TOXICOLOGICAL SCIENCES
·
2016
·Vol. 153
·期 2
·303-315
·
IF 3.88
Fu Juanli,Shi Qiong,Song Xiufang,Liu Zixuan,Wang Yawen,Wang Yuxin,Song Erqun,Song Yang
Tetrachlorobenzoquinone (TCBQ) is a confirmed active metabolite of a well-known environmental pollutant pentachlorophenol (PCP). Unfortunately, there is insufficient knowledge present available on TCBQ’s toxicity. Our previous studies indicated that TCBQ induces inflammatory response in vivo and in vitro; however, its exact mechanism needs further investigation. Toll-like receptors (TLRs) play a crucial role in conveying of inflammatory signaling, whilst high-mobility group box 1 (HMGB1) functions as a transcription-enhancing nuclear protein that regulates inflammation. Indeed, this study demonstrated that TCBQ induces the secretion/translocation of HMGB1, which in turn activates its receptors, TLR family gene (especially TLR4) and receptor for advanced glycation end-products (RAGE) expressions. Consistently, the binding affinity of HMGB1 with its receptors also increased. In the case of HMGB1 or TLR4 deficiency, there were decreases in TCBQ-induced neuroinflammatory cytokine production and neuropathological changes, eg, neuronal loss, astrocyte and macrophage cells activation. Moreover, we found the mobilization of TLR4 into lipid rafts occurs in response to TCBQ exposure, lipid rafts disruptors weakened this effect, suggested lipid rafts play an essential role for TLR4-mediated signal transduction and target inflammatory cytokines expressions. In summary, our current findings revealed a previously unknown mechanism of TCBQ-induced neurological inflammation related to HMGB1-TLR4 signaling.
研究领域:
毒理学
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神经科学
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免疫学
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环境健康
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DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2025
·
IF 4.6
Wen-Hui Ni,Ke Wang,Yun Wang,Jia Lu,Chun-Ting Lu,Wen Rong,Yi-Feng Gu,Wen-Juan Qian,Hai-Long Zhang
Chronic inflammatory pain is a top priority for arthritis patients seeking medical care. Despite the availability of NSAIDs and glucocorticoids, pain management becomes increasingly challenging due to central and peripheral sensitization. Previous studies have shown that Matrix metalloproteinase 2 (MMP2) promotes neuroinflammation by cleaving extracellular matrix proteins and activating pro-inflammatory cytokines. Folic acid acts as a promising candidate for the treatment of neuroinflammatory diseases due to its neuroprotective effects. However, the role of folic acid in inflammatory pain remains unclear. This study investigated the analgesic mechanisms of folic acid in inflammatory pain. Adult rats underwent inflammatory pain by injecting complete freund's adjuvant (CFA) into the right hindpaw. Behavioral tests were used to assess the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The results demonstrated that CFA injection induced abnormal mechanical and thermal pain and increased MMP2 expression in L3-L5 DRG and SDH of CFA rats. MMP2 was mainly expressed in neurons rather than glial cells in L3-L5 DRG of CFA rats. We further discovered that MMP2 inhibitor auraptene or knockdown alleviated inflammatory pain in CFA rats. Interestingly, we observed that long-term folic acid treatment reversed MMP2 overexpression, resulting in sustained relief of chronic inflammatory pain. Consistently, long-term folic acid treatment also relieved pain-induced anxiety. These results indicated that folic acid had a protective role in chronic inflammatory pain and pain-induced anxiety by repressing MMP2 expression. Folic acid or auraptene might be promising therapeutic options for the treatment of chronic inflammatory pain.
研究领域:
药理学
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神经科学
·
炎症研究
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产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
·
2023
·
IF 5.1
Di Jia,Jiahui Han,Jimin Cai,Zhirong Huan,Yan Wang,Xin Ge
Mesenchymal stem cells (MSCs) have favourable outcomes in the treatment of kidney diseases. Pre-B-cell leukaemia transcription factor 1 (PBX1) has been reported to be a regulator of self-renewal of stem cells. Whether PBX1 is beneficial to MSCs in the treatment of haemorrhagic shock (HS)-induced kidney damage is unknown. We overexpressed PBX1 in rat bone marrow-derived mesenchymal stem cells (rBMSCs) and human bone marrow-derived mesenchymal stem cells (hBMSCs) to treat rats with HS and hypoxia-treated human proximal tubule epithelial cells (HK-2), respectively. The results indicated that PBX1 enhanced the homing capacity of rBMSCs to kidney tissues and that treatment with rBMSCs overexpressing PBX1 improved the indicators of kidney function, alleviated structural damage to kidney tissues. Furthermore, administration with rBMSCs overexpressing PBX1 inhibited HS-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and the release of proinflammatory cytokines, and further attenuated apoptosis. We then determined whether NF-κB, an important factor in NLRP3 activation and the regulation of inflammation, participates in HS-induced kidney damage, and we found that rBMSCs overexpressing PBX1 inhibited NF-κB activation by decreasing the p-IκBα/IκBα and p-p65/p65 ratios and inhibiting the nuclear translocation and decreasing the DNA-binding capacity of NF-κB. hBMSCs overexpressing PBX1 also exhibited protective effects on HK-2 cells exposed to hypoxia, as shown by the increase in cell viability, the mitigation of apoptosis, the decrease in inflammation, and the inhibition of NF-κB and NLRP3 inflammasome activation. Our study demonstrates that MSCs overexpressing PBX1 ameliorates HS-induced kidney damage by inhibiting NF-κB pathway-mediated NLRP3 inflammasome activation and the inflammatory response.
研究领域:
干细胞生物学
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肾生理学
·
炎症
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Jiwen Fan,Meng Ren,Weiwei Chen,Haodong Wang,Yuquan He
Background Myocardial infarction (MI) triggers a strong inflammatory response mediating by NLRP3 inflammasome which is associated with cardiac fibrosis. The key players in this response are Interleukin (IL)-1 and IL-18, which are regulated by NLRP3 inflammasomes. Celastrol, a traditional Chinese medicine with strong anti-inflammatory activity, has recently reported as a cardioprotective agent. However, the mechanisms by which celastrol is cardioprotective in MI remain elusive. We hypothesized that Celastrol could reduce IL-1β and IL-18 expression and ameliorate myocardial fibrosis after myocardial infarction in rats, improve poor heart remodeling, and preserve heart function. Methods Myocardial infarction (MI) was caused by ligating the left anterior descending of male SD rats. Celastrol (1 mg/kg) or saline was administered every other day for 4 weeks. Heart function and fibrosis were assessed. Inflammatory and fibrotic markers in the myocardia were evaluated with immunohistochemistry, western blot, and ELISA. Molecular docking was employed to predict Celastrol's binding to NLRP3 protein. The effects of Celastrol on the expression of NLRP3 inflammasome and myocardial fibrosis genes were then examined in vitro . Results Celastrol maintained the left ventricular fractional shortening (FS) and ejection fraction (EF). Fibrosis was significantly reduced in animals treated with 1 mg/kg Celastrol (15.17 ± 1.82%) relative to controls (29.88 ± 4.28%). Celastrol also significantly reduced the NLRP3, IL-18, and IL-1β levels, together with macrophage and neutrophil infiltration in the myocardium. Molecular docking predicted that NLRP3 would bind tightly to Celastrol [Docking energy: −8.9 (kcal/mol)]. In vitro experiments showed reduced NLRP3 inflammasome and myocardial fibrosis-associated proteins expression in neonatal rat cardiac fibroblasts treated with Celastrol. Conclusions In post-MI rats, Celastrol, a naturally occurring active ingredient, was able to reduce myocardial fibrosis and improve cardiac function, according to our study. These effects may result from inhibiting the NLRP3 inflammasome and attenuating the early inflammatory storm after MI, suggesting that Celastrol may be useful in treating acute MI.
研究领域:
心脏病学
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药理学
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炎症
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分子生物学
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2020
·
IF 3.647
Jing Yang,Yiwen Zhou,Jinsong Shi
Acute pancreatitis (AP) is a noninfectious inflammatory disease with high morbidity and mortality, which is characterized by severe inflammation and tissue necrosis. Cordycepin (CRD), derived from Cordyceps militaris , possesses anti-inflammatory effects and immunomodulation properties. Here, we investigated the protective effects of CRD on pancreatic injury and clarified potential mechanisms in AP model. There were established caerulein-induced AP and CRD pretreatment models in vivo and in vitro, as showed by serum enzymes, histopathological alterations and pro-inflammatory cytokines. Pretreatment with CRD notably downregulated the serum amylase and lipase levels and apparently reduced pancreatic histopathological alterations in AP mice. Meanwhile, the MPO staining confirmed that CRD pretreatment modulated the infiltration of neutrophils in AP mice. Furthermore, CRD markedly decreased the levels of pro-inflammatory factors (IL-6, IL-1β, and TNF-α) though inhibiting the activation of nuclear factor-κB (NF-κB) and NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in AP mice. In pancreatic acinar cancer cell 266-6, CRD pretreatment decreased cholecystokinin(CCK)-induced inflammatory response was consistent with those in vivo. Mechanistically, CRD was also revealed to activate activated protein kinase (AMPK) and attenuated inflammation both in vivo and in vitro. On the whole, this study indicated that CRD protects mice from pancreatic inflammatory process and damage by suppressed NF-κB and NLRP3 inflammasome activation via AMPK, which probably contributed to the potential therapy for AP.
研究领域:
药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Yonglan Ruan,Jinying Ling,Fan Ye,Nuo Cheng,Fei Wu,Zongxiang Tang,Xiaolan Cheng,Hongquan Liu
Background Treatment of chronic inflammatory pain remains a major goal in the clinic. It is thus of prime importance to characterize inherent pathophysiological pathways to design new therapeutic strategies and analgesics for pain management. Paeoniflorin (PF), a monoterpenoid glycoside from Paeonia lactiflora Pallas plants, possesses promising anti-nociceptive property. However, therapeutic effect and underlying mechanism of action of PF on inflammatory pain have not yet been fully elucidated. In this study, we aim to investigate the analgesic effect further and clarify its mechanism of action of PF on complete freund’s adjuvant (CFA)-evoked inflammatory pain. Methods Twenty-four male mice were divided into 3 groups: sham, CFA, and CFA + PF groups (n = 8/group). Mice were treated with normal saline or PF (30 mg/kg) for 11 days. Footpad swelling (n = 8/group), mechanical (n = 8/group) and thermal hypersensitivity (n = 8/group) were measured to evaluate the analgesic effect of PF on CFA-injected mice. At the end of the animal experiment, blood and L4-L6 dorsal root ganglion neurons were collected to assess the therapeutic effect of PF on CFA-induced inflammatory pain. Next, hematoxylin and eosin, quantitative realtime PCR, ELISA, capsaicin and dimethyl succinate induced pain test (n = 8/group), motor coordination test (n = 8/group), tail flicking test (n = 8/group), pyruvate and succinate dehydrogenase assay (n = 6/group), immunohistochemical staining, were performed to clarify the action mechanism of PF on CFA-evoked inflammatory pain. Besides, the effect of PF on TRPV1 was evaluated by whole-cell patch clamp recording on primary neurons (n = 7). Finally, molecular docking further performed to evaluate the binding ability of PF to TRPV1. Results PF significantly relieved inflammatory pain ( P < 0.001 ) and paw edema ( P < 0.001 ) on a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model. Furthermore, PF inhibited neutrophil infiltration ( P < 0.01 ), IL-1β increase ( P < 0.01 ), and pain-related peptide substance P release ( P < 0.001 ). Intriguingly, CFA-induced succinate aggregation was notably reversed by PF via modulating pyruvate and SDH activity ( P < 0.01 ). In addition, PF dampened the high expression of subsequent succinate receptor SUCNR1 ( P < 0.01 ), HIF-1α ( P < 0.05 ), as well as the activation of NLPR3 inflammasome ( P < 0.05 ) and TRPV1 ( P < 0.05 ). More importantly, both capsaicin and dimethyl succinate supplementation obviously counteracted the pain-relieving effect of PF and TRPV1 ( P < 0.01 or P < 0.001 ). Conclusion Our findings suggest that PF can significantly relieve CFA-induced paw swelling, as well as mechanical and thermal hyperalgesia. PF alleviated inflammatory pain partly through inhibiting the activation of TRPV1 and succinate/SUCNR1-HIF-1α/NLPR3 pathway. Furthermore, we found that PF exerted its analgesic effect without affecting motor coordination and pain-related cold ion-channels. In summary, this study may provide valuable evidence for the potential application of PF as therapeutic strategy for inflammatory pain treatment.
研究领域:
药理学
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疼痛管理
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神经科学
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炎症
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EMBO REPORTS
·
2022
·Vol. 23
·期 11
·e54569
·
IF 9.071
Yueke Lin,Xiaoting Lv,Caiyu Sun,Yanlin Sun,Min Yang,Dapeng Ma,Weiqiang Jing,Yunxue Zhao,Yeping Cheng,Haocheng Xuan,Lihui Han
Tripartite motif protein (TRIM) 50 is a new member of the tripartite motif family, and its biological function and the molecular mechanism it is involved in remain largely unknown. The NOD-like receptor family protein (NLRP)3 inflammasome is actively involved in a wide array of biological processes while mechanisms of its regulation remain to be fully clarified. Here, we demonstrate the role of TRIM50 in NLRP3 inflammasome activation. In contrast to the conventional E3 ligase functions of TRIM proteins, TRIM50 mediates direct oligomerization of NLRP3, thereby suppressing its ubiquitination and promoting inflammasome activation. Mechanistically, TRIM50 directly interacts with NLRP3 through its RING domain and induces NLRP3 oligomerization via its coiled-coil domain. Finally, we show that TRIM50 promotes NLRP3 inflammasome-mediated diseases in mice. We thus reveal a novel regulatory mechanism of NLRP3 via TRIM50 and suggest that modulating TRIM50 might represent a therapeutic strategy for NLRP3-dependent pathologies.
研究领域:
免疫学
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分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Ding Wang,Qi Jiang,Peirong Li,Caini Yu,Renxiang Yuan,Zhefan Dong,Tingting Meng,Fuqiang Hu,Jianwei Wang,Hong Yuan
Inflammatory bowel disease (IBD) presents a significant challenge in healthcare, characterized by its chronicity and complex pathogenesis involving genetic, immune, and environmental factors. Current treatment modalities, including anti-inflammatory drugs, immunomodulators, and biologics, often lack sufficient efficacy and are accompanied by adverse effects, necessitating the urgent search for therapeutic approaches targeting mucosal barrier restoration and inflammation modulation. Precision nanomedicine emerges as a promising solution to directly address these challenges. This study introduces the development of a targeted sequential nanomedicine for precise IBD treatment. This innovative formulation combines a prodrug carrier containing quercetin to restore intestinal barrier integrity through the regulation of tight junctions and an anti-inflammatory agent dexamethasone acetate to alleviate inflammation. Surface modification with pectin enables colon-specific drug delivery, facilitated by degradation by colon-specific microbiota. Responsive drug release, controlled by reactive oxygen species-sensitive chemical bonds within the carrier, ensures both spatial and temporal accuracy. In vitro and in vivo investigations confirm the nanomedicine’s favorable physicochemical properties, release kinetics, and therapeutic efficacy, elucidating potential underlying mechanisms. Oral administration of the nanomedicine shows promising results in restoring intestinal barrier function, reducing inflammation, and modulating the gut microbiota. Consequently, this study presents a promising nanomedicine candidate for advancing IBD treatment paradigms.
研究领域:
药理学
·
纳米技术
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消化系统疾病
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产品关联
DOI
PubMed
高影响因子
GENES AND IMMUNITY
·
2025
·
IF 4.5
Lin Shizhao,Liang Feihong,Chen Changgan,Lin Jiajing,Wu Yuwei,Hou Zelin,Huang Heguang,Fang Haizong,Pan Yu
Severe acute pancreatitis (SAP) poses significant challenges due to its complex pathophysiology, which includes inflammatory-immune responses that cause considerable damage to both the pancreas and other tissues. In this study, we explored the role of Annexin A1 (Anxa1), a glucocorticoid-regulated protein recognized for its anti-inflammatory properties, in regulating inflammation during acute pancreatitis. Using flow cytometry, single-cell RNA sequencing, and gene expression analysis, we examined how Anxa1 expression is regulated in myeloid cells throughout acute pancreatitis, employing various animal models to evaluate the consequences of modulating Anxa1 on injuries induced by SAP. Our findings revealed dynamic regulation of Anxa1 expression in myeloid cells, with mice lacking Anxa1 exhibiting worsened pancreatic injury and heightened systemic inflammation, resulting in significant damage to extra-pancreatic organs such as the lungs, liver, and kidneys. In contrast, treatment with Ac2-26, a synthetic peptide derived from Anxa1, effectively mitigated both pancreatic and extra-pancreatic inflammation and tissue damage. Overall, this study highlights the critical role of Anxa1 in modulating inflammatory responses during acute pancreatitis. Targeting Anxa1 presents a promising therapeutic strategy to mitigate pancreatic injury and prevent systemic complications associated with severe acute pancreatitis.
研究领域:
医学
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免疫学
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病理学
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DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2024
·
IF 3.5
Xu Ren,Yun-Fei Li,Tian-Wei Pei,Hao-Sheng Wang,Yu-Hai Wang,Tao Chen
Background Traumatic brain injury (TBI) is a leading cause of high mortality and disability worldwide. Overactivation of astrocytes and overexpression of inflammatory responses in the injured brain are characteristic pathological features of TBI. Rosiglitazone (ROS) is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist known for its anti-inflammatory activity. However, the relationship between the inflammatory response involved in ROS treatment and astrocyte A1 polarization remains unclear. Objective This study aimed to investigate whether ROS treatment improves dysfunction and astrocyte A1 polarization induced after TBI and to elucidate the underlying mechanisms of these functions. Methods SD rats were randomly divided into sham operation group, TBI group, TBI+ROS group, and TBI+ PPAR-γ antagonist group (GW9662 + TBI). The rat TBI injury model was prepared by the CCI method; brain water content test and wire grip test scores suggested the prognosis; FJB staining showed the changes of ROS on the morphology and number of neurons in the peripheral area of cortical injury; ELISA, immunofluorescence staining, and western blotting analysis revealed the effects of ROS on inflammatory response and astrocyte activation with the degree of A1 polarization after TBI. Results Brain water content, inflammatory factor expression, and astrocyte activation in the TBI group were higher than those in the sham-operated group (P < 0.05); compared with the TBI group, the expression of the above indexes in the ROS group was significantly lower (P < 0.05). Compared with the TBI group, PPAR-γ content was significantly higher and C3 content was considerably lower in the ROS group (P < 0.05); compared with the TBI group, PPAR-γ content was significantly lower and C3 content was substantially higher in the inhibitor group (P < 0.05). Conclusion ROS can exert neuroprotective effects by inhibiting astrocyte A1 polarization through the PPAR-γ pathway based on the reduction of inflammatory factors and astrocyte activation in the brain after TBI.
研究领域:
神经科学
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药理学
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炎症
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创伤
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DOI
PubMed
高影响因子
Natural Product Communications
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2021
·
IF 0.986
Wenyu Xin,Ming Jing,Junjie Yang,Meiling Wang,Guige Hou,Qiaoyun Wang,Leiming Zhang,Chunhua Wang
Emerging evidence indicates that NOD-like receptor protein 3 (NLRP3) inflammasome-induced inflammation plays a critical role in the pathogenesis of Parkinson’s disease (PD). Baicalein has been considered as a possible option for PD treatment based on its anti-neuroinflammatory effects. However, no studies have elucidated the precise mechanisms underlying the anti-neuroinflammatory activity of baicalein, particularly inflammasome-mediated effects. In this present study, rotenone-induced PD mice and BV2 microglia were used to investigate the anti-neuroinflammatory effects of baicalein and explore its underlying mechanism in vivo and in vitro. The results demonstrated that baicalein alleviated motor impairments and attenuated several inflammatory responses in rotenone-induced PD mice. Also, baicalein inhibited the expression of NLRP3 and activated caspase-1 in brain tissues. Correspondingly, baicalein prominently suppressed the inflammatory response in BV2 microglia induced by rotenone. Furthermore, in vitro data showed that baicalein suppressed the expression of NLRP3 and activated caspase-1 by abrogating the upregulation of ROS, as well as by inhibiting the TLR4/NF-κB signaling cascade. Overall, the results of the present study indicated that baicalein exerted anti-neuroinflammatory effects partly by inhibiting activation of the NLRP3 inflammasome, and targeting NLRP3 inflammasome signaling offers a novel therapeutic strategy for PD treatment.
研究领域:
神经科学
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药理学
·
炎症
✓ 已验证
产品关联
DOI
高影响因子
npj Biofilms and Microbiomes
·
2021
·Vol. 7
·期 1
·1-10
·
IF 7.29
Yao Mingfei,Lu Yanmeng,Zhang Ting,Xie Jiaojiao,Han Shengyi,Zhang Shuobo,Fei Yiqiu,Ling Zongxin,Wu Jingjing,Hu Yue,Ji Shouling,Chen Hao,Berglund Björn,Li Lanjuan
The low viability during gastrointestinal transit and poor mucoadhesion considerably limits the effectiveness of Ligilactobacillus salivarius Li01 (Li01) in regulating gut microbiota and alleviating inflammatory bowel disease (IBD). In this study, a delivery system was designed through layer-by-layer (LbL) encapsulating a single Li01cell with chitosan and alginate. The layers were strengthened by cross-linking to form a firm and mucoadhesive shell (~10 nm thickness) covering the bacterial cell. The LbL Li01 displayed improved viability under simulated gastrointestinal conditions and mucoadhesive function. Almost no cells could be detected among the free Li01 after 2 h incubation in digestive fluids, while for LbL Li01, the total reduction was around 3 log CFU/mL and the viable number of cells remained above 6 log CFU/mL. Besides, a 5-fold increase in the value of rupture length and a two-fold increase in the number of peaks were found in the (bacteria-mucin) adhesion curves of LbL Li01, compared to those of free Li01. Oral administration with LbL Li01 on colitis mice facilitated intestinal barrier recovery and restoration of the gut microbiota. The improved functionality of Li01 by LbL encapsulation could increase the potential for the probiotic to be used in clinical applications to treat IBD; this should be explored in future studies.
研究领域:
微生物学
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医药科学
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食品科学
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DOI
PubMed
高影响因子
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