BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Tiantian Wan,Xiya Wang,Xue Mei,Shubin Guo
Ubiquitin C-terminal hydrolase 1 (UCHL1), a critical deubiquitinating enzyme (DUB), cleaves ubiquitin/polyubiquitin chains from substrate proteins and has been shown to promote oxidative stress and inflammatory response. However, UCHL1′s precise role in sepsis-induced liver injury (SILI) pathogenesis remains unknown. Here, we show elevated UCHL1 in cecal ligation puncture (CLP)-induced livers and lipopolysaccharide (LPS)-treated bone marrow-derived macrophages (BMDMs). Deficiency or pharmacological inhibition of UCHL1 with LDN-57444 (LDN) conferred protection against SILI by inhibiting oxidative stress and M1 macrophage polarization through targeting the degradation of glucose-6-phosphate isomerase (Gpi) and suppressing Gpi–mediated glycolysis. In contrast, the overexpression of Gpi reversed the inhibitory effects of UCHL1 deficiency on sepsis. Bone marrow transplantation combined with in vitro studies further showed that myeloid UCHL1 deficiency similarly improved SILI through suppression of Gpi stabilization and glycolysis. Hence, targeting UCHL1 in myeloid cells emerged as a protective strategy against SILI, highlighting its potential as a novel therapeutic avenue for patient care.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Ying-Xin Zhao,Ke-Tian Zhu,Yu-Xuan Tong,Qi-Qian Wang,Jin-Long Li
Abstract Di-2-ethylhexyl phthalate (DEHP) accumulates in the food chain, threatening human and animal health. However, how DEHP induces neurotoxicity by interfering with microglia has not been fully revealed. Our research aims to explore the effects of DEHP on microglia and identify relevant targets that cause neurotoxicity. The results indicated that DEHP damaged neurons, leading to swelling, demyelination, and abnormal autophagy. Inhibition of autophagy resulted in α-Syn misfolding, characterized by an increase in dimers with increasing additive concentrations (P = 0.0096). Dimer formation was promoted by the addition of additives, which increased the electrostatic force, along with interactions between Glu106, Gly51, and Val66. Transmitted from neurons to microglia (Pearson r2 = 0.889), pathological aggregates under DEHP exposure induced microglial M1 subtype switching. This study elucidated a novel mechanism by which DEHP damages the nerves of birds and provided a therapeutic target for the neurotoxic disease risk caused by the transmission of plastic additives through the food chain.
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BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Delong Meng,Qian Su,Kejuan Jia,Mengjie Jin,Wenting Liu,Shiqi Yang,Zhiqiang Su
Ischemic stroke is a kind of cerebrovascular disease with high mortality. The expression of ETS variant transcription factor 5 (ETV5) is down-regulated in ischemic stroke, but the specific role and mechanism remain unclear. In this study, the effects of ETV5 on ischemic stroke were investigated in vivo and in vitro by establishing the middle cerebral artery occlusion/reperfusion (MCAO/R) animal model and oxygen-glucose deprivation/reoxygenation (OGD/R) microglia model, respectively. We found that ETV5 reduced the infarct size, neurological deficit, microglia M1 polarization, and neuron pyroptosis level. Mechanistically, we further examined the expression of the HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1 (HACE1) and nuclear factor erythroid 2-related factor 2 (Nrf2) based on animal and cellular models to assess whether ETV5 affects ischemic stroke through the HACE1/Nrf2 signaling pathway. We found that ETV5 promoted the expression of HACE1 and Nrf2 in microglia and that HACE1 was transcriptionally activated by ETV5, which in turn competed with the E3 ligase KEAP1 for binding of Nrf2 and enhances the protein stability and nuclear expression of Nrf2. Our results suggest that ETV5 can ameliorate brain injury caused by ischemic stroke and this is closely related to inducing the HACE1/Nrf2 pathway to inhibit microglia M1 polarization.
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NEUROCHEMISTRY INTERNATIONAL
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2025
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IF 4
Ling Zhu,Congyan Liu,Yang Wang,Xuanang Zhu,Lei Wu,Lvan Chen,Jing Zhou,Fan Wang
Background Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD. Method Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N 6 -methyladenosine (m 6 A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF. Results Stimulation with Aβ 1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m 6 A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα. Conclusion Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.
研究领域:
神经生物学
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医学
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Nanoscale
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2020
·Vol. 12
·期 16
·8664-8678
·
IF 6.895
Xin Chang,Lei Xing,Yi Wang,Tian-Jiao Zhou,Li-Jun Shen,Hu-Lin Jiang
Effective treatment in clinic for idiopathic pulmonary fibrosis (IPF) remains a challenge due to low drug accumulation in lungs and imbalanced polarization of pro/anti-inflammatory macrophages (M1/M2 macrophages). Herein, a novel endogenous cell-targeting nanoplatform (PNCE) is developed for enhanced IPF treatment efficacy through modulating M1/M2 macrophages into the balanced status to suppress fibroblast over-activation. Notably, PNCE loaded with nintedanib (NIN) and colchicine (COL) can firstly target endogenous monocyte-derived multipotent cells (MOMCs) and then be effectively delivered into IPF lungs due to the homing ability of MOMCs, and detached sensitively from MOMCs by matrix metalloproteinases-2 (MMP-2) over-expressed in IPF lungs. After PNCE selectively accumulated within fibrosis foci, COL can mildly modulate the polarization of M1 macrophages into M2 macrophages to balance innate immune responses, which can enhance the suppressing effect of NIN on fibroblast activation, further improving the IPF therapy. Altogether, PNCE has two collaborative steps including the inhibition of innate immune responses accompanied by the decrease of fibroblast populations in IPF lungs, achieving a stronger and excellent anti-fibrotic efficacy both in vitro and in vivo. This endogenous cell-based engineered liposomal nanoplatform not only allows therapeutic drugs to take effect selectively in vivo, but also provides an alternative strategy for an enhanced curative effect by modulating innate immune responses in IPF therapy.
研究领域:
药理学
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纳米技术
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免疫学
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肺科学
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MEDIATORS OF INFLAMMATION
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2023
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IF 4.6
Zhousheng Yang,Tianyu Li,Chunyan Wang,Mingyu Meng,Shenglan Tan,Lei Chen
Dihydromyricetin (DMY), a natural flavonoid compound extracted from the stems and leaves of Ampelopsis grossedentata, has been found as a potential therapeutic chemical for treating atherosclerosis. This study explores the underlying mechanism of DMY repressing M1 macrophage polarization in atherosclerosis. We showed that DMY treatment markedly decreased M1 macrophage markers (e.g., Tnf-α and IL-1β) and p65-positive macrophage numbers in the vessel wall of Apoe-deficient (Apoe–/–) mice. Overexpression of miR-9 or knockdown of SIRT1 in macrophages reversed the effect of DMY on M1 macrophage polarization. The data we presented in the study indicate that the miR-9-mediated SIRT1/NF-κB pathway plays a pivotal role in M1 macrophage polarization and is one of the molecular mechanisms underlying the anti-atherosclerosis effects of DMY. We provide new solid evidence that DMY may be explored as a potential therapeutic adjuvant for treating atherosclerosis.
研究领域:
药理学
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免疫学
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心血管疾病
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INFLAMMATION
·
2026
·Vol. 49
·期 1
·79
·
IF 5.4
Hu Rui-Jie,Ying Xiao-Long,Zhang Cheng,Wang Xu,Zhan Chang-Sheng
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) constitutes a clinically complex urological condition defined by the persistence of pelvic pain and chronic inflammation. Emerging evidence underscores the critical involvement of macrophage-mediated immune dysregulation, particularly the dominance of pro-inflammatory M1 macrophages, in driving CP/CPPS pathogenesis. Leonurine, a bioactive alkaloid derived from leonuri, exhibits various pharmacological properties and has been shown to regulate macrophage polarization in rheumatoid arthritis. This study aimed to evaluate leonurine’s therapeutic efficacy in a murine experimental autoimmune prostatitis (EAP) model, established by subcutaneous injection of complete Freund’s adjuvant-emulsified prostate antigens. Leonurine administration in EAP mice markedly reduced prostatic inflammatory responses, mitigated chronic pain, and inhibited the expression of pro-inflammatory cytokines. Likewise, leonurine decreased inducible nitric oxide synthase (iNOS) expression levels, an established marker for M1 macrophage polarization. Leonurine has been found to suppress M1 polarization and decrease the secretion of M1-related cytokines (IL-1β and TNF-α) in immortalized bone marrow-derived macrophages (iBMDMs) under in vitro conditions. Mechanistic investigations demonstrated that leonurine mediates its therapeutic effects by modulating the TLR4/NF-κB signaling pathway in both macrophages and EAP models. Molecular docking and dynamics simulations demonstrated stable binding interactions between leonurine and key proteins involved in the TLR4/NF-κB signaling cascade. As a whole, these findings verify that leonurine relieves experimental autoimmune prostatitis (EAP) by regulating M1 macrophage polarization through the TLR4/NF-κB signaling cascade.
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CANCER LETTERS
·
2026
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IF 11.8
Shuangshuang Ma,Minxin Chen,Xiaozheng Sun,Baochao Wei,Fengxin Sun,Xueqi Xie,Yiheng Huang,Zhaoyun Liu,Rong Xiao,Ling Wei,Fei Wang,Ying Xu,Jinming Yu,Dawei Chen,Meng Wu
Tamoxifen has been commonly used in endocrinotherapy for estrogen receptor (ER)-positive breast cancer. In recent years, the immunomodulatory effects of high-dose tamoxifen have been discovered. The immunosuppressive tumor microenvironment (TME), however, remains a major obstacle to the efficacy of radiotherapy. Whether high-dose tamoxifen can reprogram TME to synergistically enhance radiation efficacy is still ambiguous. Here, we have found high-dose tamoxifen could dramatically enhance radiation-induced antitumor effects without significant side effects in immunocompetent mice. Flow cytometry and multiplex immunofluorescence experiments revealed that radiation combined with tamoxifen resulted in significant enrichment of effector CD8 + T cells and M1 tumor associated macrophages (TAMs). While depletion of TAMs and CD8 + T cells impaired the synergistic antitumor effects mediated by combination treatment of radiation and tamoxifen. Furthermore, spatial proximity analysis demonstrated a dramatically reduced nearest-neighbor distance between CD8 + T cells and M1-like TAMs in the combination group, indicating enhanced cellular interaction within the TME. In vitro experiments demonstrated that tamoxifen directly acted on TAMs, rather than CD8 + T cells, to promote M1 polarization and subsequently enhanced the activation and effector function of CD8 + T cells, regardless of ER expression in tumor cells and macrophages. Mechanistically, RNA-sequencing and experimental validation uncovered that tamoxifen and tumor cell-derived TNF-α and IL-1β after irradiation synergistically activated the JNK/c-JUN pathway and promoted M1 polarization of TAMs. In conclusion, our study revealed the immunomodulatory effects of high-dose tamoxifen in the context of radiation and provided preclinical evidence for combination therapy of high-dose tamoxifen and radiotherapy in both ER-positive and ER-negative cancers.
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BIOSENSORS & BIOELECTRONICS
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2017
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IF 7.78
Wei-Jia Zeng,Ni Liao,Yan-Mei Lei,Jing Zhao,Ya-Qin Chai,Ruo Yuan,Ying Zhuo
In this work, hemin was firstly used as electrochemically regenerable co-reaction accelerator for signal amplification to develop an ultrasensitive aptasensor for Aflatoxin M1 (AFM1) detection. Initially, the perylenetetracarboxylic acid (PTCA) was directly employed as luminophore to construct the ECL sensing nano-platform by combining Au nanoparticles (Au NPs) for immobilizing thiol-terminated hairpin probe (H1). Then with the help of hairpin H2, H3, the AFM1-catalyzed hairpin assembly (CHA) was executed to produce the H1-H3 duplex, which could further initiate the hybridization chain reaction (HCR) to generate dendritic DNA polymers consisting of G-rich sequence for capturing large quantities of hemin on the electrode surface . Herein, hemin as electrochemically regenerable co-reaction accelerator could interact with the co-reactant (S 2 O 8 2− ) to obviously improve the luminous efficiency of the PTCA. Therefore, a strong and stable ECL signal was achieved by the employment of hemin as electrochemically regenerable co-reaction accelerator. The proposed aptasensor determined AFM1 down to 0.09 pg mL −1 within a linear range of 0.4 pg mL −1 to 400 ng mL −1 . With excellent sensitivity and stability, the strategy provided an efficient and simple method for the trace detection of biomolecules in clinical analysis.
研究领域:
分析化学
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生物医学工程
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MICROBIOLOGICAL RESEARCH
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2026
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IF 8.5
Heqi Zhou,Qiuhong You,Routing Wang,Zhixian Lan,Zhou Zhao,Yuchuan Chen,Dekai Zheng,Kaikai Zhang,Jian Sun
Liver injury and persistent inflammation are common processes underlying liver disease pathogenesis, ultimately leading to fibrosis/cirrhosis and carcinoma. Clostridium sporogenes , a commensal gut bacterium, can produce bioactive metabolites to inhibit colon inflammation and promote neuronal repair. However, there is little information on how C. sporogenes affects injury and inflammation in the liver. Here, we found that live C. sporogenes supplementation significantly attenuates hepatic injury across multiple animal models. Including acute and chronic carbon tetrachloride (CCl 4 ) induced liver damage, as well as methionine-choline-deficient (MCD) diet-induced steatohepatitis. Metabolomics analysis in the supernatants and fecal sample of mice treated with C. sporogenes revealed that live C. sporogenes was able to generate a vital bioactive molecule 5-aminovaleric acid (5-AVA). 5-AVA exerted protective effects against liver damage in both acute and chronic liver models. Furthermore, both C. sporogenes and 5-AVA significantly prevented LPS-induced M1 macrophage activation in vivo and in vitro . The hepatoprotective effects of C. sporogenes in CCl 4 -exposed mice were abolished with macrophage depletion. Mechanistically, 5-AVA upregulated interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), which inhibited NF-κB pathway activation, suppressed pro-inflammatory cytokine expression, and attenuated liver inflammation. These findings demonstrate that C. sporogenes and 5-AVA ameliorate hepatic injury by suppressing M1 macrophage activation via the IFIT1-NF-κB signaling pathway, highlighting their potential as novel therapeutic candidates after successful translation into clinical applications. Synopsis Clostridium sporogenes alleviates acute and chronic liver injury and inflammation through its metabolite 5-aminovaleric acid (5-AVA). 5-AVA suppresses M1 macrophage activation by upregulating IFIT1, inhibiting the NF-κB pathway, and exerting hepatoprotective effects.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Jinren Liu,Yifei Jiang,Linghui Zhong,Jiajia Lu,Rongrong Li,Yifei Pei,Linyi Tang,Meng Sun,Meng Lv,Xingmin Shi,Fuliang Gong,Xili Wu
Macrophage-mediated tumor clearance is frequently restricted by the immunosuppressive tumor microenvironment. This study investigates the immunomodulatory effects of plasma-activated medium (PAM) on macrophage pro-inflammatory activation and antitumor function. Murine RAW264.7 and primary bone marrow-derived macrophages were treated with PAM generated by a helium atmospheric pressure plasma jet. Phenotypic changes and underlying signaling mechanisms were assessed. Functional enhancements in macrophage recruitment and tumor engulfment were quantified using chemotaxis and 3D confocal co-culture assays with Panc02 pancreatic cancer cells. Results show that PAM promotes macrophage activation by increasing spatial recruitment via pro-inflammatory chemokine secretion and enhancing tumor cell engulfment. Mechanistically, PAM drives this functional shift through hierarchical activation of the TLR4/NF-κB and PI3K/AKT signaling cascades. Furthermore, while hydrogen peroxide alone triggers a compensatory upregulation of the inhibitory SIRPα receptor, the reactive oxygen and nitrogen species (RONS) in PAM bypass this negative feedback to directly downregulate SIRPα. These findings demonstrate that PAM-mediated oxidative modulation effectively suppresses the “don't-eat-me” signal and enhances innate antitumor immunity, providing a potential strategy for cancer immunotherapy.
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FOOD CHEMISTRY
·
2025
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IF 9.8
Wenjing Qian,Yumei Chen,Hongliang Liu,Yankai Liu,Chao Liang,Xifang Zhu,Enping Liu,Aiping Wang,Jingming Zhou
A novel electrochemical immunosensor was proposed for rapid determination of virginiamycin M1 (VIR M1). To enhance the sensitivity, anti-VIR M1 monoclonal antibody (mAb) and silver nanoparticles-Zinc 2-methylimidazole MOF (AgNPs-ZIF-8) nanocomposite were used as bio-recognition element and electrode modification material for signal amplification, respectively. The characterization of nanocomposite was performed using ultraviolet visible spectrophotometry (UV–Vis), X-ray diffraction (XRD), fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Under optimal conditions, proposed immunosensor achieved quantitative detection of VIR M1 in range from 0.4 to 20 ng/mL, with a detection limit (LOD) of 0.32 ng/mL. The immunosensor was applied to feed and food of animal origin with recoveries ranging from 90.51 % to 101.17 %, featuring RSDs within 2.8 % to 8.8 %. Therefore, the immunosensor could be a promising tool for determining VIR M1 levels in feed and residues in food of animal origin.
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