目的研究分析维持性血液透析患者血清巨噬细胞炎性蛋白-1α(macrophage inflammatory protein-1α,MIP-1α)、几丁质酶-3样蛋白1(chitinase-3-like protein 1,CHI3L1/YKL-40)、含pyrin结构域的NOD样受体3(NOD like receptor family pyri...目的研究分析维持性血液透析患者血清巨噬细胞炎性蛋白-1α(macrophage inflammatory protein-1α,MIP-1α)、几丁质酶-3样蛋白1(chitinase-3-like protein 1,CHI3L1/YKL-40)、含pyrin结构域的NOD样受体3(NOD like receptor family pyrin domain-containing protein 3,NLRP3)水平与导管相关性感染及预后的相关性。方法选取泸州市中医医院在2020年1月─2024年8月收治的维持性血液透析患者296例,根据是否发生导管感染分为感染组(n=68)和未感染组(n=228),根据预后情况分为预后良好组(n=42)和预后不良组(n=26),经ELISA检测血清MIP-1α、YKL-40、NLRP3水平,收集分析一般临床资料,多因素Logistic回归分析患者预后影响因素,受试者工作特征(receiver operating characteristic,ROC)曲线分析MIP-1α、YKL-40、NLRP3对患者预后的预测价值,Pearson及Spearman法分析MIP-1α、YKL-40、NLRP3与炎症因子及预后的相关性。结果与非感染组相比,感染组的血清MIP-1α、YKL-40、NLRP3、C反应蛋白(C-reactive protein,CRP)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、降钙素原(procalcitonin,PCT)水平显著升高(t=14.532、14.561、22.823、28.495、11.487、22.234,均P<0.001);预后不良组的透析龄、透析频率、MIP-1α、YKL-40、NLRP3、CRP、TNF-α、PCT水平显著高于预后良好组(t=3.293、3.293、8.410、7.432、7.511、15.045、3.694、4.007,P=0.002、0.001、<0.001、<0.001、<0.001、<0.001、<0.001、<0.001);ROC曲线显示MIP-1α、YKL-40、NLRP3三者联合对患者预后预测的AUC显著高于MIP-1α(Z=2.101,P=0.036)、YKL-40(Z=2.610,P=0.009)、NLRP3(Z=2.965,P=0.003)单独预测;MIP-1α、YKL-40、NLRP3与炎症因子CRP(r=0.462、0.466、0.472,均P<0.001)、TNF-α(r=0.436、0.426、0.451,均P<0.001)、PCT(r=0.450、0.444、0.455,均P<0.001)以及预后(r=0.521、0.502、0.504,P<0.001)均呈正相关。结论血清MIP-1α、YKL-40、NLRP3与维持性血液透析患者的导管相关性感染及预后具有一定相关性。展开更多
The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation...The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome,Muckle-Wells syndrome,and familial cold autoinflammatory syndrome 1.To date,a great effort has been made to decode the underlying mechanisms of NLRP3 activation.The priming and activation of NLRP3 drive the maturation and release of active interleukin(IL)-18 and IL-1βto cause inflammation and pyroptosis,which can significantly trigger many diseases including inflammatory diseases,immune disorders,metabolic diseases,and neurodegenerative diseases.The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials.Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields.In this minireview,we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways.We then reviewed the molecular and cellular pathways of NLRP3 in many diseases,including obesity,diabetes,and other metabolic diseases.In addition,we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy.Finally,clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.展开更多
BACKGROUND The role of NLR family pyrin domain containing 3(NLRP3)in post-endoscopic submucosal dissection(ESD)esophageal stricture remains incompletely understood.The effect of celastrol(CEL)on the prevention of esop...BACKGROUND The role of NLR family pyrin domain containing 3(NLRP3)in post-endoscopic submucosal dissection(ESD)esophageal stricture remains incompletely understood.The effect of celastrol(CEL)on the prevention of esophageal strictures has not yet been investigated.AIM To explore the effect of CEL on the prevention of esophageal stricture in rats.METHODS NLRP3,interleukin(IL)-1β,and IL-18 mRNA levels were measured in patients’tissues after esophageal ESD.NLRP3 expression in esophageal fibroblasts was determined using immunohistochemistry and immunofluorescence staining.Lentiviral transfection was used to induce NLRP3 overexpression and thioredoxin reductase 1(TXNRD1)silencing.The CCK8 assay was used to determine the optimal CEL concentration.Reactive oxygen species(ROS)generation was detected via fluorescence and flow cytometry.Masson’s trichrome staining and barium esophagography were performed to assess collagen deposition and esophageal stenosis.RESULTS The mRNA levels of NLRP3 and IL-1βwere higher in human tissues from the ESD resection bed than in normal esophageal mucosa.NLRP3 overexpression in primary rat esophageal fibroblasts led to high collagen 1 expression.Thus,NLRP3 participated in esophageal inflammation and tissue repair after ESD.Comparable to prednisolone,CEL significantly inhibited NLRP3 activation in vitro and in vivo,and esophageal strictures were markedly alleviated.Mechanistically,CEL upregulated TXNRD1 expression and reduced ROS production,thereby inhibiting NLRP3 expression.This effect was reversed by TXNRD1 silencing.Furthermore,TXNRD1 interacted with NLRP3 and promoted its ubiquitination.CONCLUSION CEL is a promising alternative therapeutic agent for the prevention of post-ESD esophageal strictures.展开更多
OBJECTIVE: To evaluate the effectiveness of Sini powder for the treatment of non-alcoholic fatty liver disease(NAFLD) in rats and the molecular mechanisms involved.METHODS: A rat model of stress-induced NAFLD was esta...OBJECTIVE: To evaluate the effectiveness of Sini powder for the treatment of non-alcoholic fatty liver disease(NAFLD) in rats and the molecular mechanisms involved.METHODS: A rat model of stress-induced NAFLD was established by a combination of long-term tethering and feeding of a high-fat, high-calorie diet. These rats were then intragastrically administered with either simvastatin, Sini powder, or vehicle for 1 week. The body mass and field test scores for each group were recorded weekly. Serum aspartate aminotransferase and alanine aminotransferase activities, and triglyceride, total cholesterol,and free fatty acid concentrations were measured.Liver tissue histopathology was examined on hematoxylin and eosin-stained paraffin sections and oil red O-stained frozen sections. The hepatic m RNA expression of nuclear factor kappa-B(NF-κB),NOD-, LRR-, and pyrin domain-containing protein 3(NLRP3), apoptosis-associated speck-like protein containing CARD(ASC), and caspase-1 were measured by reverse transcription-polymerase chain reaction(RT-PCR). The hepatic protein concentrations of NF-κB and NLRP3, ASC, caspase-1, interleukin-1β(IL-1β), interleukin-6(IL-6), and the serum concentrations of IL-1β and IL-6 were measured by enzyme-linked immunosorbent assay.RESULTS: Compared with the Blank group, rats in the Compound model group showed significant pathologic manifestations of NAFLD, and the expression of NF-κB, NLRP3, ASC, caspase-1, IL-1βand IL-6 were significantly higher(all P < 0.01). Both simvastatin and Sini powder significantly ameliorated the NAFLD pathology and the abnormal expression of NF-κB, NLRP3, ASC, caspase-1, IL-1β, and IL-6(all P < 0.01).CONCLUSION: Sini powder inhibits the inflamma-tory response in rats with NAFLD, which is mediated by NF-κB/NLRP3, IL-1β, and IL-6, reduces the effects of psychological stress, and improves lipid metabolism. Therefore, Sini powder may be effective for the treatment of stress-related NAFLD through multiple mechanisms.展开更多
OBJECTIVE:To investigate the impact of Yemazhui(Herba Eupatorii Lindleyani,HEL)against lipopolysaccharide(LPS)-induced acute lung injury(ALI)and explore its underlying mechanism in vivo.METHODS:The chemical constituen...OBJECTIVE:To investigate the impact of Yemazhui(Herba Eupatorii Lindleyani,HEL)against lipopolysaccharide(LPS)-induced acute lung injury(ALI)and explore its underlying mechanism in vivo.METHODS:The chemical constituents of HEL were analyzed by ultra-high performance liquid chromatographyquadrupole time-of-flight mass spectrometry method.Then,HEL was found to suppress LPS-induced ALI in vivo.Six-week-old male Sprague-Dawley rats were randomly divided into 6 groups:control,LPS,Dexamethasone(Dex),HEL low dose 6 g/kg(HEL-L),HEL medium dose 18 g/kg(HEL-M)and HEL high dose 54 g/kg(HEL-H)groups.The model rats were intratracheally injected with 3 mg/kg LPS to establish an ALI model.Leukocyte counts,lung wet/dry weight ratio,as well as myeloperoxidase(MPO)activity were determined followed by the detection with hematoxylin and eosin staining,enzyme linked immunosorbent assay,quantitative real time polymerase chain reaction,western blotting,immunohistochemistry,and immunofluorescence.Besides,to explore the effect of HEL on ALI-mediated intestinal flora,we performed 16s rRNA sequencing analysis of intestinal contents.RESULTS:HEL attenuated LPS-induced inflammation in lung tissue and intestinal flora disturbance.Mechanism study indicated that HEL suppressed the lung coefficient and wet/dry weight ratio of LPS-induced ALI in rats,inhibited leukocytes exudation and MPO activity,and improved the pathological injury of lung tissue.In addition,HEL reduced the expression of tumor necrosis factoralpha,interleukin-1beta(IL-1β)and interleukin-6(IL-6)in bronchoalveolar lavage fluid and serum,and inhibited nuclear displacement of nuclear factor kappa-B p65(NF-κBp65).And 18 g/kg HEL also reduced the expression levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88,NF-κBp65,phosphorylated inhibitor kappa B alpha(phospho-IκBα),nod-like receptor family pyrin domain-containing 3 protein(NLRP3),IL-1β,and interleukin-18(IL-18)in lung tissue,and regulated intestinal flora disturbance.CONCLUSIONS:In summary,our findings revealed that HEL has a protective effect on LPS-induced ALI in rats,and its mechanism may be related to inhibiting TLR4/NF-κB/NLRP3 signaling pathway and improving intestinal flora disturbance.展开更多
OBJECTIVE:To investigate the efficacy of Qingchi San(青赤散,QCS),a preparation of Traditional Chinese Medicine,on ulcerative colitis(UC)in mice by inhibiting the nuclearfactor-kappa B(NF-κB)signaling pathway and nucl...OBJECTIVE:To investigate the efficacy of Qingchi San(青赤散,QCS),a preparation of Traditional Chinese Medicine,on ulcerative colitis(UC)in mice by inhibiting the nuclearfactor-kappa B(NF-κB)signaling pathway and nucleotide-binding oligomerization domain,leucine-rich repeat and pyrin domain-containing 3(NLRP3)inflammasome formation.METHODS:The UC model was established with male C57BL/6J as the animal model.Bodyweight,Disease Activity Index(DAI),colon length and weight were detected.Furthermore,colonic histology was performed by hematoxylin-eosin(HE)staining.interleukin-1β(IL-1β),interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),myeloperoxidase(MPO)and superoxide dismutase(SOD)were performed by enzyme-linked immunosorbent assay.Cyclooxygenase 2(COX2)and inducible nitric oxide synthase(iNOS)mRNA expression were conducted by real-time quantitative polymerase chain reaction(RT-qPCR).NF-κB,inhibitor of NF-κBα(iκBα),Phosphorylated inhibitor of NF-κBα(p-iκBα),caspase-1,NLRP3 and Apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC)protein expression were conducted by Western blotting.RESULTS:Compared with UC model group,Bodyweight was significantly increased in QCS treatment.At the same time,DAI was significantly decreased in QCS treatment.Colon length and weight and colonic histology were significantly improved in QCS treatment.Furthermore,the expression of IL-1β,IL-6,TNF-α,MPO,SOD,COX2,and iN OS were significantly decreased in QCS treatment.Finally,the expression of NF-κB signaling pathway-related proteins NF-κB,iκBα,p-iκBα,and the expression of NLRP3 inflammasome related proteins caspase-1,NLRP3 and ASC were significantly decreased in QCS treatment.CONCLUSION:Traditional Chinese drug QCS could treat UC by inhibiting the NF-κB signaling pathway and NLRP3 inflammasome formation in mice.展开更多
BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology.Long noncoding RNAs(lncRNAs)are active participators of diabetic nephropathy(DN).X inactive specific transcript(X...BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology.Long noncoding RNAs(lncRNAs)are active participators of diabetic nephropathy(DN).X inactive specific transcript(XIST)expression has been reported to be elevated in the serum of DN patients.AIM To evaluate the mechanism of lncRNA XIST in renal tubular epithelial cell(RTEC)pyroptosis in DN.METHODS A DN rat model was established through streptozotocin injection,and XIST was knocked down by tail vein injection of the lentivirus LV sh-XIST.Renal metabolic and biochemical indices were detected,and pathological changes in the renal tissue were assessed.The expression of indicators related to inflammation and pyroptosis was also detected.High glucose(HG)was used to treat HK2 cells,and cell viability and lactate dehydrogenase(LDH)activity were detected after silencing XIST.The subcellular localization and downstream mechanism of XIST were investigated.Finally,a rescue experiment was carried out to verify that XIST regulates NLR family pyrin domain containing 3(NLRP3)/caspase-1-mediated RTEC pyroptosis through the microRNA-15-5p(miR-15b-5p)/Toll-like receptor 4(TLR4)axis.RESULTS XIST was highly expressed in the DN models.XIST silencing improved renal metabolism and biochemical indices and mitigated renal injury.The expression of inflammation and pyroptosis indicators was significantly increased in DN rats and HG-treated HK2 cells;cell viability was decreased and LDH activity was increased after HGtreatment. Silencing XIST inhibited RTEC pyroptosis by inhibiting NLRP3/caspase-1. Mechanistically,XIST sponged miR-15b-5p to regulate TLR4. Silencing XIST inhibited TLR4 by promotingmiR-15b-5p. miR-15b-5p inhibition or TLR4 overexpression averted the inhibitory effect ofsilencing XIST on HG-induced RTEC pyroptosis.CONCLUSIONSilencing XIST inhibits TLR4 by upregulating miR-15b-5p and ultimately inhibits renal injury inDN by inhibiting NLRP3/caspase-1-mediated RTEC pyroptosis.展开更多
OBJECTIVE:To investigate the effects of Qingre Jianpi decoction(清热健脾汤,QRJPD)on dextran sulfate sodium(DSS)-induced colitis mice and explore its mechanism.METHODS:All mice were randomly divided into six groups.Wei...OBJECTIVE:To investigate the effects of Qingre Jianpi decoction(清热健脾汤,QRJPD)on dextran sulfate sodium(DSS)-induced colitis mice and explore its mechanism.METHODS:All mice were randomly divided into six groups.Weight changes,disease activity index values,and histological damage were detected.Inflammatory cytokines and immune cell infiltration were measured using enzyme-linked immunosorbent assays(ELISA)and immunohistochemistry(IHC)method.The key protein expression levels of the NOD-like receptor family pyrin domain-containing 3(NLRP3)inflammasome were detected by western blot analysis,IHC,and quantitative reverse transcription polymerase chain reaction.RESULTS:QRJPD played an anti-inflammatory role in the treatment of ulcerative colitis(UC),reduced the secretion of inflammatory cytokines,and inhibited the inflammatory infiltration of immune cells by suppressing DSS-induced activation of the NLRP3 inflammasome.CONCLUSION:QRJPD exerts protective effects by inhibiting DSS-induced NLRP3 inflammasome activation.展开更多
文摘目的研究分析维持性血液透析患者血清巨噬细胞炎性蛋白-1α(macrophage inflammatory protein-1α,MIP-1α)、几丁质酶-3样蛋白1(chitinase-3-like protein 1,CHI3L1/YKL-40)、含pyrin结构域的NOD样受体3(NOD like receptor family pyrin domain-containing protein 3,NLRP3)水平与导管相关性感染及预后的相关性。方法选取泸州市中医医院在2020年1月─2024年8月收治的维持性血液透析患者296例,根据是否发生导管感染分为感染组(n=68)和未感染组(n=228),根据预后情况分为预后良好组(n=42)和预后不良组(n=26),经ELISA检测血清MIP-1α、YKL-40、NLRP3水平,收集分析一般临床资料,多因素Logistic回归分析患者预后影响因素,受试者工作特征(receiver operating characteristic,ROC)曲线分析MIP-1α、YKL-40、NLRP3对患者预后的预测价值,Pearson及Spearman法分析MIP-1α、YKL-40、NLRP3与炎症因子及预后的相关性。结果与非感染组相比,感染组的血清MIP-1α、YKL-40、NLRP3、C反应蛋白(C-reactive protein,CRP)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、降钙素原(procalcitonin,PCT)水平显著升高(t=14.532、14.561、22.823、28.495、11.487、22.234,均P<0.001);预后不良组的透析龄、透析频率、MIP-1α、YKL-40、NLRP3、CRP、TNF-α、PCT水平显著高于预后良好组(t=3.293、3.293、8.410、7.432、7.511、15.045、3.694、4.007,P=0.002、0.001、<0.001、<0.001、<0.001、<0.001、<0.001、<0.001);ROC曲线显示MIP-1α、YKL-40、NLRP3三者联合对患者预后预测的AUC显著高于MIP-1α(Z=2.101,P=0.036)、YKL-40(Z=2.610,P=0.009)、NLRP3(Z=2.965,P=0.003)单独预测;MIP-1α、YKL-40、NLRP3与炎症因子CRP(r=0.462、0.466、0.472,均P<0.001)、TNF-α(r=0.436、0.426、0.451,均P<0.001)、PCT(r=0.450、0.444、0.455,均P<0.001)以及预后(r=0.521、0.502、0.504,P<0.001)均呈正相关。结论血清MIP-1α、YKL-40、NLRP3与维持性血液透析患者的导管相关性感染及预后具有一定相关性。
文摘The nucleotide-binding domain,leucine-rich repeat,and pyrin domain-containing protein 3(NLRP3)inflammasome is a critical modulator in inflammatory disease.Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome,Muckle-Wells syndrome,and familial cold autoinflammatory syndrome 1.To date,a great effort has been made to decode the underlying mechanisms of NLRP3 activation.The priming and activation of NLRP3 drive the maturation and release of active interleukin(IL)-18 and IL-1βto cause inflammation and pyroptosis,which can significantly trigger many diseases including inflammatory diseases,immune disorders,metabolic diseases,and neurodegenerative diseases.The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials.Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields.In this minireview,we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways.We then reviewed the molecular and cellular pathways of NLRP3 in many diseases,including obesity,diabetes,and other metabolic diseases.In addition,we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy.Finally,clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.
基金Supported by National Natural Science Foundation of China,No.82002609.
文摘BACKGROUND The role of NLR family pyrin domain containing 3(NLRP3)in post-endoscopic submucosal dissection(ESD)esophageal stricture remains incompletely understood.The effect of celastrol(CEL)on the prevention of esophageal strictures has not yet been investigated.AIM To explore the effect of CEL on the prevention of esophageal stricture in rats.METHODS NLRP3,interleukin(IL)-1β,and IL-18 mRNA levels were measured in patients’tissues after esophageal ESD.NLRP3 expression in esophageal fibroblasts was determined using immunohistochemistry and immunofluorescence staining.Lentiviral transfection was used to induce NLRP3 overexpression and thioredoxin reductase 1(TXNRD1)silencing.The CCK8 assay was used to determine the optimal CEL concentration.Reactive oxygen species(ROS)generation was detected via fluorescence and flow cytometry.Masson’s trichrome staining and barium esophagography were performed to assess collagen deposition and esophageal stenosis.RESULTS The mRNA levels of NLRP3 and IL-1βwere higher in human tissues from the ESD resection bed than in normal esophageal mucosa.NLRP3 overexpression in primary rat esophageal fibroblasts led to high collagen 1 expression.Thus,NLRP3 participated in esophageal inflammation and tissue repair after ESD.Comparable to prednisolone,CEL significantly inhibited NLRP3 activation in vitro and in vivo,and esophageal strictures were markedly alleviated.Mechanistically,CEL upregulated TXNRD1 expression and reduced ROS production,thereby inhibiting NLRP3 expression.This effect was reversed by TXNRD1 silencing.Furthermore,TXNRD1 interacted with NLRP3 and promoted its ubiquitination.CONCLUSION CEL is a promising alternative therapeutic agent for the prevention of post-ESD esophageal strictures.
基金Supported by the General Program of the National Natural Science Foundation of China(No.81774122):Exploring the Role of Psychological Stress in the Pathogenesis of NASH and the Intervention Mechanism of Sini Powder from the"NLRP3/IL-1β"Signaling Pathway and the Young and Middle-aged Teachers Project of Beijing University of Chinese Medicine(No.2017-JYB-JS-002)Psychological Stress Induced by GC/NLRP3 Pathway in Molecular Mechanism of Non-Alcoholic Fatty Liver Disease and Treatment Mechanism of Chaihu Jiangzhi Decoction。
文摘OBJECTIVE: To evaluate the effectiveness of Sini powder for the treatment of non-alcoholic fatty liver disease(NAFLD) in rats and the molecular mechanisms involved.METHODS: A rat model of stress-induced NAFLD was established by a combination of long-term tethering and feeding of a high-fat, high-calorie diet. These rats were then intragastrically administered with either simvastatin, Sini powder, or vehicle for 1 week. The body mass and field test scores for each group were recorded weekly. Serum aspartate aminotransferase and alanine aminotransferase activities, and triglyceride, total cholesterol,and free fatty acid concentrations were measured.Liver tissue histopathology was examined on hematoxylin and eosin-stained paraffin sections and oil red O-stained frozen sections. The hepatic m RNA expression of nuclear factor kappa-B(NF-κB),NOD-, LRR-, and pyrin domain-containing protein 3(NLRP3), apoptosis-associated speck-like protein containing CARD(ASC), and caspase-1 were measured by reverse transcription-polymerase chain reaction(RT-PCR). The hepatic protein concentrations of NF-κB and NLRP3, ASC, caspase-1, interleukin-1β(IL-1β), interleukin-6(IL-6), and the serum concentrations of IL-1β and IL-6 were measured by enzyme-linked immunosorbent assay.RESULTS: Compared with the Blank group, rats in the Compound model group showed significant pathologic manifestations of NAFLD, and the expression of NF-κB, NLRP3, ASC, caspase-1, IL-1βand IL-6 were significantly higher(all P < 0.01). Both simvastatin and Sini powder significantly ameliorated the NAFLD pathology and the abnormal expression of NF-κB, NLRP3, ASC, caspase-1, IL-1β, and IL-6(all P < 0.01).CONCLUSION: Sini powder inhibits the inflamma-tory response in rats with NAFLD, which is mediated by NF-κB/NLRP3, IL-1β, and IL-6, reduces the effects of psychological stress, and improves lipid metabolism. Therefore, Sini powder may be effective for the treatment of stress-related NAFLD through multiple mechanisms.
基金Natural Science Foundation Project of Chongqing Municipality:a Metabolome-based Study on the Protective Mechanism of Yemazhui(Herba Eupatorii Lindleyani)Sesquiterpene Lactones Against Acute Lung Injury(No.cstc2021jcyj-msxmX0365)Science and Technology Research Program of Chongqing Municipal Education Commission:a Cytokine Storm-based Study of the Protective Effect of Yemazhui(Herba Eupatorii Lindleyani)Extract Intervention on COVID-19 Lung Injury(No.KJZD-K202215101)。
文摘OBJECTIVE:To investigate the impact of Yemazhui(Herba Eupatorii Lindleyani,HEL)against lipopolysaccharide(LPS)-induced acute lung injury(ALI)and explore its underlying mechanism in vivo.METHODS:The chemical constituents of HEL were analyzed by ultra-high performance liquid chromatographyquadrupole time-of-flight mass spectrometry method.Then,HEL was found to suppress LPS-induced ALI in vivo.Six-week-old male Sprague-Dawley rats were randomly divided into 6 groups:control,LPS,Dexamethasone(Dex),HEL low dose 6 g/kg(HEL-L),HEL medium dose 18 g/kg(HEL-M)and HEL high dose 54 g/kg(HEL-H)groups.The model rats were intratracheally injected with 3 mg/kg LPS to establish an ALI model.Leukocyte counts,lung wet/dry weight ratio,as well as myeloperoxidase(MPO)activity were determined followed by the detection with hematoxylin and eosin staining,enzyme linked immunosorbent assay,quantitative real time polymerase chain reaction,western blotting,immunohistochemistry,and immunofluorescence.Besides,to explore the effect of HEL on ALI-mediated intestinal flora,we performed 16s rRNA sequencing analysis of intestinal contents.RESULTS:HEL attenuated LPS-induced inflammation in lung tissue and intestinal flora disturbance.Mechanism study indicated that HEL suppressed the lung coefficient and wet/dry weight ratio of LPS-induced ALI in rats,inhibited leukocytes exudation and MPO activity,and improved the pathological injury of lung tissue.In addition,HEL reduced the expression of tumor necrosis factoralpha,interleukin-1beta(IL-1β)and interleukin-6(IL-6)in bronchoalveolar lavage fluid and serum,and inhibited nuclear displacement of nuclear factor kappa-B p65(NF-κBp65).And 18 g/kg HEL also reduced the expression levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88,NF-κBp65,phosphorylated inhibitor kappa B alpha(phospho-IκBα),nod-like receptor family pyrin domain-containing 3 protein(NLRP3),IL-1β,and interleukin-18(IL-18)in lung tissue,and regulated intestinal flora disturbance.CONCLUSIONS:In summary,our findings revealed that HEL has a protective effect on LPS-induced ALI in rats,and its mechanism may be related to inhibiting TLR4/NF-κB/NLRP3 signaling pathway and improving intestinal flora disturbance.
基金Supported by the National Key Research and Development Program(Grant 2018YFC1705403):Clinical Effect Evaluation of Chinese Medicine on Moderately Active Ulcerative ColitisNatural Science Foundation of Tianjin(Grant18JCYBJC26000):Study on the Mechanism of Qingchi San Treating Ulcerative Colitis By Regulating Gut Microflora+1 种基金Scientific Research Program of Tianjin Education Commission(Grant 2017KJ155):based onγδT-NLRP3 Inflammasome-Caspase PathwayQingchi San Regulates Gut Microflora to Treat UC。
文摘OBJECTIVE:To investigate the efficacy of Qingchi San(青赤散,QCS),a preparation of Traditional Chinese Medicine,on ulcerative colitis(UC)in mice by inhibiting the nuclearfactor-kappa B(NF-κB)signaling pathway and nucleotide-binding oligomerization domain,leucine-rich repeat and pyrin domain-containing 3(NLRP3)inflammasome formation.METHODS:The UC model was established with male C57BL/6J as the animal model.Bodyweight,Disease Activity Index(DAI),colon length and weight were detected.Furthermore,colonic histology was performed by hematoxylin-eosin(HE)staining.interleukin-1β(IL-1β),interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),myeloperoxidase(MPO)and superoxide dismutase(SOD)were performed by enzyme-linked immunosorbent assay.Cyclooxygenase 2(COX2)and inducible nitric oxide synthase(iNOS)mRNA expression were conducted by real-time quantitative polymerase chain reaction(RT-qPCR).NF-κB,inhibitor of NF-κBα(iκBα),Phosphorylated inhibitor of NF-κBα(p-iκBα),caspase-1,NLRP3 and Apoptosis-associated speck-like protein containing a caspase recruitment domain(ASC)protein expression were conducted by Western blotting.RESULTS:Compared with UC model group,Bodyweight was significantly increased in QCS treatment.At the same time,DAI was significantly decreased in QCS treatment.Colon length and weight and colonic histology were significantly improved in QCS treatment.Furthermore,the expression of IL-1β,IL-6,TNF-α,MPO,SOD,COX2,and iN OS were significantly decreased in QCS treatment.Finally,the expression of NF-κB signaling pathway-related proteins NF-κB,iκBα,p-iκBα,and the expression of NLRP3 inflammasome related proteins caspase-1,NLRP3 and ASC were significantly decreased in QCS treatment.CONCLUSION:Traditional Chinese drug QCS could treat UC by inhibiting the NF-κB signaling pathway and NLRP3 inflammasome formation in mice.
基金Supported by Natural Science Foundation of Shenzhen University General Hospital (SUGH2020QD011)
文摘BACKGROUND NLRP3-mediated pyroptosis is recognized as an essential modulator of renal disease pathology.Long noncoding RNAs(lncRNAs)are active participators of diabetic nephropathy(DN).X inactive specific transcript(XIST)expression has been reported to be elevated in the serum of DN patients.AIM To evaluate the mechanism of lncRNA XIST in renal tubular epithelial cell(RTEC)pyroptosis in DN.METHODS A DN rat model was established through streptozotocin injection,and XIST was knocked down by tail vein injection of the lentivirus LV sh-XIST.Renal metabolic and biochemical indices were detected,and pathological changes in the renal tissue were assessed.The expression of indicators related to inflammation and pyroptosis was also detected.High glucose(HG)was used to treat HK2 cells,and cell viability and lactate dehydrogenase(LDH)activity were detected after silencing XIST.The subcellular localization and downstream mechanism of XIST were investigated.Finally,a rescue experiment was carried out to verify that XIST regulates NLR family pyrin domain containing 3(NLRP3)/caspase-1-mediated RTEC pyroptosis through the microRNA-15-5p(miR-15b-5p)/Toll-like receptor 4(TLR4)axis.RESULTS XIST was highly expressed in the DN models.XIST silencing improved renal metabolism and biochemical indices and mitigated renal injury.The expression of inflammation and pyroptosis indicators was significantly increased in DN rats and HG-treated HK2 cells;cell viability was decreased and LDH activity was increased after HGtreatment. Silencing XIST inhibited RTEC pyroptosis by inhibiting NLRP3/caspase-1. Mechanistically,XIST sponged miR-15b-5p to regulate TLR4. Silencing XIST inhibited TLR4 by promotingmiR-15b-5p. miR-15b-5p inhibition or TLR4 overexpression averted the inhibitory effect ofsilencing XIST on HG-induced RTEC pyroptosis.CONCLUSIONSilencing XIST inhibits TLR4 by upregulating miR-15b-5p and ultimately inhibits renal injury inDN by inhibiting NLRP3/caspase-1-mediated RTEC pyroptosis.
基金Supported by National Science Foundation program of China(Activation of colonic mucosal mast cells and ion transport associated with serotonin receptors in the study of the role of soothing the liver and strengthening the spleen in the treatment of diarrheal irritable bowel syndrome,No.81473644)。
文摘OBJECTIVE:To investigate the effects of Qingre Jianpi decoction(清热健脾汤,QRJPD)on dextran sulfate sodium(DSS)-induced colitis mice and explore its mechanism.METHODS:All mice were randomly divided into six groups.Weight changes,disease activity index values,and histological damage were detected.Inflammatory cytokines and immune cell infiltration were measured using enzyme-linked immunosorbent assays(ELISA)and immunohistochemistry(IHC)method.The key protein expression levels of the NOD-like receptor family pyrin domain-containing 3(NLRP3)inflammasome were detected by western blot analysis,IHC,and quantitative reverse transcription polymerase chain reaction.RESULTS:QRJPD played an anti-inflammatory role in the treatment of ulcerative colitis(UC),reduced the secretion of inflammatory cytokines,and inhibited the inflammatory infiltration of immune cells by suppressing DSS-induced activation of the NLRP3 inflammasome.CONCLUSION:QRJPD exerts protective effects by inhibiting DSS-induced NLRP3 inflammasome activation.
