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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(11): 981-986, 2021 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-34809737

RESUMO

Objective To investigate how ephrin-A receptor 2 (EphA2) involves in pyroptosis in invasive breast cancer tissues. Methods The protein expression levels of EphA2, NLR family pyrin domain containing 3 (NLRP3), caspase-1, interleukin-1ß (IL-1ß), and intercellular adhesion molecule-1 (ICAM-1) in cancer tissues, paracancerous tissues, and normal breast tissues of breast cancer patients were detected by Western blot; the expression of EPHA2 in cancer tissues and paracancerous tissues of 45 patients with breast cancer was detected by immunofluorescence assay; and the correlation between protein expression of EphA2 and NLRP3, caspase-1, and IL-1ß in patients' cancer tissues was analyzed by Pearson correlation coefficient. Results The protein expression levels of NLRP3, caspase-1, IL-1ß, and ICAM-1 were significantly decreased and the protein expression of EphA2 was significantly increased in cancer tissues compared with those in normal breast tissues and paracancerous tissues. EphA2 level was negatively correlated with the levels of NLRP3, caspase-1 and IL-1ß. Conclusion EphA2 is overexpressed in breast cancer tissues and negatively correlated with pyroptosis.


Assuntos
Neoplasias da Mama , Piroptose , Neoplasias da Mama/genética , Caspase 1/genética , Efrinas , Feminino , Humanos , Inflamassomos , Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
2.
Phytomedicine ; 93: 153792, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34735906

RESUMO

BACKGROUND: Kai Xin San (KXS) was widely applied for the treatment of depression for thousands of years. However, the underlying antidepressant mechanism of KXS remains not clear. PURPOSE: This study aimed to investigate whether NLRP3 inflammasome and autophagy are involved in inflammation-induced depression and antidepressant mechanism of KXS. METHODS: Wistar rats were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks, and KXS (3, 5, and 10 g/kg/d) was administrated during the last 2 weeks of CUMS procedure. The effects of KXS on depressive-like behaviors, neuroinflammation, NLRP3 inflammasome activation, and autophagy were investigated in CUMS rats. Rat astrocytes were employed to further explore the potential mechanism of KXS in regulating NLRP3 inflammasome and autophagy. Autophagy inhibitor 3-methyladenine (3-MA, 5 mM) was used in vitro to elucidate the role of autophagy in the antidepressant mechanism of KXS. RESULTS: In vivo, KXS improved depressive-like behaviors of CUMS rats in sucrose preference test, open field test and forced swimming test. Moreover, KXS inhibited the neuroinflammation induced by CUMS and promoted autophagy in prefrontal cortex of rats. The results in vitro further validated the anti-inflammatory and proautohapgic effects of KXS. More importantly, autophagy inhibitor 3-MA diminished the inhibitory effect of KXS on NLRP3 inflammasome activation in rat astrocytes. CONCLUSION: KXS ameliorated CUMS-induced depressive behaviors in rats and inhibited the NLRP3 inflammasome-mediated inflammation in vivo and in vitro. These effects might be regulated by KXS-induced autophagy.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Antidepressivos/farmacologia , Autofagia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Ratos , Ratos Wistar , Estresse Psicológico
3.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(5): 788-795, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34728041

RESUMO

Alzheimer's disease(AD)is a chronic neurodegenerative disease whose cause remains unclear.The ß-amyloid plaques in the brain are one of the major pathological features of AD.However,the drugs targeting extracellular ß-amyloid plaques have failed to cure the disease.Innate immunity and neuroinflammation play a role in the pathogenesis and progression of AD.As the macrophages existing in the central nervous system,microglia are related with extracellular ß-amyloid deposition,intracellular neurofibrillary tangle formation,and neuron injury.Accumulating evidence demonstrates that the activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3(NLRP3)inflammasome in microglia plays a role in AD,suggesting new therapeutic target for AD in this signaling pathway.This article reviewed the studies about the activation and regulation of NLRP3 inflammasome in the pathogenesis and progression of AD as well as the development of AD therapies targeting this pathway,aiming to provide reference for further studies in this field.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Inflamassomos , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nucleotídeos , Domínio Pirina
4.
Zhongguo Zhong Yao Za Zhi ; 46(20): 5210-5217, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34738421

RESUMO

Pyroptosis is a pro-inflammatory programmed cell death, and its role in cardiac inflammatory response has become a hot topic. The activation of nucleotide binding oligomerization domain like receptor protein 3(NLRP3) inflammasome is an important mechanism for pyroptosis induced by cysteinyl aspartate specific proteinase 1(caspase-1). The existing studies have shown that cardiomyocyte pyroptosis participates in the pathogenesis of different cardiovascular diseases and the NLRP3 inflammasome-mediated cardiomyocyte pyroptosis has been most widely studied. Also, the intervention in NLRP3 inflammasome activation and cardiomyocyte pyroptosis contributes to ameliorating myocardial injury, which may be the main mechanism of many traditional Chinese medicines in exerting the cardio-protective effects. Therefore, this paper reviewed the studies on cardiomyocyte pyroptosis mediated by NLRP3 inflammasome and put forward the importance of exploring traditional Chinese medicine intervention in the activation of NLRP3 inflammasome.


Assuntos
Inflamassomos , Piroptose , Medicina Tradicional Chinesa , Miócitos Cardíacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
5.
Zhongguo Gu Shang ; 34(11): 1058-64, 2021 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-34812025

RESUMO

NOD-like receptor protein 1 (NLRP1) inflammasome plays an important role in the innate immune response of human body. It can promote the activation of cysteinyl aspartate specific proteinases(Caspases), further activate interleukin-18 and interleukin-1 ß, and mediate pyroptosis. NlRP1 inflammasome plays a role in traumatic central nervous system injury. In this study, the structure of NLRP1 inflammasome, the activation of NLRP1 inflammasome in traumatic central nervous system injury and the treatment with NLRP1 inflammasome as a target are reviewed.


Assuntos
Sistema Nervoso Central/lesões , Inflamassomos , Proteínas NLR , Humanos , Proteínas NLR/metabolismo
6.
Arch Oral Biol ; 131: 105269, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34601319

RESUMO

OBJECTIVE: We aim to investigate whether lipopolysaccharide-stimulated activition of Nod-like receptor protein 3 (NLRP3) Inflammasome inhibits osteogenesis in Human periodontal ligament cells (HPDLCs). Futhermore, to study whether MCC950 (a inhibitor of NLRP3 Inflammasome) rescues lipopolysaccharide-induced inhibition of osteogenesis in HPDLCs as well as the underlying mechanisms. METHODS: HPDLCs were isolated from periodontal ligament of healthy orthodontic teeth from teenagers, and cells surface marker protein were detected by flow cytometry. Cells viability were determined by Cell Counting kit 8 assay. Enzyme-linked immunosorbent assay was used to analyze the secretion of proinflammatory factors. Western blot and real-time quantitative polymerase chain reaction (RT-qPCR) were measured assessing the expression of NLRP3 and Caspase-1. RT-qPCR, Alizarin red staining and Alkaline phosphatase staining were tested to determine the osteogenic differentiation capacity of HPDLCs. RESULTS: It was found that lipopolysaccharide in the range of concentrations from 10 to 100 µg/ml significantly inhibited HPDLCs viability at 24 h and significantly improved proinflammatory cytokine expressions at 8 h and 24 h. MCC950 reversed lipopolysaccharide-stimulated proinflammatory cytokine expressions including interleukin-1ß and interleukin-18, but not tumor necrosis factor-α. In addition, MCC950 rescued the lipopolysaccharide-inhibited osteogenic gene (Alkaline phosphatase, Runt-related transcription factor 2, and Osteocalcin). Moreover, MCC950 downregulated lipopolysaccharide-induced relative protein of NLRP3 Inflammasome signaling pathway, such as NLRP3 and Caspase-1. CONCLUSION: MCC950 rescues lipopolysaccharide-induced inhibition of osteogenesis in HPDLCs via blocking NLRP3 Inflammasome signaling pathway, and it may be used as a promising therapeutic agent for periodontitis or periondontal regenerative related disease.


Assuntos
Furanos/farmacologia , Indenos/farmacologia , Osteogênese , Ligamento Periodontal/citologia , Sulfonamidas/farmacologia , Adolescente , Células Cultivadas , Humanos , Inflamassomos , Lipopolissacarídeos , Proteína 3 que Contém Domínio de Pirina da Família NLR
7.
Curr Cardiol Rep ; 23(11): 157, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599390

RESUMO

PURPOSE OF REVIEW: Pericarditis is a generally benign disease, although complications and/or recurrences may occur in up to 30% of cases. New evidence on the pathophysiology of the disease has accumulated in recent years. RECENT FINDINGS: Recently, it has been shown that the activation of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome is central in the pathophysiology of pericarditis. These findings derive from clinical data, an experimental animal model of acute pericarditis supporting a role for the NLRP3 inflammasome in pericarditis, and from indirect evidence of inhibitors of NLRP3 inflammasome in clinical trials. Pericarditis is regarded as a stereotypical response to an acute damage of the mesothelial cells of the pericardial layers. NLRP3 inflammasome, a macromolecular structure sensing damage and releasing pro-inflammatory cytokines, is centrally involved as it releases interleukin (IL)-1ß, whose auto-induction feeds an autoinflammatory disease, mostly responsible for recurrences. Colchicine, an inhibitor of NLRP3 inflammasome formation, and IL-1-targeted therapies, such as anakinra and rilonacept, were found to effectively blunt the acute inflammation and reduce the risk for recurrences.


Assuntos
Cardiopatias , Inflamassomos , Animais , Citocinas , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR
8.
Chaos ; 31(9): 093103, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34598451

RESUMO

The crosstalk between pyroptosis and apoptosis pathways plays crucial roles in homeostasis, cancer, and other pathologies. However, its molecular regulatory mechanisms for cell death decision-making remain to be elucidated. Based on the recent experimental studies, we developed a core regulatory network model of the crosstalk between pyroptosis and apoptosis pathways. Sensitivity analysis and bifurcation analysis were performed to assess the death mode switching of the network. Both the approaches determined that only the level of caspase-1 or gasdermin D (GSDMD) has the potential to individually change death modes. The decrease of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Seven biochemical reactions among the 21 reactions in total that are essential for determining cell death modes are identified by using sensitivity analysis. While with bifurcation analysis of state transitions, nine reactions are suggested to be able to efficiently switch death modes. Monostability, bistability, and tristability are observed under different conditions. We found that only the reaction that caspase-1 activation induced by stimuli can trigger tristability. Six and two of the nine reactions are identified to be able to induce bistability and monostability, respectively. Moreover, the concurrence of pyroptosis and apoptosis is observed not only within proper bistable ranges, but also within tristable ranges, implying two potentially distinct regulatory mechanisms. Taken together, this work sheds new light on the crosstalk between pyroptosis and apoptosis and uncovers the regulatory mechanisms of various stable state transitions, which play important roles for the development of potential control strategies for disease prevention and treatment.


Assuntos
Inflamassomos , Peptídeos e Proteínas de Sinalização Intracelular , Apoptose , Morte Celular , Inflamassomos/metabolismo , Proteínas de Ligação a Fosfato
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(5): 1566-1569, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34627441

RESUMO

OBJECTIVE: To clarify the significance of inflammasome NLRP3 in children with immune thrombocytopenia (ITP) by detecting its changes before and after treatment. METHODS: Twenty children with ITP diagnosed and treated in Xuzhou Children's Hospital were enrolled as observation group, and 10 healthy children as control group. The mRNA levels of NLRP3, ASC, and Caspase-1 were measured by real-time quantitative PCR (RT-qPCR), the serum levels of IL-18, IL-1ß, and high mobility group protein B1 (HMGB1) were detected by ELISA, and the protein level of NLRP3 was detected by Western blot. RESULTS: In newly diagnosed ITP children, the serum levels of IL-18, IL-1ß and HMGB1 significantly decreased after treatment (P<0.05). After treatment, NLRP3, ASC, and Caspase-1 mRNA levels in peripheral blood mononuclear cells were significantly lower than those before treatment (P<0.05). NLRP3 protein expression decreased significantly after treatment. CONCLUSION: Expression of NLRP3 inflammasome and downstream inflammatory factors are decrease after treatment in children with ITP, which may be used as effective prognostic markers.


Assuntos
Proteína HMGB1 , Púrpura Trombocitopênica Idiopática , Criança , Humanos , Inflamassomos , Leucócitos Mononucleares , Proteína 3 que Contém Domínio de Pirina da Família NLR
10.
Int J Mol Sci ; 22(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34639062

RESUMO

The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis.


Assuntos
Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Autoimunidade , DNA/imunologia , Humanos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Especificidade de Órgãos/imunologia , Transplante de Órgãos , Processamento de Proteína Pós-Traducional
11.
Nat Commun ; 12(1): 5862, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615873

RESUMO

NLRP3 controls the secretion of inflammatory cytokines IL-1ß/18 and pyroptosis by assembling the inflammasome. Upon coordinated priming and activation stimuli, NLRP3 recruits NEK7 within hetero-oligomers that nucleate ASC and caspase-1 filaments, but the apical molecular mechanisms underlying inflammasome assembly remain elusive. Here we show that NEK7 recruitment to NLRP3 is controlled by the phosphorylation status of NLRP3 S803 located within the interaction surface, in which NLRP3 S803 is phosphorylated upon priming and later dephosphorylated upon activation. Phosphomimetic substitutions of S803 abolish NEK7 recruitment and inflammasome activity in macrophages in vitro and in vivo. In addition, NLRP3-NEK7 binding is also essential for NLRP3 deubiquitination by BRCC3 and subsequently inflammasome assembly, with NLRP3 phosphomimetic mutants showing enhanced ubiquitination and degradation than wildtype NLRP3. Finally, we identify CSNK1A1 as the kinase targeting NLRP3 S803. Our findings thus reveal NLRP3 S803 phosphorylation status as a druggable apical molecular mechanism controlling inflammasome assembly.


Assuntos
Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/química , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Caseína Quinase II , Caseína Quinase Ialfa , Caspase 1/metabolismo , Citocinas/metabolismo , Enzimas Desubiquitinantes , Células HEK293 , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Quinases Relacionadas a NIMA/metabolismo , Fosforilação , Piroptose , Ubiquitinação
12.
Int J Mol Sci ; 22(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34638670

RESUMO

Platelets, cellular mediators of thrombosis, are activated during sepsis and are increasingly recognized as mediators of the immune response. Platelet activation is significantly increased in sepsis patients compared to ICU control patients. Despite this correlation, the role of activated platelets in contributing to sepsis pathophysiology remains unclear. We previously demonstrated NOD-like receptor protein 3 inflammasome (NLRP3) inflammasome activation in sepsis-induced platelets from cecal-ligation puncture (CLP) rats. Activated platelets were associated with increased pulmonary edema and glomerular injury in CLP vs. SHAM controls. In this study, we investigated whether inhibition of platelet activation would attenuate NLRP3 activation and renal and pulmonary injury in response to CLP. CLP was performed in male and female Sprague Dawley (SD) rats (n = 10/group) to induce abdominal sepsis and SHAM rats served as controls. A subset of CLP animals was treated with Clopidogrel (10 mg/kg/day, CLP + CLOP) to inhibit platelet activation. At 72 h post-CLP, platelet activation and NLRP3 inflammasome assembly were evaluated, IL-1ß and IL-18 were measured in plasma, and tissues, renal and pulmonary pathology, and renal function were assessed. Activated platelets were 7.8 ± 3.6% in Sham, 22 ± 6% in CLP and significantly decreased to 14.5 ± 0.6% in CLP + CLOP (n = 8-10/group, p < 0.05). NLRP3 inflammasome assembly was inhibited in platelets of CLP + CLOP animals vs. CLP. Significant increases in plasma and kidney IL-1ß and IL-18 in response to CLP were decreased with Clopidogrel treatment. Renal injury, but not lung histology or renal function was improved in CLP + CLOP vs. CLP. These data provide evidence that activated platelets may contribute to sepsis-induced renal injury, possibly via NLRP3 activation in platelets. Platelets may be a therapeutic target to decrease renal injury in septic patients.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Sepse/metabolismo , Animais , Feminino , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Ligadura , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Proteínas NLR/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
13.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639204

RESUMO

NLRP3 is an important pattern recognition receptor in the innate immune system, and its activation induces a large number of pro-inflammatory cytokines, IL-1ß and IL-18 which are involved in the development of various diseases. In recent years, it has been suggested that mitochondria are the platform for NLRP3 inflammasome activation. Additionally, exercise is considered as an important intervention strategy to mediate the innate immune responses. Generally, chronic moderate-intensity endurance training, resistance training and high-intensity interval training inhibit NLRP3 inflammasome activation in response to various pathological factors. In contrast, acute exercise activates NLRP3 inflammasome. However, the mechanisms by which exercise regulates NLRP3 inflammasome activation are largely unclear. Therefore, the mechanism of NLRP3 inflammasome activation is discussed mainly from the perspective of mitochondria in this review. Moreover, the effect and potential mechanism of exercise on NLRP3 inflammasome are explored, hoping to provide new target for relevant research.


Assuntos
Exercício Físico , Imunidade Inata/imunologia , Inflamassomos/imunologia , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Humanos , Inflamassomos/metabolismo , Mitocôndrias/imunologia
14.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638553

RESUMO

Low-grade chronic inflammation plays a pivotal role in the pathogenesis of insulin resistance (IR), and skeletal muscle has a central role in this condition. NLRP3 inflammasome activation pathways promote low-grade chronic inflammation in several tissues. However, a direct link between IR and NLRP3 inflammasome activation in skeletal muscle has not been reported. Here, we evaluated the NLRP3 inflammasome components and their role in GLUT4 translocation impairment in skeletal muscle during IR. Male C57BL/6J mice were fed with a normal control diet (NCD) or high-fat diet (HFD) for 8 weeks. The protein levels of NLRP3, ASC, caspase-1, gasdermin-D (GSDMD), and interleukin (IL)-1ß were measured in both homogenized and isolated fibers from the flexor digitorum brevis (FDB) or soleus muscle. GLUT4 translocation was determined through GLUT4myc-eGFP electroporation of the FBD muscle. Our results, obtained using immunofluorescence, showed that adult skeletal muscle expresses the inflammasome components. In the FDB and soleus muscles, homogenates from HFD-fed mice, we found increased protein levels of NLRP3 and ASC, higher activation of caspase-1, and elevated IL-1ß in its mature form, compared to NCD-fed mice. Moreover, GSDMD, a protein that mediates IL-1ß secretion, was found to be increased in HFD-fed-mice muscles. Interestingly, MCC950, a specific pharmacological NLRP3 inflammasome inhibitor, promoted GLUT4 translocation in fibers isolated from the FDB muscle of NCD- and HFD-fed mice. In conclusion, we found increased NLRP3 inflammasome components in adult skeletal muscle of obese insulin-resistant animals, which might contribute to the low-grade chronic metabolic inflammation of skeletal muscle and IR development.


Assuntos
Transportador de Glucose Tipo 4/metabolismo , Inflamassomos/metabolismo , Resistência à Insulina/fisiologia , Interleucina-1beta/metabolismo , Músculo Esquelético/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Caspase 1/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/química , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Obesidade/induzido quimicamente , Obesidade/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Sulfonamidas/farmacologia
15.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638790

RESUMO

Idiopathic pulmonary fibrosis (IPF), one of the most common fibrosing interstitial lung diseases (ILD), is a chronic-age-related respiratory disease that rises from repeated micro-injury of the alveolar epithelium. Environmental influences, intrinsic factors, genetic and epigenetic risk factors that lead to chronic inflammation might be implicated in the development of IPF. The exact triggers that initiate the fibrotic response in IPF remain enigmatic, but there is now increasing evidence supporting the role of chronic exposure of viral infection. During viral infection, activation of the NLRP3 inflammasome by integrating multiple cellular and molecular signaling implicates robust inflammation, fibroblast proliferation, activation of myofibroblast, matrix deposition, and aberrant epithelial-mesenchymal function. Overall, the crosstalk of the NLRP3 inflammasome and viruses can activate immune responses and inflammasome-associated molecules in the development, progression, and exacerbation of IPF.


Assuntos
Fibrose Pulmonar Idiopática/imunologia , Inflamassomos/imunologia , Doenças Pulmonares Intersticiais/imunologia , Miofibroblastos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Viroses/imunologia , Animais , Humanos , Fibrose Pulmonar Idiopática/virologia , Doenças Pulmonares Intersticiais/virologia
16.
Molecules ; 26(20)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34684819

RESUMO

The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory agents and are usually regarded to have potential applications as complementary or alternative therapeutic agents against chronic inflammatory disorders. Various in vitro and in vivo studies have reported the anti-inflammatory role of berberine (BRB), an organic heteropentacyclic phytochemical and natural isoquinoline, in inhibiting NLRP3 inflammasome-dependent inflammation against many disorders. This review summarizes the mechanism and regulation of NLRP3 inflammasome activation and its involvement in inflammatory diseases, and discusses the current scientific evidence on the repressive role of BRB on NLRP3 inflammasome pathways along with the possible mechanism(s) and their potential in counteracting various inflammatory diseases.


Assuntos
Berberina/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Humanos , Inflamassomos/química , Inflamação/metabolismo , Doenças Metabólicas/tratamento farmacológico , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/química , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Compostos Fitoquímicos/farmacologia , Fitoterapia , Transdução de Sinais/efeitos dos fármacos
17.
Free Radic Biol Med ; 176: 378-391, 2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34644617

RESUMO

Acute lung injury (ALI) is associated with overproduction of inflammatory mediators in lung tissue. Previous studies have revealed that inflammation induces activation of phosphodiesterase 4B (PDE4B) accompanied by the production of inflammatory mediators, but the detailed mechanism remains unclear. Here, we focused on the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome complexes to study the crosstalk between PDE4B and NF-E2-related factor 2 (Nrf2). We used global knockout PDE4B or Nrf2 mice to prepare LPS induced acute lung injury model by intratracheally administration, and LPS primed bone marrow-derived macrophages (BMDMs), following overexpression of PDE4B or Nrf2, luciferase activity analysis, and chIP-qPCR analyses. We found that deficiency of PDE4B could potently attenuate the lung histopathological changes, suppress the secretion of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, IL-18, and cleaved caspase-1, 8, and GSDMD accompanied with defective activation of the ROS/Nrf2/NLRP3. Meanwhile deficiency of Nrf2 showed the similar results. Furtherly, overexpression by PDE4B or Nrf2 plasmid transfection in MH-S cells could enhance the Nrf2 or PDE4B expression. Luciferase analysis suggested that Nrf2 activated PDE4B promoter activity, while PDE4B could increase Nrf2 substrate ARE activity in MH-S cells in dose dependent manners. ChIP-qPCR analyses showed that Nrf2 bound to the PDE4B promoter region at Ì´ 1532 to Ì´1199 position in macrophages. Altogether, deficiency of PDE4B inhibit the inflammasome activation and pyroptosis in LPS stimulated lung injury model and macrophages by regulating ROS/Nrf2/NLRP3 activation. The study provides new insight that PDE4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2.


Assuntos
Lesão Pulmonar Aguda , Inflamassomos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Retroalimentação , Inflamassomos/genética , Interleucina-1beta , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fator 2 Relacionado a NF-E2/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
18.
Invest Ophthalmol Vis Sci ; 62(13): 11, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34643663

RESUMO

Purpose: This exploratory study aimed to investigate the morphological and pathological alterations of the meibomian gland (MG) with the Staphylococcus aureus crude extracts (SACEs) treatment. Methods: Mouse MG explants were cultured and differentiated with or without SACEs for 48 hours. Explant's viability and cell death were determined by thiazolyl blue tetrazolium bromide (MTT) assay and TUNEL assay. MG morphology was observed by Hematoxylin and Eosin staining. Lipid droplet production was detected by Nile Red staining and LipidTox immunostaining. The pro-inflammatory cytokines were detected by ELISA. The relative gene and protein expression in MG explants was determined via quantitative RT-PCR, immunostaining, and immunoblotting. The components of the SACEs were analyzed by immunoblotting and silver staining. Results: Our findings demonstrated that the SACEs treatment induced overexpression of keratin 1 (Krt1) in the ducts and acini of MG explants, accompanied by a decrease in viability and an increase in cell death in explants. Furthermore, the SACEs treatment dose-dependently increased the levels of TNF-α, IL-1ß, and IL-6 in MG explants. The SACEs treatment induced activation of the nuclear factor kappa B (NF-κB) and AIM2 (absent in melanoma 2)/ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) inflammasome signaling pathway in explants. Further investigation showed expression of the key adipogenesis-related molecule peroxisome proliferator-activated receptor γ was decreased after SACEs treatment. However, no change was found in the lipid synthesis of MG explants after treatment with the SACEs. Staphylococcal enterotoxins B (SEB) was detected in the SACEs. SEB induced the overexpression of Krt1 and IL-1ß in ducts and acini of MG explants. Conclusions: Our findings confirm that Staphylococcus aureus induced hyperkeratinization and pro-inflammatory cytokines expression in MG explants ducts and acini. These effects might be mediated by SEB. Activation of the NF-κB and AIM2/ASC signaling pathway is involved in this process.


Assuntos
Citocinas/genética , Infecções Oculares Bacterianas/metabolismo , Regulação da Expressão Gênica , Disfunção da Glândula Tarsal/metabolismo , Glândulas Tarsais/metabolismo , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/isolamento & purificação , Animais , Apoptose , Citocinas/biossíntese , Modelos Animais de Doenças , Regulação para Baixo , Infecções Oculares Bacterianas/microbiologia , Infecções Oculares Bacterianas/patologia , Inflamassomos/metabolismo , Masculino , Disfunção da Glândula Tarsal/microbiologia , Disfunção da Glândula Tarsal/patologia , Glândulas Tarsais/patologia , Camundongos , Transdução de Sinais , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia
19.
Phytomedicine ; 93: 153741, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34656886

RESUMO

BACKGROUND: Pancreatic inflammation plays a key role in diabetes pathogenesis and progression. Urolithin A (UA), an intestinal flora metabolite of pomegranate, has anti-diabetic, anti-inflammatory and kidney protection effects among others. However, its effects on pancreatic inflammation and the potential mechanisms have not been clearly established. PURPOSE: This study aimed at investigating the molecular mechanisms of UA anti-pancreatic inflammation under a diabetic environment. METHODS: Diabetes induction in male C57BL/6 mice was achieved by a high fat diet and intraperitoneal streptozotocin injections. Then, diabetic mice were orally administered with UA for 8 weeks. In vitro, endoplasmic reticulum stress and MIN6 pancreatic ß cell inflammation were induced using 25 mM glucose and 0.5 mM palmitic acid. The effects of UA were evaluated by immunohistochemistry, Western blot, and enzyme linked immunosorbent assays. Finally, the underlying mechanisms were elucidated using an autophagy inhibitor (chloroquine, CQ) and an AMPK inhibitor (dorsomorphin dihydrochloride). RESULTS: UA significantly inhibited IL-1ß secretion and TXNIP/NLRP3 expression in the pancreas of diabetic mice and in MIN6 pancreatic cells. UA downregulated the ER stress protein, p-PERK, and promoted AMPK phosphorylation. UA activated autophagy to inhibit TXNIP/NLRP3 IL-1ß inflammatory signal, an effect that was reversed by CQ. Dorsomorphin 2HCL, reversed the autophagy-activation and anti-inflammatory effects of UA. Verapamil, clinically applied as an antiarrhythmic drug, is a TXNIP inhibitor for prevention of beta cell loss and diabetes development, but limited by its cardiac toxicity. In this study, verapamil (as positive control) inhibited NLRP3 /IL-1ß signaling in MIN6 cells. Inhibitory effects of UA on TXNIP and IL-1ß were weaker than those of verapamil (both at 50 µM, p < 0.05, p < 0.01). Conversely, inhibitory effects of UA on p62 were stronger, relative to those of verapamil (p < 0.05), and there were no differences in AMPK activation and LC3 enhancement effects between UA and verapamil. CONCLUSION: UA is a potential anti-pancreatic inflammation agent that activates AMPK and autophagy to inhibit endoplasmic reticulum stress associated TXNIP/NLRP3/IL-1ß signal pathway.


Assuntos
Diabetes Mellitus Experimental , Células Secretoras de Insulina , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Autofagia , Proteínas de Transporte , Cumarínicos , Diabetes Mellitus Experimental/tratamento farmacológico , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tiorredoxinas/metabolismo
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