POULTRY SCIENCE
·
2026
·Vol. 105
·期 12
·107847
·
IF 4.5
Shunxing Liu,Yanling Xiong,Zhentao Cheng,Anchun Cheng,Rutao Lin,Hui Li,Yao Huang,Binlan Zhou,Ting Yang,Chunlan Shan
Mycoplasma gallisepticum ( MG ), a significant pathogen, causes chronic respiratory disease (CRD) in poultry, characterized by coughing, wheezing, and dyspnea. This widespread disease severely impedes the healthy development of the poultry industry. Hydroxytyrosol (HT), a plant-derived monomeric compound, possesses diverse bioactivities, including antibacterial, antioxidant, and cardiovascular protective properties. This study aimed to investigate HT's protective effect against MG -induced inflammatory damage in HD11 cells. The findings revealed that MG infection activated the TLR4/NF-κB signaling pathway and the NLRP3 inflammasome, resulting in macrophage accumulation and inflammatory damage in the lung tissue of chicks. HT mitigated MG -induced inflammatory damage in HD11 cells, inhibited the M1 phenotype shift, and reduced the secretion of pro-inflammatory factors. Molecular docking and molecular dynamics simulations demonstrated HT's stable, spontaneous binding to NLRP3. Further investigations showed that HT alleviates oxidative stress-induced cellular damage, diminishes pathological apoptosis and pore formation, and concurrently reduces NLRP3 activation by regulating the TLR4/NF-κB pathway, thereby downregulating the expression of key pyroptosis factors. In summary, HT reduces NLRP3 inflammasome activation by specifically inhibiting the TLR4/NF-κB signaling axis, consequently alleviating inflammation-induced damage, oxidative stress, and pyroptosis in HD11 cells caused by MG infection.
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KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
·
2025
·
IF 3.1
Meng-Si Li,Kai Liu
IgA nephropathy (IgAN), the most common form of glomerulonephritis, is a major and growing public health issue. It results from intestinal barrier dysfunction that leads to mesangial deposition of pathogenic galactose-deficient IgA1 (Gd-IgA1) and renal inflammation. This study aimed to investigate the therapeutic effects and associated mechanisms of forsythiaside A on intestinal barrier injury in IgAN in animal models. Rats were treated with bovine serum albumin (BSA), carbon tetrachloride (CCl 4 ), and lipopolysaccharide (LPS) to induce IgAN, followed by intragastric administration of forsythiaside A once daily from weeks 15 to 20 after model establishment. Biochemical markers, including 24-h urinary protein, blood urea nitrogen (BUN), serum creatinine (SCr), renal and intestinal tissue pathology, and levels of pro-inflammatory cytokines in the serum, kidney, and intestine, intestinal tight junction proteins, and TLR4/NF-κB pathway components were examined. The results showed that forsythiaside A decreased 24-h urinary protein, BUN, and SCr levels, alleviated renal damage, and attenuated glomerular and tubular lesions, collagen deposition, and glomerular IgA deposition in IgAN rats. Forsythiaside A treatment inhibited CD68-positive macrophage infiltration in renal tissues and downregulated serum and renal levels of IL-1β, IL-6, and TNF-α, while also alleviating intestinal barrier injury and intestinal inflammation, as shown by reduced levels of IL-1β, IL-6, and TNF-α and increased expression of the intestinal tight junction proteins occludin and ZO-1. Lastly, forsythiaside A treatment lowered serum LPS concentrations, as well as renal and intestinal levels of TLR4, p-NF-κB p65, and p-IκBα, and raised both renal and intestinal levels of IκBα. Collectively, forsythiaside A was found to ameliorate the progression of IgAN in rats by alleviating inflammation and intestinal barrier injury by suppression of TLR4/NF-κB signaling.
研究领域:
肾病学
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免疫学
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药理学
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分子生物学
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胃肠病学
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INFLAMMATION
·
2026
·Vol. 49
·期 1
·41
·
IF 5
Zheng-qing Hu,Ruijie Ma,Hang Zhang,Jiahao Miao,Jia-qing Sun,Jinlong Yuan,Jiaqiang Liu,Zihuan Zhang,Dayong Xia
This study aims to elucidate the mechanism by which Heat Shock Protein 60 (HSP60) mediates microglial pyroptosis in the context of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and to investigate the effects of HSP60 inhibition on EBI after SAH. A mouse subarachnoid hemorrhage (SAH) model was established using prechiasmatic cistern blood injection. In vitro, microglia were stimulated with 25 µmol/L oxyhemoglobin (OxyHB) to simulate the SAH pathological environment. In vivo, mice received 100 mg/kg Mizoribine, while in vitro, 80 µmol/L Mizoribine was used to suppress SAH-induced HSP60 upregulation. Techniques including Western blotting, immunofluorescence, immunohistochemistry, transmission electron microscopy, ELISA, modified Garcia neurological scoring, beam walking, brain water content measurement, Morris water maze, TUNEL staining, and Nissl staining were employed to systematically investigate the role of HSP60 inhibition in neuroinflammation and microglial pyroptosis after SAH. Compared to the sham group, both in vivo and in vitro studies with blinded, random sampling of six groups demonstrated a significant increase in HSP60 expression post-SAH. In vivo, 100 mg/kg Mizoribine alleviated blood-brain barrier disruption, cerebral edema, neuronal apoptosis/necrosis, and improved neurological deficits and cognitive impairment. In vitro, 80 µmol/L Mizoribine markedly attenuated microglial activation and pyroptosis, downregulated pro-inflammatory cytokines, and mitigated neuroinflammation. The upregulation of HSP60 after SAH promotes NLRP3 inflammasome assembly by activating the TLR4/MyD88/NF-κB signaling pathway, thereby inducing microglial pyroptosis and exacerbating the progression of early brain injury. Inhibition of HSP60 represents a potential therapeutic strategy for ameliorating EBI after SAH.
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TOXICOLOGY LETTERS
·
2017
·
IF 3.858
Huaicheng Chen,Zongming Song,Shilong Ying,Xi Yang,Wei Wu,Qiufan Tan,Xin Ju,Wencan Wu,Xin Zhang,Jia Qu,Yi Wang
Retinal ischemia reperfusion (I/R) injury is common in many ophthalmic diseases. Recent studies have shown that toll-like receptor 4 (TLR4) is involved in ischemic retinal injury. Activation of TLRs requires specific accessory proteins such as myeloid differentiation protein 2 (MD2), which facilitate in ligand responsiveness. Therefore, inhibiting MD2 may be a novel approach to modulate TLR4 signaling and deleterious downstream effects in ischemic retinal injury. We used human Müller MIO-M1 cells treated with tert-butyl hydroperoxide (TBHP) to establish an in vitro I/R model of oxidative injury and tested the therapeutic effect of inhibiting MD2. Furthermore, we inhibited MD2 in a mouse model of retinal I/R injury and confirmed the results using MD2 knockout mice. Our studies show that pharmacological inhibition of MD2 prevented TBHP-induced reactive oxygen species (ROS) generation, inflammation and subsequent apoptosis in Müller cells. We also show that retinal I/R injury in mice induced functional deficits, increased ROS levels, inflammation and apoptosis. These pathological changes were not observed in MD2 knockout mice and attenuated when MD2 was inhibited in wildtype mice. In addition, we discovered that the mechanism of these therapeutic effects involved regulation of NADPH oxidase 4 (NOX4)-MD2-TLR4 complex formation. This study provides evidence that MD2 plays a key role in the pathogenesis of retinal I/R damage by participating in TLR4-NOX4 complex formation and elaboration of oxidative and inflammatory damage. Hence, inhibition of MD2 may reduce TLR-dependent damage during retinal I/R injury.
研究领域:
眼科学
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免疫学
·
分子生物学
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药理学
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EXPERIMENTAL BIOLOGY AND MEDICINE
·
2023
·
IF 3.2
Jinhong Tian,Shuaishuai Zhang,Lu Li,Xueman Lin,Yongmei Li,Kunlu Zhao,Fengxin Zheng,Yongjun Chen,Yang Yang,Ting Wu,Jianxin Pang
Excessive acetaminophen (APAP) application is a major cause of drug-induced liver injury (DILI). Febuxostat (Feb), a drug for reducing uric acid (UA) levels, was demonstrated to relieve hepatic inflammation and reverse organ functions. However, the effect of Feb on APAP-induced DILI and its mechanisms have not been fully explored. In this study, Feb (10 mg/kg) was given to mice by gavage 1 h after APAP (300 mg/kg, i.g.) induction. Serum and liver samples were collected 12 or 3 h after APAP challenge. Feb treatment was found to remarkably improve APAP-induced DILI, as evidenced by reduced serum ALT, AST and UA levels, pathomorphology, inflammatory, and oxidative responses. Consistently, treatment with Feb also reduced the cell injury induced by APAP in LO2 cells. Mechanistically, Feb induced GPX4 expression, activated the Keap1/Nrf2 pathway, and inhibited the TLR4/NF-κB p65 pathway. Feb also inhibited glutathione (GSH) depletion and Jun N-terminal kinase (JNK) activation in the early injury phase. Notably, pretreatment with Feb for 3 days also revealed preventive effects against APAP-induced DILI in mice. Overall, our data revealed a potential health impact of Feb on APAP-mediated DILI in vivo and in vitro, suggesting that Feb might be a potential candidate for treating DILI.
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INFLAMMATION
·
2021
·Vol. 44
·期 5
·2018-2032
·
IF 4.092
Zhou Changkai,Gao Jing,Ji Hongyan,Li Wenjing,Xing Xiaomin,Liu Donghua,Guo Qie,Zhou Lihua,Jing Fanbo
Previous studies have shown that benzoylaconine (BAC), a representative monoester alkaloid, has a potential anti-inflammatory effect. This study investigated the underlying molecular mechanisms using the mode of LPS-activated RAW264.7 macrophage cells. Our findings showed that BAC significantly suppressed the release of pro-inflammatory cytokines and mediators, including IL-6, TNF-α, IL-1β, ROS, NO, and PGE 2 . BAC treatment also effectively downregulated the elevated protein levels of iNOS and COX-2 induced by LPS in a dose-dependent manner. In this study, we found that BAC inhibited LPS-induced NF-κB activation by reducing the phosphorylation and degradation of IκBα by western blotting and blocking the nuclear translocation of p65 using an immunofluorescence assay. The elevated protein levels of JNK, p38, and ERK phosphorylation after LPS stimulation were restored effectively by BAC treatment. The protein expression of Toll-like receptor 4 (TLR4) and LPS-induced phosphorylation of TAK1, which is a crucial upstream regulatory factor of TLR-induced MAPK and NF-κB signaling, were inhibited by BAC in activated RAW264.7 macrophages. Moreover, BAC decreased the levels of TAK1 phosphorylation and pro-inflammatory cytokines and mediators associated with MAPK and NF-κB activation, similar to TLR4 inhibitor TAK-242. These findings demonstrated that BAC exhibited an anti-inflammatory effect by the inhibition of TLR-induced MAPK and NF-κB pathways, indicating that it could potentially be used for treating inflammatory diseases.
研究领域:
免疫学
·
药理学
·
细胞生物学
·
炎症研究
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BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Hailin Liu,Lian Zhou,Xifeng Wang,Qingcui Zheng,Fenfang Zhan,Lanqian Zhou,Yao Dong,Yanhong Xiong,Pengcheng Yi,Guohai Xu,Fuzhou Hua
The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca 2+ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca 2+ influx and cytoskeletal remodelling. The increase in intracellular Ca 2+ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca 2+ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.
研究领域:
免疫学
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药理学
·
细胞生物学
·
分子生物学
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高影响因子
Frontiers in Pharmacology
·
2020
·
IF 4.225
Wei Aiwu,Xiao Huidongzi,Xu Guangli,Yu Xile,Guo Jingjing,Jing Zhuqing,Shi Shaoqi,Song Yanli
Anticardiolipin antibody (aCL), an important characterization of antiphospholipid syndrome, shows an intense association with vascular endothelial injury. Hyperoside is a flavonoid extracted from medicinal plants traditionally used in Chinese medicines, displaying anti-inflammatory, anti-cancer, and anti-oxidative properties in various diseases. Recent studies have shifted the focus on the protective effects of hyperoside on vascular endothelial injury. However, little is known about the mechanisms involved. In the present study, we investigated the effect of hyperoside on aCL-induced injury of human umbilical vein endothelial cells (HUVECs) in vitro. Our data illustrated that aCL induced HUVEC injury via inhibiting autophagy. Hyperoside reduced aCL-induced secretion of proinflammatory cytokines IL-1β and IL-8 and endothelial adhesion cytokines TF, ICAM1, and VCAM1 in HUVECs. Additionally, hyperoside activated autophagy and suppressed the mTOR/S6K and TLR4/Myd88/NF-κB signaling transduction pathways in aCL-induced HUVECs. To the best of our knowledge, this is the first study to investigate the effect of hyperoside on aCL-induced injury, as well as offer insights into the involved mechanisms, which is of great significance for the treatment of antiphospholipid syndrome.
研究领域:
免疫学
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药理学
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细胞生物学
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血管生物学
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2017
·Vol. 175
·期 5
·840-854
·
IF 5.491
Yali Zhang,Tingting Xu,Zheer Pan,Xiangting Ge,Chuchu Sun,Chun Lu,Hongjin Chen,Zhongxiang Xiao,Bing Zhang,Yuanrong Dai,Guang Liang
Background and Purpose Acute lung injury (ALI) is a challenging clinical syndrome, which manifests as an acute inflammatory response. Myeloid differentiation protein 2 (MD2) has an important role in mediating LPS-induced inflammation. Currently, there are no effective molecular-based therapies for ALI or viable biomarkers for predicting the severity of disease. Recent preclinical studies have shown that shikonin, a natural naphthoquinone, prevents LPS-induced inflammation. However, little is known about the underlying mechanisms. Experimental Approach The binding affinity of shikonin to MD2 was analysed using computer docking, surface plasmon resonance analysis and elisa . In vitro , the anti-inflammatory effect and mechanism of shikonin were investigated through elisa , real-time quantitative reverse transcription PCR, Western blotting and immunoprecipitation assay. In vivo , lung injury was induced by intratracheal administration of LPS and assessed by changes in the histopathological and inflammatory markers. The underlying mechanisms were investigated by immunoprecipitation in lung tissue. Key Results Shikonin directly bound to MD2 and interfered with the activation of toll-like receptor 4 (TLR4) induced by LPS. In cultured macrophages, shikonin inhibited TLR4 signalling and pro-inflammatory cytokine production. These effects were produced through suppression of key signalling proteins including the NF-κB and the MAPK pathway. We also showed that shikonin inhibits MD2–TLR4 complex formation and reduces LPS-induced inflammatory responses in a mouse model of ALI. Conclusions and Implications Our studies have uncovered the mechanism underlying the biological activity of shikonin in ALI and suggest that the targeting of MD2 may prove to be beneficial as a treatment option for this condition.
研究领域:
药理学
·
免疫学
·
分子生物学
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Xin-Yu Shen,Jing-Mei Lu,Yu-Nan Lu,Guang-Nan Jin,Jing-Wen Ma,Jing-He Wang,Yu Wang,Xiang Xu,Lian-Xun Piao
Toxoplasma gondii ( T. gondii ) is an obligate intracellular protozoan parasite that causes pulmonary toxoplasmosis, although its pathogenesis is incompletely understood. There is no cure for toxoplasmosis. Coixol, a plant polyphenol extracted from coix seeds, has a variety of biological activities. However, the effects of coixol on T. gondii infection have not been clarified. In this study, we infected a mouse macrophage cell line (RAW 264.7) and BALB/c mice with the T. gondii RH strain to establish infection models in vitro and in vivo , respectively, to explore protective effects and potential mechanisms of coixol on lung injury caused by T. gondii infection. Anti- T. gondii effects and underlying anti-inflammatory mechanisms of coixol were investigated by real-time quantitative PCR, molecular docking, localized surface plasmon resonance, co-immunoprecipitation, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence microscopy. The results show that coixol inhibits T. gondii loads and T. gondii -derived heat shock protein 70 ( T.g. HSP70) expression. Moreover, coixol reduced inflammatory cell recruitment and infiltration, and ameliorated pathological lung injury induced by T. gondii infection. Coixol can directly bind T.g. HSP70 or Toll-like receptor 4 (TLR4) to disrupt their interaction. Coixol prevented overexpression of inducible nitric oxide synthase, tumor necrosis factor-α, and high mobility group box 1 by inhibiting activation of the TLR4/nuclear factor (NF)-κB signaling pathway, consistent with effects of the TLR4 inhibitor CLI-095. These results indicate that coixol improves T. gondii infection-induced lung injury by interfering with T.g. HSP70-mediated TLR4/NF-κB signaling. Altogether, these findings suggest that coixol is a promising effective lead compound for the treatment of toxoplasmosis.
研究领域:
寄生虫学
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免疫学
·
药理学
·
分子生物学
·
细胞生物学
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PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Zhen-Zhen Wang,Lihua Cao,Zhenzhu Zhao,Mengke Zhao,Yanyan Lu,Yanhui Zhu,Weijie Xie,Ping Li,Siqi Liu,Xuejiao Li,Kang Yang,Xiaobo Sun
TLR4 activation and the cascade of neutrophil extracellular trap (NET) formation exacerbate excessive inflammation and organ damage in the pathogenesis of acute lung injury (ALI), yet effective pharmacological interventions remain unavailable. Nanoaggregates derived from natural products offer promising avenue by leveraging synergistic anti-inflammatory effects. In this study, we surprisingly discovered that leonurine and ursolic acid spontaneously self-assemble into nanoparticles (LUNP) through non-covalent interactions, achieving a drug loading capacity of 100%. The LUNP platform exhibits superior biophysical properties, including enhanced mucus penetration, pH-responsive drug release, improved cellular uptake, and prolonged retention within inflamed lung tissue. Mechanistically, LUNP ameliorates ALI by dampening TLR4/MyD88/NF-κB-driven inflammatory activation, thereby remodeling the microenvironment to limit NOX4-PAD4-mediated NET formation. Notably, inhalational LUNP exhibits outstanding biosafety with minimal off-target distribution. Overall, this work introduces a synergistic self-assembled nanoplatform for precise pulmonary intervention in ALI, showcasing its ability to safely and effectively orchestrate the coordinated modulation of multiple pathological pathways. In summary, by inhibiting both TLR4 activation and NET formation, the synergistic LUNP platform offers an efficient, safe, and easily accessible therapeutic strategy for ALI, providing a promising solution for clinical translation.
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NEUROSCIENCE LETTERS
·
2026
·
IF 2.2
Wuwei Xu,Yanxin Xu,Chunyan Yao,Xianmei Fu,Xiaoling Liu,Jinping Fan,Kexue Wang,Yumeng Zhou,Yuefei Li,Ting Hu,Yan Sai,Peng Luo,Tongjian Cai
T-2 toxin is a widely distributed environmental mycotoxin that poses severe neurotoxic risks to humans and animals. Neuroinflammatory responses constitute a key mechanism underlying the neurotoxicity of T-2 toxin. However, its molecular mechanisms for inducing inflammatory responses in the nervous system remain incompletely understood. This study investigated the role of B-cell translocation gene 2 (BTG2) in T-2 toxin-induced microglial activation and evaluated the neuroprotective potential of resveratrol (Res). In vivo experiments demonstrated that exposure to T-2 toxin resulted in spatial learning, memory impairments and locomotor deficits in mice. These behavioral phenotypes were accompanied by neuroinflammation in the hippocampus and cerebral cortex, characterized by microglial activation and the upregulation of BTG2. Res pre-treatment effectively reversed these neurobehavioral deficits and suppressed the neuroinflammatory response. Mechanistic analyses revealed that Res considerably alleviated T-2 toxin-induced TLR4/MyD88/NF-κB pathway activation. In vitro studies using BV-2 microglial cells confirmed these findings. Notably, siRNA-mediated knockdown of BTG2 also abolished TLR4 pathway activation and subsequent cytokine expression induced by T-2 toxin, establishing BTG2 as a critical upstream regulator. Furthermore, RNA sequencing systematically verified that BTG2 regulates the immune response network, specifically targeting the TLR4 cascades. Collectively, these findings provide novel evidence that Res may target the BTG2-regulated TLR4/MyD88/NF-κB signal pathway to exert neuroprotection, providing a promising intervention option for reducing the environmental and health hazards associated with exposure to T-2 toxin
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