Cancer Biomarkers
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2019
·Vol. 25
·期 2
·193-201
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IF 2.859
Xu Jin-huan,Wang Yan,Xu Dong
Circular RNAs (circRNAs) have gained attention for their involvement in carcinogenesis, but its functional effects in breast cancer (BC) remains largely unclear. In this study, we aimed to explore the expressing pattern, clinical significance and potential function of a newly identified circRNA, hsa_circ_001569, in BC. RT-PCR was performed to detect the expression of hsa_circ_001569 in both BC tissues and cell lines. The associations between hsa_circ_001569 expression and clinicopathological features and prognosis in BC patients were statistically analyzed. Next, we investigated the effects of hsa_circ_001569 on the proliferation, apoptosis, migration and invasion in BC cells lines. The effects of abnormal hsa_circ_001569 expression on EMT pathway and PI3K/AKT pathway were determined using Western blot. We found that hsa_circ_001569 expression was significantly up-regulated in both BC tissues and cell lines. Overexpression of hsa_circ_001569 was associated with Lymph node metastasis, advanced clinical stage and shorter overall survival. Multivariate assay confirmed that hsa_circ_001569 expression was an independent prognostic factor for 5-year overall survival. Furthermore, functional investigations revealed that knockdown of hsa_circ_001569 significantly suppressed the growth and metastatic potentials of BC cells. Besides, molecular mechanistic study revealed that depression of hsa_circ_001569 impeded the activation of PI3K-AKT signaling in BC cells. Our results indicated that hsa_circ_001569 upregulation was associated with BC lymph-node metastasis, clinical stage, and poor prognosis. Hsa_circ_001569 might contribute to progression of BC by modulating PI3K-AKT pathway.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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高影响因子
TISSUE & CELL
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2022
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IF 2.586
Xinyan Huang,Songzhao Zhang,Wenxi Wang
Purpose Artesunate (ART) is recognized for its anticancer activity , but a few studies concentrate on its anti-skin cancer effect. This study emphazied this aspect and preliminarily discussed the impact and mechanism of ART on cutaneous squamous cell carcinoma (CSCC). Methods The viability of HaCaT and CSCC cells treated with ART (0, 30, 60, 90, 120, 150, 180, or 210 μmol/L) for 48 h were assessed utilizing cell counting kit-8. Next, the migration, invasion, proliferation, apoptosis, and cell cycle of CSCC cells treated with ART were evaluated by dint of cell function experiments. Then, cell cycle-, apoptosis-, and phosphatidylinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway-related markers were examined via western blot or quantitative real-time PCR. Moreover, the influences of ART and PI3K/AKT agonist IGF-I on CSCC cell biological behaviors were gauged again. Results The suppressive role of ART (30, 60, 90, 120, 150, 180, or 210 μmol/L) was stronger in viability of CSCC cells than in viability of HaCaT cells. ART evidently attenuated the migration, invasion and proliferation, lessened cell numbers at G2/M phase and triggered apoptosis of CSCC cells. At the molecular level, ART regulated cell cycle-, apoptosis-, and PI3K/AKT pathway-related markers in CSCC cells. Moreover, the suppression of ART on CSCC cell malignant phenotypes was reversed by PI3K/AKT agonist IGF-I. Conclusion ART restrains the malignant progression of CSCC, which may be intensely related to the PI3K/AKT pathway repression.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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药理学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
·
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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Pharmaceutics
·
2026
·Vol. 18
·期 1
·102
·
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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Frontiers in Bioscience-Landmark
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2026
·Vol. 31
·期 8
·
IF 4.1
Jinhui Zhang,Chao Wei,Dongyan Wang,Renmi He,Xiangdan Xiao,Jianwei Xu,Junhou Lu
Background: Glioblastoma is the most aggressive primary malignant brain tumor of the central nervous system and remains difficult to treat because of rapid progression, diffuse invasion, and frequent recurrence. This study aimed to identify a potential natural compound against glioblastoma using a reverse network pharmacology strategy and to investigate its anti-glioma effects and underlying mechanism. Methods: Glioblastoma-related targets were collected from public disease databases and integrated with differentially expressed genes from a public transcriptomic dataset to identify intersecting targets. Protein-protein interaction analysis, hub target screening, functional enrichment analysis, and reverse network pharmacology were performed to identify candidate compounds. Molecular docking and 100-ns molecular dynamics simulations were used to assess interactions between 20-hydroxyecdysone and pathway-related targets. Cell viability, colony formation, apoptosis, migration, and protein expression were examined in U251 and U87 glioma cells. Statistical differences were analyzed using a paired Student’s t-test for two-group comparisons or one-way analysis of variance (ANOVA) followed by Dunnett’s multiple-comparisons test for multi-group comparisons, as appropriate. Results: A total of 136 intersecting targets and 18 hub targets were identified. Functional enrichment analysis indicated that the phosphatidylinositol 3-kinase/protein kinase B signaling pathway was one of the key enriched pathways. Reverse network pharmacology identified 20-hydroxyecdysone as a candidate compound. Molecular docking showed relatively strong binding of 20-hydroxyecdysone to epidermal growth factor receptor, fms-related receptor tyrosine kinase 1, and integrin subunit alpha 5, and molecular dynamics simulations supported the stability of these complexes. In vitro experiments showed that 20-hydroxyecdysone inhibited cell viability, clonogenicity, and migration, while promoting apoptosis. It also reduced the phosphorylation levels of phosphatidylinositol 3-kinase, protein kinase B, and glycogen synthase kinase 3 beta at Ser9 without markedly altering total protein expression. Conclusion: Treatment with 20-Hydroxyecdysone showed anti-glioma activity in vitro and may exert its effects, at least in part, through suppression of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway. These findings support its further evaluation as a potential therapeutic candidate for glioblastoma.
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Cell and Bioscience
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2026
·Vol. 16
·期 1
·88
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IF 6.5
Chen Xin,Zhang Qing,Xie Fen,Zhai Huilan,Li Chuanhong,Zhou Weifeng,Zhang Nuobei
Background Hepatocellular carcinoma (HCC) is a lethal malignancy driven by cancer stem cells, which drive progression and therapeutic resistance. Nuclear pore protein ELYS is implicated in tumorigenesis, but its role in HCC stemness remains unclear. Methods Transcriptome sequencing identified ELYS-induced differentially expressed genes (DEGs). Functional impacts of ELYS on malignant phenotypes and stemness were assessed in vitro. Signaling pathway activation was confirmed using inhibitors of Hedgehog (GANT-61) and AKT (MK-2206 2HCl). Bioinformatics analysis, luciferase reporter, and ChIP assays elucidated the FOXO6-NUP205 axis. Xenograft models validated the findings in vivo. Clinical relevance was evaluated using TCGA-HCC data and immunohistochemistry in clinical samples. Results DEGs in ELYS-overexpressing cells were enriched in PI3K/AKT and Hedgehog (Hh) pathways. ELYS facilitated Gli-1 nuclear translocation by activating PI3K/AKT, placing it upstream of Hh. Bioinformatic and experimental analyses identified FOXO6 and its target NUP205 as key effectors. ELYS upregulated FOXO6, which directly activated NUP205 transcription. FOXO6 knockdown suppressed ELYS-induced effects on NUP205, Gli-1 nuclear translocation, and stemness factors. In vivo, ELYS promoted tumor growth and lung metastasis via PI3K/AKT/Hh. Clinically, ELYS, FOXO6, and NUP205 were overexpressed in HCC, correlating with advanced features and poor survival. Conclusion This study defines an oncogenic axis wherein ELYS promotes HCC stemness and metastasis by activating PI3K/AKT, triggering a FOXO6-NUP205 cascade to drive Hedgehog, representing a pivotal mechanism and therapeutic target. Graphical abstract
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IMMUNOLOGY
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2026
·
IF 5.4
Sisi Zhang,Zhou Jingxiang,Caixia Tan,Yuanyuan Xiao,Ju Zou,Biyue Tian,Anhua Wu,Chunhui Li
Clostridioides difficile infection (CDI) remains a major cause of antibiotic-associated colitis and is characterized by excessive intestinal inflammation, epithelial barrier disruption and impaired mucosal repair. Although sodium butyrate (NaB), a microbiota-derived short-chain fatty acid, has demonstrated anti-inflammatory and barrier-protective properties, the immunological mechanisms underlying its protective effects during CDI remain incompletely understood. In this study, we investigated the role of NaB in regulating macrophage polarization and epithelial repair using murine CDI models, primary bone marrow-derived macrophages, THP-1-derived macrophages, Caco-2 epithelial cells and macrophage–epithelial co-culture systems. NaB treatment significantly alleviated CDI-associated weight loss, colonic shortening, histopathological injury and inflammatory cytokine production while restoring epithelial barrier integrity and tight junction protein expression. Mechanistically, NaB promoted macrophage polarization towards an anti-inflammatory M2 phenotype, characterized by increased CD206 and IL-10 expression and reduced CD86 and IL-1β expression. These immunomodulatory effects were accompanied by suppression of PI3K/Akt/mTOR signalling in both colonic tissues and macrophages. Pharmacological inhibition and activation studies further supported the involvement of this pathway in NaB-mediated macrophage reprogramming. Importantly, conditioned medium from NaB-treated macrophages enhanced epithelial viability, migration and barrier-associated protein expression, whereas IL-10 neutralization partially abolished these protective effects, highlighting a critical role for macrophage–epithelial crosstalk. Collectively, our findings demonstrate that low-dose NaB protects against CDI-induced intestinal injury through coordinated regulation of macrophage polarization and epithelial barrier repair, at least in part via modulation of PI3K/Akt/mTOR signalling. These results identify NaB as a promising host-directed therapeutic strategy for CDI and provide new insights into microbiota-derived metabolite–immune interactions during intestinal inflammation.
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KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
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2026
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IF 3.1
Shan-Shan Wang,Hong-Cheng Wei,Lin Jiang,Yi-Sen Shao
Tongue squamous cell carcinoma, the most aggressive subtype of oral squamous cell carcinoma, which is associated with high mortality, frequent recurrence, and early lymph-node metastasis. Triptolide, a bioactive diterpenoid from Tripterygium wilfordii , exhibits broad anticancer activity. Although its inhibitory action on OSCC has been established, its specific molecular regulatory mechanisms in TSCC, a distinct and aggressive subtype, remain largely underexplored. The present study investigates the regulatory role of triptolide in the PI3K–AKT signaling pathway, which is a critical axis intimately linked to tumor survival and metastasis. A network-pharmacology workflow was used to intersect triptolide putative targets with TSCC-related genes. Core hubs were identified with Cytoscape; KEGG and GO analyses highlighted the PI3K–AKT axis as the top enriched pathway. Binding kinetics were quantified by molecular docking and surface plasmon resonance (SPR). Cellular assays (CCK-8, Transwell, wound-healing, Western blot and immunofluorescence) validated the predictions. We retrieved 389 common targets and shortlisted eight key nodes (JUN, MAPK1, MAPK3, AKT1, TP53, BCL2, STAT3, MYC). SPR revealed high-affinity binding of triptolide to AKT1 and PI3K. Functionally, triptolide dose-dependently suppressed TSCC cell proliferation, invasion, and migration, downregulated PI3K–AKT signaling proteins, and reduced the colocalization and phosphorylation levels of p-PI3K and p-AKT. This study is the first to demonstrate the pivotal role of the PI3K–AKT signaling pathway in mediating the antitumor effects of triptolide in tongue squamous cell carcinoma. Our findings thereby provide a novel theoretical foundation for the development of traditional Chinese medicine-based therapeutic strategies targeting this malignancy.
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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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Pharmaceuticals
·
2026
·Vol. 19
·期 6
·965
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IF 5.7
Mei Mei,Huawei Sun,Kai Zhang,Feng Zhang,Shiqing Sun,Enbin Yu,Yu Zhang
Background:To investigate the protective effects ofPhellodendron amurenseRupr. polysaccharides (PAP), alkaloids, and flavonoids in alleviating diabetic kidney disease (DKD) and to elucidate the role of the PI3K/AKT/GSK-3β/Nrf2 signaling pathway.Methods:Active components were extracted and quantified. In vitro, high-glucose (HG)-induced human kidney-2 (HK-2) cells were used to screen the optimal fraction via CCK-8, reactive oxygen species (ROS), TdT-mediated dUTP Nick-End Labeling (TUNEL), and Western Blot (WB) assays. In vivo, a DKD rat model was established using 2% Streptozotocin (STZ) and a high-fat with high-sugar diet. Rats were treated with PAP and LY294002. Renal damage and signaling pathway proteins were evaluated using histological staining and WB.Results:Among the tested components, PAP conferred the most pronounced cytoprotection against HG-induced injury in HK-2 cells. PAP significantly reduced glomerular damage, collagen deposition, and glycogen accumulation in the kidneys of DKD rats. Mechanistically, PAP activated the PI3K/AKT/GSK-3β/Nrf2 pathway, upregulating HO-1 and NQO1, while inhibiting the TGF-β1/Smad2 pathway and Bcl-2/Bax-mediated apoptosis. These protective effects were significantly attenuated by LY294002.Conclusions:Among the tested fractions under the present experimental conditions, PAP exhibited the most pronounced protective activity. These protective effects were partially mediated through the PI3K/AKT/GSK-3β/Nrf2 pathway, which enhanced antioxidant capacity while reducing fibrosis and apoptosis.
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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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