JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
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2016
·
IF 2.135
Wu Li,Minqiang Liu,Jianping Xie
The pathogenesis of tuberculosis, caused by Mycobacterium tuberculosis, is largely because of the pathogen's successful entry and survival within macrophages. We predicted that rv3369, a gene encoding a conserved protein, might play a role in the interactions with host cells. To test this, rv3369 gene was heterologously expressed in a nonpathogenic fast-growing Mycobacterium smegmatis strain. The recombinant strain survives better than the control within macrophages, accompanied by more host cell death and a marked higher secretion of interleukin-1β (IL-1β). Furthermore, pharmacological inhibition experiments showed that the NF-κB and ERK pathways were involved in the Rv3369-triggered IL-1β changes. These results provided evidence for the engagement of Rv3369 in the interaction between mycobacteria and host.
研究领域:
微生物学
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免疫学
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感染病学
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分子生物学
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细胞生物学
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病原生物学
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DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2026
·
IF 3.2
Lili Liu,Zhengyao Li,Xinlei Peng,Hongli Zhang,Yuying Yang,Jun Liu,Min Liu
TPs reduced oxidative stress in PFOA-exposed mice. • TPs reduced intestinal permeability and ERK/NF-κB pathway in the ileal tissue. • TPs reduced harmful bacteria and increased beneficial bacteria in PFOA-exposed mice. • TPs as a potential dietary intervention alleviate pollutant-induced enterotoxicity. Perfluorooctanoic acid (PFOA), a persistent environmental contaminant, has been found to induce intestinal damage. Dietary tea polyphenols (TPs) have been reported to alleviate gastrointestinal diseases, however, the underlying mechanism through which TPs alleviate PFOA-induced ileal barrier injury remains unclear. Here, the effects of TPs on oxidative stress, intestinal permeability, extracellular signal-regulated kinase (ERK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, and gut microbiota in mice were evaluated. The results showed that TPs alleviated oxidative stress by elevating the serum GSH and CAT activities, and reducing MDA levels. Moreover, TPs decreased intestinal permeability by reducing serum DAO and LPS levels, upregulating the expression of claudin-1 and occludin, and inhibiting the phosphorylation of ERK and NF-κB in the ileum. Additionally, 16S rRNA gene sequence analysis revealed that TPs reversed PFOA-induced gut dysbiosis by decreasing harmful bacteria of Desulfovibrio and Ileibacterium , and increasing beneficial bacteria of Lachnospiraceae_NK4A136_grou p and Ligilactobacillus . This study reveals positive effects of TPs as a potential dietary intervention against pollutant-induced enterotoxicity. Download: Download high-res image (250KB) Download: Download full-size image
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高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
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2026
·
IF 4.1
QiWei Yang,Lin Yu,Ran Tang,YiShan Peng,Tao Huang,HaoQi Chen,WenFeng Zhu,Qing Yuan,Wei Wang,Xiaojian Jiang,ZhiLi Ma,Lei Yuan,SuMei Wang,XiaoWen Wang,GenShu Wang
Environmental chemical exposure has emerged as an important modulator of cancer progression and therapeutic outcomes. Di-2-ethylhexyl phthalate (DEHP), a ubiquitous environmental plasticizer, has been widely recognized for its endocrine-disrupting effects; however, its impact on intracellular signaling reprogramming and cancer drug responsiveness remains incompletely understood. In this investigation, we aimed to elucidate the toxicological mechanisms by which DEHP alters cellular phenotypes and therapeutic sensitivity in hepatocellular carcinoma (HCC) cells. We demonstrate that DEHP exposure does not primarily promote cancer cell proliferation but instead induces epithelial–mesenchymal transition (EMT), leading to enhanced migratory and invasive capacities and reduced responsiveness to the tyrosine kinase inhibitor lenvatinib. Notably, integrative bioinformatic analyses combined with functional validation identified sperm-associated antigen 4 (SPAG4) as a key DEHP-responsive regulator mediating toxicant-induced cellular reprogramming. Mechanistic studies revealed that DEHP-induced upregulation of SPAG4 activates the MAPK/ERK signaling pathway, thereby driving EMT and attenuating lenvatinib responsiveness. Genetic silencing of SPAG4 or pharmacological inhibition of MAPK/ERK signaling effectively reversed DEHP-induced EMT and drug resistance. In conclusion, we highlight DEHP as a signaling-disrupting environmental toxicant that reprograms cancer cell states and modulates therapeutic responses through a SPAG4-dependent MAPK/ERK pathway. These findings provide mechanistic insight into how environmental chemical exposure can reshape intracellular signaling networks and influence cancer treatment outcomes, underscoring a previously underappreciated aspect of chemical toxicology.
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Xiangyu Cai,Zhaoyu Yang,Yingyu Xiao,Qiongyu Yuan,Wanyue Gao,Jing Dong,Weidong Zeng,Yuling Mi,Caiqiao Zhang
Background Ovarian aging is characterized by progressive impairments of follicular development and reproductive performance. Increasing evidence indicates that metabolic dysregulation plays a central role in the decline of ovarian function. Chlorogenic acid (CGA), a widely distributed plant-derived polyphenol, is known for its antioxidant, anti-inflammatory, and metabolic properties. However, its potential role in ovarian aging and the underlying mechanisms remain unexplored. Methods D-galactose-induced granulosa cell (GC) senescence model and naturally aging laying chickens were used for evaluating the protective effects of CGA on ovarian aging. Cellular senescence, mitochondrial function, lipid metabolism, and steroidogenic capacity were evaluated through molecular, biochemical, transcriptomic, and histological analyses. Mechanistic studies employed pharmacological inhibition and genetic knockdown to delineate the signaling hierarchy. Results In D-gal-induced GCs, CGA mitigated cellular senescence, improved mitochondrial function, and restored key steroidogenic gene expression ( STAR, CYP11A1 , and CYP19A1 ). Mechanistically, CGA reversed metabolic dysregulation by suppressing ERK1/2 phosphorylation to restore PPARα activity. This mechanism was supported by pharmacological ERK1/2 inhibition, which amplified these benefits, and siRNA-mediated PPARα silencing, which blunted CGA-induced steroidogenic recovery. In naturally aging laying chickens, CGA supplementation enhanced serum estradiol and antioxidant capacity. Crucially, CGA positively modulated the liver-ovary axis by rejuvenating hepatic lipid metabolism and systemic transport, thereby promoting yolk deposition, follicular development, and egg-laying performance. Conclusion These findings suggest that CGA mitigates ovarian aging by coordinating mitochondrial homeostasis, lipid metabolism, and steroidogenesis via the ERK/PPARα pathway. The result provides mechanistic insight into the potential of plant-derived polyphenols as metabolic regulators for preserving ovarian function.
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
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IF 2.5
Chunhui Shan,Qi Bing,Gang Qiu,Hui Zhang,Yingmin Chen
Galectin-3 disrupts microglial P2X7R/MerTK balance after stroke • ERK/ROS/BRD4 axis mediates Gal-3-induced P2X7R upregulation • Gal-3 promotes cGAS-STING inflammation and apoptosis via HIF1α/P2X7R • TD-139 restores P2X7R/MerTK balance and reduces cerebral infarction • Targeting Gal-3 improves motor, cognitive, and grip strength in MCAO rats This study demonstrates that Galectin-3 (Gal3) exacerbates cerebral infarction progression by modulating the P2X7R/MerTK equilibrium in microglia via the ERK/BRD4/HIF1α signaling axis, with reactive oxygen species (ROS) serving as a potential intermediate mediator linking ERK activation to BRD4 upregulation based on prior literature evidence. Single-cell transcriptomic analysis revealed that ischemia drives microglia from a homeostatic state to an activated disease phenotype, and virtual Gal3 knockout predicted corresponding downregulation of BRD4. Using a rat model of cerebral infarction, we found that the Gal3 inhibitor TD-139 significantly reduced infarct volume, promoted M2 polarization of microglia, and improved neurological function in behavioral assays. Mechanistic investigations in BV2 microglia revealed that Gal3 activates ERK1/2, leading to ROS accumulation, BRD4 upregulation, and subsequent HIF1α-mediated P2X7R transcription, while suppressing KLF4 and MerTK. This cascade increased P2X7R expression and suppressed MerTK/KLF4 expression, generating a pro-inflammatory and pro-apoptotic microenvironment. Notably, pharmacological inhibition of Gal3 enhanced efferocytosis and reduced apoptosis, whereas P2X7R blockade exerted similar neuroprotective effects. These findings identify Gal3 as a key regulator of microglial polarization via the experimentally validated ERK/BRD4/HIF1α-P2X7R signaling cascade, where P2X7R activation concurrently triggers cGAS-STING-mediated pro-inflammatory/pyroptotic responses and suppresses the KLF4/MerTK efferocytosis axis. Targeting this regulatory network could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Targeting this pathway could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Data were analysed using one-way ANOVA followed by Tukey's post-hoc test for multiple comparisons; P < 0.05 was considered statistically significant.
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DOI
高影响因子
PharmaNutrition
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2026
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IF 2.9
Junyan Zhang,Yao Zhang,Yuting Ren,Chao Tang,Juan Kan,Jun Liu
In contemporary society, unhealthy dietary patterns increase the risk of intestinal inflammation. Regrettably, intestinal inflammation is also associated with an elevated risk of other inflammatory disorders and metabolic syndrome. Therefore, it is essential to alleviate intestinal inflammation. Natural plant polysaccharides are widely used to alleviate intestinal inflammation owing to their desirable anti-inflammatory properties. In this study, a water-soluble polysaccharide (WSP) is isolated and purified from purple sweet potato (variety of Xuzi 3). The in vivo anti-inflammatory effects of WSP are determined using dextran sulfate sodium (DSS)- and lipopolysaccharide (LPS)-treated mice. From a phenotypic perspective, WSP effectively alleviates DSS and LPS-induced colonic lesions and reduces disease activity index. WSP markedly reduces the levels of ROS, MDA, and pro‑inflammatory cytokines, and increases the activities of antioxidant enzymes in the serum and colonic tissues, thus mitigating oxidative stress and inflammatory response. WSP significantly upregulates the expression of tight junction protein ZO-1 in the colon and further strengthens intestinal physical barrier. At the molecular level, WSP blocks TLR-4/NF-κB and MAPK ERK/JNK signaling cascades. Protein analysis also confirms that WSP does not alleviate endoplasmic reticulum stress in the colon, and WSP promotes mitochondrial fusion and inhibits abnormal mitochondrial fission. In conclusion, WSP improves mitochondrial dynamics and decreases ROS production, which in turn suppresses TLR‑4/NF‑κB and MAPK ERK/JNK pathways and reduces the secretion of pro‑inflammatory cytokines.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2019
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IF 4.825
Wensong Yao,Zhen Lin,Peiying Shi,Bing Chen,Gang Wang,Jianyong Huang,Yuxia Sui,Qicai Liu,Shaoguang Li,Xinhua Lin,Qicai Liu,Hong Yao
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron , showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo . It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis , the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca 2+ in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo . In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND FUNCTION
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2023
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IF 3.6
Jing Luo,Yijue Deng,Yi Ding,Chenguang Tang,Mengqing Wang
This study aimed to determine the effects of Xiebai Zengye decoction (XBZY) on airway inflammation and respiratory function in rats with postinfectious cough (PIC), and its regulatory effects on the extracellular signal-regulated kinase (ERK) signaling pathway. Compared with the normal group, the rats from the PIC group had significantly shortened expiratory time (TE) and enhanced pause (EEP), increased resistance (RT), and enhanced pause (Penh), along with increased levels of serum interleukin-4 (IL-4) and IL-6, and decreased levels of IL-10. The lung and colon tissues of rats from the PIC group showed histopathological changes, including inflammatory cell infiltration, damaged mucosal epithelium, and crypt structure, with significantly increased ERK mRNA and protein expression levels. Treatment with XBZY and montelukast sodium (MAS) improved the respiratory function and serum cytokine levels, reduced tissue inflammation, and decreased ERK mRNA and protein expression levels in the lung and colon tissues. In the lung tissues, XBZY treatment significantly decreased the expression of phosphorylated-ERK (p-ERK) protein, as well as p-MEK1/2, p-ERK1/2, and p-c-Fos proteins, while in the colon tissues, XBZY significantly decreased the expression of p-ERK1/2 and p-c-Fos proteins. However, MAS treatment only showed significant improvement in the lung tissue inflammation score, and the expression level of p-ERK protein in the lung tissue was decreased. In conclusion, the present study suggests that XBZY has a potential therapeutic effect on PIC by improving respiratory function and attenuating inflammation, and this effect may be associated with the inhibition of the ERK signaling pathway. These findings could provide a new direction for the development of treatments for PIC. However, further research is needed to elucidate the underlying molecular mechanisms of XBZY and to confirm its safety and efficacy in clinical trials. Significance statement Postinfectious cough (PIC) accounts for 21.73% of the causes of chronic cough in Chinese children and has a higher incidence rate in preschool children. This study aims to observe the effects of Xiebai Zengye decoction (XBZY) on airway inflammation and reactivity in young rat model of PIC cough, and to explore its regulatory effects on the ERK signaling pathway, to preliminarily elucidate the mechanism of XBZY in treating PIC.
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 12
·10031
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IF 5.6
Haiping Liu,Haixiang Ma,Xingyue Zeng,Chengyan Wu,Srijan Acharya,Sarabjeet Kour Sudan,Xiaohan Zhang
A class-A GPCR dopamine D2 receptor (D2R) plays a critical role in the proper functioning of neuronal circuits through the downstream activation of both G-protein- and β-arrestin-dependent signaling pathways. Understanding the signaling pathways downstream of D2R is critical for developing effective therapies with which to treat dopamine (DA)-related disorders such as Parkinson’s disease and schizophrenia. Extensive studies have focused on the regulation of D2R-mediated extracellular-signal-regulated kinase (ERK) 1/2 signaling; however, the manner in which ERKs are activated upon the stimulation of a specific signaling pathway of D2R remains unclear. The present study conducted a variety of experimental techniques, including loss-of-function experiments, site-directed mutagenesis, and the determination of protein interactions, in order to investigate the mechanisms underlying β-arrestin-biased signaling-pathway-mediated ERK activation. We found that the stimulation of the D2R β-arrestin signaling pathway caused Mdm2, an E3 ubiquitin ligase, to move from the nucleus to the cytoplasm and interact with tyrosine phosphorylated G-protein-coupled receptor kinase 2 (GRK2), which was facilitated by Src, a non-receptor tyrosine kinase. This interaction led to the ubiquitination of GRK2, which then moved to the plasma membrane and interacted with activated D2R, followed by the phosphorylation of D2R as well as the mediation of ERK activation. In conclusion, Mdm2-mediated GRK2 ubiquitination, which is selectively triggered by the stimulation of the D2R β-arrestin signaling pathway, is necessary for GRK2 membrane translocation and its interaction with D2R, which in turn mediates downstream ERK signaling. This study is primarily novel and provides essential information with which to better understand the detailed mechanisms of D2R-dependent signaling.Keywords:GRK2 ubiquitination;D2R-biased signaling;Src;ERK signaling
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产品关联
DOI
PubMed
高影响因子
Cancer Management and Research
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2020
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IF 2.886
Yanshi Wang,Shaojie Yang,Shanshan Zhang,Xin Wu
Purpose To evaluate the anti-tumor effects of oxymatrine in vulvar squamous cell carcinoma (VSCC) cells and to explore the underlying mechanisms. Methods We selected SW962 and A431 VSCC cell lines. Cell proliferation was examined using MTT assay. Cell cycle and apoptosis were detected using flow cytometry. Migration and invasion were evaluated using transwell and wound-healing assays. The relevant protein expression and signaling pathways were analyzed using Western blotting. Results Oxymatrine inhibited the proliferation of SW962 and A431 VSCC cells in a time- and dose-dependent manner. Oxymatrine induced cell cycle arrest in the G2/M phase by increasing the protein expression of P21 and decreasing levels of cyclin B1 and CDC2. Oxymatrine upregulated the expression of cleaved-caspase 3 and BAX and downregulated the expression of BCL2, which led to an increase in apoptosis. Oxymatrine also suppressed the migration and invasion of SW962 and A431 cells by reducing levels of MMP2 and MMP9. After treatment with oxymatrine or a RAS inhibitor (salirasib), expression levels of RAS, p-RAF, p-MEK, p-ERK, C-MYC, and MMP2 were reduced. When TGF-β1 was used to stimulate SW962 and A431 cells, the expression of the above proteins increased; this increase was reversed by using oxymatrine or salirasib again. Conclusion Oxymatrine inhibits proliferation and migration of VSCC cells by blocking the RAS/RAF/MEK/ERK pathway.
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产品关联
DOI
PubMed
高影响因子
NEUROSCIENCE
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2019
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IF 3.244
Lanqiu Zhang,Jinlu Zhang,Xiaolin Jiang,Lei Yang,Qi Zhang,Botao Wang,Lihua Cui,Ximo Wang
Neuroinflammation has been implicated in the mechanism underlying the progression of neurodegeneration and infectious neuropathology. Growing evidence suggest that hydroxytyrosol (3,4-dihydroxyphenil-ethanol, HT), one of the main polyphenols presented in extra virgin olive oil (EVOO), has shown potential anti-inflammatory and neuroprotective effects. However, the potential anti-neuroinflammation activity and underlying mechanism of HT remain poorly understood. The present study aimed to investigate the effects of HT on lipopolysaccharide (LPS)-induced inflammation in both in vitro and in vivo models and the associated molecular mechanism. Our results revealed that HT significantly reduced the production of pro-inflammatory mediators in BV2 microglia and primary microglia cells. Phenotypic analysis showed that HT significantly reduced M1 marker CD86 expression and increased M2 marker CD206 expression. In addition, HT significantly decreased the levels of phospho-NF-κB p65 and phospho-extracellular signal-regulated kinase (ERK) in a dose-dependent manner. Moreover, HT suppressed the LPS-induced Toll like receptor 4 (TLR4) in BV2 microglia. In vivo administration of HT following LPS injection significantly reduced some proinflammatory mediator levels and microglia/astrocyte activation in the brain. Together, these results suggest that HT suppressed the LPS-induced neuroinflammatory responses via modulation of microglia M1/M2 polarization and downregulation of TLR-4 mediated NF-κB activation and ERK signaling pathway.
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PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2019
·Vol. 235
·期 3
·2847-2856
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IF 4.522
Jiabing Zhang,Leili Wang,Wei Xie,Shunying Hu,Hao Zhou,Pingjun Zhu,Hang Zhu
Septic cardiomyopathy is associated with mitochondrial damage and endoplasmic reticulum (ER) dysfunction. However, the upstream mediator of mitochondrial injury and ER stress has not been identified and thus little drug is available to treat septic cardiomyopathy. Here, we explored the role of B-cell receptor-associated protein 31 (BAP31) in septic cardiomyopathy and figure out whether melatonin could attenuate sepsis-mediated myocardial depression via modulating BAP31. Lipopolysaccharide (LPS) was used to establish the septic cardiomyopathy model. Pathway analysis was performed via western blot, quantitative polymerase chain reaction and immunofluorescence. Mitochondrial function and ER stress were detected via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. After exposure to LPS, cardiac function was reduced due to excessive inflammation response and extensive cardiomyocyte death. Mechanistically, melatonin treatment could dose-dependently improve cardiomyocyte viability via preserving mitochondrial function and reducing ER stress. Further, we found that BAP31 transcription was repressed by LPS whereas melatonin could restore BAP31 expression; this effect was dependent on the MAPK-ERK pathway. Inhibition of the ERK pathway and/or knockdown of BAP31 could attenuate the beneficial effects of melatonin on mitochondrial function and ER homeostasis under LPS stress. Altogether, our results indicate that ERK-BAP31 pathway could be used as a critical mediator for mitochondrial function and ER homeostasis in sepsis-related myocardial injury. Melatonin could stabilize BAP31 via the ERK pathway and thus contribute to the preservation of cardiac function in septic cardiomyopathy.
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PubMed
高影响因子
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