iScience
·
2023
·Vol. 26
·期 5
·106558-106558
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IF 5.8
Xuelian Zhang,Ming Li,Wenjie Li,Linxiu Yue,Taiyuan Zhang,Qi Tang,Naidan Zhang,Xianyong Lan,Chuanying Pan
Chlorpyrifos (CPF) has been shown to have male reproductive toxicity in mice and rat. However, the association of CPF and male reproduction in pigs remains unknown. Therefore, this study attempts to investigate the damage of CPF on male reproduction in pigs and its potential molecular mechanisms. First, ST cells and porcine sperms were treated with CPF and then cell proliferation, apoptosis, motility of sperm, and oxidative stress levels were examined, respectively. Meanwhile, RNA sequencing was performed on ST cells before and after the treatment of CPF. The results of experiments in vitro showed that CPF had broad-spectrum toxic effects on ST cells and porcine sperms. The RNA-sequencing data and WB results indicated that CPF may regulate cell survival through the PI3K-AKT pathway. In conclusion, this study may lay the foundation for improving male fertility in pigs and provide theoretical information for human infertility.
研究领域:
生殖毒理学
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分子生物学
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动物科学
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PubMed
高影响因子
Scientific Reports
·
2026
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IF 4.9
Liu Siqi,Fang Fei,Jiang Yu
Chronic administration of glucocorticoids are being linked to an increased risk of osteoporosis. 5-Hydroxymethylfurfural (5-HMF) is a natural compound that possesses various biological activities, including osteogenic regulation. In this research, we sought to investigate the potential of 5-HMF to exert protective effects against glucocorticoid-induced osteoporosis. In cellular investigations, we deployed Western Blot (WB), Real-Time Quantitative real-time PCR (qRT-PCR), Alkaline phosphatase (ALP) and Alizarin S-red (ARS) staining to scrutinize the expression of osteogenic differentiation markers within MC3T3-E1 pre-osteoblasts and BMSCs. We used dexamethasone to establish a mouse model for glucocorticoid-Induced osteoporosis and administered 5-HMF to evaluate its influence on bone density and architecture through the use of micro-CT and histological analysis. In addition, we employed network pharmacology to elucidate the potential pathways and targets of 5-HMF. Finally, we explored the effect of AKT knockout on the treatment of 5-HMF. We found that 5-HMF significantly enhanced VEGFR2 phosphorylation, reestablishing angiogenesis and activating the PI3K/AKT pathway in vitro and in vivo. 5-HMF also inhibited Dexamethasone -induced apoptosis by regulating Bax and Bcl-2 expression. MK2206, an AKT inhibitor, abrogated 5-HMF’s protective properties against GCs. These results indicate that 5-HMF counteracts the negative effects of GCs on osteoblasts and has good bone-promoting differentiation effects.
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TISSUE & CELL
·
2023
·
IF 2.6
Ying Wang,Yongjun Li,Dongxia Liu
Background This study aimed to investigate role of erythropoietin in atherosclerosis and explore whether underlying mechanism is associated with PI3K/AKT/mTOR pathway. Methods High-fat-diet-induced atherosclerosis model was established in apolipoprotein E knockout mice (C57BL/6 genetic background). Mice were randomly divided into the control group and the EPO group. Hematoxylin-eosin was performed for the determination of atherosclerotic lesions. The expression levels of related proteins were detected by western blot analysis . Results Erythropoietin significantly enhanced the incidence of hemorrhage in atherosclerotic plaques compared with the control group. The proteins’ expression signaling pathways (including PI3K , AKT, and mTOR) and angiogenesis-related proteins (VEGF, COX-2, and HIF-1α) were proved to be up-regulated by erythropoietin. Additionally, erythropoietin significantly enhanced the incidence of hemorrhage in the atherosclerotic plaques compared with the control group. The vitro experiments were conducted in macrophages at 21% O 2 or 1% O 2 . The data showed that expression of p -PI3K, p -AKT, p -mTOR, VEGF, COX-2, and HIF-1α related proteins increased in 1% O 2 group than 21% O 2 group. Moreover, compared with control group, protein expression including p -PI3K, p -AKT, p -mTOR, VEGF, COX-2, and HIF-1α was markedly increased in EPO group, decreased in inhibitors group, and similar results were observed in EPO+ inhibitors group. Conclusion The present study demonstrated that erythropoietin might promote angiogenesis in atherosclerotic vulnerable by activating PI3K/AKT/mTOR signaling pathway in atherosclerotic, providing a novel therapeutic target for atherosclerotic targeted therapy.
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Experimental and Therapeutic Medicine
·
2018
·Vol. 17
·期 1
·393-397
·
IF 1.41
Rendong Wei,Haidong Liu,Ru Chen,Yunjian Sheng,Tao Liu
Astragaloside Ⅳ (AS‑Ⅳ) in improving liver cirrhosis injury in rats and its effect on the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathway were observed. Rat model of liver cirrhosis was induced by injection of carbon tetrachloride (CCl4). A total of 36 Sprague‑Dawley (SD) rats were randomly divided into three groups: the normal control group (n=10), the model control group (n=13), and the AS‑Ⅳ group (n=13). The normal control group was injected with olive oil and given carboxymethyl cellulose (CMC)‑Na (10 ml/kg/day), the model control group was given CMC‑Na (10 ml/kg/day), and the AS‑Ⅳ group underwent intragastric administration of AS‑Ⅳ (20 ml/kg/day). The content of alanine transaminase (ALT) and aspartate transaminase (AST) of rats was detected. The levels of tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6 and IL‑1β in serum were detected via enzyme‑linked immunosorbent assay (ELISA). Hematoxylin and eosin (H&E) staining was applied to observe morphological changes in liver tissues. The expression of collagens in liver tissues was detected via Masson's trichrome staining. Additionally, the expression of proteins in liver tissues was detected via western blotting. Compared with those in the blank group, the levels of AST, ALT, TNF‑α, IL‑6 and IL‑1β were higher, the expression level of collagens in liver tissues was increased, and the expression ratios of phosphorylated (p)‑PI3K/PI3K, p‑Akt/Akt and p‑mTOR/mTOR proteins were increased in the model group. Compared with the model group, AS‑Ⅳ could significantly decrease the content of AST, ALT, TNF‑α, IL‑6 and IL‑β in serum of rats, obviously inhibit the expression of collagens in liver tissues and decrease the expression ratios of p‑PI3K/PI3K, p‑Akt/Akt and p‑mTOR/mTOR proteins in liver tissues. AS‑Ⅳ can inhibit the inflammatory response so as to reduce the expression of collagens, and its mechanism may play a key role by inhibiting the PI3K/Akt/mTOR signaling pathway.
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Oncotarget
·
2017
·
IF 5.168
Jingwei Shao,Guirong Zheng,Hongning Chen,Jian Liu,Aixiao Xu,Fan Chen,Tao Li,Yusheng Lu,Jianguo Xu,Ning Zheng,Lee Jia
Therapies targeting epidermal growth factor receptor (EGFR) can effectively treat with non-small cell lung cancer (NSCLC), but NSCLC’s drug resistance makes it intractable. Herein, we showed that RU486 metabolite metapristone inhibited the proliferation of various NSCLC cell lines with either wild (A549, H1299, H520) or mutated EGFR (H1975, HCC827). The suppression was resulted from inhibition by metapristone of EGFR signaling pathways through down-regulating the EGFR, PTEN, as well as AKT and ERK proteins. In addition, metapristone inhibited anti-apoptotic marker Bcl-2, and activated pro-apoptotic key signaling proteins caspase-3, and poly (ADP-ribose) polymerase. Metapristone induced A549 and H1975 cell cycle via arrest at the G0-G1 stage. What’s more, metapristone inhibited the growth of NSCLC xenografts in BALB/c nude mice through decreasing the expression of tumor growth biomarkers PCNA and EGFR. Taken together, the present study demonstrated that metapristone suppressed NSCLC proliferation by promoting apoptosis via decrease the cellular EGFR-mediated PI3K/AKT pathways. The results suggest metapristone a new treatment for EGFR-overexpressed NSCLC.
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JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2025
·
IF 4.9
Jiayin Zhang,Rong Zhang,Lemei Sun,Bingqi Chen,Xiaohan Li,Jing Duan
Urolithin A (UA), a gut microbiota-derived metabolite of ellagic acid, exhibits diverse biological activities. Emerging evidence suggests its anti-tumor potential, possibly mediated through gut microbiota modulation, yet its role in lung cancer remains unclear. In this study, UA dose- and time-dependently suppressed lung cancer cell proliferation. Mechanistically, UA triggered autophagy, as evidenced by increased LC3-II protein levels, and transcriptome analysis revealed this effect was mediated through inhibition of the PI3K/AKT/mTOR pathway. In vivo , UA supplementation markedly inhibited tumor growth in H1975 xenograft models, concomitant with enhanced autophagy and downregulation of associated proteins. Notably, 16S rRNA sequencing demonstrated that UA modulated gut microbiota composition, increasing Lactobacillus while decreasing Desulfovibrio abundance. Spearman’s correlation analysis further linked these microbial shifts to altered expression of autophagy-related genes. Collectively, our findings highlight UA as a promising gut microbial metabolite for lung cancer intervention via coordinated autophagy induction and microbiota remodeling.
研究领域:
癌症生物学
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微生物学
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药理学
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分子生物学
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Frontiers in Bioscience-Landmark
·
2024
·Vol. 29
·期 9
·325
·
IF 3.3
Ziwei Guo,Sixu Bao,Zehui Shi,Xuejiao Li,Peijin Li,Bin Zhong,Ming Zhang,Qiyong Wu
Background: Platelets have the hemostatic function, and their aberrant activation is associated with occlusive thrombus formation. Plasma exosomes are rich in platelets containing ubiquitin-specific peptidase 15 (USP15). Herein, we aim to explore the effect of USP15 on thrombosis, as well as expounding whether USP15 acts as an upstream target of FK506 binding protein 5 (FKBP5) to regulate occlusive thrombus formation. Methods: Washed human platelets were treated with thrombin for measurement of USP15 and FKBP5 expressions. USP15 loss/gain-of-function variant in HEK293 cells was performed by cell transfection, and the interaction between USP15 and FKBP5 was examined using immunoprecipitation and ubiquitination assays. Mice with USP15-knockout platelets (Plt USP15-/-) were modeled, and subjected to calculation of bleeding time, artery thrombosis imaging and clot retraction assay. FKBP5 expression and the inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE)/phosphatidylinositol 3-kinase (PI3K)/Rap1 pathway in wild-type and Plt USP15-/- mice-derived platelets were detected using Western blot. The activation of αIIbβ3 in washed platelets was analyzed using flow cytometry. Results: USP15 and FKBP5 expressions were upregulated in platelets after thrombin treatment. Following transfection of USP15 knockdown and USP15 overexpression plasmids into HEK293 cells, FKBP5 protein expression was downregulated by USP15 knockdown while being upregulated by USP15 overexpression. USP15 bound to FKBP5 and protected FKBP5 against ubiquitination. Knockdown of platelet USP15 prolonged bleeding time, inhibited arterial thrombosis and delayed clot retraction in mice. Knockdown of platelet USP15 also decreased protein expressions of FKBP5, IKBKE and Rap1, p-PI3K/PI3K ratio, and activation of αIIbβ3 in mice. Conclusion: USP15 knockdown in platelets affects thrombosis in mice by promoting the instability of FKBP5 to repress the activation of IKBKE/PI3K/Rap1 pathway-mediated αIIbβ3.
研究领域:
血液学
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分子生物学
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血栓
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细胞信号传导
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ACTA HISTOCHEMICA
·
2025
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IF 2.4
Xiaorui Dong,Xixi Chen,Mengling Xue,Yina Zhang,Peiyue Jiang
Background Cervical cancer (CC) is a common gynecological disease that seriously threatens women’s health. This study aims to explore key genes and pathways related to CC prognosis through bioinformatics, providing new insights for further treatment of CC. Methods CC patient data were analyzed from the public databases. The enrichment analyses explored the roles and pathways of CC-related differentially expressed genes (DEGs). A prognostic key gene was identified using Venn diagrams and subjected to survival analysis. Gene Set Enrichment Analysis (GSEA) was employed to investigate the potential pathways of key genes. Correlations between the key gene and clinical features were examined. The function of the key gene was validated through immunohistochemistry, flow cytometry, transwell, MTT, and Western blot assays in vitro and in vivo . Results Our research identified 2459 upregulated genes among DEGs between healthy and tumor cervical tissues. These DEGs were primarily enriched in the PI3K-AKT and MAPK pathways. Moreover, EFNA1 was recognized as a key prognostic gene in CC, with elevated expression compared to normal tissue. A negative correlation between EFNA1 levels and patient survival rates was corroborated by Kaplan-Meier analysis. Furthermore, EFNA1 expression correlated with the cancer stage and was linked to antigen presentation, folate synthesis, and IL-17 signaling. Knockdown of EFNA1 enhanced apoptosis and reduced migration, invasion, and proliferation in vitro and in vivo , inhibiting EMT and MAPK pathways. Conclusion This study revealed the key signaling pathways in CC progression and identified EFNA1 as a crucial prognostic biomarker, potentially impacting CC treatment.
研究领域:
肿瘤学
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生物信息学
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分子生物学
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HEREDITAS
·
2026
·Vol. 163
·期 1
·43
·
IF 2.6
Wu Ting,Jiang Jingwen,Zhang Yunfang,Zhang Hui,Fu Mingquan,Chen Fazhang,Fan Yilin,Yuan Huan,Wang Kaining
Background Colorectal cancer (CRC) remains one of the most commonly diagnosed malignancies worldwide and is associated with high recurrence and poor survival outcomes, particularly in its advanced stages. Zi-Shen-Gu-Sui Decoction (ZSGSD), a traditional Chinese medicinal formula, has been clinically applied in CRC treatment and postoperative rehabilitation; however, its pharmacological mechanisms are not yet fully elucidated. This study aimed to explore the anti-CRC efficacy and molecular mechanisms of ZSGSD, with particular attention to the PI3K/AKT/mTOR signaling axis. Methods UPLC-Q-Orbitrap HRMS was utilized to characterize the chemical profile of ZSGSD. Network pharmacology was employed to identify key signaling pathways and bioactive compounds, and molecular docking was conducted to predict potential interactions between major constituents and PI3K/AKT/mTOR proteins. A xenograft mouse model of CRC was established to evaluate tumor suppression. Histological staining was used to assess apoptosis, and the expression of PI3K, AKT, and mTOR was quantified via RT-qPCR, Western blotting, and immunofluorescence assays. Results Sixty compounds were identified in ZSGSD, with flavonoids comprising approximately 50%. Network analysis suggested potential involvement of the PI3K/AKT/mTOR pathway, and docking results indicated favorable predicted binding between key flavonoids (including Genistein, Apigenin, and Naringenin) and proteins within this pathway. In vivo, ZSGSD treatment suppressed tumor growth in a dose-responsive fashion, with tumor inhibition rates ranging from 30.83% to 75.23% ( p < 0.05). Histological evaluations revealed reduced nuclear-to-cytoplasmic ratios and enhanced apoptotic activity, as confirmed by TUNEL staining ( p < 0.05). Molecular analyses showed a dose-related reduction in PI3K, AKT, and mTOR expression at the transcript and protein levels, indicating that this pathway may be modulated during ZSGSD treatment ( p < 0.05). Conclusion ZSGSD demonstrates notable tumor-suppressive and pro-apoptotic effects in a CRC xenograft model. These outcomes appear to be associated with modulation of the PI3K/AKT/mTOR signaling pathway, although further functional studies are required to confirm pathway specificity and clarify causal mechanisms.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
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IF 2.5
Yaling Cheng,Chen Liang,Zhou Qi,Binbin Zhang,Shiwen Guo
Glioma is the most common primary intracranial tumor and is characterized by poor prognosis and high invasiveness. Currently, treatment options remain limited. Accumulating evidence has demonstrated the efficacy of diverse natural compounds in cancer treatment. In this study, we evaluated the anticancer effects of scutellarein on gliomas and its underlying mechanisms. Cell proliferation, migration, invasion, and apoptosis were evaluated by CCK-8 assay, colony formation assay, wound healing assay, Transwell assay, and flow cytometry. Network pharmacology, transcriptomics, and western blotting were conducted to investigate the underlying mechanisms. The in vivo effect of scutellarein was evaluated using an intracranial xenograft model. Our results showed that scutellarein significantly inhibited proliferation, invasion, and migration of glioma cells. Furthermore, scutellarein induced glioma cell apoptosis by triggering oxidative stress. This was evidenced by the elevation of reactive oxygen species and malondialdehyde, alongside the suppression of superoxide dismutase and catalase activities. Network pharmacology and transcriptomic analyses suggested that scutellarein may target SRC, EGFR, and AKT1; and exerts its effects through the PI3K/AKT signaling pathway, which was subsequently verified by further experiments. Rescue experiments showed that activation of the PI3K/AKT signaling pathway markedly reversed scutellarein-induced apoptosis and oxidative stress. In an intracranial xenograft model, mice treated with scutellarein survived significantly longer. Moreover, no significant histological differences were observed in the hearts, lungs, spleens, livers, and kidneys of treated mice compared with the controls. In conclusion, our study demonstrates that scutellarein inhibits glioma proliferation, invasion, and migration by modulating the PI3K/AKT signaling pathway and inducing oxidative stress, showing promising therapeutic potential.
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PHYTOTHERAPY RESEARCH
·
2026
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IF 8.1
Pengru Wang,Xin Hu,Haiyan Pu,Junjie Bai,Lei Sun,Tingting Ma,Yichao Du,Wenguang Fu
Hepatic ischemia–reperfusion (I/R) injury complicates transplantation, resection, and shock, yet lacks effective pharmacotherapy. We evaluated Leonurine (SCM-198) as a hepatoprotective agent. Male C57BL/6 mice were pretreated with SCM-198 for 7 days, then subjected to hepatic I/R and sampled at the reperfusion endpoint. AML12 cells were pretreated with SCM-198 for 24 h, exposed to hypoxia/reoxygenation (H/R), and immediately analyzed. Injury, inflammation, apoptosis, and cell-cycle changes were assessed using assay kits, histology, IHC, WB, and qPCR; network pharmacology, docking, and MD simulations explored potential targets. SCM-198 sharply cut hepatic necrosis and serum transaminases, suppressed pro-inflammatory cytokines, reduced leukocyte infiltration, blocked apoptosis and restored cyclin D1/cyclin E1. In hypoxia-reoxygenation AML12 cells, it improved viability, limited oxidative stress and mirrored the anti-apoptotic effects. Network and dynamic simulation identified stable phosphoinositide 3-kinase (PI3K) binding, and the compound raised PI3K, protein kinase B and mammalian target of rapamycin phosphorylation; the PI3K inhibitor LY294002 abolished these changes. SCM-198 protects liver I/R by curbing inflammation, apoptosis, and cell-cycle arrest via PI3K/AKT/mTOR activation, offering a promising therapeutic candidate.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2017
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IF 2.956
Qianyun Chen,Xueyun Duan,Heng Fan,Meng Xu,Qing Tang,Lijuan Zhang,Zhexing Shou,Xingxing Liu,Dongmei Zuo,Jia Yang,Shuangjiao Deng,Yalan Dong,Hui Wu,Yujin Liu,Zhen Nan
Oxymatrine (OMT), an alkaloid derived from the root of the Sophora flavescens , has been reported to possess a significant effect on relieving UC owing to its anti-inflammatory property. But the other therapeutic mechanism of OMT remains unclear. Recent studies have found, PI3K/AKT signaling pathway is involved in the pathogenesis of UC by pro-inflammatory effects and activating T cells . Moreover, PI3K/AKT pathway is one of the most important pathways for regulating cell apoptosis . Thus, we aim to explore whether OMT protects against UC by targeting PI3K/AKT pathway. We established the UC mice models, using LY294002 (a specific inhibitor of PI3K/AKT) as a positive control, to observe the effect of low, medium and high dose of OMT on UC and its influence on PI3K/AKT signaling pathway. Our data indicated that OMT can significantly ameliorate UC through anti-inflammatory, pro-apoptotic, down-regulating the differentiation of Th1 and Th17 cells via PI3K/AKT pathway. This study reveals that PI3K/AKT signaling pathway is a potential mechanism of OMT-induced UC remission and suggests that OMT is a promising therapeutic agent for the treatment of UC.
研究领域:
药理学
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免疫学
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胃肠病学
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