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1.
Biosci Biotechnol Biochem ; 84(1): 134-142, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31490096

RESUMO

Plumbagin (PLB), an alkaloid obtained from the roots of the plants of Plumbago genus, is an inhibitor of NADPH oxidase 4 (NOX4). This study aimed to investigate the beneficial effect of PLB against oxygen-glucose deprivation/reoxygenation (OGDR)-induced neuroinjury in human SH-SY5Y neuronal cultures. Our results showed that OGD/R stimulated NOX4 protein expression and reactive oxygen species (ROS) production in SH-SY5Y cells, whereas increased 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) production, resulting in the activation of the NLRP3 inflammasome. And PLB pretreatment reduced the ROS production by regulating the expression of NOX4 and downregulated NF-κB signaling which was induced by OGDR. Furthermore, PLB inhibited OGDR induced NLRP3 inflammasome activation but not PARP1. Overall, PLB improved OGDR induced neuroinjury by inhibiting NOX4-derived ROS-activated NLRP3 inflammasome.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Glucose/deficiência , Inflamassomos/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Naftoquinonas/farmacologia , Neurônios/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas/química , Plumbaginaceae/química
2.
Gastroenterology ; 158(1): 253-269.e14, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593700

RESUMO

BACKGROUND & AIMS: Pancreatitis starts with primarily sterile local inflammation that induces systemic inflammatory response syndrome, followed by compensatory anti-inflammatory response syndrome (CARS). We investigated the mechanisms of these processes in mice and human serum. METHODS: We induced severe acute pancreatitis by partial duct ligation with caerulein stimulation or intraperitoneal injection of l-arginine in mice with deletion of interleukin (IL)12B, NLRP3, or IL18 and in mice given MCC950, a small molecule inhibitor of the NLRP3-inflammasome. Pancreata were collected from mice and analyzed by histology, and cytokine levels were measured in serum samples. We measured activation of adaptive immune responses in mice with pancreatitis by flow cytometry analysis of T cells (CD25 and CD69) isolated from the spleen. Differentiation of T-helper (Th1) cells, Th2 cells, and T-regulatory cells was determined by nuclear staining for TBET, GATA3, and FOXP3. We performed transcriptome analysis of mouse lymph nodes and bone marrow-derived macrophages after incubation with acini. We measured levels of cytokines in serum samples from patients with mild and severe acute pancreatitis. RESULTS: Activation of the adaptive immune response in mice was initiated by macrophage-derived, caspase 1-processed cytokines and required activation of NLRP3 (confirmed in serum samples from patients with pancreatitis). Spleen cells from mice with pancreatitis had increases in Th2 cells but not in Th1 cells. Bone marrow-derived macrophages secreted IL1B and IL18, but not IL12, after co-incubation with pancreatic acini. T-cell activation and severity of acute pancreatitis did not differ significantly between IL12B-deficient and control mice. In contrast, NLRP3- or IL18-deficient mice had reduced activation of T cells and no increase in Th2 cell-mediated responses compared with control mice. The systemic type 2 immune response was mediated by macrophage-derived cytokines of the IL1 family. Specifically, IL18 induced a Th2 cell-mediated response in the absence of IL12. MCC950 significantly reduced neutrophil infiltration, T-cell activation, and disease severity in mice. CONCLUSIONS: In mice with severe pancreatitis, we found systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome developed in parallel. Infiltrating macrophages promote inflammation and simultaneously induce a Th2 cell-mediated response via IL18. Inhibition of NLRP3 reduces systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome and might be used to treat patients with severe pancreatitis.


Assuntos
Furanos/administração & dosagem , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pancreatite/imunologia , Sulfonamidas/administração & dosagem , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Células Acinares , Imunidade Adaptativa , Animais , Arginina/toxicidade , Células Cultivadas , Ceruletídeo/toxicidade , Citocinas/sangue , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Interleucina-18/imunologia , Interleucina-18/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pâncreas/citologia , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Cultura Primária de Células , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Células Th2/imunologia , Células Th2/metabolismo
3.
Eur J Med Chem ; 185: 111822, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699536

RESUMO

NLRP3 (Nod-like receptor protein 3) belongs to the NOD-like receptor family, which is activated by pathogen and damage-associated signals to form a multimeric protein complex, known as the NLRP3 inflammasome. NLRP3 inflammasome activation leads to release of proinflammatory cytokines IL-1ß and IL-18, thus inducing pyroptosis, a programmed cell death mechanism. Dysregulation of the NLRP3 inflammasome pathway is closely related to the development of many human diseases, such as neuroinflammation, metabolic inflammation, and immune inflammation. Emerging studies have suggested NLRP3 inflammasome as a potential drug-target for inflammatory diseases. Several small molecules have recently been identified to target the NLRP3 inflammasome pathway directly or indirectly and alleviate related disease pathology. This review summarizes recent evolving landscape of small molecule inhibitor development targeting the NLRP3 inflammasome pathway.


Assuntos
Inflamassomos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Humanos , Inflamassomos/metabolismo , Inflamação/metabolismo , Estrutura Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
4.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(5): 672-678, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31762236

RESUMO

OBJECTIVE: To determine the impact olanzapine (OLA) on the hippocampal neuron of model rats with depression. METHODS: Rats were divided into five groups: control, chronic unpredicted stress (CUS), OAL (0.5, 1, 2 mg/kg), si-Atg5, and OAL (2 mg/kg)+si-Atg5. Open field and sucrose preference tests were performed to evaluate rat behaviors. Cell apoptosis was detected with Tunnel. The concentrations of interleukin (IL)-1ß and IL-18 were determined by ELISA. The expressions of cleaved Caspase-3, cleaved Caspase-9, LC3, Beclin1, P62, NLRP3 and cleaved Caspase-1 were measured by Western blot. RESULTS: OAL (0.5, 1, 2 mg/kg) increased the total moving distance, sucrose consumption and preference rate of CUS rats, and decreased serum IL-18, cell apoptosis and the expressions of cleaved Caspase-9, cleaved Caspase-1 and NLRP3 in the CA3 region of hippocampus. Although OAL (1, 2 mg/kg) decreased the expression of cleaved Caspase-3 and serum IL-1ß, OAL (0.5 mg/kg) showed no detectable effects. Si-Atg5 decreased the total moving distance, sucrose consumption and preference rate of CUS rats, enhanced the expressions of cleaved Caspase-3, cleaved Caspase-9, cleaved Caspase-1 and NLRP3, and weakened the effect of OAL (2 mg/kg). OAL (0.5, 1, 2 mg/kg) also increased the LC3Ⅱ/LC3Ⅰ ratio and the expression of Beclin1 in the CA3 region of hippocampus. OAL (1, 2 mg/kg) reduced the expression of p62, but not when it was reduced to 0.5 mg/kg. Si-Atg5 reduced the LC3Ⅱ/LC3Ⅰ ratio and the expression of Beclin1, and weakened the function of OAL (2 mg/kg). CONCLUSION: OAL can protect the hippocampal neuron of CUS rats via inhibiting NLRP3 inflammasome activation.


Assuntos
Depressão/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Olanzapina/farmacologia , Animais , Hipocampo/citologia , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos
5.
Life Sci ; 237: 116978, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31644893

RESUMO

AIMS: The activation of NLRP3 inflammasome, which initiates an inflammatory cascade and triggers inflammatory death, plays a crucial role in the pathogenesis of spinal cord injury (SCI). Echinacoside (ECH) is a phenylethanoid glycoside possessing prominent anti-inflammatory effects and various neuroprotective properties in the central nervous system, but the effect of ECH on SCI was rarely studied. Therefore, the purpose of this experiment was to look into the therapeutic effects of ECH on SCI and the underlying mechanisms. MAIN METHODS: Basso-Beattie-Bresnahan (BBB) locomotion scale, Nissl staining, and hematoxylin-eosin (HE) staining was employed to examine the therapeutic effects of ECH on SCI. In addition, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) in BV-2 cells stimulated with lipopolysaccharides and adenosine 5'-triphosphate were examined. The expression levels of proteins involving NLRP3 inflammasome-related pathway were measured. KEY FINDINGS: The in vivo experiment indicated that administration of ECH significantly enhanced the BBB scores, reduced the neuron loss, and ameliorated the tissue architecture after SCI. Additionally, ECH dramatically inhibited NLRP3 inflammasome activation in the rat SCI model. In vitro study indicated that ECH significantly reduced ROS level, improved the MMP, blocked activation of NF-κB, and inhibited the NLRP3 inflammasome signaling pathway. The effect of ECH on inhibition of NLRP3 inflammasome signaling pathway was partially governed by suppression of the generation of ROS and activation of NF-κB. SIGNIFICANCE: ECH can accelerate motor function recovery in rats following SCI by inhibiting NLRP3 inflammasome-related signaling pathway, suggesting that ECH may serve as a potential therapeutic agent for treating SCI.


Assuntos
Glicosídeos/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/prevenção & controle , Animais , Inflamação/complicações , Locomoção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/patologia
6.
Infect Immun ; 87(12)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31570558

RESUMO

Schistosomiasis is a parasitic helminth disease that can cause severe inflammatory pathology, leading to organ damage, in humans. During a schistosomal infection, the eggs are trapped in the host liver, and products derived from eggs induce a polarized Th2 cell response, resulting in granuloma formation and eventually fibrosis. Previous studies indicated that the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in schistosomiasis-associated liver fibrosis and that taurine could ameliorate hepatic granulomas and fibrosis caused by Schistosoma japonicum infection. Nevertheless, the precise role and molecular mechanism of the NLRP3 inflammasome and the protective effects of taurine in S. japonicum infection have not been extensively studied. In this study, we investigated the role of the NLRP3 inflammasome and the hepatoprotective mechanism of taurine in schistosoma-induced liver injury in mice. NLRP3 deficiency ameliorated S. japonicum-infection-induced hepatosplenomegaly, liver dysfunction, and hepatic granulomas and fibrosis; it also reduced NLRP3-dependent liver pyroptosis. Furthermore, taurine suppressed hepatic thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in mice with S. japonicum infections, thereby inhibiting the activation of downstream inflammatory mediators such as interleukin-1ß and subsequent pyroptosis. Our results suggest that the TXNIP/NLRP3 inflammasome pathway and mediating pyroptosis are involved in S. japonicum-induced liver injury and may be a potential therapeutic target for schistosomiasis treatment. In addition, taurine may be useful to alleviate or to prevent the occurrence of schistosomiasis-associated liver fibrosis.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Taurina/farmacologia , Tiorredoxinas/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Fígado/lesões , Fígado/parasitologia , Cirrose Hepática/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose/imunologia , Esquistossomose Japônica/parasitologia , Transdução de Sinais/imunologia
7.
Phytother Res ; 33(10): 2737-2748, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31338905

RESUMO

Coriolus versicolor (CV) is a traditional medicine and food mushroom. Our previous study demonstrated that CV extract exhibited anti-hyperglycemia and anti-insulin resistance effects. However, the effect of CV on cardiac function in diabetic cardiomyopathy (DCM) remains unclear. Therefore, we aimed to investigate the effect of CV on cardiac function in diabetes mellitus (DM) rats. We found that the cardiac dysfunction of DM rats was markedly improved by CV extract treatment. CV extract administration significantly attenuated cardiac fibrosis in DM rats, which was accompanied by suppressed transforming growth factor beta 1 (TGF-ß1)/Smad signaling as indicated by decreased levels of TGF-ß1, p-Smad2, and p-Smad3 and increased Smad7 expression. Moreover, CV extract treatment significantly alleviated cardiac inflammation as shown by decreased levels of NLRP3 receptor, cleaved caspase-1, IL-1ß, and IL-18 in DM rats at least partly due to the inhibition of the NF-κB. In addition, high-glucose treatment induced cardiac fibrosis and increased cardiac inflammation in cardiac fibroblast cells, but these effects were ameliorated by CV extract treatment. Therefore, we conclude that the protective effect of CV on DCM is associated with the suppression of TGF-ß1/Smad signaling and attenuation of NLRP3 inflammasome activation, suggesting that CV extract may be a potential therapeutic agent for DCM.


Assuntos
Agaricales , Cardiomiopatias Diabéticas/tratamento farmacológico , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Fibrose , Masculino , NF-kappa B/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
8.
Int Immunopharmacol ; 74: 105575, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31299609

RESUMO

BACKGROUND/AIMS: Early inflammatory responses after myocardial infarction (MI) are likely to increase myocardial fibrosis and subsequent cardiac remodeling. MCC950, a specific NLRP3 inhibitor, was previously found to effectively inhibit the release of inflammatory factors IL-18 and IL-1ß. In this study, we evaluated the effect of MCC950, as a potential new treatment strategy for MI, on myocardial fibrosis and cardiac remodeling using an experimental mouse model. METHODS: Male C57BL/6 mice were subjected to left coronary artery ligation to induce MI and then treated with MCC950 (10 mg/kg) or PBS for 14 days. After 30 days, echocardiography was performed to assess cardiac function and myocardial fibrosis was evaluated using H&E- and Masson's Trichrome-stained sections. Myocardial expression of inflammatory factors and fibrosis markers was analyzed by western blotting, immunofluorescence, ELISA, and real-time quantitative PCR. RESULTS: The ejection fraction in the 10 mg/kg group (40.7 ±â€¯4.2%; N = 6, p = 0.0029) was statistically preserved compared to that in the control group (14.0 ±â€¯4.4%). Myocardial fibrosis was also reduced in MCC950-treated animals (MCC950, 23.2 ±â€¯3.0 vs PBS, 36.2 ±â€¯3.7; p < 0.05). Moreover, myocardial NLRP3, cleaved IL-1ß, and IL-18 levels were reduced in MCC950-treated animals. H&E and molecular examination revealed decreases in inflammatory cell infiltration and inflammatory factor expression in the heart. In vitro, MCC950 inhibited NLRP3, reduced caspase-1 activity, and further downregulated IL-1ß and IL-18. CONCLUSION: MCC950, as a specific NLRP3 inhibitor, can alleviate fibrosis and improve cardiac function in a mouse model by suppressing early inflammatory responses post-MI.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cardiotônicos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inflamassomos/antagonistas & inibidores , Infarto do Miocárdio/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Cardiotônicos/farmacologia , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonas/farmacologia , Remodelação Ventricular/efeitos dos fármacos
9.
Life Sci ; 233: 116631, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31278945

RESUMO

AIMS: Prior to reperfusion, Calpains remain inactive due to the acidic pH and elevated ionic strength in the ischemic myocardium; but Calpain is activated during myocardial reperfusion. The underlying mechanism of Calpain activation in the ischemia-reperfusion (I/R) is yet to be determined. Therefore, the present study aims to investigate the mechanism of Calpain in I/R-induced mice. MAIN METHODS: In order to detect the function of Calpain and the NLRP3/ASC/Caspase-1 axis in cardiomyocyte pyroptosis, endoplasmic reticulum (ER) stress and myocardial function, the cardiomyocytes were treated with hypoxia-reoxygenation (H/R), and NLRP3 were silenced, Calpain was overexpressed and Caspase-1 inhibitors were used to determine cardiomyocyte pyroptosis. The results obtained from the cell experiments were then verified with an animal experiment in I/R mice. KEY FINDINGS: There was an overexpression in Calpain, ASC, NLRP3, GRP78 and C/EBP homologous protein (CHOP) in cardiomyocytes following H/R. A significant increase was witnessed in lactic acid dehydrogenase (LDH) activity, cardiomyocyte pyroptosis rate, Calpain activity, reactive oxygen species (ROS) concentration, as well as activation of ER stress in cardiomyocytes after H/R. However, opposing results were observed in H/R cardiomyocytes that received siRNA Calpain, siRNA NLRP3 or Caspase-1 inhibitor treatment. Overall, the results obtained from the animal experiment were consistent with the results from the cell experiment. SIGNIFICANCE: The silencing of Calpain suppresses the activation of the NLRP3/ASC/Caspase-1 axis, thus inhibiting ER stress in mice and improving myocardial dysfunction induced by I/R, providing a novel therapeutic pathway for I/R.


Assuntos
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Calpaína/antagonistas & inibidores , Caspase 1/química , Estresse do Retículo Endoplasmático , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Calpaína/genética , Calpaína/metabolismo , Caspase 1/genética , Caspase 1/metabolismo , Células Cultivadas , Inflamassomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RNA Interferente Pequeno/genética
10.
Phytomedicine ; 63: 153019, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302317

RESUMO

BACKGROUND: Obovatol, a biphenolic chemical originating from Magnolia obovata, has been utilized as a traditional medicine for the treatment of inflammatory diseases. Inflammasome induces maturation of inflammatory cytokines in response to intracellular danger signals, and its dysregulation induces inflammatory diseases. PURPOSE: The effect of obovatol on inflammasome activation has not been reported, although its anti-inflammatory properties have been studied. STUDY DESIGN/METHODS: Obovatol was treated to macrophages with inflammasome triggers, and secretions of interleukin (IL)-1ß, IL-18, and caspase-1 were measured as readouts of inflammasome activation. In addition, Asc pyroptosome formation, caspase-1 activity, and mitochondrial reactive oxygen species (ROS) production were analyzed in mechanical studies. Anti-inflammasome properties of obovatol were confirmed in an animal model. RESULTS: Obovatol inhibited NLRP3, AIM2, and non-canonical inflammasomes through inhibition of Asc pyroptosome formation and mitochondrial ROS generation. In addition, obovatol disrupted the priming step of inflammasome activation and inhibited transcription of inflammatory cytokines. In mice, obovatol attenuated serum IL-1ß elevation in response to monosodium urate crystals. CONCLUSION: Obovatol is suggested as an inhibitor of NLRP3, AIM2, and non-canonical inflammasomes.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Bifenilo/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Éteres Fenílicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/química , Caspase 1/metabolismo , Citocinas/genética , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peritonite/tratamento farmacológico , Éteres Fenílicos/química , Espécies Reativas de Oxigênio/metabolismo , Ácido Úrico/farmacologia
11.
Med Sci Monit ; 25: 4723-4733, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31237865

RESUMO

BACKGROUND Electroacupuncture (EA) has been commonly used to treat stroke in China. However, the underlying mechanism remains largely unknown. The present study investigated the neuroprotective effects of EA in middle cerebral artery occlusion (MCAO) rats and elucidated the possible anti-inflammatory mechanisms. MATERIAL AND METHODS In this study, modified neurological severity scoring (mNSS) was used to assess neurological deficits, and TTC staining and brain water content were measured to evaluate the degree of brain damage. HE staining, Nissl staining, and TUNEL staining were employed to evaluate apoptotic neuronal death. Molecular biological methods were used to measure the levels of miR-233, NLRP3, caspase-1, IL-1ß, and IL-18 in the peri-infarct cortex. RESULTS Our results showed that EA treatment significantly decreased the neurological deficit score and infarct volume of MCAO rats. The level of miR-223 was increased, while the levels of NLRP3, caspase-1, IL-1ß, and IL-18 were decreased in the peri-infarct cortex of EA-treated MCAO rats. However, the neuroprotective effect of EA was partially blocked by antagomir-223. CONCLUSIONS These data suggest that EA treatment can alleviate neuroinflammation by inhibiting the miR-223/NLRP3 pathway, thus playing a neuroprotective role in MCAO in rats.


Assuntos
Isquemia Encefálica/terapia , Eletroacupuntura/métodos , Infarto da Artéria Cerebral Média/terapia , MicroRNAs/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Pontos de Acupuntura , Animais , Encéfalo/metabolismo , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/terapia
12.
J Orthop Surg Res ; 14(1): 167, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146750

RESUMO

BACKGROUND: Excessive inflammatory response under hyperglycemia can impair alveolar bone defect healing under diabetic conditions. NLRP3 (NACHT [nucleotide-binding oligomerization], LRR [leucine-rich repeat], and PYD [pyrin domain] domains-containing protein 3) inflammasome has been considered to play a crucial role in the inflammatory response, but its correlation with the impaired alveolar bone repair in diabetes still remains unclarified. The objective of the current study is to investigate the effect of NLRP3 inflammasome inhibition by a lentiviral short hairpin RNA (shRNA) targeting NLRP3 on alveolar bone defect healing in diabetic rats. METHODS: Diabetes was induced in rats by high-fat diet and streptozotocin injection, and alveolar bone defects in both maxillae were created by surgery. Then, the lentiviral shRNA targeting NLRP3 was applied in the defect. Eight weeks after surgery, the alveolar bone regeneration was examined using hematoxylin and eosin (H&E) staining, and the gene expression in the bone healing site was detected using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis and western blot analysis. RESULTS: H&E staining showed that treatment with lentiviral shRNA targeting NLRP3 could increase the bone regeneration score in the alveolar bone defect of diabetic rats. Additionally, qRT-PCR analysis and western blot analysis of the bone defect demonstrated that this shRNA inhibited the expression of NLRP3, apoptosis-associated speck-like protein containing a CARD, caspase-1, and proinflammatory cytokine interleukin-1ß and increased the expression of osteogenic markers Runt-related transcription factor 2 and osteocalcin. CONCLUSIONS: Our findings suggested that inhibition of NLRP3 inflammasome could improve alveolar bone defect healing in diabetic rats. The beneficial effect may correlate with reduced proinflammatory cytokine production and increased osteogenic gene expression in hyperglycemia.


Assuntos
Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/patologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Perda do Osso Alveolar/tratamento farmacológico , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Masculino , RNA Interferente Pequeno/administração & dosagem , Ratos , Ratos Wistar
13.
Food Funct ; 10(7): 3898-3908, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31187838

RESUMO

Inflammatory liver diseases present a significant public health problem. Green tea polyphenols (GTPs) have a myriad of health benefits in animals and humans, including alleviating of hepatic inflammation; however, the underlying mechanisms are complicated and remain unclear. The current study investigated the preventive effects and mechanism of GTPs on lipopolysaccharide (LPS)-induced inflammatory liver injury in mice. The ICR mice received intragastric GTPs once per day for 7 consecutive days prior to LPS stimulation (15 mg kg-1, intraperitoneally) and liver damage and oxidative stress, pro-inflammatory cytokines, and the hepatic nuclear factor-κB (NF-κB) and Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes were observed. Our results showed that GTP supplementation significantly reduced LPS-induced plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and hepatic malondialdehyde (MDA) levels; and LPS-induced reduction of glutathione (GSH) levels and total superoxide dismutase (T-SOD) activities was drastically improved by GTP pretreatment. GTP supplementation significantly reduced plasma contents and hepatic mRNA levels of interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor (TNF)-α, compared with LPS-treated mice which did not receive GTP treatment. In addition, the production of cytokines, such as IL-1ß, IL-18, IL-6, and TNF-α in mice livers, and acute-phase response (plasma levels of nitric oxide and C-reactive protein) were also decreased following GTP pre-treatment. Furthermore, GTPs reduced LPS-induced hepatic NF-κB signaling and NLRP3 inflammasome activation. GTPs exert protective effects against inflammatory liver injury by regulating NF-κB signaling and the NLRP3 inflammasome activation. Our findings suggest that dietary GTP supplementation may be an adjunctive prevention and treatment for acute liver injury-associated inflammation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Inflamassomos/antagonistas & inibidores , Lipopolissacarídeos/efeitos adversos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Chá/química , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase
14.
Int J Mol Sci ; 20(12)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200447

RESUMO

Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in the pathophysiology of several neurological and psychiatric diseases (i.e., Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and major depressive disorder), metabolic disorders (i.e., obesity and type 2 diabetes) and chronic inflammatory diseases (i.e., intestinal inflammation, arthritis, and gout). Intensive research efforts are being made to achieve an integrated view about the pathophysiological role of NLRP3 inflammasome pathways in such disorders. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome by phytochemicals could represent a promising molecular target for the therapeutic management of neurological, psychiatric, metabolic, and inflammatory diseases. The present review article has been intended to provide an integrated and critical overview of the available clinical and experimental evidence about the role of NLRP3 inflammasome in the pathophysiology of neurological, psychiatric, metabolic, and inflammatory diseases, including PD, AD, MS, depression, obesity, type 2 diabetes, arthritis, and intestinal inflammation. Special attention has been paid to highlight and critically discuss current scientific evidence on the effects of phytochemicals on NLRP3 inflammasome pathways and their potential in counteracting central neuroinflammation, metabolic alterations, and immune/inflammatory responses in such diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inflamassomos/metabolismo , Doenças Metabólicas/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Fitoquímicos/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Compostos Fitoquímicos/uso terapêutico
15.
Drug Des Devel Ther ; 13: 1545-1554, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123394

RESUMO

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-1ß 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-1ß signaling pathway than the levels of FFAs or TLR4 pathway.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Glibureto/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Inflamassomos/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Oleico , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
16.
Nat Chem Biol ; 15(6): 556-559, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086327

RESUMO

Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.


Assuntos
Trifosfato de Adenosina/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/farmacologia , Trifosfato de Adenosina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Hidrólise/efeitos dos fármacos , Inflamassomos/biossíntese , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonas/química
17.
Nat Chem Biol ; 15(6): 560-564, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086329

RESUMO

NLRP3 (NOD-like receptor pyrin domain-containing protein 3) is an innate immune sensor that contributes to the development of different diseases, including monogenic autoinflammatory syndromes, gout, atherosclerosis, and Alzheimer's disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, and demonstrate that MCC950 closes the 'open' conformation of active NLRP3.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Células HEK293 , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Conformação Proteica , Sulfonas/química
18.
Stroke ; 50(5): 1232-1239, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31009361

RESUMO

Background and Purpose- A major process contributing to cell death in the ischemic brain is inflammation. Inflammasomes are multimolecular protein complexes that drive inflammation through activation of proinflammatory cytokines, such as IL (interleukin)-1ß. Preclinical evidence suggests that IL-1ß contributes to a worsening of ischemic brain injury. Methods- Using a mouse middle cerebral artery thrombosis model, we examined the inflammatory response after stroke and the contribution of the NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome to ischemic injury. Results- There was a marked inflammatory response after stroke characterized by increased expression of proinflammatory cytokines and NLRP3 and by recruitment of leukocytes to the injured tissue. Targeting NLRP3 with the inhibitor MCC950, or using mice in which NLRP3 was knocked out, had no effect on the extent of injury caused by stroke. Conclusions- These data suggest that the NLRP3 pathway does not contribute to the inflammation exacerbating ischemic brain damage, contradicting several recent reports to the contrary.


Assuntos
Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Trombose Intracraniana/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Acidente Vascular Cerebral/metabolismo , Animais , Lesões Encefálicas/patologia , Isquemia Encefálica/patologia , Furanos/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamassomos/deficiência , Trombose Intracraniana/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Acidente Vascular Cerebral/patologia , Sulfonamidas/farmacologia
19.
J Neuroinflammation ; 16(1): 81, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975164

RESUMO

BACKGROUND: Neuroinflammation is an essential player in many neurological diseases including traumatic brain injury (TBI). Recent studies have identified that inflammasome complexes are responsible for inflammatory responses in many pathological conditions. Inflammasomes are intracellular multiprotein complexes which regulate the innate immune response, activation of caspase-1, production of pro-inflammatory cytokines IL-1ß and IL-18, and induction of cell death (pyroptosis). Among inflammasome family members, the nucleotide-binding domain leucine-rich repeats family protein 3 (NLRP3) is the most extensively studied and its activation is induced following TBI. As a novel target, drug development targeting the formation and activation of NLRP3 inflammasome is a prospective therapy for TBI. We have recently developed a small molecule JC124 with specificity on NLRP3 inflammasome. In this study, we explored the therapeutic value of JC124 for TBI treatment. METHODS: Adult male Sprague-Dawley rats were subjected to a moderate cortical impact injury. Following TBI, animals received 4 doses of JC124 treatment with the first dose starting at 30 min, the second dose at 6 h after TBI, the third and fourth doses at 24 or 30 h following TBI, respectively. Animals were sacrificed at 2 days post-injury. Brain tissues were processed either for ELISA and western blotting analysis for inflammatory response, or for histological examination to assess degenerative neurons, acute inflammatory cell response and lesion volume. RESULTS: We found that post-injury treatment with JC124 significantly decreased the number of injury-induced degenerating neurons, inflammatory cell response in the injured brain, and cortical lesion volume. Injured animals treated with JC124 also had significantly reduced protein expression levels of NLRP3, ASC, IL-1 beta, TNFα, iNOS, and caspase-1. CONCLUSION: Our data suggest that our novel NLRP3 inhibitor has a specific anti-inflammatory effect to protect the injured brain following TBI.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Encefalite/tratamento farmacológico , Encefalite/etiologia , Glibureto/uso terapêutico , Inflamassomos/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Análise de Variância , Animais , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fluoresceínas/metabolismo , Cadeias alfa de HLA-DR/metabolismo , Inflamassomos/química , Interleucina-18/metabolismo , Interleucina-1beta/sangue , Masculino , Ratos , Ratos Sprague-Dawley
20.
J Immunol Res ; 2019: 7264383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30937316

RESUMO

Aim: To investigate the protective effects of budesonide against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in a murine model and its underlying mechanism. Methods: Adult male C57BL/6 mice were divided into three groups: control, ALI, and ALI + budesonide groups. LPS (5 mg/kg) was intratracheally injected to induce ALI in mice. Budesonide (0.5 mg/kg) was intranasally given 1 h before LPS administration in the ALI + budesonide group. Twelve hours after LPS administration, all mice were sacrificed. Hematoxylin-eosin staining and pathological scores were used to evaluate pathological injury. Bronchoalveolar lavage was performed. The numbers of total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid (BALF) were counted. Enzyme-linked immunosorbent assay was employed to detect the proinflammatory cytokines in BALF and serum, including tumor necrosis factor- (TNF-) α, monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 1ß. The expression of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome was detected by western blotting. A lethal dose of LPS (40 mg/kg, intraperitoneally) was injected to evaluate the effects of budesonide on survival rates. Results: Budesonide pretreatment dramatically attenuated pathological injury and reduced pathological scores in mice with ALI. Budesonide pretreatment obviously reduced the numbers of total cells, neutrophils, and macrophages in the BALF of mice with ALI. Additionally, budesonide dramatically reduced TNF-α and MCP-1 expression in the BALF and serum of mice with ALI. Budesonide significantly suppressed NLRP3 and pro-caspase-1 expression in the lung and reduced IL-1ß content in the BALF, indicating that budesonide inhibited the activation of the NLRP3 inflammasome. Furthermore, we found that budesonide improved the survival rates of mice with ALI receiving a lethal dose of LPS. Conclusion: Suppression of NLRP3 inflammasome activation in mice via budesonide attenuated lung injury induced by LPS in mice with ALI.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Budesonida/administração & dosagem , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Budesonida/farmacologia , Caspase 1/genética , Citocinas , Inflamação , Interleucina-1beta/genética , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de Sinais/efeitos dos fármacos
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