INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Xinyi Li,Hui Song,Yiwen Yuan,Na Jiang,Wei Duan,Tianzhao Xu,Chang Liu,Xinghui Liu
Cardiovascular diseases have long posed a significant threat to public health. Among them, myocarditis is a major category of cardiovascular disorders that is characterized by high mortality during its acute phase, necessitating urgent medical attention. This study aims to explore the therapeutic effects and underlying mechanisms of Spi1-mediated gene regulation in chemotherapy induced cardiomyopathy. To validate our findings, we employed bioinformatics analysis methods and established myocarditis models using the chemotherapeutic drug doxorubicin in both cellular and animal models. Our results demonstrated that the inhibition of Spi1 significantly suppressed inflammatory factor expression in H9C2 rat cardiomyocytes. Furthermore, in C57BL/6 mouse model, Spi1 inhibition was shown to improve cardiac function and alleviate both myocardial inflammation and fibrosis in mice with doxorubicin-induced myocarditis. Mechanistic investigations revealed that Spi1 suppression altered the expression of genes associated with immune response, cell differentiation and proliferation. Notably, Spi1 modulates the expression of YTHDF2, thereby influencing the PI3K/AKT/mTOR signaling pathway and subsequently regulating the inflammatory response. Collectively, these findings suggest that Spi1 plays a pivotal role in doxorubicin-induced myocarditis by mitigating inflammatory responses and myocardial injury through the regulation of YTHDF2 and the PI3K/AKT/mTOR signaling pathways, offering a promising therapeutic target for the treatment of myocarditis.
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Journal of Inflammation Research
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2025
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IF 4.1
Mingyang Gu,Jiongbo Xu,Zhihan Liao,Jinhai Lin,Rui Li,Wei Wu,Yijun Qiu
Purpose: Modulation of the AKT signaling pathway can effectively regulate endoplasmic reticulum stress (ERS) and inhibit ischemia-induced cardiomyocyte apoptosis in myocardial ischemia-reperfusion injury (MIRI). The present study was designed to investigate the role of AKT and ERS in the modulation of MIRI by Huanglian Jiedu Decoction (HLJDD) through in vitro and in vivo experiments.Methods: In vivo studies employed a rat model of MIRI with three HLJDD dosage groups and a nicorandil control group. Comprehensive evaluations were conducted, including assessments of cardiac function, histopathological analysis, apoptosis detection, and immunohistochemical examination of ERS markers. For in vitro validation, H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation conditions, and cellular viability assays were combined with ultrastructural and molecular analyses. Investigations guided by network pharmacology focused on the PERK/eIF2α/CHOP signaling pathway and AKT phosphorylation.Results: HLJDD demonstrated dose-dependent cardioprotective effects through attenuation of myocardial apoptosis and ERS activation. Mechanistic studies revealed its ability to restore AKT phosphorylation and suppress the PERK/eIF2α/CHOP signaling cascade. The cardioprotective effects were abolished upon AKT inhibition, thereby confirming the specificity of this pathway.Conclusion: HLJDD may serve as a potential therapeutic candidate for ischemia-induced cardiomyocyte apoptosis during MIRI. HLJDD exerts its effects by inhibiting the AKT-mediated PERK/eIF2α/CHOP signaling pathway, attenuating ERS and thereby reducing MIRI-induced apoptosis.
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Results in Chemistry
·
2025
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IF 4.2
Jiabao Cai,Qian Zhang,Jiani Fan,Shengguang Chen
Baicalin, a flavonoid derived from Scutellaria baicalensis, exhibits broad antitumor activity. However, its effects on anaplastic thyroid cancer (ATC) C643 cells remain unclear. This study investigated the inhibitory capacity and underlying mechanisms of baicalin against C643 cells using both in vitro and in vivo models. In vitro, including CCK-8 viability assay, scratch-wound healing assay, Transwell migration, Annexin V-FITC/PI apoptosis, cell-cycle and JC-1 mitochondrial membrane potential assays demonstrated that baicalin reduced cell viability and migration in a concentration-and time-dependent manner, induced G2-phase arrest and decreased mitochondrial membrane potential. Integrated transcriptome sequencing identified BCL2 and the PI3K-AKT pathway as key targets. qPCR and Western blot confirmed that baicalin down-regulated BCL2 in a dose-dependent manner, selectively activated the PI3K-AKT cascade, promoted TP53 recruitment to the BAX/BIM promoters and up-regulated their transcription, accompanied by increased p-PI3K and p-AKT levels. In vivo, daily intraperitoneal administration of 50 mg/kg baicalin for 21 days led to a 55.6 % reduction in C643 xenograft volume. Immunohistochemistry revealed decreased BCL2 and Ki-67 expression in tumor tissues, indicating impaired anti-apoptotic activity and proliferative capacity. Importantly, histopathological examination of major organs (heart, liver, spleen, lung and kidney) showed no treatment-related toxicity, confirming the safety of baicalin. These findings demonstrate that baicalin is a safe, multi-target therapeutic candidate with a well-defined mechanism, offering a novel and effective targeted option for aggressive anaplastic thyroid cancer.
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LIFE SCIENCES
·
2025
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IF 5.1
Wen Zhang,Manzhi Qi,Xiaojing Zhao,Ying Zhong,Weilong Xu,Liang Sheng,Liu Yang
Background Hepatic steatosis is a hallmark of alcohol-associated liver disease (ALD) and interacts with hepatic inflammation to drive disease progression. NF-κB-inducing kinase (NIK) has been established as a bridge linking inflammation to steatosis in ALD. Intriguingly, while hepatocyte-specific NIK deficiency attenuated ALD in the chronic-plus-binge model, it paradoxically exacerbated the disease under chronic ethanol exposure, suggesting a complex, context-dependent role for NIK. Methods To elucidate the mechanism underlying this protective effect in chronic ethanol exposure, we employed transcriptomics and proteomics analyses in hepatocyte-specific NIK knockout (NIK Δhep ) mice. Key findings were validated using immunoblotting, co-immunoprecipitation, and loss-of-function experiments both in vivo and in vitro. Results We demonstrated that NIK deficiency activated AKT, enhancing ATP-citrate lyase (ACLY)-mediated lipogenesis. Transcriptomics and proteomic screening identified inositol polyphosphate-5-phosphatase B (INPP5B) as the critical mediator suppressing AKT signaling downstream of NIK. Furthermore, we mechanistically established that NIK stabilizes INPP5B by recruiting it into the adaptor protein APPL1 complex, thereby reducing its ubiquitination and subsequent degradation. Conclusion Our study unveils a novel protective dimension of NIK, whereby it ameliorates chronic ethanol-induced hepatic steatosis by stabilizing INPP5B to suppress the AKT/ACLY lipogenic pathway. This finding provides a crucial mechanistic explanation for the context-dependent functions of NIK in ALD and redefines its role as a potential metabolic safeguard in chronic liver disease.
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CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
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2021
·Vol. 99
·期 12
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IF 2.273
Dongdong Zhang,Dongxu Qi,Yi Xu,Chunhe Hu,Xiao Zhang,Qingjian Yang,Zikun Shang,Guisheng Zhang
Skin flap transfer is an important method to repair and reconstruct various tissue defects; however, avascular necrosis largely affects the success of flap transfer. The sphingosine 1-phosphate receptor 1 (S1PR1) agonist SEW2871 has been proven to ameliorate ischemic injury; however, its effect on flap survival has not been reported. In this study, an experimental skin flap model was established in rats to investigate the roles of SEW2871. The results indicated that SEW2871 greatly increased the survival of the skin flap, alleviated pathological injury, promoted the angiogenesis, and inhibited cells apoptosis in skin flap tissues. SEW2871 activated S1PR1 downstream signaling pathways, including heat shock protein 27 (HSP27), extracellular regulated protein kinases (ERK), and protein kinase B (Akt). In addition, SEW2871 promoted the expression of S1PR1. These findings may provide novel insights for skin flap transfer.
研究领域:
药理学
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外科手术
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分子生物学
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Foods
·
2025
·Vol. 14
·期 24
·4267
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IF 5.1
Jing Xu,Wen-Zhao Wen,Jun-Hui Zhao,Jun-Rong Guo,Zhuo-Ya Zhang,Ping Xiong
Citri grandis exocarpium ( Citri grandis ) has been consumed by human beings for fifteen hundred years. It is commonly consumed as a health drink and dietary supplement in China. However, its nutritional and healthcare functions are still not fully understood. Objective: Our previous study found that oral administration of Citri grandis extract can significantly decrease the blood lipid levels of hyperlipidemic mice fed a high-fat diet. The aim of this study was to confirm the preventative effects of Citri grandis extract against atherosclerosis. Methods: Atherosclerotic lesion models were induced in HUVECs and apoE −/− C57BL/6J mice. ApoE −/− mice fed a high-fat diet were orally administered Citri grandis extract (0.4, 0.8, and 1.6 g/kg/d BW) and Simvastatin (1 mg/kg/d BW) on the first day of model establishment. After a 16-week treatment, serum samples and aorta and liver tissues were collected. Observation of pathological changes in aortic and liver tissues was performed using a light microscope with oil red O, H&E, Masson’s trichrome staining, and TEM. Biochemical detection was employed to determine the serum levels of TC, TG, LDL-C, and HDL-C as well as the activities of AST and ALT. In addition, expression studies of TGF-β, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1 were performed via qPCR and Western blot analysis. Results: Compared with cholesterol-induced HUVECs, Citri grandis extract significantly enhanced cell viability, attenuated the morphological changes in HUVECs, and reduced LDH release. Furthermore, after treatment with Citri grandis extract, the levels of TC, TG, and LDL-C significantly decreased in the atherosclerosis model apoE −/− mice after 16 weeks, and aortic plaque, lipid deposition, and endothelial injury were obviously ameliorated. The mRNA and protein expression of TGF-β, PPAR-γ, LXR-α, and ABCA1 in aortic and liver of atherosclerosis apoE −/− mice were upregulated ( p < 0.05, p < 0.01), while those of PI3K and Akt1 were suppressed ( p < 0.05, p < 0.01). Conclusions: Citri grandis extract can significantly decrease the high circulating lipid levels and the liver lipid deposition of high-fat-diet-fed apoE −/− mice and reduce aorta lipid accumulation and atherosclerotic plaques by regulating the expression of TGF-β1, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1. Citri grandis extract can be used as a healthcare dietary supplement for the prevention of abnormal lipid metabolism and atherosclerosis.
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Oxidative Medicine and Cellular Longevity
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2018
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IF 4.936
Liming Yu,Zhi Li,Xue Dong,Xiaodong Xue,Yu Liu,Shu Xu,Jian Zhang,Jinsong Han,Yang Yang,Huishan Wang
Diabetes exacerbates oxidative/nitrative stress during myocardial ischemia-reperfusion (MI/R) injury. Recent studies highlighted the cardioprotective actions of polydatin. However, its effect on diabetic MI/R injury and the underlying mechanisms remain unknown. This work was undertaken to evaluate the effect of polydatin on diabetic MI/R injury with a focus on Notch1/Hes1 signaling and myocardial oxidative/nitrative stress. Streptozotocin- (STZ-) induced diabetic rats were administered with polydatin (20 mg/kg/d) in the absence or presence of DAPT (a γ-secretase inhibitor) or LY294002 (a PI3K/Akt inhibitor) and then subjected to MI/R injury. Polydatin administration preserved cardiac function and reduced myocardial infarct size. Moreover, polydatin ameliorated myocardial oxidative/nitrative stress damage as evidenced by decreased myocardial superoxide generation, malondialdehyde, gp91phox expression, iNOS expression, NO metabolite level, and nitrotyrosine content and increased eNOS phosphorylation. However, these effects were blocked by DAPT administration. DAPT also inhibited the stimulatory effect of polydatin on the Notch1/Hes1-Pten/Akt signaling pathway in a diabetic myocardium. Additionally, LY294002 not only abolished polydatin’s antiapoptotic effect but also reversed its inhibitory effect on myocardial oxidative/nitrative stress. Polydatin effectively reduced MI/R injury and improved left ventricular functional recovery under diabetic condition by ameliorating oxidative/nitrative stress damage. Importantly, Notch1/Hes1-mediated activation of Pten/Akt signaling played a crucial role in this process.
研究领域:
心脏病学
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药理学
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分子生物学
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糖尿病研究
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PHYTOMEDICINE
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2026
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IF 11.3
Qiaomei Zheng,Xia Zhang,Shaozhan Chen,Shaoyu Wang,Lihong Chen,Jinhua Wang
Purpose This study investigated indirubin's effects on ovarian cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), both in vitro and in vivo, while exploring its underlying mechanisms. Methods The anti-tumor activity of indirubin was evaluated using ovarian cancer cell lines (A2780, SKOV-3, OVCAR-3) through MTT, colony formation, wound healing, and Transwell assays. Patient-derived organoids and a nude mouse xenograft model were employed for further validation. Mechanistic studies integrated bioinformatics analysis (SymMap database and transcriptome sequencing) with experimental assessment of EMT markers and PI3K/AKT pathway activity, including the use of specific inhibitors (MK2206, SB 216763). Results Indirubin significantly suppressed ovarian cancer cell proliferation, colony formation, migration, and invasion, as well as inhibited patient-derived organoid growth. In a xenograft model, indirubin effectively attenuated tumor growth without inducing pathological changes in major organs. Through SymMap database and transcriptomic analyses, indirubin was shown to modulate multiple signaling pathways, particularly impairing cell adhesion. Mechanistically, indirubin downregulated AKT and GSK-3β phosphorylation in the PI3K/AKT pathway, and upregulated E-cadherin while suppressing Vimentin and N-cadherin, thereby inhibiting EMT. Notably, indirubin, the PI3K/AKT inhibitor MK2206, and the GSK-3β inhibitor SB216763 all exhibited strong antitumor efficacy in vivo. Conclusion Indirubin exerts broad anti-ovarian cancer effects by inhibiting proliferation, migration, invasion as well as EMT, with demonstrated efficacy in xenograft models and no observed organ toxicity. Its mechanistic overlap with PI3K/AKT inhibitors underscores its potential as a multitargeted therapeutic agent.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8.2
Yi Chen,Zhaoyu Liu,Zesen Mai,Yongbing Zhou,Huiwen Wen,Gaowen Qu,Runhao Zeng,Jianfu Zhao,Dongmei Zhu,Yuxiong Lai,Xue Liang
Non-small cell lung cancer (NSCLC) remains a lethal malignancy due to therapy resistance and recurrence. Ferroptosis, a regulated form of cell death, is a promising strategy to overcome cancer drug resistance, yet its mechanisms remain incompletely defined. Here, we report that Immediate Early Response 3 (IER3) is significantly upregulated in NSCLC tumors and linked to advanced stage and poor prognosis. Using IER3-overexpressing and knockout models in A549 and H1299 cells, we found that IER3 promotes NSCLC cell proliferation, migration, and invasion by suppressing ferroptosis. Conversely, IER3 knockout induced ferroptosis and reduced malignancy—effects reversed by the ferroptosis inhibitor Fer-1. Mechanistically, IER3 sustained AKT phosphorylation to inactivate GSK3β, both blocking GSK3β-dependent proteasomal degradation of NRF2 and enhancing its nuclear translocation, which collectively led to the transactivation of downstream ferroptosis-suppressive gene programs. This program maintained glutathione homeostasis, sequestered labile iron, scavenged ROS, and ultimately inhibited lipid peroxidation to counter ferroptosis. Rescue assays confirmed NRF2 overexpression or AKT/GSK3β activation reversed IER3 knockout-induced ferroptosis and viability loss. Additionally, low-IER3 NSCLC tumors were more sensitive to clinical/preclinical agents targeting survival/stress pathways. Collectively, our findings establish IER3 as an NSCLC oncogenic driver—suppressing ferroptosis via AKT/GSK3β/NRF2 to sustain malignancy—highlighting its potential as a prognostic biomarker and therapeutic target for improved NSCLC outcomes.
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JOURNAL OF HUMAN GENETICS
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2025
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IF 2.5
Yin Bin,Li Mu-Jia,Sun Jia-Lin,You Yue,Zhang Si-Di,Wan Qian-Xue,Yao Mei-Lin,Yang Cheng-Wei,Sun Hua-Qin,Lin Zi-Yuan,Shi Bing,Jia Zhong-Lin
The biological interactions between genetic and environmental modifiers play critical roles in the etiology of non-syndromic orofacial cleft (NSOC), but it is rarely studied. This study selected 47 environmental related genes from the metabolic pathways of smoking, drinking, hypoxia, and vitamins (including vitamin A, vitamin B9 (folic acid), vitamin C (ascorbic acid), vitamin D, and vitamin E), and test their associations with NSOC and its subtypes. We found that a novel gene SLC23A2 , the vitamin C transporter gene is significantly associated with non-syndromic cleft palate only (NSCPO) ( p = 3.25E-07, OR = 8.45, 95%CI:3.73–19.17). SLC23A2 is expressed in the craniofacial region of zebrafish (24hpf to 120hpf), obvious craniofacial abnormalities appeared in zebrafish (48hpf) when knock down the slc23a2 ( slc23a2 -MO). Knock down SLC23A2 in human embryonic palatal mesenchymal cell line (HEPM) induced decreased intracellular ascorbic acid (AA), increased reactive oxygen species (ROS), inhibited cell proliferation and triggered apoptosis, activated the PI3K-AKT-mTOR signaling pathway and inhibited autophagy; ROS levels and apoptosis ratio significantly decreased when we supplemented AA to HEPM cells with high ROS levels induced by Sin-1 (an exogenous ROS mimic). Knocked down SLC23A2 in HEPM cells or zebrafish, they became more sensitive to Sin-1, and AA supplementation was ineffective. In conclusion, we identified a novel susceptibility gene SLC23A2 for NSCPO, it may function by decreasing AA level, increasing the ROS levels, inducing apoptosis, and inhibiting autophagy through the activation of the PI3K-AKT-mTOR pathway in etiology of cleft palate.
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LIVER INTERNATIONAL
·
2026
·Vol. 46
·期 6
·e70696
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IF 6.2
Ling Liu,Jintao Zheng,Ye Wang,Chenao Yang,Yuqiang Shan,Changku Jia
Background & Aims Hepatic fibrosis (HF) is a key pathological process in the development of chronic liver disease, and the activation of hepatic stellate cells (HSCs) is its core driving factor. Although curcumin, as a natural polyphenolic compound, has therapeutic potential, its specific mechanism in HF is still unclear. Methods This study used the CCl4-induced mouse HF model and explored its mechanism through single-cell RNA sequencing (scRNA-seq) combined with in vitro and in vivo experimental systems. Results The results showed that curcumin attenuated liver injury and fibrosis levels in mice with HF in a dose-dependent way, alleviated liver pathological damage, improved liver function indicators, and inhibited the release of inflammatory factors. ScRNA-seq analysis revealed a significant reduction in the number of activated HSCs after curcumin treatment, and the key gene Crispld2 was identified through perturbation model prediction and pseudo-temporal analysis. Curcumin significantly downregulated the expression of Crispld2 and inhibited the activation of the PI3K/AKT signalling pathway. In the TGF—β—induced LX-2 cell activation model, curcumin inhibited HSC proliferation, promoted apoptosis, reduced fibrosis-related protein expression, and decreased inflammatory cytokine secretion by regulating Crispld2. Overexpression of Crispld2 reversed the anti-fibrotic effect of curcumin, while the PI3K/AKT pathway inhibitor LY294002 restored its therapeutic effect. Animal experiments further confirmed that curcumin improved HF by regulating the Crispld2/PI3K/AKT axis. Conclusions This study elucidates the molecular mechanism by which curcumin exerts anti-HF effects by inhibiting the activation of the PI3K/AKT pathway mediated by Crispld2, providing a new strategy for targeted therapy of Crispld2. Lay Summary This study investigated the ameliorative effects of curcumin, a natural compound, on hepatic injury and fibrosis in mouse models of liver fibrosis. The underlying mechanism involves the suppression of the key gene Crispld2, which subsequently blocks the aberrant activation of the PI3K/AKT signalling pathway, thereby inhibiting the activation of hepatic stellate cells and exerting hepatoprotective functions. These findings furnish novel scientific evidence supporting the therapeutic application of curcumin in patients with liver fibrosis and shed new light on the development of Crispld2-targeted pharmaceutical agents. Curcumin can alleviate liver injury and fibrosis in mice with hepatic fibrosis. The underlying mechanism is that curcumin blocks the PI3K/AKT signalling pathway by targeting and inhibiting Crispld2, thereby suppressing the activation of HSCs and ameliorating hepatic fibrosis.
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FITOTERAPIA
·
2026
·
IF 2.9
Zihan Zhou,Fanxing Zhou,Xudong Xing,Zuguo Zheng,Guangji Wang,Hua Yang
QGJZF reduces aortic plaque in AS mice with PCSK9 overexpression induced by HFD. • 16 blood-absorbed components and 23 metabolites identified from QGJZF in vivo . • Network pharmacology and omics reveal QGJZF modulates lipid metabolism via PI3K-AKT. • QGJZF suppresses macrophage foam cell formation. • QGJZF activates PI3K-AKT pathway and upregulates ABCA1 for cholesterol export. Objective Qigui Jiangzhi Formula (QGJZF) is a traditional Chinese medicine formulation developed based on the principles of regulating Qi, warming Yang, and resolving dampness. All of its herbs have historically been used to treat obesity, hypertension, and hyperlipidemia. However, its therapeutic mechanism in atherosclerosis (AS)-related cardiovascular disease remains unclear. This study aimed to investigate the anti-atherosclerotic activity and explain the mechanism of QGJZF. Methods PCSK9 overexpressing mice induced by high-fat diet were used to establish an in vivo model. Aortic pathology and inflammation were assessed via histology, immunofluorescence, and Enzyme-linked immunosorbent assay. Chemical characterisation was performed by LC-MS. Network pharmacology and multi-omics were combined to elucidate the mechanism of QGJZF, validated by molecular docking and surface plasmon resonance (SPR). An in vitro foam cell model using ox-LDL-induced RAW264.7 macrophages was analysed by qPCR and Western blot. Results QGJZF effectively reduced aortic lipid plaque deposition, ameliorated plaque pathology, and suppressed macrophage infiltration in AS mice. LC-MS identified 93 non-volatile components, including 16 blood-entering constituents and 23 metabolites. Network pharmacology and multi-omics analyses indicated QGJZF regulates lipid metabolism via the PI3K-AKT pathway. Molecular docking and SPR confirmed strong binding of five major blood-entering components to PI3K/AKT proteins. In vitro , QGJZF activates the PI3K-AKT pathway, upregulated ABCA1 expression, inhibited macrophage foam cell formation, and improved lipid metabolism. Conclusion QGJZF inhibits the formation of foam macrophages through the PI3K-AKT-ABCA1 signalling pathway, thereby improving AS. This provides a scientific foundation for the clinical application of QGJZF in AS-related cardiovascular disease. Download: Download high-res image (195KB) Download: Download full-size image
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