CELL BIOCHEMISTRY AND BIOPHYSICS
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2024
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IF 1.8
Zhang Qi,Yang Xi-Rui,Deng Yao
Iguratimod (T-614) is a compound widely used as anti-rheumatic drug. This study investigated the effect and underlying mechanism of T-614 on experimental Sjögren’s syndrome (ESS). ESS mice model was established by injection of submandibular gland protein. Mice were randomly divided into control, experimental Sjögren’s syndrome (ESS), ESS + T-614 (10 mg/kg), ESS + T-614 (20 mg/kg), and ESS + T-614 (30 mg/kg) groups. Human submandibular gland (HSG) were cultured with 0, 0.5, 5, or 50 μg/ml T-614 in the absence or presence of interferon-α (IFN-α). Haematoxylin and eosin (H&E) and cytokine levels were used to detect immune cells activation in submandibular glands. Apoptosis in submandibular glands tissues and cells was determined by TUNEL and flow cytometry. Apoptosis and NLRP3 inflammasome-related proteins were detected by western blotting. T-614 treatment attenuated submandibular gland damage in ESS mice. T-614 administration inhibited submandibular gland cell apoptosis in ESS mice. Furthermore, T-614 blocked inflammatory factor levels and NLRP3 inflammasome activation in the submandibular glands. In vitro, results corroborated that T-614 could protect HSG cells from IFN-α-induced cell apoptosis and inflammation by inhibiting NLRP3 inflammasome activation. Our results expounded that T-614 alleviated ESS by inhibiting NLRP3 inflammasome activation.
研究领域:
免疫学
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药理学
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风湿病学
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2025
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IF 2.8
Shuge Shu,Xinting Chen,Jiawen Ren,Xiangyu Yu,Hao Zhang,Yongquan Yu
Glyphosate is reported to compromise the central nervous system and induce behavioral disorders in mammals. However, evidence is deficient with respect to the potential mechanisms involved. In this study, C57BL/6 mice were orally exposed to glyphosate at doses ranging from 0 to 200 mg/kg/day for 16 weeks. The results of behavioral tests showed that glyphosate decreased time spent and distance traveled within the central area of open field test, decreased the retention time and number of entries into the open arms, and increased the retention time and number of entries into the close arms of elevated plus maze test. The expressions of anxiety-related genes htr5 , htr6 , and tmem132d were also significantly upregulated by glyphosate. This behavioral phenotype was linked to the permeation of glyphosate into the brain via disrupting the functional tight junctions of blood–brain barrier (BBB). As a result, glyphosate directly compromised the morphological structure of neurons, increased the number of IBA-1 microglia, and activated the expression of NLRP3-mediated pyroptosis pathway (NLRP3, Caspase-1, GSDMD, and IL-18) in the hippocampus of mice. Moreover, the glyphosate-induced activation of NLRP3 pathway in microglia was markedly reversed by NLRP3 inhibitor MCC950. The conditional mediums from glyphosate-treated BV2 cells aggravated the cytotoxicity of HT-22 neurons, which was also rescued by MCC950. In conclusion, this work demonstrated that microglia-mediated activation of NLRP3 pyroptosis pathway plays a detrimental role in glyphosate-behavioral disorders and neuron damage. These findings provide novel evidence for glyphosate-induced neurotoxicity and support the growing association between glyphosate exposure and neurobehavioral disorders in humans.
研究领域:
神经科学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
Foods
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2024
·Vol. 13
·期 4
·591
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IF 4.7
Xi Peng,Kai Liu,Xing Hu,Deming Gong,Guowen Zhang
Background: Hyperuricaemia (HUA) is a disorder of purine metabolism in the body. We previously synthesized a hesperitin (Hsp)-Cu(II) complex and found that the complex possessed strong uric acid (UA)-reducing activity in vitro. In this study we further explored the complex’s UA-lowering and nephroprotective effects in vivo. Methods: A mouse with HUA was used to investigate the complex’s hypouricemic and nephroprotective effects via biochemical analysis, RT-PCR, and Western blot. Results: Hsp-Cu(II) complex markedly decreased the serum UA level and restored kidney tissue damage to normal in HUA mice. Meanwhile, the complex inhibited liver adenosine deaminase (ADA) and xanthine oxidase (XO) activities to reduce UA synthesis and modulated the protein expression of urate transporters to promote UA excretion. Hsp-Cu(II) treatment significantly suppressed oxidative stress and inflammatory in the kidney, reduced the contents of cytokines and inhibited the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory pathway. Conclusions: Hsp-Cu(II) complex reduced serum UA and protected kidneys from renal inflammatory damage and oxidative stress by modulating the NLRP3 pathway. Hsp-Cu(II) complex may be a promising dietary supplement or nutraceutical for the therapy of hyperuricemia.
研究领域:
药理学
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生物化学
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分子生物学
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炎症研究
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DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
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2024
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IF 13.7
Cai Jiangxue,Li Chenxuan,Liu Suyuan,Tan Meiling,Sun Yiran,Sun Xiaoxiao,Yang Miaoxin,He Bin
The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated transfer RNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5′-tsRNAs inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5′-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a new light on the role of Ang-induced 5′-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.
研究领域:
免疫学
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分子生物学
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炎症
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代谢紊乱
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DOI
PubMed
高影响因子
DIGESTIVE DISEASES AND SCIENCES
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2025
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IF 2.5
Gao Tao,Zhang Huaisheng,Xu Yuan,He Guosong,Ma Huicong,Zheng Chuanming,Li Lei,Cheng Feng,Dou Hehe,Zhang Fulong,Zhao Heng,Qiu Zhaolei
Background Severe Acute Pancreatitis (SAP) is associated with significant intestinal injury and inflammation. Hypoxia-Inducible Factor-1α (HIF-1α) and NLRP3 inflammasome have been implicated in this process, but their specific roles remain unclear. Objective This study aims to elucidate the roles of HIF-1α and NLRP3 in the pathogenesis of SAP and their effects on intestinal injury, barrier function, and inflammatory responses. Methods A SAP rat model was established, and histological changes were assessed via HE staining. Western blot was used to analyze HIF-1α and NLRP3 expression in intestinal mucosa. The effects of HIF-1α modulation were examined using the activator DMOG and inhibitor BAY87-2243. Immunohistochemistry, ELISA, and TUNEL staining were used to evaluate intestinal barrier function, permeability markers, and apoptosis. Results HIF-1α and NLRP3 expression significantly increased in SAP rats, peaking at 72 h. HIF-1α activation aggravated intestinal injury and barrier dysfunction, decreasing tight junction protein levels and increasing epithelial apoptosis. Enhanced intestinal permeability and elevated pro-inflammatory cytokines were also observed. Furthermore, HIF-1α activation promoted NLRP3 inflammasome assembly, resulting in increased caspase-1 and IL-1β expression. Conclusion HIF-1α exacerbates intestinal injury and inflammation in SAP, likely through NLRP3 inflammasome activation. Targeting HIF-1α may offer a potential therapeutic approach for SAP-induced damage and inflammation.
研究领域:
医学
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分子生物学
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PubMed
高影响因子
BIOMATERIALS
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2024
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IF 12.8
Xudan Xing,Zunlei Gong,Chuke Chen,Yeyin Lin,Peiyi Liu,Tianhua Xiao,Hui Yu,Yuanxin Li,Yucong Lin,Guoxin Tan,Chengyun Ning,Zenghui Wu,Le Wang,Lei Zhou
Diabetes is associated with excessive inflammation, which negatively impacts the fracture healing process and delays bone repair. Previously, growing evidence indicated that activation of the nod-like receptor (NLR) family, such as nod-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome induces a vicious cycle of chronic low-grade inflammatory responses in diabetic fracture. Here, we describe the synthesis of a bone adhesive hydrogel that can be locally injected into the fracture site and releases a natural inhibitor of NLRP3 (rutin) in response to pathological cue reactive oxygen species activity (ROS). The hydrogel (denoted as RPO) was facilely formed by the cross-linking of rutin-functionalized gelatin, poly(vinyl alcohol), and oxidized starch based on the dynamic schiff base and boronate ester bond. Specifically, rutin is conjugated in the RPO hydrogel via a ROS linker and is released as the linker is cleaved by active ROS. In vitro studies demonstrate that RPO hydrogel effectively mitigates oxidative stress, alleviates mitochondrial dysfunction, and limits the overactivation of NLRP3 inflammasome in bone marrow derived macrophages, thereby promoting osteogenic differentiation of bone marrow mesenchymal stem cells. In a diabetic rat fracture model, RPO hydrogel significantly accelerates bone repair by modulating the inflammatory microenvironment. Our results demonstrate that local, on-demand NLRP3 inhibition for the treatment of diabetic fracture is achievable by using an injectable bioresponsive adhesive RPO hydrogel.
研究领域:
生物材料学
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炎症生物学
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骨科医学
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DOI
PubMed
高影响因子
CELL RESEARCH
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2025
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IF 25.9
Zou Gonglu,Tang Yuluan,Yang Jie,Fu Shuo,Li Yuheng,Ren Xuanyao,Zhou Nanhai,Zhao Wenlong,Gao Juyi,Ruan Ziran,Jiang Zhengfan
NLRP3 inflammasome is activated by diverse stimuli including infections, intracellular and environmental irritants. How NLRP3 senses these unrelated stimuli and what activates NLRP3 remain unknown. Here we report that signal-dependent NLRP3 phase separation initiated its activation, in which the palmitoyltransferase ZDHHC7-mediated tonic NLRP3 palmitoylation and an IDR region in the FISNA domain of NLRP3 play important roles. Moreover, three conserved hydrophobic residues in the IDR critically mediate multivalent weak interactions. NLRP3-activating stimuli including K + efflux and NLRP3-interacting molecules imiquimod, palmitate, and cardiolipin all cause NLRP3 conformational change and induce its phase separation and activation in cells and/or in vitro. Surprisingly, amphiphilic molecules like di-alcohols used to inhibit biomolecular phase separation and chemotherapeutic drugs doxorubicin and paclitaxel activate NLRP3 independently of ZDHHC7 by directly inducing NLRP3 phase separation. Mechanistically, amphiphilic molecules decrease the solubility of both palmitoylated and non-palmitoylated NLRP3 to directly induce its phase separation and activation while NLRP3 palmitoylation reduces its solubility to some extent without activation. Therefore, ZDHHC7-mediated NLRP3 palmitoylation in resting cells licenses its activation by lowering the threshold for NLRP3 phase separation in response to any of the diverse stimuli whereas NLRP3 solubility-reducing molecules like di-alcohols and chemotherapeutic drugs activate NLRP3 directly. The signal-induced NLRP3 phase separation likely provides the simplest and most direct mechanistic basis for NLRP3 activation.
研究领域:
免疫学
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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
PHYSIOLOGICAL RESEARCH
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2024
·Vol. 73
·期 5
·779
·
IF 1.9
Lu BAI,Qian CHEN,Yanqing LI,Fen WU,Mingzhe JIN,Yuhong CHEN,Xu TENG,Sheng JIN,Huanfang FAN,Yuming WU
Trimethylamine N-oxide (TMAO), a bioactive metabolite of gut microbes, plays a pivotal role in the pathogenesis of kidney diseases by activating programmed cell death (PCD) pathways. However, whether trimethylamine (TMA) contributes to chronic kidney injury and which kind of PCD is involved in TMA-induced chronic kidney injury has not been previously evaluated. To observe the effect of TMA, male C57BL/6J mice were randomly divided into two groups: the Control group and the TMA group. The mice in the TMA group were intraperitoneally injected with 100 μmol/kg/day TMA for three months, whereas the mice in the Control group were injected with normal saline for the same period. After three months, plasma creatinine and blood urea nitrogen levels, indicators of kidney function, increased significantly in the TMA group as compared with those in the Control group. Furthermore, Masson staining assay showed that TMA treatment led to a larger area of fibrosis than the Control group. TMA treatment did not change the Bax/Bcl-2 ratio, RIP1, RIP3 and MLKL phosphorylation, or iron and malondialdehyde levels in kidney tissues, indicating that apoptosis, ferroptosis and necroptosis were not involved in TMA-induced chronic kidney injury. However, compared with the Control group, TMA treatment significantly upregulated NLRP3, Caspase-1, IL-1β, cleaved-Caspase 8, Caspase-8, and ZBP1 protein expression in kidney tissues. These results indicated that the ZBP1-NLRP3 inflammasome pathway was involved in TMA-induced chronic kidney injury. In conclusion, our studies revealed that the ZBP1-NLRP3 inflammasome may take part in the progression of TMA induced chronic kidney injury.
研究领域:
肾脏病学
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免疫学
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微生物学
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分子生物学
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病理学
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DOI
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Xue Yang,Jinni Yang,Anhui Wang,Yuan Zheng,Jiachun Lin,Ziwen Kong,Yuan Tian,Haijuan Dong,Zunjian Zhang,Rui Song
Background : Ulcerative colitis (UC) has demonstrated an escalating global incidence and prevalence, thereby posing substantial challenges to public health. Despite recent advancements in therapeutic interventions, the clinical management of UC remains suboptimal, underscoring the urgent need for novel treatment strategies. Saikosaponin A (SSa), a bioactive compound derived from the traditional Chinese herb Radix Bupleuri (RB), exhibits potent anti-inflammatory and immunomodulatory effects. However, its effects on UC and the underlying molecular mechanisms remain to be thoroughly explored. Purpose : This study aims to elucidate the underlying mechanisms of SSa in ameliorating UC and establish a pharmacological foundation for developing novel treatment modalities to address unmet clinical needs in UC treatment. Methods : The protective effects of SSa against DSS-induced acute colitis were evaluated in a 3% DSS-treated mouse model. Histological (H&E staining) and molecular analyses (RT-qPCR, ELISA, Western blotting, and flow cytometry) were performed to assess colonic tissue damage and inflammatory responses. Macrophage depletion via tail vein injection of clodronate liposomes confirmed the pivotal role of macrophages in UC pathogenesis and SSa's anti-inflammatory effects. The inhibitory effects of SSa on NLRP3 inflammasome activation were analyzed in vivo and in LPS/ATP-stimulated bone marrow-derived macrophages (BMDMs) using RT-qPCR, ELISA, and Western blotting. Bioinformatics analysis, targeted LC-MS/MS, and molecular docking were employed to identify potential molecular targets and mechanisms of SSa. Drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and CH25H siRNA knockdown assays were used to validate CH25H as the direct target of SSa. Results : SSa effectively attenuated DSS-induced colitis in mice by alleviating colonic inflammation, preserving intestinal barrier integrity, reducing LPS translocation, and mitigating systemic organ injury in the liver and spleen. The inflammatory response of macrophages and the production of IL-1β were identified as key pathogenic components in colitis, and the clearance of macrophages significantly ameliorated colitis progression while SSa administration post-macrophage clearance did not further alter the disease phenotype. Mechanistically, SSa inhibited the NLRP3 inflammasome activation-mediated IL-1β secretion in macrophages. The sterol metabolism played a crucial role in the activation of the NLRP3 inflammasome. SSa also restored the disturbed sterol homeostasis in the colon under inflammatory conditions, especially promoted the synthesis of 25-hydroxycholesterol (25-OHC). Further investigation revealed that SSa primarily exerts its therapeutic effects by directly targeting cholesterol 25-hydroxylase (CH25H), which promotes the production of 25-OHC and inhibits macrophage NLRP3 inflammasome activation. Conclusion : This pioneering study demonstrated the therapeutic effect of SSa on DSS-induced colitis by targeting CH25H to enhance 25-OHC biosynthesis, which subsequently inhibited NLRP3 inflammasome activation in IL-1β-producing macrophages. These findings reveal a novel mechanism of SSa in UC treatment through cholesterol metabolism-regulated cascade immune modulation, providing strong pharmacological support for its development as a potential UC therapy.
研究领域:
免疫学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
EXPERIMENTAL NEUROLOGY
·
2024
·
IF 4.6
Tingwang Guo,Gang Chen,Lin Yang,Jia Deng,Yun Pan
In intracerebral hemorrhage (ICH), the mechanical brain injury is a considerable and indispensable factor determining the neurological functions and poor outcomes. Previous studies indicate the mechanically gated ion channel-Piezo1 can transduce mechanical effects following ICH. Isoquercitrin (ISQ) is a well-studied ion channel inhibitor. Furthermore, whether the following Piezo1-mediated neurological impairment can be ameliorated by ISQ remains unclear. Herein, we constructed the hydrostatic pressure model and ICH rat model. Firstly, we found that Piezo1 agonists Yoda1 and Jedi1 facilitated extracellular calcium influx dramatically, but ISQ could depress intracellular Ca 2+ overload under hydrostatic pressure in primary neurons. Then we detected the expression profile of Piezo1, NLRP3 and NF-κB p-p65 after ICH, and found that the expression of Piezo1 was much earlier than NLRP3 and NF-κB p-p65. Furthermore, by western blot and immunofluorescence, ISQ decreased the expression of Piezo1 and NLRP3 dramatically like GsMTx4, but Nigericin as a NLRP3 agonist failed to affect Piezo1. Besides, both ISQ and interfering Piezo1 suppressed the upregulated caspase-1, NF-κB p-p65, p-IκBα, Tunel-positive cells and inflammatory factors (IL-1β, IL-6 and TNF-α) in ICH. At last, the hydrostatic pressure or hematoma induced disturbed neural viability, disordered neural cytomorphology, and increased neurobehavioral and cognitive deficits, but they were improved by ISQ and GsMTx4 strongly. Therefore, ISQ could alleviate neurological injuries induced by Piezo1 via NLRP3 pathway. These observations indicated that Piezos might be the new therapeutic targets, and blocking Piezos/NLRP3 pathway by ISQ could be an auspicious strategy for the treatment of ICH.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
CARDIOVASCULAR DRUGS AND THERAPY
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2024
·
IF 3.1
Ye Bozhi,Cai Xueli,Liang Xiaohe,Chen Yunxuan,Dai Shanshan,Huang Zhuqi,Huang Weijian,Zhang Lei,Wang Zixuan,Xing Jincheng,Lai Xianhui,Huang Zhouqing,Jia Zhuyin
Purpose Inflammatory responses induced by NLRP3 inflammasome contribute to the progression of atherosclerosis. This study seeks to investigate the effect of emodin on the NLRP3 inflammasome in atherogenesis and to probe the underlying mechanism. Methods ApoE-knockout (ApoE −/− ) mice were treated with a high-fat diet (HFD) for 12 weeks and intragastrically with emodin for 6 weeks. Human mononuclear cell line THP-1 was pretreated with emodin or signaling pathway inhibitors and induced into macrophages using phorbol 12-myristate 13-acetate (PMA) for 48 h. The NLRP3-mediated inflammatory response was studied both in vivo and in vitro. The level of the inflammation was detected by western blot, real-time PCR analysis, and ELISA. Results Emodin attenuated atherosclerotic lesions in HFD-treated ApoE −/− mice. Emodin dramatically decreased the expression of NLRP3, GSDMD, IL-1β, and IL-18 in HFD-treated ApoE −/− mice and PMA-induced macrophages. Moreover, emodin significantly hindered the activation of nuclear factor kappa-B (NF-κB) by inhibiting the formation of the TLR4/MyD88 complex in PMA-induced macrophages. Conclusion Our data demonstrate that emodin can inhibit the development of atherosclerotic plaques by alleviating NLRP3/GSDMD-induced inflammation through repressing the TLR4/MyD88/NF-κB signaling pathway in macrophages. This finding suggests that emodin can be a potential candidate for the treatment of atherosclerosis.
研究领域:
免疫学
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心血管疾病
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药理学
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Xiuhui Chen,Yutong Zheng,Xiaofeng Zhang,Anran Zheng,Junjun Huang,Guoliang Deng,Xuna Wu,Yuying Peng,Xiaoling Zhang,Renshan Chen,Qing Xiao,Weijun Ye
Aberrant activation of the NLRP3 inflammasome is critically involved in sepsis-induced acute lung injury (ALI), with inhibition of this pathway emerging as a promising therapeutic approach. This study identifies Dipyridamole, an FDA-approved drug, as a novel inhibitor of the NLRP3 inflammasome. Mechanistically, Dipyridamole suppresses mitochondrial ROS release and directly interacts with NEK7, thereby preventing its association with NLRP3 and impeding inflammasome complex assembly. In an LPS-induced sepsis model, Dipyridamole significantly ameliorated ALI, reduced inflammatory responses, and improved survival rates in model mice. Additionally, Dipyridamole effectively inhibited NLRP3 inflammasome activation in lung tissue. These findings position Dipyridamole as a potent NLRP3 inflammasome inhibitor with substantial therapeutic potential for managing sepsis-induced ALI.
研究领域:
免疫学
·
药理学
·
病理学
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产品关联
DOI
PubMed
高影响因子
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