BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
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IF 2.5
Hai Huang,Liwei Guo,Hansong Sun,Yunhong Liu,Jun Zhang,Weijie Tang,Xiaodong Xia,Yu Wang,Ni Chen,Dong Lv,Jing Yang
Objective To investigate the mechanism of action of saikosaponin D (SSD) on bladder cancer (BCa) and evaluate its synergistic antitumor efficacy with the chemotherapeutic agent gemcitabine (GEM). Methods MTT, colony formation, Transwell, and scratch wound healing assays detected SSD's effects on the proliferation, invasion, and migration of RT112 and T24 cells. Specific inhibitors identified cell death mode. Western blotting, immunohistochemistry, and flow cytometry verified ferroptosis-related protein expression and oxidative stress. Network pharmacology predicted core pathways, validated by examining PI3K/AKT pathway activity. Animal models evaluated the synergistic effect of SSD and GEM. Results In vitro, SSD dose-dependently inhibited the BCa cells proliferation, invasion, and migration, and upregulating E-cadherin whilst downregulating N-cadherin, Vimentin, and Snail. The effects were blocked by the ferroptosis inhibitor Fer-1. Network pharmacology identified the PI3K/AKT pathway as a core target. Moreover, SSD regulated the GPX4/SLC7A11/ACSL4, suppressed PI3K/AKT phosphorylation, and triggered lipid peroxidation and reactive oxygen species accumulation, partially reversed by a PI3K-specific phosphopeptide agonist. In vivo, SSD inhibited tumor growth, and its combination with GEM showed superior efficacy. The combination therapy most effectively downregulated SLC7A11, GPX4, Vimentin, N-cadherin and Snail, while upregulating the ACSL4 and E-cadherin. Conclusion SSD inhibits the malignant phenotype of BCa by targeting PI3K/AKT to trigger ferroptosis. Its synergistic effect with GEM from the dual mechanisms of ferroptosis sensitization and epithelial-mesenchymal transition inhibition, providing an innovative combination strategy based on natural product active ingredients to overcome bladder cancer chemoresistance.
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Dose-Response
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2026
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IF 2.8
AiJiao Sun,CuiYu Yu,FeiYan Zhu,Jing Chen,LiangChuan Chen,ZePing Hu,WeiBing Wang
BackgroundExtracellular matrix (ECM) deposition and excessive fibrosis are important factors in the deterioration of cardiac function after myocardial ischaemia‒reperfusion injury (I/RI). However, therapeutic strategies for inhibiting ECM deposition and excessive fibrosis have still not been elucidated.Methods and resultsSingle-nucleus RNA sequencing (snRNA-seq) revealed that the overexpression of type VI collagen-α 3 (Col6a3) in fibroblasts in the myocardial infarction area strongly promotes the process of myocardial fibrosis. Consistent results were not observed in the infarcted myocardial tissues of mice treated with 4,8-dicarboxyl-8,9-iridoid-1-glycoside (BIG). Echocardiography confirmed that BIG alleviated cardiac dysfunction in mice after myocardial I/RI, TTC and Evans blue double staining revealed that BIG reduced the myocardial infarction size and area at risk. BIG inhibited inflammatory responses, apoptosis, and matrix metalloproteinase (MMP) secretion both in vivo and in vitro. Immunofluorescence staining revealed that BIG downregulated the expressions of TGF‒β and Col6a3 in cardiac fibroblasts but not in cardiomyocytes. The PI3K-specific inhibitor LY294002 and AKT inhibitor were utilitzed to confirm that BIG suppressed myocardial fibrosis and alleviated cardiac dysfunction by activating the PI3K/AKT pathway.ConclusionsThe results provide valuable information for the treatment of myocardial fibrosis induced by myocardial I/RI and highlight the therapeutic potential of BIG in reducing collagen deposition.
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Animals
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2026
·Vol. 16
·期 9
·1310
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IF 3.2
Binwen Zhang,Zheng Wei,Mei Yang,Xin Wang,Qiang Shan,Zheng Cao
Simple SummaryMastitis is a common disease in dairy cows, with major pathogens includingStaphylococcus aureusandEscherichia coli. Although berberine has antibacterial and anti-inflammatory properties, it is poorly absorbed after oral administration. We developed a novel berberine-loaded hydrogel that can be applied to the udder, delivering the drug directly to the mammary tissue. Experimental results showed that this hydrogel is stable, safe, and capable of sustained drug release. Tests in a mouse model demonstrated that it effectively reduces bacteria-induced inflammation, protects the mammary barrier, and minimizes cell damage. Its mechanism of action is related to the regulation of intracellular NF-κB and PI3K/Akt signaling pathways. This study suggests that the hydrogel offers a new topical strategy for treating mastitis, solving the problem of poor oral absorption through local application. It holds promise for providing dairy cows with a more convenient and effective treatment option in the future.Mastitis is a common disease in dairy cows, mainly caused by Staphylococcus aureus and Escherichia coli. Berberine (BBR) has antibacterial and anti-inflammatory potential, but its application is limited due to poor oral absorption and difficulty in reaching mammary tissue. To address this, this study developed a BBR-loaded composite ethosome hydrogel (BBR-CEH) to achieve targeted mammary delivery through local transdermal administration. The experimental results showed that BBR-CEH has good chemical stability and biosafety. Subsequently, a mouse mastitis model was established by intraductal injection of 50 µL of bacterial mixture (E. coli:S. aureus= 1:1, each at 1 × 107CFU/mL). The results showed that after BBR-CEH treatment, the mRNA expression ofTNF-α(tumor necrosis factor-alpha),IL-6(interleukin-6), andIL-1β(interleukin-1 beta) was significantly decreased, the mRNA expression ofZO-1(zonula occludens-1),Occludin, andClaudin-4was significantly increased, andBax/Bcl-2(Bcl-2-associated X protein/B-cell lymphoma 2) was significantly reduced (p< 0.01), indicating alleviation of mastitis by reducing inflammation, improving tight junctions, and inhibiting apoptosis. Finally, network pharmacology and in vivo experiments confirmed that its mechanism involves the NF-κB (nuclear factor kappa-B) and PI3K/Akt (phosphoinositide 3-kinase/protein kinase B) pathways. Thus, topical BBR-CEH may represent a promising new strategy for mastitis treatment.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Lili Fan,Shukun Qu,Chenxue Miao,Dongjie Wu,Yuan Rao,Weisong Xu,Yanping He,Guang Song
Oxidative stress is a key pathological factor that contributes to blood–brain barrier (BBB) disruption during ischemic injury. Panax notoginseng saponins (PNS), the primary bioactive components of Panax notoginseng , possess potent antioxidative and vasoprotective activities. This study aimed to elucidate the molecular mechanisms by which PNS regulate endothelial integrity and BBB permeability under oxidative stress conditions. Mouse brain microvascular endothelial cells (bEnd.3) were treated with hydrogen peroxide to induce oxidative damage, followed by intervention with PNS. Transcriptomic and proteomic analyses revealed that Akap12 (A-kinase anchoring protein 12) and Aquaporin 1 (AQP1) were key molecules involved in PNS-mediated endothelial protection. H₂O₂ exposure markedly suppressed Akap12 expression and inhibited the PI3K/AKT signaling pathway, leading to elevated AQP1 expression and increased BBB permeability. PNS treatment reversed these effects by restoring Akap12 expression, reactivating PI3K/AKT signaling, and reducing AQP1 levels. Functional validation further showed that AQP1 dysregulation altered the expression balance of tight junction proteins, including Claudin-5 and ZO-1, thereby impairing barrier function. Collectively, these findings demonstrate that PNS protect endothelial cells from oxidative injury by activating Akap12-dependent PI3K/AKT signaling and modulating AQP1-associated tight junction remodeling. This study provides new mechanistic insights into the molecular basis of PNS-mediated BBB protection and suggests potential therapeutic targets for oxidative or ischemic cerebrovascular diseases.
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CANCER LETTERS
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2026
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IF 11.8
Huaning Li,Run Shi,Yapeng Gao,Xing Cheng,Zhichao Wang,Yu Gao,Zhumei Shi,Mengjie Guo,Yongping You,Xiefeng Wang
Meningioma is the most common central nervous system tumor and high-grade tumors frequently show progressive growth or recurrence, posing substantial therapeutic challenges. However, the lack of effective chemotherapy and targeted therapies contributes to poor prognoses in patients with high-grade disease. In this study, we evaluated KRT18 expression in meningiomas and examined its correlation with patient prognosis using RNA sequencing and immunofluorescence staining. The oncogenic role of KRT18 in high-grade meningioma was further investigated using IOMM-Lee and CH157-MN cells, xenograft mouse models, and paraffin-embedded meningioma tissue sections. Finally, small-molecule inhibitors targeting KRT18-related mechanisms were explored. Analysis of clinical specimens across different meningioma grades demonstrated that KRT18 overexpression is associated with more advanced clinical features and poorer prognosis. Functional studies showed that KRT18 promotes meningioma cell proliferation and facilitates cell cycle progression by activating the PI3K/AKT signaling pathway. Mechanistically, KRT18 interacted with LDHA, an upstream regulator of PI3K/AKT signaling, and enhanced LDHA stability via inhibition of ubiquitination, which drives oncogenic growth by activating glycolysis and the PI3K/AKT signaling pathway. These findings were corroborated in a xenograft model. Finally, Fluvastatin was identified as a novel inhibitor that specifically targets the interaction between KRT18 and LDHA, thereby inhibiting meningioma proliferation by suppressing glycolysis and PI3K/AKT signaling. Collectively, these findings indicate that KRT18 serves as a potential diagnostic, prognostic, aggressiveness-related, and potential grading biomarker. It also functions as an oncogene by activating glycolysis and the PI3K/AKT signaling pathway through interaction with LDHA. Additionally, Fluvastatin is identified as a candidate for drug repurposing in high-grade meningioma.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2026
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IF 3.6
Jingjing Chen,Bin Liu,Yuanyuan Li,Binwu Zhuang,Dong Su,Yunlong Sang,Zibo Dong,Hao Liu
Pyrazole permethrin (also known as pyraclostrobin, abbreviated as PP) is a widely used fungicide that is chemically stable and fat-soluble; however, due to its accumulation in the environment and bioaccumulation, it poses potential health risks.This study systematically elucidates PP-induced liver injury through a combination of network toxicology and in vitro/in vivo investigations. Network toxicology identified 328 potential targets and 12 core genes associated with PP-induced liver injury. GO and KEGG enrichment analyses revealed pathway enrichment emphasizing biological processes such as inflammation, oxidative stress, apoptosis, and lipid metabolism. In vivo experiments in mice revealed that after 28 days of exposure, histopathological analysis showed minor local inflammatory cell infiltration and extensive hepatocyte necrosis and vacuolation in both low- and high-dose groups. High-dose PP significantly elevated serum transaminase (AST and ALT) activity. Biochemical analysis revealed that PP treatment reduced antioxidant enzyme activity (CAT, T-AOC, GSH-Px) while increasing malondialdehyde (MDA) levels, inducing oxidative stress. Additionally, PP exposure enhanced the expression of inflammatory cytokines (IL-1β, TNF-α). This indicates activation of oxidative stress and inflammatory pathways: oxidative damage occurs via depletion of the antioxidant enzyme system, while inflammatory cascades are mediated through the PI3K/AKT/NF-κB signaling axis. This study reveals key molecular targets and pathways involved in PP-induced hepatotoxicity, suggesting that subacute exposure risks should be fully considered when establishing safety standards for agricultural chemical use.
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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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Translational Cancer Research
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2025
·Vol. 14
·期 6
·3758
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IF 1.7
Shaojun Cai,Liyong Zhang,Tenghong Liu,Bo Wang,Shouyi Yan,Sisi Wang,Jiafan Yu,Sibin Wu,Siying Lin,Wenxin Zhao
Background Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive type of thyroid cancer derived from follicular cells of the thyroid gland. Due to the rapid growth of neck masses in ATC patients, which can lead to asphyxia, multimodality therapy, including surgery, chemotherapy, and radiotherapy, is essential in the treatment of ATC. Theaflavin (TF) has anti-cancer effects; however, no study has examined whether TF inhibits the malignant progression of ATC. Therefore, this study was conducted to explore the effects of TF on ATC and to provide a preliminary exploration of its mechanism. Methods The effects of TF on the half-maximal inhibitory concentration (IC 50 ) and proliferation of 8305C cells were determined by Cell Counting Kit-8 (CCK-8) assay. The effects of TF on the invasion and migration of 8305C cells were determined by transwell assay. Cell apoptosis was evaluated by flow cytometry. Labeled 8305C cells were injected into the yolk sac of zebrafish, and the progression of the 8305C cells was observed in vivo . Fluorescence real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) were used to detect the expression of proteins related to the lipid metabolism pathway and cell apoptosis. Network pharmacology was used to study the predicted mechanisms of the TF action on 8305C cells. Results The IC 50 of TF in the treatment of 8305C cells for 48 h was 21.79 µg/mL. TF inhibited the proliferation, migration, and invasion of the 8305C cells at a concentration of 1/2 IC 50 , and induced the apoptosis of the 8305C cells. TF also inhibited the proliferation of the 8305C cells in vivo . TF significantly increased the expression of the caspase3, caspase8, and caspase9 proteins in vivo and in vitro , and significantly inhibited the expression of the survivin protein. TF also inhibited the messenger RNA (mRNA) expression of SREBP1 and PPARD , and increased the mRNA expression of HNF4 . The network pharmacology results revealed that the PI3K/AKT signaling pathway is an important pathway by which TF acts on 8305C cells, and that TF was able to inhibit the proliferation, migration, and invasion, increase the apoptosis, inhibit the mRNA expression of SREBP1 , and increase the mRNA expression of HNF4 in the 8305C cells when the PI3K/AKT signaling pathway was activated. Conclusions This study found that TF inhibits the proliferation, migration, and invasion of ATC 8305C cells, and induces 8305C cell apoptosis by regulating lipid metabolism via the PI3K/AKT signaling pathway.
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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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International Journal of Genomics
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2025
·Vol. 2025
·期 1
·9710652
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IF 1.9
Jin Cai,Shuang Shi,Yuhang Wang,Xiangdong Zhang,Xinghua Wei,Yanjing Wu,Yunlong Shi,Bin Li,Daorong Hou
Purpose This research sought to investigate the impact and underlying mechanisms of growth hormone (GH) on atherosclerosis (AS) based on the analysis of single-cell RNA sequencing (scRNA-seq) data. Methods We analyzed the impact of GH on arterial vascular smooth muscle cells (VSMCs) by utilizing scRNA-seq data obtained from both atherosclerotic and healthy vascular tissues in mice. AS was induced in C57BL/6 and ApoE −/− mice through hypophysectomy performed via the parapharyngeal approach, followed by a high-fat diet (HFD), resulting in the C57-Hx and ApoE −/− -Hx models. AS was evaluated by measuring arterial lipid deposition, plaque progression, collagen loss, vascular inflammation, and oxidative stress. Serum metabolite alterations were assessed using liquid chromatography-mass spectrometry (LC-MS). RNA sequencing was employed to examine the underlying mechanisms of GH in the context of AS treatment, with findings further confirmed through western blot analysis. In vitro experiments involved treating VSMCs with oxidized low-density lipoprotein (ox-LDL) to simulate atherosclerotic injury. The formation of foam cells was evaluated by measuring lipid accumulation, inflammatory responses, apoptosis, and the expression levels of foam cell-related markers. Finally, the PI3K/AKT inhibitor LY294002 confirmed that GH alleviates AS via the PI3K/AKT signaling pathway. Results scRNA-seq data analysis showed that growth hormone signaling was reduced in VSMCs of atherosclerotic arteries. HFD led to elevated levels of serum total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), accompanied by increased lipid deposition, inflammatory responses, and oxidative stress. In contrast, high-density lipoprotein cholesterol (HDL-C) and insulin-like growth factor 1 (IGF-1) levels were lower in C57-Hx mice. GH treatment improved HFD-induced AS in ApoE −/− -Hx mice. LC-MS analysis revealed that GH altered lipid metabolism in serum samples from C57-sham, C57-Hx, ApoE −/− -Hx, and ApoE −/− -Hx-GH(3) mice. GH maintained lipid balance by increasing 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), PE-NMe2(18:1(9z)/18:1(9z)) (DMPE), and 4-chloro-2-nitrobenzylalcohol levels and decreasing 1-heptadecanoyl-sn-glycerol-3-phosphocholine. RNA sequencing showed significant gene expression differences in the aortas of C57-sham and C57-Hx mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that GH inhibited the progression of AS by modulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, a finding that was validated through western blotting. Further in vitro studies demonstrated that GH exerted protective effects on VSMCs against ox-LDL-induced damage through activation of the PI3K/AKT pathway, as evidenced by experiments using the specific PI3K inhibitor LY294002. Conclusion GH alleviates the development of AS through the activation of the PI3K/AKT pathway. The findings of this research emphasize the therapeutic potential of GH in inhibiting AS and highlight the importance of the PI3K/AKT pathway as a promising target for clinical intervention.
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Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-16
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IF 9.6
Jing Yukai,Zhang Yunfei,Wang Xiaocui,Wang Yufen,Hu Ying,Wen Bin,Dai Xin,Duan Xuemei,Li Haonan,Dong Shumin,Yan Ze,Fan Yufeng,Wang Cong-yi,Liu Xiansheng,Zhang Ruiping
Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by the overproduction of autoantibodies and type I interferon, which damages its own tissues, causing multiple organ damage. B cells are thought to play a major role in the pathogenesis of SLE. As a DNA methylation reader, Methyl-CpG-binding domain protein 2 (MBD2) has been extensively studied in the contexts of innate immunity, adaptive immunity, and autoimmune diseases. However, its specific role in B cells and SLE remains unexamined. Herein, we found that MBD2 was highly expressed in B cells of SLE patients and positively correlated with disease activity. Knockout of MBD2 in B cells disturbed B-cell differentiation, dampened B-cell activation, B-cell receptor (BCR) signaling, and T-cell-dependent humoral immune responses in mice. What’s more, MBD2 deficiency effectively attenuated lupus-like symptoms, reduced the germinal center responses, and decreased anti-dsDNA antibodies in lupus model mice. Mechanistically, MBD2 selectively bound to the methylated CpG of Lef-1 induced by IFN-α, inhibiting the transcription and expression of Lef-1 , which repressed Pten transcription and expression, thereby promoting PI3K-Akt-mTOR signaling. This study first demonstrated the role of MBD2 in the pathogenesis of SLE and provided a new target for SLE.
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Pharmaceutics
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2026
·Vol. 18
·期 1
·102
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IF 5.5
Yujing Huangfu,Wei Chen,Dandan Guo,Peiyao Wang,Aifang Li,Yi Yang,Shuxuan Li,Qianfang Wang,Baiyan Wang,Shuying Feng
Background: As a widely used chemotherapeutic agent, cisplatin frequently induces acute kidney injury (AKI), which severely compromises patient survival and limits its clinical use. While the natural flavonoid diosmetin (Dio) shows promise in mitigating cisplatin-induced nephrotoxicity, its clinical translation is challenged by poor solubility, low bioavailability, and incompletely elucidated mechanisms. This study aimed to overcome these limitations by developing a novel drug delivery system using the microalgae Dunaliella salina ( D. salina , Ds ) to load Dio ( Ds -Dio), thereby enhancing its efficacy and exploring its therapeutic potential. Methods: We first characterized the physicochemical properties of Ds and Dio, and then Ds -Dio complex was synthesized via co-incubation. Its nephroprotective efficacy and safety were systematically evaluated in a cisplatin-induced mouse AKI model by assessing renal function (serum creatinine, blood urea nitrogen), injury biomarkers, histopathology, body weight, and organ index. The underlying mechanism was predicted by network pharmacology and subsequently validated experimentally. Results: The novel Ds -Dio delivery system has been successfully established. In the AKI model, Ds -Dio significantly improved renal function and exhibited a superior protective effect over Dio alone; this benefit is attributed to the enhanced bioavailability provided by Ds carrier. In addition, Ds -Dio also demonstrated safety performance, with no evidence of toxicity to major organs. Network pharmacology analysis predicted the involvement of PI3K/AKT pathway, which was experimentally verified. Specifically, we confirmed that Ds -Dio alleviates AKI by modulating the PI3K/AKT pathway, resulting in concurrent suppression of NF-κB-mediated inflammation and activation of NRF2-dependent antioxidant responses. Conclusions: This study successfully developed a microalgae-based drug delivery system, Ds -Dio, which significantly enhances the nephroprotective efficacy of Dio against cisplatin-induced AKI. The nephroprotective mechanism is associated with modulation of the PI3K/AKT pathway, resulting in the simultaneous attenuation of oxidative stress and inflammation.
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