BIOCHEMICAL PHARMACOLOGY
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2026
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IF 5.6
Tong Gong,Yan Jin,Hongmei Zhu,Zeying Cheng,Hong Fang,Ning Xu,Fanting Zhao,Yingqian Liu,Peng Chen
Colorectal cancer (CRC) remains one of the most prevalent and challenging cancers and advanced CRCs are resistant to targeted therapy, chemotherapy and immunotherapy. Therefore, it is urgent to develop new treatment strategies or therapeutic agents for CRC to improve clinical efficacy. Within the landscape of emerging therapeutic modalities, drug repurposing offers a particularly promising avenue for enhancing clinical outcomes. Herein, we revealed the functional repurposing of dronedarone, an FDA (the US Food and Drug Administration)-approved class III antiarrhythmic agent, demonstrating its potent anti-proliferative effects against CRC cells. Through rational drug structure modification, we synthesized thirteen dronedarone derivatives, among which derivative D4 demonstrated superior antiproliferative potency and lower toxicity both in vitro and in vivo. Mechanically, dronedarone and D4 induced mitochondrial dysfunction and suppressed both AKT (protein kinase B) and ERK (extracellular regulated protein kinase) signaling pathways simultaneously leading to CRC cells apoptosis. Collectively, our study sheds light on repurposing non-oncology drug dronedarone and its derivatives with their molecular mechanisms for CRC treatment.
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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
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2025
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IF 4.8
Xiaoqiang Liu,Luojia Liu,Qiaoling Wang,Lufan Xia,Fangqing Zuo,Jinrui Yang,Kaibang Zheng,Yunfan Tang,Jingjing Guo,Xiaoping Yu,Boye Qi,Hanghang Zhou,Ying Chen,Jiaping Zhang,Xuanfen Zhang
Skin cutaneous melanoma (SKCM), the most aggressive form of cutaneous malignancy globally, remains poorly understood in terms of its molecular drivers. Although the copper metabolism MURR1 domain (COMMD) protein family has been associated with oncogenesis, its functional relevance in SKCM is undefined. In this study, we identified COMMD4 as a prognostic biomarker of SKCM and showed that it is positively correlated with the adverse clinical outcomes of patients. COMMD4 gene knockout (COMMD4-KO) impaired the proliferative, migratory, and invasive capacities of SKCM cells in vitro and suppressed xenograft tumor growth in vivo. Mechanistically, COMMD4-KO induced G2/M phase arrest by disrupting p21-CDK1-cyclinB1 and impeded epithelial-mesenchymal transition (EMT) by reversing the E/N cadherin switch. We also demonstrate that COMMD4 activates PI3K-AKT signaling by binding PI3K-p85 to release PI3K-p110, thereby driving G2/M transition and EMT. Reactivation of PI3K-AKT signaling in COMMD4-KO cells rescued oncogenic phenotypes. By integrative Connectivity Map analysis and functional validation, we identified triamterene as a pharmacological inhibitor targeting the COMMD4-PI3K-AKT axis, which suppressed the progression of SKCM effectively in vitro and vivo. Our findings establish the COMMD4-PI3K-AKT axis as a novel and critical regulator of SKCM progression and repurpose triamterene as a promising therapeutic agent against SKCM. Graphical COMMD4 activates the PI3K-AKT signaling through binding PI3K-p85 to release PI3K-p110, driving the G2/M phase transition via p21-CDK1/cyclin B1 axis and facilitating the EMT by switching cadherin expression from the E to the N type, ultimately promoting the progression of SKCM.
研究领域:
肿瘤学
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分子生物学
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癌症信号通路
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药理学
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皮肤病学
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2026
·Vol. 58
·期 1
·1-25
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IF 8.5
Hui Fang,Min Shu,Jiaju Wang,Heng Tian,Jianguo Zhang,Ying Hu,He Li,Huan Zhou,Kangsheng Gu,Zhenhua Ren
International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.
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Frontiers in Cell and Developmental Biology
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2026
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IF 5.3
Gongyu Wu,Huilin Guan,Mengyao Lv,Zhiqiang Chen,Changjiu Gao,Wanzhen Su,Hui Fu
Background 18β-Glycyrrhetinic acid (18β-GA), a major bioactive triterpenoid from licorice, has demonstrated anti-cancer potential; however, its mechanisms against lung adenocarcinoma (LUAD) remain unclear. Methods This study employed an integrated approach combining network pharmacology, bioinformatics, and experimental validation to investigate the anti-LUAD efficacy and underlying molecular targets of 18β-GA. Results In vitro and in vivo assays demonstrated that 18β-GA dose-dependently inhibited LUAD cell proliferation, migration, and colony formation, while significantly suppressing tumor growth in a Lewis lung carcinoma (LLC) allograft model. By integrating network pharmacology with TCGA transcriptomic data, MET was identified as a core upstream target, and the PI3K/AKT signaling pathway was revealed as a significantly enriched pathway. Molecular docking and molecular dynamics simulations revealed that 18β-GA forms stable, high-affinity complexes in the catalytic pockets of both MET and AKT. Subsequent biological validations confirmed that 18β-GA attenuated the phosphorylation of critical signaling components, including MET, PI3K, AKT, and mTOR, without altering their mRNA or total protein expression. Crucially, functional rescue assays revealed that exogenous MET activation via its specific ligand HGF simultaneously reversed the 18β-GA-induced suppression of both p-MET and p-AKT. In contrast, the AKT agonist SC79 effectively restored p-AKT levels and reversed the anti-tumor efficacy of 18β-GA, but it failed to rescue the inhibition of upstream p-MET. This unidirectional reversal rigorously validates MET as the upstream regulator of AKT. Conclusion 18β-GA suppresses LUAD by targeting upstream MET to drive a top-down cascade blockade of the PI3K/AKT/mTOR signaling pathway, providing a pharmacological rationale for its application in LUAD targeted therapy.
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Food & Function
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2025
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IF 5.4
Chunyang Wang,Yimei Tang,Yanlin Zhang,Ziying Li,Jun Wang,Jinming Peng,Jie Peng
Maternal obesity impairs placental angiogenesis, increasing the risks of gestational metabolic disorders and fetal developmental compromise. Odd-chain saturated fatty acids (OCS-FAs), particularly pentadecanoic acid (PA, C15:0), demonstrate protective metabolic properties, yet their roles in placental angiogenesis remain unexplored. In this study, pregnant mice were fed a high-fat diet (HFD, 60% kcal) or isocaloric HFD supplemented with 1% (w/w) PA ethyl-ester (HFD + PA). Porcine iliac artery endothelial cells (PIEC) were used to assess angiogenic mechanisms in vitro. Our results showed that PA supplementation induced mild glucose intolerance (elevated 90/120 min glycemia, P < 0.05) without altering the body composition, fasting insulin, HOMA-IR, or plasma lipids (TG, T-CHO, HDL/LDL). PA augmented labyrinth zone (LZ) vascularization (P = 0.052) and upregulated fetal T-CHO transport (P = 0.002). RNA-seq revealed PA-activated PI3K-AKT signaling and enhanced the pro-angiogenic factor expression (HIFα, Lrp1, Flt4, MMP2/14, P < 0.05). Immunohistochemistry confirmed PI3K activation and increased CD31 endothelium in LZ. PA promoted PIEC tube formation (12.5 µM, P < 0.01) in vitro, while heptadecanoic acid (HA, C17:0) had no such effect and inhibited PIEC (12.5–25 µM, P < 0.01). PA's pro-angiogenic effect was abolished by PI3K inhibitor 3-MA (P < 0.01). In conclusion, PA promotes placental angiogenesis by activating the placental PI3K-AKT signaling, despite mild maternal glucose intolerance. These findings highlight PA's potential as a functional nutrient for mitigating gestational metabolic complications.
研究领域:
生殖生物学
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营养科学
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分子信号传导
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发育生理学
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代谢紊乱
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Translational Oncology
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2025
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IF 4.1
Ying Shi,Hongda An,Wenshuang Wang,Dong Nan,Yingzhe Cui,Mingyuan He,Jianxiu Lian,Xiaoxiao Zhang,Jing Peng,Xiuhua Yang,Pengfei Liu
Purpose Glioblastoma (GBM), an extremely lethal and aggressive cancer with a poor prognosis and limited therapeutic outcomes, exhibits strong resistance to standard therapies owing to anoikis resistance indicating the need for novel treatments. In this study, we used thermoradiotherapy as an integrative approach for GBM to sensitize its resistance to anoikis. Experimental Design The therapeutic effects of thermoradiotherapy were assessed using cell counting kit-8, colony formation, Transwell, and anoikis assays. Proteomic analysis was performed to identify potential therapeutic targets for thermoradiotherapy. The impact of certain therapeutic target on GBM proliferation, metastasis, and anoikis was identified using EdU, colony formation, Transwell, and anoikis assays. Western blotting and qRT-PCR were used to explore the relevant molecular mechanisms. Results Thermoradiotherapy inhibited proliferation and metastasis of GBM, and reverses anoikis resistance to improve therapeutic outcomes. Proteomic analysis revealed ITGA5 as a prospective therapeutic target. In vitro and in vivo studies identified that ITGA5 promoted GBM proliferation, metastasis, and anoikis resistance by regulating PI3K/AKT pathway activation. Conclusions This study presents a novel thermoradiotherapy for GBM, integrating potent antitumour efficacy and negligible side effects. ITGA5 is a underlying therapeutic target for thermoradiotherapy which related to proliferation, metastasis, and anoikis resistance of GBM.
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Chinese Herbal Medicines
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2023
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IF 3.8
Jie Gao,Manqian Zhang,Xingwang Zu,Xue Gu,Erwei Hao,Xiaotao Hou,Gang Bai
Objective Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism. It is not clear whether phenolic acids or their metabolites play a major role in vivo . In this study, caffeic acid (CA) and ferulic acid (FA), the two most ingested phenolic acids, and their glucuronic acid metabolites, caffeic-4′- O -glucuronide (CA4G) and ferulic-4′- O -glucuronide (FA4G), were investigated. Methods Three insulin resistance models in vitro were established by using TNF-α, insulin and palmitic acid (PA) in HepG2 cells, respectively. We compared the effects of FA, FA4G, CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels. The potential targets and related pathways were predicted by network pharmacology. Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target. To investigate the binding mode, molecular docking was performed. Then, we performed membrane recruitment assays of the AKT pleckstrin homology (PH) domain with the help of the PH-GFP plasmid. AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds. Finally, the downstream signaling pathway of AKT was investigated by Western blot analysis. Results The results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption. AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis. The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds. The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site. CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane, while increasing the activity of AKT. Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3β in the AKT signaling pathway to increase glucose consumption. Conclusion In conclusion, our results suggested that the metabolites of phenolic acids, which contain glucuronic acid, are the key active substances and that they activate AKT by targeting the PH domain, thus improving glucose metabolism.
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NEPHROLOGY
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2023
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IF 2.5
Ziyuan Liu,Huilong Xiang,Qin Deng,Wanting Fu,Yang Li,Zejun Yu,Yinsheng Qiu,Zhinan Mei,Lingyun Xu
Aim Inflammation and apoptosis are main pathological processes that lead to the development of hyperuricemic nephropathy (HN). This study aims to explore whether baicalin (BA) and baicalein (BAI) can relieve the damage through PI3K/AKT/NF-κB signal pathway and provide more reliable and precise evidence for the treatment of HN. Methods HN mice were induced by yeast extract with potassium oxonate (PO), and HK-2 cells were induced by monosodium urate (MSU). Molecular docking, western blot, q-PCR, and other methods were used to explore the changes of various indicators in HN mice and HK-2 cells. Results Molecular docking results showed that BA and BAI had good binding ability with PI3K, AKT, p65 and IκBα. BA and BAI significantly ameliorated the levels of renal function, decreased the p-PI3K, p-AKT and p-p65 expression, down-regulated the BAX/BCL2 and CASP3, and blunted the mRNA levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-18 in both renal tissue of HN mice and HK-2 cells induced by MSU. BA and BAI also decreased the oxidative stress level of MSU-induced HK-2 cells. Conclusion BA and BAI were confirmed to attenuate HN through alleviating renal inflammatory and apoptosis in cells and tissues by inhibiting PI3K/AKT/NF-κB pathway. BA and BAI were expected to be developed as new anti-HN drugs.
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Chemical Biology & Drug Design
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2023
·Vol. 102
·期 1
·115-125
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IF 3
Yan Zhang,Kun Dai,Dedong Xu,Hua Fan,Nannan Ji,Di Wang,Yunlu Zhao,Rui Liu
Saikosaponin A (SSA) has been revealed to have anti-breast cancer (BC) effect. However, the association between SSA and BC glycolysis is obscure. We want to probe the function and mechanism of SSA on BC glycolysis. Kaplan–Meier plotter revealed the relationship between STAT3 and the survival curve of BC. The protein kinase B (Akt)/signal transducer and activator of transcription 3 (STAT3) pathway and the viability in cells treated with or without 0, 5, 10, and 15 μM SSA were assessed by Western blot and cell counting kit-8. The biological behaviors, lactate, and ATP contents, glucose uptake, and Akt/STAT3 pathway-related markers in BC cells treated with colivelin or SSA were evaluated using cell function experiments, kit, and Western blot. Then, the impacts of colivelin and SSA on BC cells were tested again. The overexpressions of p-STAT3 and p-Akt in BC cells were weakened by 5, 10, and 15 μM SSA. Colivelin boosted the BC cell viability and proliferation and impeded apoptosis, while SSA did the opposite. Meanwhile, colivelin intensified lactate and ATP contents, glucose uptake, and Akt/STAT3 pathway-related markers level in BC cells, while SSA was the opposite. The modulation of SSA on the biological behavior, lactate and ATP productions, glucose uptake, and Akt/STAT3 pathway was rescued by colivelin. Our research unveiled new insights into SSA as a valuable candidate therapeutic agent for weakening glycolysis, and protruded the Akt/STAT3 pathway as a latent molecular target for SSA and glycolysis modulation.
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MOLECULAR AND CELLULAR BIOCHEMISTRY
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2023
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IF 4.3
Lu Yanyu,Min Qianqian,Zhao Xiaoyan,Li Li,Zhao Guojun,Dong Jianzeng
Eupatilin is a pharmacologically active flavonoid with a variety of biological activities, such as anticancer, anti-inflammatory, antioxidant, neuroprotective, anti-allergic and cardioprotective effects. However, whether eupatilin has protective effects on doxorubicin-induced cardiotoxicity remains unknown. Thus, this study aimed to investigate the role of eupatilin in doxorubicin-induced cardiotoxicity. Mice were exposed to a single dose of doxorubicin (15 mg/kg) to generate doxorubicin-induced cardiotoxicity or normal saline as a control. To explore the protective effects, mice were intraperitoneally injected with eupatilin daily for 7 days. Then, we examined the changes in cardiac function, inflammation, apoptosis, and oxidative stress to evaluate the effects of eupatilin on doxorubicin-induced cardiotoxicity. Additionally, RNA-seq analysis was introduced to explore the potential molecular mechanisms. Eupatilin ameliorated doxorubicin-induced cardiotoxicity by attenuating inflammation, oxidative stress, and cardiomyocyte apoptosis and ameliorated doxorubicin-induced cardiac dysfunction. Mechanistically, eupatilin activated the PI3K-AKT signaling pathway, as evidenced by RNA-seq analysis and Western blot analysis. This study provides the first evidence that eupatilin ameliorates doxorubicin-induced cardiotoxicity by attenuating inflammation, oxidative stress, and apoptosis. Pharmacotherapy with eupatilin provides a novel therapeutic regimen for doxorubicin-induced cardiotoxicity.
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Journal of Orthopaedic Surgery and Research
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2023
·Vol. 18
·期 1
·1-13
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IF 2.6
Zhang Yang,Liu Wenguang,Liu Zhonghao,Liu Yi
Background Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and intra-articular inflammation. Daurisoline (DAS) is an isoquinoline alkaloid isolated from Rhizoma Menispermi, whose antitumor and anti-inflammatory pharmacological effects have been demonstrated, but the effects of DAS on OA have rarely been researched. In this study, we aimed to explore the potential role of DAS in OA and its partial mechanism.
Materials and methods The cytotoxicity of H 2 O 2 and DAS toward chondrocytes was detected by the Cell Counting Kit-8 assay. Safranin O staining was used to detect chondrocyte phenotype changes. Cell apoptosis was measured by both flow cytometry and quantitative analysis of the protein levels of the apoptosis-related factors Bax, Bcl-2 and cleaved caspase-3 by western blot. Western blotting and immunofluorescence were used to assess the expression of the autophagy-related proteins LC3, Beclin-1 and p62. In addition, key signal pathway targets and matrix-degrading indicators were measured by western blot. Results Our results indicated that H 2 O 2 induced human chondrocyte apoptosis and activated autophagy in a dose-dependent manner. DAS treatment dose-dependently reversed the expression of apoptosis-related proteins (Bax, Bcl-2 and cleaved caspase3) and the apoptosis rate induced by H 2 O 2 . Western blot and immunofluorescence analyses showed that DAS decreased the H 2 O 2 -induced upregulation of the autophagy marker Beclin-1 and the LC3 II/LC3 I ratio and upregulated the p62 protein level. Mechanistically, DAS inhibited autophagy through the activation of the classical PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis. In addition, DAS alleviated the H 2 O 2 -induced degradation of type II collagen and the high expression of matrix metalloproteinase 3 (MMP3) and MMP13. Conclusion Our research demonstrated that DAS alleviated chondrocyte autophagy caused by H 2 O 2 through activation of the PI3K/AKT/mTOR signaling pathway and protected chondrocytes from apoptosis and matrix degradation. In conclusion, these findings suggest that DAS may serve as a promising therapeutic strategy for OA.
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Food & Nutrition Research
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2022
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IF 3.221
Tongxu Guan,Yingce Zheng,Shengzi Jin,Shuang Wang,Mengxin Hu,Xingyao Liu,Siqi Huang,Yun Liu
Background Troxerutin is a flavonoid compound and possesses potential anti-cancer, antioxidant, and anti-inflammatory activities. Besides, cisplatin is one of the most widely used therapeutic agents, but the clinical uses of cisplatin are often associated with multiple side effects, among which nephrotoxicity is more common. Objective and design This study explored the protective effects of troxerutin (150 mg kg −1 day −1 for 14 days) against cisplatin-induced kidney injury and the potential mechanism using Wistar rats as an experimental mammalian model. Results We discovered that troxerutin could significantly alleviate cisplatin-induced renal dysfunction, such as increased levels of blood urea nitrogen and creatinine ( P < 0.01), as well as improved abnormal renal tissue microstructure and ultrastructure. Additionally, troxerutin significantly decreased malondialdehyde (MDA), hydrogen peroxide (H 2 O 2 ), NO, inducible nitric oxide synthase (iNOS) levels ( P < 0.01), p-NF-κB p65/NF-κB p65, TNF-α, Pro-IL-1β, IL-6, B cell lymphoma-2 (Bcl-2)/Bcl-xl associated death promoter (Bad), Cytochrome C (Cyt C), Cleaved-caspase 9, Cleaved-caspase 3, and Cleaved-caspase 8 protein levels ( P < 0.01) in the kidney tissues of cisplatin-treated rats; and increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), total antioxidant capacity (T-AOC) activities ( P < 0.01), IL-10, Bcl-2 protein levels ( P < 0.01). Conclusion These results suggested that the underlying mechanism might be attributed to the regulation of Phosphoinositide 3 kinase/Protein kinase B (PI3K/AKT) pathway via enhancing MAP4 expression to attenuate cellular apoptosis, alleviating oxidative stress and inflammatory response.
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