Small Structures
·
2024
·
IF 13.9
Yuyao Liu,Jiayin Yan,Luxian Chen,Yuwei Liao,Lijia Huang,Jiali Tan
Alveolar bone resorption caused by bacteria-induced periodontitis remains challenging due to sustained inflammation. Periodontal pathogens like Porphyromonas gingivalis launch the primed signal of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in macrophages; consequent overproduction of proinflammatory cytokines and reactive oxygen species (ROS) leads to tissue destruction. This provides potential targets for a new therapeutic strategy. Herein, a multifunctionalized and dual-crosslinked hydrogel pGM/cPL@NI with NLRP3 inhibitor MCC950 loaded is prepared. Driven by the strategic functionalization of gelatin methacryloyl and ε -poly-lysine with phenylboronic acid and catechol, respectively, pGM/cPL@NI containing dynamic and photo-crosslinking networks demonstrates superior mechanical strength and stimuli-responsive behavior, as well as the overwhelmed performance in bacteria killing and ROS scavenging. Crucially, pGM/cPL@NI restores the compromised osteogenesis by specifically suppressing the proinflammatory cytokine cascade triggered by NLRP3 inflammasome activation and promoting anti-inflammatory polarization of macrophages. Collectively, pGM/cPL@NI presents robust potential as an effective “cocktail therapy” by combining antibacterial, antioxidant, inflammation resolution, and tissue regenerative functions. The present study reveals the underlying mechanism of the bacterial-immune-regeneration cascade and provides an extended approach for periodontal tissue engineering.
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POULTRY SCIENCE
·
2024
·
IF 3.8
Xinzhang Chen,Xu Lin
Trimethyl tin (TMT) is a good stabilizer for plastic products but is also a toxic environmental pollutant. Selenium has good antioxidant and anti-inflammatory properties and has been widely used in the poultry industry. However, it has not been reported whether selenium enrichment can antagonize TMT-induced viral hepatitis in poultry. To fill this gap, AA broiler models exposed to TMT for 42 d were established and fed a Se-enriched diet at the same time. H&E staining showed that selenium could significantly alleviate TMT-induced liver inflammation. Further analysis of the underlying mechanism revealed that TMT induced nitrosation stress (RNS), increased NO content and iNOS expression, which in turn activated the NF-κB/NLRP3 pathway and induced pyroptosis. However, selenium enrichment can reverse this situation, that is, reduce the occurrence of RNS, reduce the degree of pyroptosis, and thus alleviate the occurrence of inflammation. In our study, we demonstrated for the first time that TMT could induce hepatotoxicity other than neurotoxicity in poultry and that selenium could antagonize TMT-induced hepatotoxic hepatitis in chickens through the RNS/NF-κB/NLRP3 pathway.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Zhengyuan Huang,Guanghui Chen,Zhongyu Ren,Ling Xiao,Ziyue Chen,Yinping Xie,Gaohua Wang,Benhong Zhou
The management of cognitive impairments in schizophrenia presents a considerable challenge, with a strong association between neuroinflammation and its progression. Urolithin A (UA) demonstrates important anti-inflammatory properties in multiple neurological disease models, contributing to the enhancement of cognitive deficits. However, it remains uncertain if UA can produce comparable neuroregulatory effects in female rat models of schizophrenia. Eight-week-old female Sprague Dawley rats received either 0.1 mg/kg of MK801 or volume-matched saline via intraperitoneal injection for 5 consecutive days. Furthermore, they were administered 150 mg/kg of UA through oral gavage for 4 weeks. Behavioral assessments were performed to evaluate cognitive function and behavior after UA treatment. Immunofluorescence staining was employed to assess microglial activity in the hippocampus, while Western blot analysis was conducted to investigate the expression of neuroinflammation-associated proteins. Prolonged exposure to MK801 induces schizophrenia-like behaviors and cognitive deficits in female rats. It also elevates the expression of NLRP3, Caspase-1, IL-1β, and IL-18 proteins in the hippocampus, accompanied by the activation of microglial cells. However, UA treatment can reverse the expression of these inflammatory proteins and the activation of microglial cells induced by MK801. This is the first study to evaluate the effects of UA on behavior and cognition in a female rat model of schizophrenia. The findings indicate that UA mitigates MK-801-induced cognitive deficits in female rats by inhibiting neuroinflammation and microglial activation via modulation of the NLRP3 signaling pathway. These findings offer preclinical data endorsing the possible application of UA as a dietary supplement to prevent cognitive deficits in schizophrenia.
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NEUROPHARMACOLOGY
·
2025
·
IF 4.6
Yang Wang,Zhihan Wan,Ning Wang,Qian Wu,Saiwang Seto
Pyroptosis is a type of proinflammatory programmed cell death, that closely related to the progress of cerebral ischemia / reperfusion injury (CIRI), and NLRP3 inflammasome is the most classic pathway mediating pyroptosis. Ligustilide (LIG) is a natural compound derived from the traditional Chinese herb chuanxiong hort and angelica sinensis which can penetrate the blood-brain barrier and has a good neuroprotective effect. However, it remains unclear whether LIG could alleviate CIRI by inhibiting pyroptosis. Here, the neuroprotective effect of LIG was verified by reducing NLRP3-mediated pyroptosis, and further exploring whether the inhibition of LIG on pyroptosis was related to Nuclear factor-erythropoietin 2-related factor 2(Nrf2)activation. The results showed that LIG can reduce the injury of brain tissue after ischemia, as well as NLRP3 inflammasome-mediated pyroptosis and neuroinflammation response after MCAO/R in rats. Mechanistically, the effect of LIG on Nrf2 was detected by molecular docking, protein levels and immunofluorescence analysis. We found that LIG promoted the Nrf2 expression and reduced the production of mitochondrial ROS (mtROS), and than inhibited NLRP3 inflammasome-mediated pyroptosis. Particularly revealing was that ML385, the inhibitor of Nrf2, partly blocked the above effects of LIG. All these findings suggest that LIG may ameliorate CIRI through inhibiting NLRP3 inflammasome-mediated pyroptosis dependent on Nrf2 signaling.
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FASEB JOURNAL
·
2025
·Vol. 39
·期 9
·e70561
·
IF 4.2
Haocong Zhang,Xianyun Qin,Hong Yuan,Liangbi Xiang,Hailong Yu
Neuronal inflammation and apoptosis aggravate the secondary injury after spinal cord injury (SCI). Cathepsin L (CTSL) is a lysosomal cysteine protease with effects on the regulation of inflammation, but its role in SCI remains unclear. The in vivo T10 mouse spinal cord contusion model was established. The results showed that CTSL expression was increased following SCI and then gradually decreased. Moreover, CTSL was mainly expressed in microglia. To detect the function of CTSL, after contusive injury, the mice were immediately injected with lentiviruses carrying CTSL shRNA. The results showed that CTSL depletion promoted functional recovery, accompanied by increased locomotor ability. CTSL deficiency reduced lesion cavity areas by inhibiting neuronal apoptosis and neuroinflammation. Indeed, CTSL deficiency decreased the secretion of TNF-α, IL-6, and MCP-1 and M1 microglia polarization in the spinal cord. CTSL depletion inhibited the expression and assembly of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. In vitro, CTSL expression was increased in LPS-treated BV2 cells. CTSL silencing repressed LPS-induced M1 polarization, as evidenced by the reduction in TNF-α, IL-6, and MCP-1 expression in the supernatant of BV2 cells. CTSL knockdown induced the downregulation of NLRP3 expression and activation. The inhibition role of CTSL knockdown in microglial inflammation and M1 polarization was reversed by NLRP3 agonist. Collectively, the study suggests that CTSL induces the microglia M1 polarization-mediated inflammation via promoting NLRP3 activation and thereby inhibits functional recovery after SCI. Graphical The inhibition of CTSL improves functional recovery and alleviates neuroinflammation through microglial polarization after spinal cord injury. Mechanically, CTSL knockdown inhibited NLRP3 expression and activation, which repressed the production of pro-inflammatory cytokines in M1 microglia, thereby inhibiting spinal cord injury-induced neuroinflammation.
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TOXICOLOGY LETTERS
·
2025
·
IF 2.9
Leina Jia,Xiaoning Meng,Yu Ma,Jinyu Luo,Xiaoqi Luo,Huifang Yang,Jian Zhou
Cypermethrin (CYP, IUPAC name: [cyano-(3-phenoxyphenyl)methyl] 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate), a type II pyrethroid insecticide, is suggested to have potential adverse effects on human endocrine, immune, and neurotoxic systems. Objectives: In this study, we aimed to investigate whether CYP causes oxidative stress and pyroptosis in thyroid follicle epithelial cells through the activation of the ROS-NFκB-NLRP3 pathway, thereby causing inflammatory responses. Methods: Nthy-ori 3-1 cells were used as an in vitro model and exposed to CYP at different doses (0, 100, 200, 400, 800, and 1600 μmol/L) for 24 h. Results: CYP treatment enhanced oxidative damage in Nthy-ori 3-1 cells, characterized by cellular crumpling, indistinct borders, increased cellular gaps, appearance of intercellular grease droplets, and increased pyroptosis. Subsequent treatment with the caspase-1 inhibitor VX-765 enhanced cell viability in the VX-765+CYP group, improving cell morphology, reducing pyroptotic vesicles, suppressing oxidative stress, and downregulating Interleukin-18(IL-18) (an inflammatory factor) level. Conclusion: The results demonstrate that CYP induces pyroptosis in Nthy-ori 3-1 cells through activation of the reactive oxygen species (ROS)-NF-κB-NLRP3 pathway.
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CARDIOVASCULAR DRUGS AND THERAPY
·
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.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2021
·Vol. 25
·期 18
·8997-9010
·
IF 5.31
Chaoqun Nie,Rentong Zou,Shuang Pan,Rong A,Yunan Gao,Hongxiao Yang,Juncai Bai,Shuiqing Xi,Xue Wang,Xiaojian Hong,Wei Yang
It is noteworthy that prolonged cardiac structural changes and excessive fibrosis caused by myocardial infarction (MI) seriously interfere with the treatment of heart failure in clinical practice. Currently, there are no effective and practical means of either prevention or treatment. Thus, novel therapeutic approaches are critical for the long-term quality of life of individuals with myocardial ischaemia. Herein, we aimed to explore the protective effect of H 2 , a novel gas signal molecule with anti-oxidative stress and anti-inflammatory effects, on cardiac remodelling and fibrosis in MI rats, and to explore its possible mechanism. First, we successfully established MI model rats, which were then exposed to H 2 inhalation with 2% concentration for 28 days (3 hours/day). The results showed that hydrogen gas can significantly improve cardiac function and reduce the area of cardiac fibrosis. In vitro experiments further proved that H 2 can reduce the hypoxia-induced damage to cardiomyocytes and alleviate angiotensin II-induced migration and activation of cardiac fibroblasts. In conclusion, herein, we illustrated for the first time that inhalation of H 2 ameliorates myocardial infarction-induced cardiac remodelling and fibrosis in MI rats and exert its protective effect mainly through inhibiting NLRP3-mediated pyroptosis.
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Drug Design Development and Therapy
·
2022
·
IF 4.319
Hong Chen,Yongjie Ding,Wei Chen,Yun Feng,Guochao Shi
Background: Pulmonary fat embolism (PFE) is one of the important causes of acute lung injury (ALI), but its pathogenesis is unclear. In recent years, it has been found that the NLRP3 inflammasome is closely related to inflammatory response. However, there are no reports about the involvement of NLRP3 in PFE- associated ALI. Glibenclamide is a kind of hypoglycaemic drug with anti-inflammatory effect. It has been reported to have the anti-inflammatory effect related to inhibiting NLRP3.Objective: To determine whether NLRP3 inflammasome was involved in ALI induced by PFE or whether glibenclamide had therapeutic effects on such lung injury, we designed this experiment.Materials and methods: The rat model of intravenous injection of oleic acid (OA) was used to simulate PFE. Rats were divided into three groups: control, OA and glibenclamide treatment group. Blood free fatty acid (FFA) concentration was determined by ACS-ACOD. Histopathological examinations were taken to assess the severity of lung injury. The expression of NLRP3 pathway and its downstream products were analyzed by IHC, WB, qPCR and ELISA.Results: Four hours after intravenous OA injection, the typical pathological manifestations of ALI accompanied by elevated levels of plasma FFAs were found. The activity of NLRP3 inflammasomes increased in OA group, too. Pretreatment with glibenclamide partly inhibited the increase in NLRP3, caspase-1 and IL-1β expression induced by OA, simultaneously attenuated the lung injury. But it has little effect on the expression of Toll-like receptor 4 (TLR4) expression in this experiment.Conclusion: NLRP3 inflammasome, one of the main components of innate immune response, involved in ALI induced by OA. Glibenclamide can alleviate this kind of ALI by inhibiting rather the NLRP3/caspase-1/IL-1β signaling pathway than the levels of FFAs or TLR4 pathway.
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Molecular Medicine Reports
·
2017
·Vol. 16
·期 6
·8413-8419
·
IF 1.692
Qian An,Qian Hu,Bing Wang,Wenjun Cui,Fei Wu,Yu Ding
The overexpression of inflammasome components is correlated with diabetes‑associated complications. Oleanolic acid is a triterpenoid compound which is important in arterial injury. The present study evaluated whether oleanolic acid improved diabetic rat carotid artery injury through the inhibition of nucleotide‑binding domain, leucine‑rich‑containing family, pyrin domain‑containing‑3 (NLRP3) inflammasomes signaling pathways. A diabetic rat model was induced using streptozotocin (60 mg/kg) and underwent carotid artery injury. Morphometric analysis was performed using hematoxylin and eosin staining. The mRNA and protein levels were assayed by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. It was found that oleanolic acid (100 mg/kg/day) improved body weight, glucose metabolic disorders, neointimal hyperplasia and endothelial dysfunction in diabetic rats with carotid artery injury. In addition, oleanolic acid administration significantly downregulated the mRNA and protein expression levels of endothelin 1 in diabetic rats. Oleanolic acid decreased the intimal area and the ratio of neointima to media in diabetic rats. Serum levels of tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and IL‑18 in the oleanolic acid‑treated diabetic rats were downregulated. Consistent with the serum results, it was demonstrated that oleanolic acid administration caused a significant decrease in the levels of NLRP3, caspase‑1 and IL‑1β in the carotid arteries of diabetic rats. Taken together, these observations suggested that oleanolic acid attenuated carotid artery injury in diabetic rats and the underlying mechanism was mediated, at least partially, through the suppression of NLRP3 inflammasome signaling pathways.
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Pharmaceuticals
·
2026
·Vol. 19
·期 2
·325
·
IF 5.7
Yan Wang,Yuqin Peng,Hao Sun,Kai Zhu,Ning Wang,Changzhong Wang
Background : Plasma fibrinogen (FIB) levels exhibit a significant elevation during the acute phase of ischemic stroke (IS), and their dynamic fluctuations serve as important biomarkers for stroke onset, disease progression, and long-term prognosis. Tong-Qiao-Huo-Xue Decoction (TQHXD) is highly effective in treating blood stasis syndromes affecting the head and face. Nevertheless, the association between TQHXD and FIB in the underlying mechanism of treating IS warrants further investigation. Methods : Proteomics analysis predicted the potential therapeutic targets of TQHXD for IS. An in vivo model of middle cerebral artery occlusion followed by reperfusion (MCAO/R) was created in mice. To explore the interaction between FIB and NLRP3, as well as to verify the particular healing outcomes of TQHXD. Results : An increased blood–brain barrier (BBB) permeability was observed after MCAO/R, accompanied by substantial accumulation of FIB in the brain. In vivo experiments demonstrated that FIB triggered the activation of the NLRP3 inflammasome in microglia. Proteomic analysis revealed a significant increase in FIB levels following model induction, which were markedly reduced after treatment with TQHXD; KEGG pathway enrichment analysis indicated that these changes were primarily associated with the NOD-like receptor signaling pathway. Laser speckle contrast imaging showed that TQHXD treatment significantly improved cerebral blood flow and attenuated brain injury in mice. Fluorescence imaging, ELISA, and Western blotting results collectively demonstrated that TQHXD effectively reduced FIB accumulation and suppressed NLRP3 inflammasome activation. MD and pull-down experiments further demonstrated a strong interaction strength between FIB and NLRP3. Conclusions : FIB accumulates in the ischemic penumbra following CIRI, while TQHXD can effectively down-regulate FIB expression and inhibit NLRP3 inflammasome activation to mitigate CIRI. These findings provide a novel theoretical foundation and treatment direction for stroke management in clinical settings.
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CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.4
Lili Wu,Siyu Chen,Qiyuan Yang,Xing Li,Lingyan Liu,Shengjun Ji,Shuaiyuan Tang,Sihui Zhang,Yan Wang,Runzhi Chen,Zhikun Zhan
Emodin, a bioactive compound abundant in Chinese medicinal herbs, possesses broad therapeutic potential but raises safety concerns due to conflicting reports of hepatotoxicity. This study investigated the toxicological mechanisms underlying emodin-induced liver injury. Emodin (25-100 μM) elicited dose-dependent cytotoxicity in HepG2 cells, with the cytochrome P450 (CYP) enzymes CYP1A2 and CYP3A4 identified as the primary enzymes metabolizing emodin into hydroxylated products (M1-M3). The comparative cytotoxicity assay of emodin and its metabolites in HepG2 cells indicated that CYP-mediated metabolism functions as a critical detoxification pathway. Moreover, inhibition of CYP with 1-aminobenzotriazole (ABT, 500 μM) markedly enhanced emodin (12.5-100 μM) cytotoxicity in HepG2 cells. Similarly, ABT (50 mg/kg) markedly exacerbated emodin (400 mg/kg)-induced hepatotoxicity in mice following three weeks of co-administration. Transcriptomic profiling and validation experiments demonstrated that activation of the NF-κB/NLRP3 signaling axis contributes to emodin-induced hepatic injury. Metabolomic analyses further revealed perturbations in key pathways, including lipopolysaccharide (LPS) biosynthesis, sphingolipid metabolism, and cholesterol metabolism. Integrated multi-omics analysis identified a significant positive correlation between these metabolites (LPS, sphingosine, cholesterol) and NF-κB/NLRP3 pathway genes. These findings suggest that emodin-mediated upregulation of LPS, sphingosine, and cholesterol activates the NF-κB/NLRP3 pathway, subsequently triggering hepatic injury. Collectively, this study delineates the metabolic detoxification routes of emodin and provides mechanistic insight into its hepatotoxic potential.
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