RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY
·
2018
·
IF 1.792
Bo Wang,Wenyang Li,Hongyu Jin,Xinshi Nie,Hui Shen,Erran Li,Wei Wang
Chronic intermittent hypoxia (CIH) is one of the main features of obstructive sleep apnea (OSA), which is also commonly associated with neurocognitive impairments. The present study aimed to elucidate the beneficial effect of curcumin on CIH-induced brain injuries. Male balb/c mice (6 ∼ 8 weeks) were exposed to normoxia or a pattern of CIH (8 h/day, cycles of 180 s each, hypoxia: 5% O 2 for 50 s, reoxygenation: 21% O 2 for 50 s) for 10 weeks, along with daily curcumin treatment (50, 100, or 200 mg/kg, intragastrically) or its vehicle. The results showed that CIH induced significant brain edema, as well as neuronal apoptosis and astrogliosis in the cerebral cortex, brainstem, and cerebellum regions of brain. In addition, increased astrocytic AQP4 expression and activation of p38 MAPK pathway were observed after CIH exposure. Curcumin dose-dependently mitigated the brain edema and relevant cell alterations, showing a neuroprotective effect in CIH-induced brain injury. Together, these results suggest curcumin ameliorates the CIH-induced brain injuries, including brain edema, neuronal death and astrogliosis. The beneficial role of curcumin is mediated partially by regulating AQP4 and p38 MAPK pathway.
研究领域:
神经科学
·
药理学
·
睡眠医学
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DOI
PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Wang Xiang,Luo Kai,Bai He,Zhang Xudong,Qu Jialin,Wang Xiaoqing,Sun Xu,Zhao Yuting,Wang Bin,Zhang Guixin
Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive liver malignancy with rising global incidence and poor prognosis. Despite recent advances in treatment strategies, effective therapeutic options for ICC remain limited. Solamargine (SM), a natural steroidal alkaloid, has demonstrated anticancer activity, yet its mechanisms in ICC are not fully understood. This study shows that SM inhibits ICC progression by inducing both apoptosis and ferroptosis in vitro and in vivo. SM significantly suppressed proliferation, migration, and invasion of ICC cells (HUCCT-1 and HCCC-9810), with minimal cytotoxicity toward normal biliary epithelial cells (HIBEC). Mechanistically, SM induced mitochondrial dysfunction, ROS accumulation, and lipid peroxidation, leading to apoptosis and ferroptosis. Transcriptome sequencing and gene set enrichment analysis (GSEA) revealed that SM treatment activated apoptosis- and ferroptosis-related pathways, including MAPK signaling. Western blot analysis and pharmacological inhibition assays confirmed that p38 MAPK activation was essential for SM-induced cell death, with ROS acting as an upstream activator. In vivo, SM significantly inhibited tumor growth in both orthotopic and subcutaneous ICC mouse models and showed better tolerability than gemcitabine. Tumor tissue analysis further confirmed increased markers of apoptosis and ferroptosis, along with p38 MAPK activation. These findings suggest that SM exerts dual antitumor effects in ICC, which are associated with the induction of apoptosis and ferroptosis and may involve the ROS/p38 MAPK signaling axis, highlighting its potential as a therapeutic candidate for ICC.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Lei Wang,Wan-Yang Xu,Yi-Wen Tang,Feng Hu
Pulmonary fibrosis is common in the development of inflammatory lung diseases with no effective clinical drug treatment currently. As an essential redox enzyme, thioredoxin (Trx) has been reported to be involved in pulmonary fibrosis, but the mechanism is to be revealed. Therefore, in bleomycin-indued pulmonary fibrosis model in C57 mice, Trx activity and nitrated Trx were examined.,p38-MAPK apoptosis pathway was determined in lung tissues. Additionally, before BLM administration, C57/BL6 mice were treated with aminoguanidine (AG, a peroxynitrite scavenger), recombinant human Trx-1 (rhTrx-1), or SIN-1 (a peroxynitrite donor) nitrated Trx-1 ( N -Trx-1). In bleomycin (BLM)-induced pulmonary fibrosis model in C57/BL6 mice, we observed that nitrated Trx increased, while its activity decreased, with the increase of alveolar epithelial cells (AECs)apoptosis by p38-MAPK pathway. We demonstrated that AG or rhTrx-1, but not N -Trx-1 significantly reduced pulmonary fibrosis. Taken together, the results above revealed that blockade of Trx-1 nitration, or supplementation of exogenous rhTrx-1, might represent novel therapies to attenuate pulmonary fibrosis in idiopathic pulmonary fibrosis patients.
研究领域:
医学
·
药理学
·
病理学
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DOI
PubMed
高影响因子
BIOLOGY BULLETIN
·
2025
·Vol. 52
·期 8
·271
·
IF 0.5
Li Sun,Yang Jianbo,Jin Jian
Fumonisin B1 (FB1), a water-soluble mycotoxin produced by Fusarium moniliforme, poses significant health risks to both humans and animals through widespread contamination of agricultural commodities. Paeoniflorin (PF), a bioactive monoterpene glycoside extracted from Paeonia lactiflora , exhibits potent anti-inflammatory and antioxidant properties. This study investigated the protective effects of PF against FB1-induced cytotoxicity in porcine alveolar macrophages (3D4/21) and explored the underlying molecular mechanisms. Cells were treated with FB1 (50 μg/mL) in combination with PF (100 μg/mL) for 24 h. Results demonstrated that PF significantly attenuated FB1-induced cytotoxicity by improving cell viability, restoring cytoskeletal and tight junction protein expression (α-Tubulin and ZO-1), and reducing apoptosis and oxidative stress. PF treatment successfully restored the balance of inflammatory cytokines (including IL-6, IL-8, IL-1β, IFN-α, and INF-γ) that had been dysregulated in 3D4/21 cells upon FB1 exposure. Transcriptomic analysis revealed that PF reversed FB1-induced gene expression alterations, particularly within clusters associated with cellular stress responses. Further investigation identified the p38 MAPK pathway as a critical mechanism through which PF exerts its protective effects, with significant downregulation of key pathway components including MAPK14 , MAP2K3 , ATF2 , and MAPKAPK2 in cells co-treated with PF and FB1. These findings provide mechanistic insights into the protective effects of PF against environmental mycotoxins and suggest its potential application in mitigating FB1-induced agricultural and ecological toxicity.
研究领域:
毒理学
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分子生物学
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免疫学
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药理学
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兽医学
·
环境健康
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产品关联
DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Zhenyu Yang,Ziming Wang,Jingsheng Huang,Meiqi Luo,Xinling Luo,Weiqi Zeng,Yingxin Gao,Fei Huang,Zhizhao Deng,Dongdong Yuan
Ischemia-reperfusion injury (IRI) remains the leading cause of early graft failure following liver transplantation (LT). Traditional paradigms have centered on hepatocyte death, yet the decisive contribution of liver sinusoidal endothelial cells (LSECs) as the first vascular barrier has long been overlooked. Here, single-cell RNA sequencing of human livers comparing normal controls with those exposed to transplantation-induced IRI, identified EMP1 as the most upregulated gene in LSECs. In LSECs and BRL3A hepatocytes subjected to hypoxia/reoxygenation (H/R), EMP1 silencing with an siRNA, ferroptosis modulation via ferrostatin-1 (Fer-1) or RSL3, and p38 signaling intervention using the p38 activator berberine chloride collectively revealed that EMP1 drives ferroptosis in LSECs in a p38-dependent manner. The results demonstrated that LSECs constituted the predominant hepatic endothelial population, whose numbers decline precipitously after transplantation. EMP1 emerged as the most markedly up-regulated gene in LSECs, correlating closely with the severity of injury. Silencing of EMP1 restored fenestral architecture, reduced VCAM-1 and E-selectin expression levels, suppressed Fe 2+ accumulation and lipid peroxidation, down-regulated ACSL4, and reinstated GPX4, thereby halving the hepatocyte death effects phenocopied by Fer-1 and reversed by RSL3, confirming that ferroptosis as the central mechanism. Furthermore, EMP1 exerted its effects solely via p38 signaling and its depletion selectively abolished p38 phosphorylation, whereas the p38 activator berberine chloride fully reinstated ferroptotic phenotypes and hepatocyte injury. Collectively, these data establish EMP1/p38-driven LSEC ferroptosis as a direct cause of hepatocyte damage, offering a fundamentally new perspective on the pathogenesis of h epatic ischemia reperfusion injury (HIRI) and a novel, potentially targeted therapeutic strategy for its prevention and treatment.
研究领域:
肝病学
·
分子生物学
·
移植医学
·
细胞死亡研究
·
信号转导
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DOI
PubMed
高影响因子
INFLAMMATION RESEARCH
·
2014
·Vol. 63
·期 7
·597-608
·
IF 2.143
Pan Xiaolong,Cao Xiang,Li Na,Xu Yimiao,Wu Qiuyue,Bai Jing,Yin Zhimin,Luo Lan,Lan Lei
Objective Forsythin (FOR) is an active ingredient extracted from the fruit of the medicinal plant Forsythia suspensa (Thunb.) Vahl. Here, we investigated the effect of FOR on LPS-induced inflammatory response and the underlying molecular mechanisms in RAW264.7 macrophages. Materials and methods RAW264.7 cells were pre-treated with or without FOR and then stimulated with or without LPS. The productions of TNF-α, IL-1β, IL-6, PGE 2 and NO were determined by ELISA and nitrite analysis, respectively. The expressions of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were measured by Western blotting and RT-PCR analysis. The activations of signaling molecules were detected by Western blotting using phosphorylation specific antibodies. Reactive oxygen species (ROS) production was determined by ROS assay. Results LPS-induced productions of IL-1β, IL-6, TNF-α, NO and PGE 2 were inhibited by FOR in a dose-dependent manner. FOR also suppressed the LPS-elevated expressions of iNOS and COX-2. Further investigations revealed that FOR significantly inhibited the LPS-induced activations of JAK-STATs and p38 MAPKs, but not of IKKα/β in LPS-stimulated RAW264.7 cells. Additionally, FOR interfered with both JAK-STATs and p38 MAPKs signaling pathways to modulate the expressions of IL-1β, IL-6, TNF-α, iNOS and COX-2. Furthermore, FOR reduced the LPS-induced ROS accumulation, validating that FOR serves as an antioxidant. Conclusions Our data suggested that FOR exerts anti-inflammatory action, at least in part, via suppressing LPS-induced activation of JAK-STATs and p38 MAPKs signalings and production of ROS in macrophage cells.
研究领域:
药理学
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免疫学
·
细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·Vol. 74
·期 32
·25102-25118
·
IF 6.7
Wang Caihong,Song Yunmeng,Ma Mingqiang,Fu Zhipeng,Zhang Nan,Jin Yuanxiang
N -(1,3-dimethylbutyl)- N ′ -phenyl- p -phenylenediamine-quinone (6PPDQ),
the primary oxidative
metabolite of rubber antioxidant N -(1,3-dimethylbutyl)- N ′ -phenyl- p -phenylenediamine (6PPD),
is an emerging global contaminant with multiorgan toxicity and has
been detected in human breast milk and urine. Its mammary toxicity
and molecular mechanisms remain poorly defined. Here, we integrated
network toxicology, transcriptomics, and in vivo/in vitro validation
to investigate 6PPDQ triggered mammary toxicity during adolescent
exposure in mice. Network toxicology screened core targets and identified
the MAPK signaling pathway as a key regulatory axis. Adolescent 6PPDQ
exposure decreased mammary gland weight and length, induced pathological
lesions, inhibited epithelial proliferation, and disrupted apoptotic
homeostasis. Further assays confirmed that 6PPDQ caused mitochondrial
dysfunction, oxidative stress, and inflammation. Mechanistically,
6PPDQ mediated mammary injury through p38 MAPK cascade activation,
and p38 inhibition alleviated such adverse effects. This study elucidates
a distinct p38 MAPK-dependent mechanism driving 6PPDQ-related developmental
mammary toxicity, advancing the mechanistic understanding of health
risks posed by rubber-derived quinone contaminants.
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高影响因子
Biology-Basel
·
2026
·Vol. 15
·期 16
·1354
·
IF 4.3
Jiangkun Yu,Yiming Liu,Yake Gao,Dingxi Pan,Mingying Li,Wei Guo
Simple SummaryHow does antibiotic administration affect the health of farmed fish? In this study, zebrafish were exposed to enrofloxacin—a common aquaculture antibiotic—to evaluate physiological, histological, and metabolic changes in the liver using either a continuous or an intermittent regimen. We found that continuous exposure caused severe liver damage and biological stress. However, giving the fish a short break (intermittent exposure) dramatically protected their livers. This break allowed the fish to adapt and heal, preventing cellular damage despite receiving the same total amount of medication. These findings suggest that adopting “pulsed” dosing could significantly improve animal welfare and promote sustainable fish farming.Enrofloxacin (ENR) has been widely used in global aquaculture production, yet its hepatotoxic impacts under different operational administration modes remain poorly understood. Current environmental risk assessments and therapeutic guidelines generally assume that cumulative exposure dose dictates biological outcomes, largely ignoring the temporal patterns of drug administration. In the present study, we systematically compared the hepatotoxic, metabolic, and molecular effects of two matched-duration ENR administration regimens, continuous versus intermittent, on adult zebrafish (Danio rerio) at environmentally realistic concentrations (0.4, 4, and 40 μg/L). Biochemical, histological, and lipidomic analyses revealed fundamentally divergent toxicological trajectories between the two regimens. While both regimens induced significant basal triglyceride and cholesterol depletion, continuous exposure drove progressive hepatocellular damage, characterized by elevated transaminase activities, unconstrained glycogen accumulation, and the eventual collapse of antioxidant defenses, culminating in severe lipid peroxidation. Mechanistically, continuous exposure triggered sustained pathological activation of the p38 MAPK signaling cascade and broad upregulation of de novo phosphatidylcholine (PC) and phosphatidylethanolamine (PE) biosynthesis. In contrast, intermittent exposure provided a critical physiological buffering window, whereby the depuration phase enabled a sustained, adaptive antioxidant response that successfully suppressed lipid peroxidation, significantly alleviated structural liver injury, and raised the activation threshold for the p38 stress response. Furthermore, lipidomic and transcriptional profiling demonstrated that intermittent exposure uniquely induced compensatory lipid remodeling, characterized by adaptive ceramide signaling and a metabolic shift. Taken together, these findings demonstrate that the temporal pattern of exposure critically dictates ENR hepatotoxicity, highlighting the need to perform discriminative risk assessment and providing a mechanistic basis for optimizing antibiotic stewardship in aquaculture.
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高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2025
·Vol. 44
·期 1
·1-22
·
IF 12.8
Zhu Susi,Zhang Xu,Liu Waner,Zhou Zhe,Xiong Siyu,Chen Xiang,Peng Cong
Background Melanoma, a highly aggressive and immunogenic skin cancer, often develops resistance to immunotherapy due to the immunosuppressive tumor microenvironment (TME). Although PD-1/PD-L1 inhibitors have significantly improved treatment outcomes, 30%-40% of patients exhibit no response or develop resistance. Mechanisms such as T-cell exhaustion within the TME limit therapeutic efficacy, necessitating the exploration of novel strategies to enhance immune responses. Methods This study evaluated the effects of Vinburnine (Vin) on melanoma cell proliferation, migration, invasion, apoptosis, and DNA damage through in vitro experiments. Transcriptomic analysis, Western blot, RT-PCR, dual-luciferase reporter assays, and ChIP experiments revealed the mechanism by which Vin regulates IL-24 via ATF3. The anti-tumor efficacy of Vin or IL-24 in combination with PD-1 monoclonal antibody, as well as their modulation of the tumor microenvironment, were validated through luciferase-mediated cytotoxicity assays and a murine melanoma model. Additionally, the correlation between IL-24 expression and patient prognosis or immunotherapy response was analyzed using public databases. Results This study delineates the phenotypic mechanisms by which vinburnine suppresses melanoma proliferation. Vin induces reactive oxygen species (ROS) generation, leading to DNA damage and the subsequent activation of the apoptotic cascade in melanoma cells. Additionally, vinburnine activates the P38/MAPK/ATF3 signaling axis, which drives the secretion of interleukin-24 (IL-24), enhancing the functionality of CD8 + T cells and modulating the tumor immune microenvironment to favor antitumor immunity. Notably, the combination of vinburnine with anti-PD-1 antibody therapy produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches. Conclusions These findings underscore the therapeutic potential of vinburnine, particularly when used in combination with immune checkpoint inhibitors, as a promising strategy for melanoma treatment.
研究领域:
肿瘤学
·
免疫学
·
药理学
·
分子生物学
·
细胞生物学
·
生物化学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2022
·
IF 10.75
Li Zhang,Linyu Zhu,Xiaohan Yao,Xiaohan Lou,Jiajia Wan,Xixi Duan,Longze Pan,Anqi Li,Zhuoyu Gu,Ming Wang,Fazhan Wang,Zhihai Qin
Chemotherapeutic drugs have been successfully used to treat several cancers, including melanoma. However, metastasis occasionally occurs after chemotherapy. Here, we reported that paclitaxel (PTX) treatment for B16F10 tumour in mice led to an enhanced lymphatic metastasis of the melanoma cells, although a significant inhibition of tumour growth at the injection site was observed. Further study demonstrated that PTX upregulated the expression of C-C chemokine receptor type 7 (CCR7) in B16F10 cells, enhancing their migration through the activation of JNK and p38 signalling pathways. Loss of CCR7 or blockade of C-C motif chemokine ligand 21 (CCL21)/CCR7 axis abolished the pro-migration effect of PTX on B16F10 melanoma cells. Importantly, combination of PTX and CCR7 mAb could simultaneously delay the tumour growth and reduce the lymphatic metastasis in B16F10 melanoma. The blockade of CCL21/CCR7 axis may collectively serve as a strategy for lymphatic metastasis in some melanoma after chemotherapy.
研究领域:
肿瘤学
·
免疫学
·
药理学
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DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2026
·
IF 5.7
Hui Zhang,Wei Dai,Xuanyu Chen,Xinru Xi,Yeqing Chen,Jingjing Song,Xiangting Ge,Qiangwei Xiang,Bing Zhang,Chengguang Zhao,Weixi Zhang,Yali Zhang
Background: Allergic asthma stands as the predominant asthma phenotype propelled by aberrant type 2 immune response. Type-2 innate lymphoid cells (ILC2s) are significant for generating IL-5 and IL-13 cytokines, highlighting their vital role in triggering and escalating the progression of asthma. Myeloid differentiation primary response protein 88 (MyD88) controls innate and adaptive immune responses by orchestrating inflammatory signals. Objective: This work focused on investigating the influence of MyD88 in governing ILC2s-driven allergic airway disease alongside its underlying molecular mechanisms. Methods: We evaluated the effects of MyD88 in IL-33-induced or allergen-induced airway hyperreactivity (AHR) and airway inflammation. The role and mechanism of MyD88 in regulating ILC2s function were examined in vivo and in vitro by using transcriptome sequencing analysis, flow cytometry, clinical samples, ILC2-specific MyD88 knockout mice, and anti-Thy1.2 antibody against ILC2s in mice. Results: The results showed heightened MyD88 expression in ILC2s sourced from allergic asthmatic patients and asthmatic mice. MyD88 knockout in ILC2s was able to mitigate IL-33-induced airway inflammation, while the MyD88 inhibitor LM8 proves efficacious in attenuating allergen-induced airway inflammation and AHR. After elimination of ILC2s via anti-Thy1.2 antibody, the pharmacological activity of LM8 diminished. Mechanistic studies revealed that MyD88 mediates the activation and proliferation of ILC2s through facilitation of P38-GATA3 complex formation. Conclusions: The research highlights MyD88 as a critical regulator of ILC2s activation, suggesting its potential utility as a therapeutic target for interventions in allergic asthma.
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2015
·
IF 3.705
Lina Gu,Xufeng Tao,Youwei Xu,Xu Han,Yan Qi,Lina Xu,Lianhong Yin,Jinyong Peng
Oxidative stress is involved in hepatic stellate cells (HSCs) activation and extracellular matrix overproduction. We previously reported the promising effects of dioscin against CCl 4 -induced liver fibrosis, but its effects and mechanisms on BDL- and DMN-induced liver fibrosis remain unknown. The results in the present study indicated that dioscin significantly inhibited HSCs activation and attenuated hepatic fibrosis in rats. Furthermore, dioscin markedly up-regulated the levels of sirtuin 1 (Sirt1), HO-1, GST , GCLC and GCLM via increasing the nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2), which in turn inhibited mitogen-activated protein kinase 14 (p38 MAPK) phosphorylation and reduced the levels of COL1A1, COL3A1, α-SMA and fibronectin . These results were further validated by knockdown of Sirt1 and Nrf2 using siRNAs silencing, and abrogation of p38 MAPK using SB-203580 (a p38 MAPK inhibitor) in HSC-T6 and LX-2 cells. Collectively, our findings confirmed the potent effects of dioscin against liver fibrosis and also provided novel insights into the mechanisms of this compound as a candidate for the prevention of liver fibrosis in the future.
研究领域:
药理学
·
肝病学
·
细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
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