EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Zhiran Ju,Junde Xu,Keshuang Tang,Fener Chen
COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles 4a - 4w , triazoles 6a - 6m , and cyclic imides 7a and 7b , were synthesized. The synthesized analogues were evaluated for their inhibitory activity against COX-2 enzyme. Among them, compound 6k exhibited potent selective COX-2 inhibition (IC 50 = 1.53 μM; selectivity ((IC 50 (COX-1)/IC 50 (COX-2) = 17.19). Treatment with compound 6k effectively suppressed the NF-κB/NLRP3 signaling pathway, resulting in reduced expression of pro-inflammatory factors. The in vivo ulcerative colitis assay demonstrated that compound 6k significantly ameliorated histological damages and showed strong protection against DSS-induced acute colitis. The collected results indicated that compound 6k displays anti-inflammatory activity through COX-2/NLRP3 inhibition. Therefore, compound 6k represents a promising candidate for further development as a new lead compound with reduced colitis side effects.
研究领域:
药理学
·
药物化学
·
炎症研究
✓ 已验证
DOI
PubMed
高影响因子
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.
研究领域:
心脏病学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2025
·
IF 15.4
Zeng Ke,Zhu Yuqi,Han Zhongxin,Xiong Siyi,Zhao Yan,Xiao Zilong,Xie Yingchao,Jin Shiyu,Dong Tingru,Lan Lan,Liu Weiwei,Du Yongzhong,Guan Cuiping,Yu Xiao,Song Xiuzu
NLRP3 functions as a critical intracellular danger sensor for inflammasome activation, playing a crucial role in autoimmune diseases. Vitiligo progression has been linked to NLRP3, yet its specific involvement in melanocytes of vitiligo remains poorly understood. In this study, we demonstrate that NLRP3 expression is significantly upregulated in the melanocytes of vitiligo patients and melanoma-Treg-induced vitiligo mouse model. Genetic knockout of NLRP3 effectively alleviates vitiligo progression in these mice. Our mechanistic investigations reveal that the downregulation of the E3 ligase β-TrCP1 in vitiligo melanocytes decreases K27-linked ubiquitination levels of NLRP3, which in turn weakens its interaction with the autophagy receptor NDP52. This disruption impairs the selective autophagic degradation of NLRP3, leading to hyperactivation of inflammation and pyroptosis in melanocytes, thereby accelerating vitiligo pathogenesis. Notably, melanocyte-specific knockdown of NLRP3 using lysine-proline-valine (KPV)-modified deformable liposomes (KPV-Lipos) carrying Nlrp3 shRNA significantly alleviates vitiligo development. This study elucidates the mechanism by which autophagy dysfunction mediated excessive NLRP3 inflammasome activation in melanocytes contributes to vitiligo pathogenesis, highlighting potential therapeutic strategies targeting these pathways for the treatment of vitiligo and other pigment-related skin diseases. Overview of disrupted NLRP3 autophagic degradation in vitiligo melanocytes . In healthy melanocytes, NLRP3 expression is upregulated when subjected to oxidative stress, along with an increase in the E3 ligase β-TrCP1, which enhances the K27-linked ubiquitination of NLRP3 and further strengthens its binding to the autophagy receptor protein NDP52, thus effectively suppressing the excessive inflammatory response. Whereas in the melanocytes of vitiligo patients, decreased expression of β-TrCP1 leads to downregulation of K27-linked ubiquitination in NLRP3, thus inhibiting its autophagic degradation. The persistent activation of NLRP3 in vitiligo melanocytes promotes the cleavage of pro-IL-1β and GSDMD. GSDMD-N subsequently forms pores on the cell membrane, which causes the release of IL-1β and results in melanocyte pyroptosis. In our study, we utilize KPV-Lipos with Nlrp3 shRNA to precisely knockdown NLRP3 expression in melanocytes and effectively alleviate vitiligo development, which provide a potentially promising strategy for the treatment of vitiligo. MC, melanocytes.
研究领域:
皮肤病学
·
免疫学
·
细胞生物学
·
自身免疫性疾病
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DAIRY SCIENCE
·
2025
·
IF 4.4
Shuang Guan,Yuanmeng Wang,Ranran Zhang,Xinyu Yao,Shujing Lu,Xuming Deng,Jing Lu
Alcohol, one of the most widely popular and consumed beverages worldwide, often leads to acute alcoholic liver injury (AALI) when excessively consumed within a short timeframe. It can further induce alcoholic hepatitis, posing a serious risk to human health and public health safety. Pyroptosis, a typical mode of programmed cell death, is closely associated with the body's inflammatory response and plays a central role in AALI. However, the role of yogurt in acute alcohol-induced pyroptosis and inflammation is unclear. In this study, we found that yogurt and its metabolite d -lactate effectively mitigate alcohol-induced liver damage in mice, reducing hepatocyte pyroptosis and attenuating the inflammatory response. For the specific mechanism, further studies have shown that yogurt may inhibit autophagy through its substance d -lactate, leading to the accumulation of P62 protein in cells. This accumulation subsequently triggers the activation of Nrf2 through nonclassical pathways. Nrf2 translocates to the nucleus to play its antioxidant role, thereby reducing intracellular reactive oxygen species levels, inhibiting the activation of the alcohol-induced NLRP3 inflammasome, and ultimately alleviating pyroptosis and inflammation. Overall, this study reveals the potential protective effect of yogurt and its metabolite d -lactate in alleviating AALI, offering new insights and scientific basis for yogurt as a dietary strategy to improve AALI.
研究领域:
肝病学
·
营养学
·
分子生物学
·
免疫学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Guosong Xin,Yanxiu Hou,Yuhan Liu,Hairu Li
Purpose This study examined the effects and underlying mechanisms of tetrandrine (TET) combined with adriamycin (ADR) in reversing multidrug resistance (MDR) in breast cancer cells. Methods Cell viability, proliferation, and drug resistance were assessed via the MTT assay. Small interfering RNA (siRNA) transfection was used to knock down GSDMD expression in MCF-7/ADR cells. Pyroptosis induction by the combined TET and ADR treatment was evaluated through morphological observations, cytotoxicity assays, and flow cytometry. The expression levels of mRNA and proteins were analyzed using qRT-PCR and western blotting, respectively. Results At non-cytotoxic concentrations, the combined treatment of TET and ADR significantly inhibited the growth of MCF-7/ADR cells, demonstrating a synergistic effect in reversing MDR. This combination effectively reduced MDR protein expression in MCF-7/ADR cells via GSDMD modulation, which diminished efflux activity and promoted ADR accumulation. The increased accumulation of ADR subsequently activated the NLRP3/Caspase-1/GSDMD signaling pathway, leading to elevated LDH release and enhanced pyroptosis rates. Conclusion The combined use of TET and ADR not only suppresses MCF-7/ADR cell growth but also reverses MDR by targeting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These findings propose a promising therapeutic strategy for combatting MDR in breast cancer and highlight the potential for further clinical application of this combination therapy.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY
·
2024
·Vol. 92
·期 1
·e13893
·
IF 2.5
Yongmei Peng,Yanan Xu,Sainan Li,Mingkun Shao,Zijia Shen,Wenjin Qi
Problem Vulvovaginal candidiasis (VVC) is a common mucosal fungal infection, and Candida albicans is the main causative agent. The NLRP3 inflammasome plays an important role in VVC, but the underlying mechanism is unknown. Method of Study Vaginal epithelial cells were divided into three groups: control, C. albicans strain SC5314 (wild-type, WT), and WT+ Matt Cooper Compound 950 (MCC950, a specific NLRP3 inhibitor). After human vaginal epithelial cells were pretreated with 1 µmol/L MCC950 for 2 h, C. albicans (MOI = 1) was cocultured with the human vaginal epithelial cells for 12 h. The cell supernatants were collected, LDH was detected, and the IL-1β and IL-18 levels were determined by ELISA. The expression of the pyroptosis-related proteins NLRP3, Caspase-1 p20 and GSDMD was measured by Western blotting analysis. The protein expression of the pyroptosis-related N-terminus of GSDMD (GSDMD-N) was detected by immunofluorescence. Results In this study, we showed that the WT C. albicans strain induced pyroptosis in vaginal epithelial cells, as indicated by the LDH and proinflammatory cytokine levels and the upregulated levels of the pyroptosis-related proteins NLRP3, Caspase-1 p20, and GSDMD-N. MCC950 reversed the changes in the expression of these proteins and proinflammatory cytokines in vaginal epithelial cells. Conclusion C. albicans activated the NLRP3 inflammasome to induce vaginal epithelial cell pyroptosis. MCC950 inhibited the NLRP3 inflammasome, reduced vaginal epithelial cell pyroptosis, and decreased the release of inflammatory cytokines.
研究领域:
微生物学
·
免疫学
·
细胞生物学
·
传染病学
✓ 已验证
DOI
PubMed
高影响因子
Food & Function
·
2025
·
IF 5.4
Yujia Zhou,Xuye Lai,Nengzhi Pang,Wenli Li,Qiuyan Li,Jie Pan,Lei Pei,Mingtao Chen,Zhenfeng Zhang,Lili Yang
Alcoholic liver disease (ALD) remains a major global health burden with limited effective nutritional strategies. We previously identified brown adipose tissue-derived extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a pathogenic factor in ALD, but the underlying mechanisms remained unclear. Here, we explored the role of eNAMPT on liver inflammation and evaluate the therapeutic potential of nicotinamide riboside (NR), a form of vitamin B3, as a potential nutritional intervention. We found that ethanol exposure significantly increased eNAMPT secretion from brown adipocytes (BACs) and elevated circulating eNAMPT levels in mice fed a chronic-plus-binge ethanol diet. RNA-seq analysis and rescue experiments showed that neutralizing eNAMPT reduced hepatic NLRP3 inflammasome activation and proinflammatory cytokine expression. In the co-culture experiment, BACs-derived eNAMPT induced NLRP3 inflammasome activation in hepatocytes and macrophages. However, this effect was abolished when eNAMPT was depleted from the conditioned medium of BACs. Furthermore, recombinant eNAMPT exerts a dose-dependent effect on the activation of the NLRP3 inflammasome in hepatocytes and macrophages. Importantly, oral supplementation with NR effectively suppressed ethanol-induced eNAMPT secretion and mitigated hepatic NLRP3 activation both in vivo and in vitro. The secretion of eNAMPT was inhibited when NAMPT was knocked down in BACs, thereby attenuating the anti-inflammatory effect of NR, indicating its protective effect is dependent on targeting eNAMPT secretion. Our findings reveal BACs-derived eNAMPT as a key mediator linking adipose–liver inflammation in ALD and support dietary NR as a promising intervention strategy by targeting eNAMPT.
研究领域:
营养学
·
肝病学
·
免疫学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Ophthalmology
·
2025
·Vol. 18
·期 1
·39
·
IF 1.8
Lin-Ping Xue,Hai-Song Feng
AIM To explore the neuroprotective effects of high mobility group box 2 ( HMGB2 ) knockdown on retinal ganglion cells (RGCs) in the retinal ischemia-reperfusion injury (RIRI). METHODS Oxygen-glucose deprivation (OGD)-injured RGCs from postnatal three-day C57BL/6 mice pups and high intraocular pressure (IOP)-induced RIRI mice were used as cellular and animal models of RIRI. The expression of HMGB2 in the retina of RIRI mice and OGD-injured RGCs was detected through reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. The effects of HMGB2 silencing on the morphological changes, RGCs survival, and cell apoptosis in mouse retinal tissues were observed through H&E staining, immunofluorescence staining with RNA-binding protein with multiple splicing (RBPMS) antibody, and TUNEL staining, respectively. RGC viability and apoptosis were examined by CCK-8 and flow cytometry assays. The levels of proteins associated with NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis [NLRP3, Caspase-1, GSDMD-N, interleukin (IL)-1β, IL-18] in vivo and in vitro were measured by Western blotting. RESULTS HMGB2 protein and NLRP3 were upregulated in the retina of RIRI mice and OGD-injured RGCs ( P <0.001). The retina was edematous, accompanied by disorganized cell arrangement and decreased thickness of all layers, and obvious vacuoles in ganglion cell layer. HMGB2 silencing alleviated the reduction in total retinal thickness and the severity of retinal tissue damage as well as suppressed RGC loss and retinal cell apoptosis in RIRI mice. OGD-induced RGC apoptosis was ameliorated after downregulation of HMGB2 in vitro . Intravitreal injection of the AAV-sh-HMGB2 and si-HMGB2 resulted in significantly decrease of NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 protein levels in the retinal tissues of RIRI mice and OGD-injured RGCs, respectively (all P <0.001). CONCLUSION HMGB2 knockdown protects against RGC apoptosis and pyroptosis after RIRI through suppressing NLRP3 inflammasome activation.
研究领域:
眼科学
·
神经科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Meng-Ke Liu,Juan-Juan Tang,Hao Li,Xu-Yang Chen,Jun-Ling Cai,Gui-Ying Lin,Kan-Yao Chen,Zhi-Peng Liu,Xiao-Fang Ji,Zhong-Jin Yang,Zi Li
Artemisitene (ATT), an artemisinin (ART) analog retaining the endoperoxide moiety and incorporating an additional α, β-unsaturated carbonyl structure, exhibits enhanced biological activities. However, its therapeutic effects on liver fibrosis remain unclear. In this study, we demonstrated that ATT significantly alleviated liver inflammation and fibrosis induced by carbon tetrachloride (CCL 4 ) in mice. ATT treatment markedly reduced the count of neutrophils in the liver, as well as macrophages in both the liver and spleen. Additionally, the frequencies of Th2 and Th17 cells were significantly lowered, while Th1 cells frequency and the Th1/Th2 index were notably increased. The frequency of ILC2 cells, correlated with ST2 and IL-33 expression levels, was also significantly lowered. Consistently, ATT inhibited NLRP3 inflammasome activation, which was positively associated with AST and ALT levels, and with the count of Neutrophils, macrophages, and ILC2 cells, but negatively correlated with Th1frequeny. Furthermore, liver fibrosis severity showed a significant positive correlation with neutrophil and Th17 cell counts in the liver, and a negative correlation with Th1 cell count and the Th1/Th2 index. Therefore, ATT alleviated CCL 4 -induced mice liver fibrosis through NLRP3 inflammasome inhibition and immunomodulation.
研究领域:
药理学
·
免疫学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2024
·
IF 3.3
Yanyan Heng,Wei Wei,Linzhong Cheng,Feifei Wu,Haoyu Dong,Jingxia Li,Jianing Fu,Bingjie Yang,Xinyue Liang,Chunyan Liu,Haiju Li,Haihua Liu,Pengfei Zhang
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-β-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-β-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.
研究领域:
内分泌学
·
心血管生物学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Shan Liu,Yue Zhang,Hao Zhou,Yating Ma,Fangzhou Huang,Tianyuan Lei,Qingbin Wang,Shangmin Yu
Ginsenoside Re (Re) was proved effective in improving depressive-like behaviors. However, the potential antidepressant mechanism of Re remains unrevealed. In this study, we investigated whether PINK1-mediated mitophagy and NLRP3 inflammasomes were linked to the antidepressant mechanism of Re in chronic unpredictable mild stress (CUMS) mice and lipopolysaccharide (LPS)-stimulated astrocytes. RNA sequencing and bioinformatics analyses were performed to discover the targets and pathways associated with Re. PTEN-induced putative kinase 1 (PINK1) knockdown was conducted to clarify the role of PINK1-mediated mitophagy in the antidepressant mechanism of Re. The outcomes showed that Re ameliorated depressive-like behaviors, activated PINK1-mediated mitophagy, and inhibited NLRP3 inflammasome activation. PINK1 knockdown attenuated the antidepressant effect of Re. The promotion of mitophagy and the decline of NLRP3 inflammasome activation caused by Re were reversed by PINK1 knockdown. In conclusion, Re inhibited NLRP3 inflammasome activation by promoting PINK1-mediated mitophagy to exert its antidepressant effect.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
·
2025
·Vol. 40
·期 5
·1-13
·
IF 3.5
Huang Ping,Sun Hao,Wang Yan,Wang Ning
Background . The post-stroke inflammatory response denotes the inflammatory damage inflicted upon brain tissue following stroke. Plasma fibrinogen (FIB) can permeate the compromised blood-brain barrier (BBB) after ischemic stroke, leading to the activation of the NLRP3 inflammasome. Tong-Qiao-Huo-Xue-Decoction (TQHXD), a traditional formula used to promote blood circulation and resolve blood stasis, has shown potential in this context. Nevertheless, the precise therapeutic mechanisms of TQHXD in mitigating cerebral ischemia-reperfusion injury remain to be fully elucidated. Objective . To examine the reparative effects and underlying mechanisms of TQHXD-CSF on inflammatory damage in BV-2 cells subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) injury. Methods . To establish an in vitro model of OGD/R injury and an inflammatory BV-2 cells model induced by FIB. The protective effects of TQHXD-CSF on OGD/R-injured cells were verified using CCK-8 and LDH assays. Immunofluorescence, SEM, Western blotting, and CHIP-PCR were employed to confirm that TQHXD reduces the inflammatory response by downregulating FIB levels. Pull-down and co-immunoprecipitation (CO-IP) assays were conducted to detect the interaction between FIB and NLRP3. Results . TQHXD-CSF can significantly inhibit the abnormal increase in LDH levels induced by OGD/R, enhance cell viability, and mitigate cell pyroptosis. Additionally, TQHXD-CSF reversed the marked upregulation of FIB, NLRP3, and GSDMD fluorescence intensity and protein expression caused by the FIB inflammation model, demonstrating an effect comparable to that of lumbrokinase, a fibrinolytic agent for FIB. Furthermore, it notably reduced the acetylation of H3 and H4 in the NLRP3 promoter. Importantly, the pull-down and CO-IP results indicated a robust binding affinity between FIB and NLRP3. Conclusion . TQHXD-CSF can inhibit inflammation by downregulating the FIB-NLRP3 pathway and exert a protective effect on BV-2 cells under OGD/R and FIB inflammatory injury. Graphical abstract
研究领域:
神经科学
·
中药学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）