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1.
Molecules ; 25(20)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066442

RESUMO

The activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and/or its components is associated with the physio-pathogenesis of many respiratory diseases including asthma, COPD (chronic obstructive pulmonary disease), SARS Cov-2 (severe acute respiratory syndrome coronavirus 2), and in several autoimmune diseases. Hibiscus noldeae Baker f. has been widely reported to be traditionally used in the treatment of different ailments, some of which are of inflammatory background such as asthma, wounds, headache, etc. However, the claims have not been supported by evidence at the molecular and functional levels. Here, we report on the bio-guided fractionation of H. noldeae and assessment of the inhibitory properties of some fractions and purified compounds on NLRP3 inflammasome and Interleukin 6 (IL-6). The activation of the NLRP3 inflammasome was determined by detecting the activity of caspase-1 and the production of Interleukin 1ß (IL-1ß) in Lipopolysaccharide (LPS) and ATP-stimulated Tamm-Horsfall Protein 1 (THP-1) macrophages, while the production of IL-6 was studied in LPS-stimulated RAW264.7 mouse macrophages. It was observed that hexane and ethyl acetate fractions of the crude extract of the aerial parts of H. noldeae, as well as caffeic acid, isoquercetin, and ER2.4 and ER2.7 fractions revealed significant inhibitory effects on Caspase-1 activities, and on IL-1ß and IL-6 production. The ER2.4 and ER2.7 fractions downregulated the production of IL-1ß and IL-6, in a similar range as the caspase-1 inhibitor AC-YVAD-CHO and the drug Dexamethasone, both used as controls, respectively. Overall, our work does provide the very first scientific based evidence for Hibiscus noldeae anti-inflammatory effects and widespread use by traditional healers in Rwanda for a variety of ailments.


Assuntos
Anti-Inflamatórios/farmacologia , Hibiscus/química , Inflamassomos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Extratos Vegetais/farmacologia , Animais , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células RAW 264.7
2.
PLoS Biol ; 18(9): e3000813, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32991574

RESUMO

Short-chain fatty acids (SCFAs) produced by gastrointestinal microbiota regulate immune responses, but host molecular mechanisms remain unknown. Unbiased screening using SCFA-conjugated affinity nanobeads identified apoptosis-associated speck-like protein (ASC), an adaptor protein of inflammasome complex, as a noncanonical SCFA receptor besides GPRs. SCFAs promoted inflammasome activation in macrophages by binding to its ASC PYRIN domain. Activated inflammasome suppressed survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages by pyroptosis and facilitated neutrophil recruitment to promote bacterial elimination and thus inhibit systemic dissemination in the host. Administration of SCFAs or dietary fibers, which are fermented to SCFAs by gut bacteria, significantly prolonged the survival of S. Typhimurium-infected mice through ASC-mediated inflammasome activation. SCFAs penetrated into the inflammatory region of the infected gut mucosa to protect against infection. This study provided evidence that SCFAs suppress Salmonella infection via inflammasome activation, shedding new light on the therapeutic activity of dietary fiber.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Ácidos Graxos Voláteis/metabolismo , Inflamassomos/imunologia , Inflamassomos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Infecções por Salmonella/prevenção & controle , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Feminino , Microbioma Gastrointestinal/imunologia , Células HEK293 , Humanos , Imunidade Inata/fisiologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Receptores Acoplados a Proteínas-G/genética , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Infecções por Salmonella/metabolismo , Salmonella typhimurium/imunologia , Células U937
3.
Eur Rev Med Pharmacol Sci ; 24(17): 9169-9171, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32965010

RESUMO

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome has recently become an intriguing target of several chronic and viral diseases. Here, we argue that targeting NLRP3 inflammasome could be a strategy to prevent cardiovascular outcomes [fulminant myocarditis, heart failure, venous thromboembolism (VTE)] and acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 infection. We discuss the rationale for NLRP3 targeting in clinical trials as an effective therapeutic strategy aimed to improve prognosis of COVID-19, analyzing the potential of two therapeutic options (tranilast and OLT1177) currently available in clinical practice.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Infecções por Coronavirus/diagnóstico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/diagnóstico , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Miocardite/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Nitrilos/uso terapêutico , Pandemias , Pneumonia Viral/virologia , Prognóstico , Tromboembolia Venosa/prevenção & controle , ortoaminobenzoatos/uso terapêutico
4.
Nat Commun ; 11(1): 4561, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917873

RESUMO

The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here we demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. We also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1ß. HMGB1 is only released under conditions that cause cell lysis (pyroptosis). When pyroptosis is prevented, HMGB1 is not released, despite inflammasome activation and IL-1ß secretion. During endotoxemia, gasdermin D knockout mice secrete HMGB1 normally, yet secretion of IL-1ß is completely blocked. Together, these data demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.


Assuntos
Proteína HMGB1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Animais , Modelos Animais de Doenças , Endotoxemia/metabolismo , Feminino , Proteína HMGB1/genética , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato/genética , Piroptose , Transdução de Sinais
5.
Ecotoxicol Environ Saf ; 202: 110903, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800238

RESUMO

Cadmium (Cd) is a type of toxic metal, in most cases, coming from fuel burning and aquatic plants. The cells of organisms can be caused serious damage, including pyroptosis, exposure to low concentrations of Cd in long-term. Pyroptosis is a recently discovered Caspase-1-mediated cell death. In this study, lymphocytes were extracted from the pronephros and spleens in carps, respectively. After treating cells with low concentration of Cd, the mRNA and protein expression levels of pyroptosis-related genes, NLRP3, Caspase-1, and pro-inflammatory cytokines, increased obviously. And the content of reactive oxygen species (ROS) and mitochondria reactive oxygen species (mtROS) increased significantly, we also found the activities of CAT, GSH-px and T-SOD reduce significantly, and the content of MDA have a clear upward trend. We then added NLRP3 inhibitor, Glyburide, to the Cd-treated group, further confirming that NLRP3 is a key gene in pyroptosis pathways by detecting the mRNA and protein expression levels. Besides, the rupture of the cell membrane was also confirmed by Hoechst/PI double staining, red fluorescence increased obviously in the Cd treatment group. The experiment revealed that Cd exposure induces pyroptosis of lymphocytes in carp pronephros and spleens by activating NLRP3. Inhibition of NLRP3 activity can slow down the degree of lymphocytes pyroptosis. Thus, the above information provides a new avenue toward understanding the partial mechanism of Cd exposure-induced pyroptosis.


Assuntos
Cádmio/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pronefro/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Cádmio/metabolismo , Carpas/metabolismo , Carpas/fisiologia , Caspase 1 , Inflamassomos/metabolismo , Linfócitos , Mitocôndrias/metabolismo , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Baço/metabolismo
6.
Nat Commun ; 11(1): 4243, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843625

RESUMO

Increased extracellular Ca2+ concentrations ([Ca2+]ex) trigger activation of the NLRP3 inflammasome in monocytes through calcium-sensing receptor (CaSR). To prevent extraosseous calcification in vivo, the serum protein fetuin-A stabilizes calcium and phosphate into 70-100 nm-sized colloidal calciprotein particles (CPPs). Here we show that monocytes engulf CPPs via macropinocytosis, and this process is strictly dependent on CaSR signaling triggered by increases in [Ca2+]ex. Enhanced macropinocytosis of CPPs results in increased lysosomal activity, NLRP3 inflammasome activation, and IL-1ß release. Monocytes in the context of rheumatoid arthritis (RA) exhibit increased CPP uptake and IL-1ß release in response to CaSR signaling. CaSR expression in these monocytes and local [Ca2+] in afflicted joints are increased, probably contributing to this enhanced response. We propose that CaSR-mediated NLRP3 inflammasome activation contributes to inflammatory arthritis and systemic inflammation not only in RA, but possibly also in other inflammatory conditions. Inhibition of CaSR-mediated CPP uptake might be a therapeutic approach to treating RA.


Assuntos
Artrite Reumatoide/imunologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Calcinose , Cálcio/metabolismo , Células Cultivadas , Humanos , Inflamação , Interleucina-1beta/metabolismo , Camundongos , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Fosfatos/metabolismo , Pinocitose , Receptores de Detecção de Cálcio/deficiência , Transdução de Sinais , Células THP-1 , alfa-2-Glicoproteína-HS/metabolismo
7.
PLoS Biol ; 18(8): e3000807, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760056

RESUMO

Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of the inflammasomes, is also activated by radiation. Remarkably, protection against the injury induced by deadly ionizing radiation occurs only when NLRP3, AIM2, or GSDMD is lost simultaneously in both the donor and host cell compartments. Thus, this study reveals a continuum of the actions of lethal radiation relayed by the inflammasome-GSDMD axis, initially affecting recipient cells and ultimately harming transplanted cells as they grow in the severely injured and toxic environment. This study also suggests that therapeutic targeting of inflammasome-GSDMD signaling has the potential to prevent the collateral effects of intense radiation regimens.


Assuntos
Células da Medula Óssea/efeitos da radiação , Transplante de Medula Óssea , Proteínas de Ligação a DNA/genética , Inflamassomos/efeitos da radiação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Ligação a Fosfato/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Proteínas de Ligação a DNA/deficiência , Feminino , Fêmur/citologia , Fêmur/metabolismo , Regulação da Expressão Gênica , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteínas de Ligação a Fosfato/deficiência , Piroptose/genética , Piroptose/efeitos da radiação , Transdução de Sinais , Baço/metabolismo , Baço/patologia , Baço/efeitos da radiação , Transplante Isogênico , Irradiação Corporal Total , Raios X
8.
PLoS One ; 15(8): e0237847, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833985

RESUMO

PROM is one of the common complications of perinatal period, which seriously threatens the mother and newborn. The purpose of this study was to identify the role of NLRC4 inflammasomes in this process and their underlying mechanisms. We performed high-throughput RNA sequencing of fetal membrane tissue from 3 normal pregnant women and 3 term-premature rupture of fetal membrane (TPROM) patients who met the inclusion criteria, and found that NLRC4 was significantly up-regulated in TPROM patients. An observational study of TPROM patients (PROM group, n = 30) and normal pregnant women (control group, n = 30) was performed at the Xuzhou Maternal and Child Health Hospital affiliated to Xuzhou Medical University from May 2018 to May 2019. The expression of genes involved in inflammasome complex including NLRC1, NLRC3, AIM2, NLRC4, ASC, caspase-1, IL-6, IL-18 and IL-1ßwas determined via real-time PCR, immunohistochemistry and immunofluorescence. Measurement of NLRC4 level in serum was conducted by ELISA assay. The results showed that the NLRC4, ASC, caspase-1, IL-1ß and IL-18 levels in fetal membrane, placental tissues and maternal serum were markedly higher in the PROM group than that in the control group. In conclusion, NLRC4 is a markedly up-regulated gene in TPROM fetal membrane tissue, suggesting that NLRC4 is involved in the occurrence and development of TPROM; NLRC4 levels in maternal blood serum are closely related to TPROM and have the potential to assist doctors in predicting and diagnosing PROM.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Ruptura Prematura de Membranas Fetais/metabolismo , Inflamassomos/metabolismo , Adulto , Proteínas Adaptadoras de Sinalização CARD/sangue , Proteínas de Ligação ao Cálcio/sangue , Feminino , Ruptura Prematura de Membranas Fetais/sangue , Humanos , Placenta/metabolismo , Gravidez
9.
J Biol Chem ; 295(41): 14040-14052, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32763970

RESUMO

Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8- and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.


Assuntos
Caspase 8/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Células Cultivadas , Coronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/veterinária , Citocinas/metabolismo , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Necroptose , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo
10.
PLoS One ; 15(8): e0237754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804985

RESUMO

A strain of lactic acid bacteria, Lactobacillus paracasei KW3110 (KW3110), activates M2 macrophages with anti-inflammatory reactions and mitigates aging-related chronic inflammation and blue-light exposure-induced retinal inflammation in mice. However, the mechanism underlying the anti-inflammatory effects of KW3110 remains unclear. In this study, we investigated the anti-inflammatory effects of KW3110 using both mouse and human immune cells and evaluated the suppressive effect of KW3110 on the inflammatory reactions of the cells stimulated with lipopolysaccharide and adenosine 5'-triphosphate (LPS/ATP). KW3110 treatment induced anti-inflammatory cytokine interleukin (IL)-10 production in the supernatants of murine macrophage-like cells, J774A.1, and suppressed IL-1ß production in the supernatants of LPS/ATP-stimulated cells. The influence of KW3110 on the production of these cytokines was inhibited by pre-treatment with phagocytosis blocker or transfection with siRNAs for IL-10 signaling components. KW3110 treatment also suppressed activation of caspase-1, an active component of inflammasome complexes, in LPS/ATP-stimulated J774A.1 cells, and its effect was inhibited by transfection with siRNAs for IL-10 signaling components. In addition to the effects of KW3110 on J774A.1 cells, KW3110 treatment induced IL-10 production in the supernatants of human monocytes, and KW3110 or IL-10 treatment suppressed caspase-1 activation and IL-1ß production in the supernatants of LPS/ATP-stimulated cells. These results suggest that KW3110 suppresses LPS/ATP stimulation-induced caspase-1 activation and IL-1ß production by promoting IL-10 production in mouse and human immune cells. Our findings reveal a novel anti-inflammatory mechanism of LAB and the effect of KW3110 on caspase-1 activation is expected to contribute to constructing future preventive strategies for inflammation-related disorders using food ingredients.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/terapia , Lactobacillus paracasei/imunologia , Probióticos/farmacologia , Animais , Caspase 1/metabolismo , Linhagem Celular , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/imunologia , Interleucina-10/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
11.
Chem Biol Interact ; 330: 109232, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32860822

RESUMO

Currently, whether nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation contributes to neuropathy induced by 2,5-Hexanedione (HD), the toxic metabolite of n-hexane, remains unknown. In this study, we found that HD intoxication elevated NLRP3 expression, caspase-1 activation and interleukin-1ß production in sciatic nerve of rats, indicating activation of NLRP3 inflammasome. The increased cleavage of gasdermin D (GSDMD) protein, an important mediator of pyroptosis, and axon degeneration were also observed in sciatic nerves of HD-intoxicated rats. Interestingly, glybenclamide, a widely used inhibitor of NLRP3 inflammasome, significantly reduced NLRP3 inflammasome activation, which was associated with decreased GSDMD cleavage and axon degeneration as well as improved motor performance of HD-intoxicated rats. Subsequently, we found that inhibition of NLRP3 inflammasome by glybenclamide attenuated macrophage infiltration, activation and M1 polarization in sciatic nerves of HD-intoxicated rats. Furthermore, decreased malondialdehyde (MDA) contents and increased glutathione (GSH) level and total anti-oxidative capacity were also observed in sciatic nerves of rats treated with combined glybenclamide and HD compared with HD alone group. Altogether, our findings suggest that NLRP3 inflammasome activation contributes to HD-induced neurotoxicity by enhancing macrophage infiltration and activation as well as oxidative stress, providing a novel mechanism of neuropathy induced by this neurotoxicant.


Assuntos
Hexanonas/toxicidade , Macrófagos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/farmacologia , Síndromes Neurotóxicas/etiologia , Animais , Antioxidantes/metabolismo , Movimento Celular/efeitos dos fármacos , Glutationa/metabolismo , Glibureto/farmacologia , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Estresse Oxidativo , Proteínas de Ligação a Fosfato/metabolismo , Piroptose , Ratos , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
12.
Int J Mol Sci ; 21(17)2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32824985

RESUMO

The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1ß, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer's disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4'-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen's disease, also diagnosed as Alzheimer's disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson's disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Dapsona/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/tratamento farmacológico , Doença de Alzheimer/patologia , Clofazimina/farmacologia , Disfunção Cognitiva/patologia , Humanos , Interleucina-1beta/metabolismo , Hanseníase/tratamento farmacológico , Hanseníase/genética , Pandemias , Transtornos Parkinsonianos/patologia , Rifampina/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Receptor 2 Toll-Like/genética
13.
PLoS One ; 15(8): e0237030, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810141

RESUMO

Curative therapeutic options for a number of immunological disorders remain to be established, and approaches for identifying drug candidates are relatively limited. Furthermore, phenotypic screening methods using induced pluripotent stem cell (iPSC)-derived immune cells or hematopoietic cells need improvement. In the present study, using immortalized monocytic cell lines derived from iPSCs, we developed a high-throughput screening (HTS) system to detect compounds that inhibit IL-1ß secretion and NLRP3 inflammasome activation from activated macrophages. The iPSCs were generated from a patient with neonatal onset multisystem inflammatory disease (NOMID) as a model of a constitutively activated NLRP3 inflammasome. HTS of 4,825 compounds including FDA-approved drugs and compounds with known bioactivity identified 7 compounds as predominantly IL-1ß inhibitors. Since these compounds are known inflammasome inhibitors or derivatives of, these results prove the validity of our HTS system, which can be a versatile platform for identifying drug candidates for immunological disorders associated with monocytic lineage cells.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Linhagem Celular , Células Cultivadas , Síndromes Periódicas Associadas à Criopirina/imunologia , Síndromes Periódicas Associadas à Criopirina/fisiopatologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Inflamassomos/fisiologia , Inflamação/metabolismo , Interleucina-1beta , Macrófagos/metabolismo , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia
14.
Eur Rev Med Pharmacol Sci ; 24(14): 7880-7885, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32744716

RESUMO

The coronavirus SARS-CoV-2 at the origin of COVID-19 shares more than 70% genetic similarity with SARS-CoV-1 that was at the origin of 2003 SARS. Infection-associated symptoms are very similar between SARS and COVID-19 diseases and are the same as community-acquired pneumonia symptoms. Antibiotics were empirically given to SARS patients in the early stages of the pathology whereas a different strategy has been decided in the management of COVID-19 pandemic with a worldwide shutdown. The cytokine storm, both identified in SARS and COVID-19 severe cases, is generated through inflammasome activation, which opens therapeutic perspectives to counteract the pathogenic inflammation. As corticoids have numerous side effects that limit their use, focusing on anti-inflammasome agents could represent a safer alternative for patients with severe COVID-19.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Corticosteroides/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Humanos , Inflamassomos/química , Inflamassomos/metabolismo , Pandemias , Pneumonia Viral/epidemiologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X7/química , Receptores Purinérgicos P2X7/metabolismo , Vírus da SARS/isolamento & purificação , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/virologia
15.
Front Immunol ; 11: 1518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655582

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1ß. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/metabolismo , Animais , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imunidade Inata , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Camundongos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Piroptose/efeitos dos fármacos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/uso terapêutico , Sulfonas/farmacologia , Sulfonas/uso terapêutico
16.
Life Sci ; 257: 118069, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32659370

RESUMO

AIM: Up-regulation of inflammasome proteins was reported in dystrophin-deficient muscles. However, it remains to be determined whether inflammasome activation plays a role in the pathogenesis of Duchenne muscular dystrophy. This study was therefore set out to investigate whether genetic disruption of the inflammasome pathway impacts the disease progression in mdx mice. MAIN METHODS: Mice deficient in both dystrophin and ASC (encoded by Pycard [PYD And CARD Domain Containing]) were generated. The impact of ASC deficiency on muscular dystrophy of mdx mice were assessed by measurements of serum cytokines, Western blot, real-time PCR and histopathological staining. KEY FINDINGS: The pro-inflammatory cytokines such as TNF-α, IL-6, KC/GRO and IL-10 were markedly increased in the sera of 8-week-old mdx mice compared to WT. Western blotting showed that P2X7, caspase-1, ASC and IL-18 were upregulated. Disruption of ASC and dystrophin expression in the mdx/ASC-/- mice was verified by Western blot analysis. Histopathological analysis did not find significant alterations in the muscular dystrophy phenotype in mdx/ASC-/- mice as compared to mdx mice. SIGNIFICANCE: Taken together, our results show that disruption of the central adaptor ASC of the inflammasome is insufficient to alleviate muscular dystrophy phenotype in mdx mice.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Distrofina/genética , Inflamassomos/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Animais , Citocinas/sangue , Modelos Animais de Doenças , Progressão da Doença , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Camundongos Knockout , Distrofia Muscular de Duchenne/genética , Regulação para Cima
17.
J Toxicol Sci ; 45(7): 373-390, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612006

RESUMO

DEHP (di-2-ethylhexyl phthalate), an environmental endocrine disruptor, is widely used in industrial products, particularly as plasticizers and softeners which could disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis. Rosmarinic acid (RA) possesses potential antioxidant and anti-inflammatory capacities in disease models. Nevertheless, evidence on the association between DEHP-induced thyroid dysfunction and inflammation, as well as the molecular mechanism underlying the protective effects of RA-mitigated DEHP-induced thyroid injury remains inconclusive. Male Sprague Dawley (SD) rats were intragastrically administered DEHP (150 mg/kg, 300 mg/kg, 600 mg/kg) once a day for 90 consecutive days. Also, FRTL-5 cells were treated with a wide range of DEHP concentrations (10-8, 10-7, 10-6, 10-5, 10-4, 10-3, 10-2 M) for 24 hr. Subsequently, RA (50 µM) was administered for 24 hr before 10-4 M DEHP challenge. We found that DEHP induced thyroid damage and inflammatory infiltration in vivo. In addition, we showed that DEHP triggered inflammatory cell death, which is mediated by multiple inflammasomes. Moreover, RA, pyroptosis inhibitor (Ac-YVAD-cmk) and antioxidant inhibitor (NAC) treatment significantly alleviated DEHP-induced thyrocyte death, suppressing pro-inflammatory cytokine production, inhibiting multiple inflammasomes activation and attenuating thyrocyte death, respectively. Collectively, our results reveal that a critical role of inflammasomes activation in DEHP-induced thyroid injury, and suggest that RA confers protection against DEHP-induced thyroid inflammation, and facilitating control of the effects of DEHP after given pyroptosis inhibitor or antioxidant inhibitor. These results indicate that it should be possible to provide novel insights into toxicologically and pharmacologically targeting this molecule to DEHP-induced inflammation.


Assuntos
Anti-Inflamatórios , Antioxidantes , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Depsídeos/farmacologia , Depsídeos/uso terapêutico , Dietilexilftalato/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/tratamento farmacológico , Inflamassomos/metabolismo , Fitoterapia , Animais , Boraginaceae , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Dietilexilftalato/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Disruptores Endócrinos/toxicidade , Hipotireoidismo/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Ratos Sprague-Dawley , Células Epiteliais da Tireoide/efeitos dos fármacos
18.
Am J Physiol Renal Physiol ; 319(2): F292-F303, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32686520

RESUMO

In proteinuric renal diseases, excessive plasma nonesterified free fatty acids bound to albumin can leak across damaged glomeruli to be reabsorbed by renal proximal tubular cells and cause inflammatory tubular cells damage by as yet unknown mechanisms. The present study was designed to investigate these mechanisms induced by palmitic acid (PA; one of the nonesterified free fatty acids) overload. Our results show that excess PA stimulates ATP release through the pannexin 1 channel in human renal tubule epithelial cells (HK-2), increasing extracellular ATP concentration approximately threefold compared with control. The ATP release is dependent on caspase-3/7 activation induced by mitochondrial reactive oxygen species. Furthermore, extracellular ATP aggravates PA-induced monocyte chemoattractant protein-1 secretion and monocyte infiltration of tubular cells, enlarging the inflammatory response in both macrophages and HK-2 cells via the purinergic P2X7 receptor-mammalian target of rapamycin-forkhead box O1-thioredoxin-interacting protein/NOD-like receptor protein 3 inflammasome pathway. Hence, PA increases mitochondrial reactive oxygen species-induced ATP release and inflammatory stress, which cause a "first hit," while ATP itself is a "second hit" in amplifying the renal tubular inflammatory response. Thus, inhibition of ATP release or the purinergic P2X7 receptor may be an approach to reduce renal inflammation and improve renal function.


Assuntos
Trifosfato de Adenosina/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Inflamassomos/metabolismo , Túbulos Renais/metabolismo , Células Epiteliais/metabolismo , Humanos , Macrófagos/metabolismo , Monócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
Mol Immunol ; 125: 24-31, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32623292

RESUMO

Toll-like receptor 9 (TLR9) has been reported to mediate airway inflammation, however, the underlying mechanism is poorly understood. In the present study, our objective was to reveal whether TLR9 regulates NLRP3 inflammasome and oxidative stress in murine allergic airway inflammation and Raw264.7 cells. Female wild type(WT)and TLR9-/-mice on C57BL/6 background were used to induce allergic airway inflammation by challenge of OVA, and Raw264.7 cells with or without TLR9 knockdown by small interfering RNA (siRNA) were stimulated by S.aureus. The results demonstrated that deletion of TLR9 effectively attenuated OVA-induced allergic airway inflammation including inflammatory cells infiltration and goblet cell hyperplasia. Meanwhile, OVA-induced protein expression of NLRP3, caspase-1(p20) and mature IL-1ß, as well as secretion of IL-1ß and IL-18 in wild type mice (WT) was obviously suppressed by TLR9 deficiency. Concomitantly, the expression of oxidative markers 8-OhDG and nitrotyrosine was increased in OVA-challenged WT mice, while TLR9 deficiency significantly inhibited such increase. Similarly, in the in vitro study, we found that knockdown of TLR9 markedly suppressed S.aureus-induced activation of NLRP3 inflammasome and oxidative stress in Raw264.7 cells. Collectively, our findings indicated that TLR9 may mediate allergic airway inflammation via activating NLRP3 inflammasome and oxidative stress.


Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Estresse Oxidativo/fisiologia , Receptor Toll-Like 9/imunologia , Animais , Asma/metabolismo , Hipersensibilidade/metabolismo , Hipersensibilidade/fisiopatologia , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Células RAW 264.7 , Receptor Toll-Like 9/metabolismo
20.
Mol Immunol ; 125: 178-186, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32717666

RESUMO

PM2.5, a major component of air pollutants, has caused severe health problems. It has been reported that PM2.5 index is closely associated with severity of influenza A virus (IAV) infection. However, the underlying mechanisms have not been addressed. NLRP3 inflammasome and type I interferon signaling regulate host defense against influenza infection. The present study investigated the potential effects of air pollutants on host defense against influenza infection in vitro and in vivo. In this study, different concentrations of PM2.5 were pre-exposed to macrophages and mice before IAV infection to assess the negative effects of air pollutants in virus infection. We found that exposure to PM2.5 deteriorated influenza virus infection via compromising innate immune responses manifested by a decrease IL-1ß and IFN-ß production in vitro. Meanwhile, mice exposed with PM2.5 were susceptible to PR8 virus infection due to down-regulation of IL-1ß and IFN-ß. Mechanistically, PM 2.5 exposure suppressed the NLRP3 inflammasome activation and the AHR-TIPARP signaling pathway, by which compromised the anti-influenza immunity. Thus, our study revealed that PM2.5 could alter macrophage inflammatory responses by suppressing LPS-induced activation of NLRP3 inflammasome and expression of IFN-ß during influenza infection. These findings provided us new insights in understanding that PM2.5 combining with influenza infection could enhance the severity of pneumonia.


Assuntos
Poluentes Atmosféricos/toxicidade , Inflamassomos/efeitos dos fármacos , Interferon beta/biossíntese , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Infecções por Orthomyxoviridae/imunologia , Material Particulado/toxicidade , Animais , Inflamassomos/imunologia , Inflamassomos/metabolismo , Vírus da Influenza A Subtipo H1N1 , Interferon beta/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Infecções por Orthomyxoviridae/metabolismo
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