhou Ping,Liu Feixue,Zhang Wei,Yang Haitao,Li Xueqing,Dong Jingquan
Abamectin is a commonly used pesticide in agriculture and fisheries and poses a risk to aquatic species. However, the mechanism of its toxic effects on fish remains to be discovered. In this study, we explored the effects of abamectin exposure at different concentrations on the respiratory system of carp. Carp were divided into three groups, namely the control group, low-dose abamectin treatment group, and high-dose abamectin treatment group. Gill tissue was collected after abamectin exposure for histopathological, biochemical, tunnel, mRNA, and protein expression analysis. Histopathological analysis indicated that abamectin damaged the gill structure. Biochemical analysis showed that abamectin triggered oxidative stress with lowered antioxidant enzyme activities and increased MDA content. Moreover, abamectin led to enhanced INOS levels and pro-inflammatory transcription, activating inflammation. Tunnel results demonstrated that exposure to abamectin induced gill cell apoptosis through an exogenous pathway. In addition, exposure to abamectin activated the PI3K/AKT/mTOR pathway, leading to inhibition of autophagy. Overall, abamectin caused respiratory system toxicity in carp via triggering oxidative stress, inflammation, and apoptosis and inhibiting autophagy. The study suggests that abamectin has a profound toxicity mechanism in the respiratory system of carp, contributing to a better understanding of pesticide risk assessment in aquatic systems.
研究领域:
水生毒理学
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环境科学
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渔业
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BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Tao Long,Xue Chen,Yue Zhang,Yu-Jia Zhou,Yan-Ni He,Yun-Fei Zhu,Hai-Jun Fu,Lu Yu,Chong-Lin Yu,Betty Yuen-Kwan Law,Jian-Ming Wu,Da-Lian Qin,An-Guo Wu,Xiao-Gang Zhou
Enhancing the clearance of proteins associated with Alzheimer's disease (AD) emerges as a promising approach for AD therapeutics. This study explores the potential of Radix Stellariae , a traditional Chinese medicine, in treating AD. Utilizing transgenic C. elegans models of AD, we demonstrated that a 75% ethanol extract of Radix Stellariae (RSE) (at 50 µg/mL) effectively diminishes Aβ and Tau protein expression, and alleviates their induced impairments including paralysis, behavioral dysfunction, neurotoxicity, and ROS accumulation. Additionally, RSE enhances the stress resistance of C. elegans . Further investigations revealed that RSE promotes autophagy, a critical cellular process for protein degradation, in these models. We found that inhibiting autophagy-related genes negated the neuroprotective effects of RSE, suggesting a central role for autophagy in the actions of RSE. In PC-12 cells, we observed that RSE not only inhibited Aβ fibril formation but also promoted the degradation of AD-related proteins and reduced their cytotoxicity. Mechanistically, RSE was found to induce autophagy via modulating PI3K/AKT/mTOR and AMPK/mTOR signaling pathways. Importantly, inhibiting autophagy counteracted the beneficial effects of RSE on the clearance of AD-associated proteins. Moreover, we identified Dichotomine B, a β-carboline alkaloid, as a key active constituent of RSE in mitigating AD pathology in C. elegans at concentrations ranging from 50 to 1000 µM. Collectively, our study presents novel discoveries that RSE alleviates AD pathology and toxicity primarily by inducing autophagy, both in vivo and in vitro. These findings open up new avenues for exploring the therapeutic potential of RSE and its active component, Dichotomine B, in treating neurodegenerative diseases like AD.
研究领域:
神经科学
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药理学
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中药学
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细胞生物学
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分子生物学
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BIOORGANIC CHEMISTRY
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2021
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IF 5.275
Yingying Ma,Xiaorong Yang,Hongwei Han,Zhongling Wen,Minkai Yang,Yahan Zhang,Jiangyan Fu,Xuan Wang,Tongming Yin,Guihua Lu,Jinliang Qi,Hongyan Lin,Xiaoming Wang,Yonghua Yang
Triple-negative breast cancer (TNBC) has an unfavorable prognosis attribute to its low differentiation, rapid proliferation and high distant metastasis rate. PI3K/Akt/mTOR as an intracellular signaling pathway plays a key role in the cell proliferation, migration, invasion, metabolism and regeneration. In this work, we designed and synthesized a series of anilide (dicarboxylic acid) shikonin esters targeting PI3K/Akt/mTOR signaling pathway, and assessed their antitumor effects. Through three rounds of screening by computer-aided drug design method (CADD), we preliminarily obtained sixteen novel anilide (dicarboxylic acid) shikonin esters and identified them as excellent compounds. CCK-8 assay results demonstrated that compound M9 exhibited better antiproliferative activities against MDA-MB-231, A549 and HeLa cell lines than shikonin (SK), especially for MDA-MB-231 (M9: IC 50 = 4.52 ± 0.28 μM; SK: IC 50 = 7.62 ± 0.26 μM). Moreover, the antiproliferative activity of M9 was better than that of paclitaxel. Further pharmacological studies showed that M9 could induce apoptosis of MDA-MB-231 cells and arrest the cell cycle in G2/M phase. M9 also inhibited the migration of MDA-MB-231 cells by inhibiting Wnt/β-catenin signaling pathway. In addition, western blot results showed that M9 could inhibit cell proliferation and migration by down-regulating PI3K/Akt/mTOR signaling pathway. Finally, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was also constructed to provide a basis for further development of shikonin derivatives as potential antitumor drugs through structure–activity relationship analysis. To sum up, M9 could be a potential candidate for TNBC therapy.
研究领域:
药理学
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肿瘤学
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药物化学
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细胞生物学
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药物设计
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American Journal of Translational Research
·
2025
·Vol. 17
·期 10
·7749
·
IF 1.6
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.
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Molecular Cancer
·
2023
·Vol. 22
·期 1
·1-20
·
IF 37.3
Song Runjie,Ma Shuoqian,Xu Jiajia,Ren Xin,Guo Peilan,Liu Huijiao,Li Peng,Yin Fan,Liu Mei,Wang Qiang,Yu Lei,Liu Jiali,Duan Binwei,Rahman Nafis A.,Wołczyński Sławomir,Li Guangming,Li Xiangdong
Background hsa_circ_0001727 (circZKSCAN1) has been reported to be a tumor-associated circRNA by sponging microRNAs. Intriguingly, we found that circZKSCAN1 encoded a secretory peptide (circZKSaa) in the liver. The present study aims to elucidate the potential role and molecular mechanism of circZKSaa in the regulation of hepatocellular carcinoma (HCC) progression.Methods The circRNA profiling datasets (RNA-seq data GSE143233 and GSE140202) were reanalyzed and circZKSCAN1 was selected for further study. Mass spectrometry, polysome fractionation assay, dual-luciferase reporter, and a series of experiments showed that circZKSCAN1 encodes circZKSaa. Cell proliferation, apoptosis, and tumorigenesis in nude mice were examined to investigate the functions of circZKSaa. Mechanistically, the relationship between the circZKSaa and mTOR in HCC was verified by immunoprecipitation analyses, mass spectrometry, and immunofluorescence staining analyses.Results Receiver operating characteristic (ROC) analysis demonstrated that the secretory peptide circZKSaa encoded by circZKSCAN1 might be the potential biomarker for HCC tissues. Through a series of experiments, we found that circZKSaa inhibited HCC progression and sensitize HCC cells to sorafenib. Mechanistically, we found that the sponge function of circZKSCAN1 to microRNA is weak in HCC, while overexpression of circZKSaa promoted the interaction of FBXW7 with the mammalian target of rapamycin (mTOR) to promote the ubiquitination of mTOR, thereby inhibiting the PI3K/AKT/mTOR pathway. Furthermore, we found that the high expression of cicZKSCAN1 in sorafenib-treated HCC cells was regulated by QKI-5.Conclusion sThese results reveal that a novel circZKSCAN1-encoded peptide acts as a tumor suppressor on PI3K/AKT/mTOR pathway, and sensitizes HCC cells to sorafenib via ubiquitination of mTOR. These findings demonstrated that circZKSaa has the potential to serve as a therapeutic target and biomarker for HCC treatment.
研究领域:
分子生物学
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癌症研究
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遗传学
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JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
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.
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