LIFE SCIENCES
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2025
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IF 5.1
Fangdi Wang,Li Hu,Xingyue Zeng,Wenbin You,Huijun Li,Bing Liu,Xiaohan Zhang
AKT is a pivotal kinase involved in diverse cellular processes, including tumorigenesis and glycogen metabolism. Ubiquitination modification of AKT has been reported as a critical cellular event that regulates its kinase activity and membrane translocation; however, the molecular mechanisms involved in AKT ubiquitination remain elusive. Here, we employed loss-of-function approaches and mutants of PDK1 with altered phosphorylation and modified nucleocytoplasmic shuttling behaviors to identify the functional roles of PDK1 on the ubiquitination of AKT. Our findings reveal that the nuclear entry of PDK1 in an importin7-dependent manner is required for insulin-induced TRAF6-mediated ubiquitination of AKT, which has been previously shown to occur in the nucleus. Moreover, the phosphorylation of PDK1 at S241 and the PI3K-mediated phosphorylation of PDK1 at S396 both regulate AKT ubiquitination by controlling nuclear entry of PDK1. These results provide new insights into the control of AKT signaling and suggest potential avenues for developing targeted AKT-modulating therapeutics.
研究领域:
分子生物学
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细胞信号传导
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生物化学
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内分泌学
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癌症生物学
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DOI
PubMed
高影响因子
ChemistryOpen
·
2024
·
IF 2.5
Wei Gao,Xiaoju Hua,Shengliang Liao,Zhikai Xiahou,Haikuan Yang,Lifang Hu,Yunyang Chi
Graphical Compound 3h has been found to show inhibitory effects on the survival of HepG2 liver cancer cells.The results show that 3h induces cell-cycle arrest in the S phase. Additionally, 3h exerts a strong pro-apoptotic effect. Specifically, compound 3h reduces the phosphorylation of PI3K, AKT, and ERK, thereby inhibiting both the MAPK/ERK and PI3K/AKT signaling pathways. 2H-pyran compound 1 synthesized from 6-methylpyridine-2,4-diol and citral, has been used for Cu-catalyzed N -arylation with a range of arylboric acids to obtain arylated pyranopyridine core structure derivatives (yield up to 77 %). Among them, compound 3 h exhibited a much better inhibitory effect on HepG2 liver cancer cells compared to citral, and the IC 50 value was 5.3 μM following exposure with the newly synthesized derivatives (herein named 3 h for short in this paper), which was lower than that of the cisplatin (6.5 μM). Meanwhile, the cell-cycle arrest of HepG2 cells occurred in the S phase, and the apoptosis of HepG2 cells was significantly increased with increasing drug concentration. In addition, real-time fluorescence quantification PCR and Western blotting experiments showed that the expression of apoptotic protein BAX was increased, while the expression of anti-apoptotic protein BCL2 was inhibited in a dose-dependent fashion. The results of these experiments indicated that apoptosis was promoted in HepG2 cells via apoptotic signaling pathway activated by 3 h . Furthermore, 3 h effectively decreased the phosphorylation levels of PI3 K, ATK and ERK, resulting in the inhibitions of MAPK/ERK and PI3 K/ATK signaling pathways. Briefly, 3 h has been found to show inhibitory effects on the survival of HepG2 liver cancer cells and may be used as anti-cancer drug in the future.
研究领域:
药理学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
World Journal of Clinical Oncology
·
2024
·Vol. 15
·期 10
·1293
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IF 2.6
Guo-Xiu Zu,Ke-Yun Sun,Xi-Jian Liu,Ji-Qin Tang,Hai-Liang Huang,Tao Han
BACKGROUND In China banxia xiexin decoction (BXD) has been used in treating gastric cancer (GC) for thousands of years and BXD has a good role in reversing GC histopathology, but its chemical composition and action mechanism are still unknown. AIM To investigate the mechanism of action of BXD against GC based on transcriptomics, network pharmacology, in vivo and in vitro experiments. METHODS The transplanted tumor model was prepared, and the nude mouse were pathologically examined after administration, and hematoxylin-eosin staining was performed. The active ingredients of BXD were quality controlled and identified using ultra-performance liquid chromatography tandem quadrupole electrostatic field orbitrap mass spectrometry (UPLC-Q-Orbitrap MS/MS), and traditional Chinese medicines systems pharmacology platform, drug bank and the Swiss target prediction platform to predict the relevant targets, the differentially expressed genes (DEGs) of GC were screened by RNA-seq sequencing, and the overlapping targets were analyzed to obtain the key targets and pathways. Cell Counting Kit-8, apoptosis assay, cell migration and Realtime fluorescence quantitative polymerase chain reaction were used for in vitro experiments. RESULTS All dosing groups inhibited the growth of transplanted tumors in laboratory-bred strain nude, with the capecitabine group and the BXD medium-dose group being the best. A total of 29 compounds and 859 potential targets in BXD were identified by UPLC-Q-Orbitrap MS/MS and network pharmacology, RNA-seq sequencing found 4767 GC DEGs, which were combined with network pharmacology and analyzed 246 potential therapeutic targets were obtained and pathway results showed that BXD may against GC through the Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKt) signaling pathway. In vitro cellular experiments confirmed that BXD-containing serum and LY294002 could inhibit the proliferation of GC cells, promote apoptosis, and inhibit the migration of GC cells by decreasing the expression of EGFR , PIK3CA , IL6 , BCL2 and AKT1 in the PI3K-Akt pathway in MGC-803 expression. CONCLUSION BXD has the effect of inhibiting tumor growth rate and delaying the development of GC. Its mechanism of action may be related to the regulation of PI3K-Akt signaling pathway.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Xiaoli Deng,Chunjie Hu,Lin Li,Guixian Yang,Chikun Li,Wanxun Zhang,Guangyu Cheng
Background Lung cancer is a leading cause of cancer-related deaths, with cisplatin being a cornerstone of treatment. However, resistance to cisplatin presents a significant challenge. β-elemene, a natural compound, has demonstrated potential to reverse cisplatin resistance. LncRNA LINC00511 has been implicated in cisplatin resistance through its role in activating the PI3K/AKT/mTOR pathway, which supports tumor survival and proliferation. Purpose This study aims to investigate the mechanism by which β-elemene overcomes cisplatin resistance in lung cancer by regulating LINC00511. Methods Human lung adenocarcinoma cells (A549 and A549/DDP) were treated with β-elemene and cisplatin. Cell proliferation and apoptosis were assessed using CCK-8, EdU staining, and flow cytometry. LINC00511 expression was measured by qRT-PCR, and protein levels of PI3K, AKT, and mTOR were evaluated via Western blot. A xenograft model was used to confirm in vivo effects. Results β-elemene significantly enhanced cisplatin-induced apoptosis in A549/DDP cells, reduced LINC00511 expression, and inhibited the PI3K/AKT/mTOR pathway. LINC00511 knockdown further potentiated these effects, both in vitro and in vivo . Xenograft models confirmed the enhanced anti-tumor effects of the combination treatment. Conclusion β-elemene overcomes cisplatin resistance in lung cancer by downregulating LINC00511 and inhibiting the PI3K/AKT/mTOR pathway. These findings propose a promising therapeutic strategy for treating cisplatin-resistant lung cancer.
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2024
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IF 3.3
Ruxia Liu,Changfu Yang,Xin Yang,Jia Yu,Wenchao Tang
As a protein kinase inhibitor , cantharidin (CTD) exhibits antitumor activities . However, CTD is highly toxic, thereby limiting clinical applications. Moreover, relatively few studies have investigated CTD-induced reproductive toxicity , thus the underlying mechanism remains unclear. In this study, the toxic effects of CTD on mouse testis were confirmed in vivo and the potential mechanism was predicted by network toxicology (NT) and molecular docking technology. Proteins involved in the signaling pathways and core targets were verified. The results showed that different concentrations of CTD induced weight loss increased the testicular coefficient, and caused obvious pathological damage to testicular cells. The NT results showed that the main targets of CTD-induced testicular injury (TI) included AKT1, Caspase 3 , Bcl-2, and Bax. The results of pathway enrichment analysis showed that CTD-induced TI was closely related to apoptosis and the PI3K/AKT and HIF-1 signaling pathways. Molecular docking methods confirmed high affinity between CTD and key targets. Western blot analysis showed that CTD inhibited expression of PI3K, AKT, and the anti-apoptotic protein Bcl-2, while promoting expression of the pro-apoptotic proteins Bax and Caspase 3. These results suggest that CTD-induced TI involves multiple targets and pathways, and the underlying mechanism was associated with inhibition of the apoptosis-related PI3K/AKT signaling pathway.
研究领域:
药理学
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生殖生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2025
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IF 2.2
Rongyan Zhu,Liu Yang,Yulan Li
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age and is frequently associated with impaired glucose metabolism. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular metabolic regulation; however, its involvement in PCOS pathogenesis remains unclear. Bioinformatics analysis revealed significantly increased TXNIP expression in both PCOS patients and mouse ovarian granulosa cells (GCs). In vivo experiments using dehydroepiandrosterone (DHEA)-induced PCOS mouse models showed that TXNIP knockdown restored the expression of glycolysis-related enzymes, including HK2, PFKM, and PKM2. This restoration enhanced glycolytic function by suppressing IRS-1 phosphorylation and activating the PI3K signaling pathway. In vitro, dihydrotestosterone (DHT)treatment elevated TXNIP expression and suppressed glycolytic activity in KGN cells. Silencing TXNIP restored glycolytic metabolites such as pyruvate and lactate and promoted glycolytic flux, while TXNIP overexpression further impaired these functions. Additionally, treatment with the IRS-1 inhibitor NT157 confirmed that TXNIP regulates glycolysis in GCs through the IRS-1/PI3K signaling axis. This study is the first to demonstrate that TXNIP contributes to glycolytic dysfunction in PCOS GCs via the IRS-1/PI3K pathway, highlighting a potential target for PCOS diagnosis and therapy.
研究领域:
生殖生物学
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代谢病学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
npj Science of Food
·
2026
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IF 9.7
Shi Yuxuan,Sun Jiayi,Chen Lin,Xu Shuang,Guo Shasha,Xu Anan,Ye Qun,Wang Yuefei,Xu Ping
While black tea’s oxidized polyphenols hold potential for gut health, the specific protective mechanisms of its ethanol-soluble fraction (BES), particularly regarding host-microbiota interactions, remain poorly defined. This study elucidated the dual mechanisms through which BES ameliorates dextran sulfate sodium (DSS)-induced colitis in mice. By integrating network pharmacology, molecular docking/dynamics simulations, RT-qPCR, and Western blot analysis, we identified the PI3K/AKT signaling axis as a potential host target. Our findings suggest that key flavonoid constituents stably bind to critical nodes, potentially downregulating the expression and activation of pathway components. Concurrently, 16S rRNA sequencing and metabolomics revealed that BES reshaped gut microbiota by suppressing Akkermansia and enriching SCFA producers such as Lactobacillus , restoring fecal SCFA levels. Fecal microbiota transplantation confirmed that BES-modulated microbiota alone transferred protection. Thus, BES acts concertedly through direct PI3K/AKT inhibition and indirect microbiota-SCFA modulation, providing a mechanistic basis for targeted use of black tea fractions in intestinal inflammation.
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
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IF 14.1
Lei Wu,Jintong Na,Xiyu Liu,Dongsheng Tang,Zhungang Yang,Zheng Cao,Xinyue He,Haihua Xiao,Liping Zhong,Yuan Liao,Yongxiang Zhao
Cuproptosis, an emerging form of programmed cell death, is capable of inducing mitochondrial dysfunction. Moreover, the PI3K-AKT-mTOR signaling pathway contributes to tumor cell progression by reprogramming mitochondrial morphology and function. In this study, we have designed copper complex nanoparticles (NP Cu ) and PI3K-AKT-mTOR inhibitor Alpelisib nanoparticles (NP ALP ) that enhance the efficacy of cuproptosis-based therapies. NP Cu triggers mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), while NP ALP inhibits the PI3K-AKT-mTOR signaling pathway to induce apoptosis. The combination of these two nanoparticles (NP Cu +NP ALP ) effectively activates the antitumor responses in the tumor microenvironment (TME). When combined with an anti-programmed cell death protein 1 antibody (α-PD-1), NP Cu +NP ALP significantly inhibits tumor progression and activates antitumor immunity, offering a promising strategy for liver cancer treatment.
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DOI
PubMed
高影响因子
American Journal of Translational Research
·
2026
·Vol. 18
·期 3
·2489
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IF 1.8
Yuqing Bi,Yanchun Chen,Jimei Jiang,Wangqi Mao,Xiao Zhang,Jiayi Liu,Xin Zhao,Yueqiu Dong,Yueqing Cai,Mei Li,Xiang Li,Yunpeng Luan,Liyun Jiang
Objective: Jiangfu Fuwei granules (JFFW) are a widely used clinical prescription for the treatment of chronic atrophic gastritis (CAG), but the underlying molecular mechanism remains to be explored. This study aimed to elucidate the therapeutic mechanism of JFFW in alleviating CAG. Methods: A CAG mouse model was established using a combined approach, and the mice were treated with JFFW for six weeks. Network pharmacology was used to screen for active ingredients and signaling pathways. Subsequently, in vivo experiments were conducted to verify the predicted mechanisms, including histologic evaluation, enzyme-linked immunosorbent assay, and immunohistochemical analysis. Furthermore, molecular docking was used to simulate the interaction between key active compounds and core protein targets. Results: In vivo experimental results demonstrated that JFFW effectively reversed gastric mucosal thinning and glandular loss in CAG mice. This treatment significantly restored serum pepsinogen levels and downregulated the expression of inflammatory cytokines, specifically interleukin-6, interleukin-1β, and tumor necrosis factor-α. Network pharmacology analysis identified 224 bioactive compounds and predicted the phosphoinositol 3-kinase (PI3K)-protein kinase B (AKT)-hypoxia-inducible factor 1-α (HIF1α) signaling pathway as a key target. Immunohistochemical results confirmed that JFFW treatment significantly inhibited the protein expression of phosphorylated AKT and HIF1α. Furthermore, reduced CD31 staining occurred consistent with a decrease in microvessel density. Molecular docking analysis further confirmed that the main components of JFFW had a good binding affinity to PI3K protein. Conclusion: The therapeutic effect of JFFW on CAG is mainly achieved by inhibiting the PI3K-AKT-HIF1α signaling pathway, thereby suppressing abnormal angiogenesis and gastric inflammation.
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Hao Li,Youyang Shi,Wenjing Zhang,Qingping Li,Yan Feng,Rongzhou Wu
Fraxin alleviates MI-induced cardiac dysfunction, oxidative stress, inflammation, and apoptosis. • Fraxin promotes HXK2 binding to VDAC, enhances its mitochondrial localization, and reduces ROS production, improving anti-MI effects. • Fraxin protects against MI via PI3K/AKT-mediated HXK2 upregulation, reducing ROS, inflammation, and apoptosis. Acute myocardial infarction (AMI) is a persistent ischaemic and anoxic necrosis of the myocardium that triggers oxidative stress and ultimately leads to remodelling and heart failure. Fraxin is a traditional Chinese medicine that is commonly used in clinical practice. In this study, Fraxin improved cardiac function, reduced the area of myocardial infarction, and reduced cardiac damage such as myocardial inflammation and fibrosis. Fraxin reduced myocardial oxidative stress injury, myocardial inflammation index and myocardial apoptosis level. Network pharmacology analysis identified hexokinase II (HXK2) as the key target protein and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway as the key signalling pathway. Molecular docking revealed strong binding affinity between Fraxin and HXK2. Fraxin was found to reduce oxidative stress damage, inflammation and apoptosis by enhancing HXK2's mitochondrial localization and its interaction with voltage-dependent anion channels (VDAC) via HXK2 inhibitors and HXK2-VDAC binding domain peptides. Furthermore, inhibition of the PI3K/AKT signalling pathway abolished the regulatory effects of Fraxin on HXK2 during myocardial infarction. Taken together, Fraxin exerts a cardioprotective effect by regulating HXK2 through PI3K/AKT signaling pathway to reduce reactive oxygen species (ROS) levels, inflammation and myocardial apoptosis. This study provides a scientific basis for the therapeutic potential of the traditional Chinese medicine Fraxin in AMI.
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DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Xinyi Li,Hui Song,Yiwen Yuan,Na Jiang,Wei Duan,Tianzhao Xu,Chang Liu,Xinghui Liu
Cardiovascular diseases have long posed a significant threat to public health. Among them, myocarditis is a major category of cardiovascular disorders that is characterized by high mortality during its acute phase, necessitating urgent medical attention. This study aims to explore the therapeutic effects and underlying mechanisms of Spi1-mediated gene regulation in chemotherapy induced cardiomyopathy. To validate our findings, we employed bioinformatics analysis methods and established myocarditis models using the chemotherapeutic drug doxorubicin in both cellular and animal models. Our results demonstrated that the inhibition of Spi1 significantly suppressed inflammatory factor expression in H9C2 rat cardiomyocytes. Furthermore, in C57BL/6 mouse model, Spi1 inhibition was shown to improve cardiac function and alleviate both myocardial inflammation and fibrosis in mice with doxorubicin-induced myocarditis. Mechanistic investigations revealed that Spi1 suppression altered the expression of genes associated with immune response, cell differentiation and proliferation. Notably, Spi1 modulates the expression of YTHDF2, thereby influencing the PI3K/AKT/mTOR signaling pathway and subsequently regulating the inflammatory response. Collectively, these findings suggest that Spi1 plays a pivotal role in doxorubicin-induced myocarditis by mitigating inflammatory responses and myocardial injury through the regulation of YTHDF2 and the PI3K/AKT/mTOR signaling pathways, offering a promising therapeutic target for the treatment of myocarditis.
研究领域:
心血管研究
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分子生物学
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药理学
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肿瘤学
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信号转导
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产品关联
DOI
PubMed
高影响因子
Results in Chemistry
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2025
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IF 4.2
Jiabao Cai,Qian Zhang,Jiani Fan,Shengguang Chen
Baicalin, a flavonoid derived from Scutellaria baicalensis, exhibits broad antitumor activity. However, its effects on anaplastic thyroid cancer (ATC) C643 cells remain unclear. This study investigated the inhibitory capacity and underlying mechanisms of baicalin against C643 cells using both in vitro and in vivo models. In vitro, including CCK-8 viability assay, scratch-wound healing assay, Transwell migration, Annexin V-FITC/PI apoptosis, cell-cycle and JC-1 mitochondrial membrane potential assays demonstrated that baicalin reduced cell viability and migration in a concentration-and time-dependent manner, induced G2-phase arrest and decreased mitochondrial membrane potential. Integrated transcriptome sequencing identified BCL2 and the PI3K-AKT pathway as key targets. qPCR and Western blot confirmed that baicalin down-regulated BCL2 in a dose-dependent manner, selectively activated the PI3K-AKT cascade, promoted TP53 recruitment to the BAX/BIM promoters and up-regulated their transcription, accompanied by increased p-PI3K and p-AKT levels. In vivo, daily intraperitoneal administration of 50 mg/kg baicalin for 21 days led to a 55.6 % reduction in C643 xenograft volume. Immunohistochemistry revealed decreased BCL2 and Ki-67 expression in tumor tissues, indicating impaired anti-apoptotic activity and proliferative capacity. Importantly, histopathological examination of major organs (heart, liver, spleen, lung and kidney) showed no treatment-related toxicity, confirming the safety of baicalin. These findings demonstrate that baicalin is a safe, multi-target therapeutic candidate with a well-defined mechanism, offering a novel and effective targeted option for aggressive anaplastic thyroid cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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天然产物研究
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细胞生物学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）