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1.
Zhen Ci Yan Jiu ; 46(4): 295-300, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33931994

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) on Cathepsin-B in the synovium of the knee joint of acute gouty arthritis(AGA) rats, so as to explore the mechanism of EA in the treatment of AGA. METHODS: A total of 60 male Wistar rats were randomly divided into normal control,model, medication and EA groups, with 15 rats in each group. Rat model of AGA was established by injection of 0.2 mL sodium urate crystal suspension into the left knee joint cavity. The rats in the medication group were treated with colchicine by gavage(0.3 mg·kg-1·d-1), and the rats in the EA group were treated with EA at the left "Sanyinjiao" (SP6) and "Zusanli"(ST36) for 10 min each time, once a day for a week. The Coderre gait grading standard was used to score the gait of rats. The pathological morphology of synovial tissue of the left knee joint was observed by H.E. staining. The expression levels of Cathepsin-B protein and Nod-like receptor pyrin domain 3(NLRP3), apoptosis-associated speck-like protein containing CARD (ASC),Caspase-1, interleukin-1ß(IL-1ß) and IL-18 mRNAs were detected by Western blot and real-time fluorescence quantitative PCR, respectively. RESULTS: Compared with the normal control group, the degree of synovitis infiltration in the model group was more serious. And the gait score,the protein expression level of Cathepsin-B and the mRNA expression levels of NLRP3,ASC,Caspase-1, IL-1ß,IL-18 were significantly increased (P<0.01).After the interventions, the degree of inflammatory infiltration was mild, The gait score, the protein expression level of Cathepsin-B and the mRNA expression levels of NLRP3 and ASC,Caspase-1,IL-1ß,IL-18 were significantly decreased in both medication and EA groups in contrast to the model group (P<0.01, P<0.05). Compared with medication group, the mRNA expression levels of Caspase-1 and IL-18 in the EA group were increased (P<0.05). CONCLUSION: EA may inhibit the activation of NLRP3 inflammasome by reducing the activity of Cathepsin-B in the synovium of the knee joint, so as to treat AGA.


Assuntos
Artrite Gotosa , Eletroacupuntura , Animais , Artrite Gotosa/genética , Artrite Gotosa/terapia , Catepsina B/genética , Inflamassomos/genética , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Ratos , Ratos Wistar
2.
Molecules ; 26(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670164

RESUMO

Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1ß and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1ß and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases.


Assuntos
Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças Neurodegenerativas/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Doenças Neurodegenerativas/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transdução de Sinais/genética
3.
Molecules ; 26(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673188

RESUMO

Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1ß (IL-1ß) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Imunidade Inata/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças Cardiovasculares/genética , Caspase 1/genética , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Transdução de Sinais/genética
4.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760111

RESUMO

Cholesteatoma constitutes an acquired benign epidermal non­permanent bone lesion that is locally destructive and patients often relapse. Inflammasomes, which mediate the maturation and production of IL­18 and IL­1ß, resulting in pyroptosis, have been documented to serve a core function in multiple inflammatory conditions. Absent in melanoma 2 (AIM2) is an inflammasome that identifies cytoplasmic DNA and has previously been reported as a pivotal modulator of inflammatory responses. Therefore, the present study aimed to determine the expression levels of AIM2 in human cholesteatoma tissues, and elucidate its function in modulating cytokine production. The expression levels of IL­18, apoptosis­associated speck­like protein containing a CARD (ASC), IL­1ß, AIM2 and caspase­1 were markedly elevated in cholesteatoma tissues. Protein expression levels of AIM2, caspase­1 and ASC were localized in the cellular cytoplasm, primarily in the granular and prickle­cell layers in the cholesteatoma epithelium. Induction using IFN­Î³, as well as cytoplasmic DNA markedly activated the AIM2 inflammasome and elevated the release of IL­18 and IL­1ß in human cholesteatoma keratinocytes. IFN­Î³ was found to enhance poly(dA:dT)­induced pyroptosis of cells and cytokine production. The results of the present study revealed that AIM2 expressed in human cholesteatoma serves a vital function in the inflammatory response by initiating the inflammasome signaling cascade in cholesteatoma.


Assuntos
Neoplasias Ósseas/genética , Colesteatoma/genética , Proteínas de Ligação a DNA/genética , Interleucina-18/genética , Interleucina-1beta/genética , Animais , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Proteínas Adaptadoras de Sinalização CARD/genética , Caspase 1/genética , Colesteatoma/patologia , Citocinas/biossíntese , Citocinas/genética , Citoplasma/genética , DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/genética , Interferon gama/genética , Interleucina-18/biossíntese , Interleucina-1beta/biossíntese , Queratinócitos/metabolismo , Neoplasias/genética , Neoplasias/patologia , Poli dA-dT/farmacologia , Piroptose/efeitos dos fármacos , Piroptose/genética
5.
Zhongguo Zhong Yao Za Zhi ; 46(6): 1474-1479, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33787146

RESUMO

To study the effect and mechanism of extract of Quzhou Aurantii Fructus(QAF) on liver inflammation in CCl_4-induced liver fibrosis mice. Totally 60 C57 BL/6 male mice were randomly divided into control group(distilled water, oral), model group(distilled water, oral), colchicines group(Col, colchicines 2 mg·kg~(-1)·d~(-1), oral), low-dose QAF group(QAF-L, QAF 100 mg·kg~(-1)·d~(-1), oral) and high-dose QAF group(QAF-H, QAF 300 mg·kg~(-1)·d~(-1), oral) by random number table method. The model group and each administration group were injected with carbon tetrachloride(CCl_4) 1 mL·kg~(-1)(CCl_4-olive oil 1∶4), twice a week, totally 6 weeks. After the last administration, the mice were sacrificed, and serum and liver tissue were collected. Serum ALT and AST levels were measured in each group to observe the liver function of mice. The pathological changes and inflammatory cell infiltration in liver were observed by HE staining and F4/80 immunohistochemical staining. The mRNA expressions of TNF-α, IL-18 and IL-1ß were detected by RT-PCR. The protein expressions of IκBα, p-IKKα/ß, p-p65, NLRP3, caspase-1 and cleaved caspase-1 were analyzed by Western blot. The results showed that QAF significantly reduced serum ALT and AST levels, and alleviated the degree of liver damage.The results of immunohistochemistry showed that QAF significantly reduced liver inflammatory cell infiltration in liver fibrosis mice. The results of RT-PCR and Western blot showed that QAF significantly inhibited mRNA expressions of TNF-α, IL-18 and IL-1ß in liver of fibrosis mice. QAF also suppressed the degradation of IκBα protein and reduced p-IKKα/ß, p-p65, NLRP3 and cleaved caspase-1 protein expressions. In conclusion, QAF improves CCl_4-induced liver fibrosis in mice. The mechanism may be related to the inhibition of NF-κB/NLRP3 inflammasome-mediated inflammation signaling pathway.


Assuntos
Inflamassomos , NF-kappa B , Animais , Inflamassomos/genética , Inflamação , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Masculino , Camundongos , NF-kappa B/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Extratos Vegetais
6.
Poult Sci ; 100(3): 100801, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33518325

RESUMO

Heat stress (HS) is a critical concern to the poultry industry as it affects both productivity and well-being. Various managerial and nutritional strategies have been proposed to mitigate the negative effects of HS in chickens, with plant-based additives showing promise. Recently, we reported the positive effect of a phytogenic feed additive (PFA) on growth performance in HS birds. Owing to the antioxidant nature of these compounds, we sought to further explore the effect of PFA on whole blood circulating chemokines, cytokines, and inflammasomes in HS broilers. Broilers (600 males, 1 d) were randomly assigned to 12 environmental chambers, subjected to 2 environmental conditions (12 h cyclic heat stress, HS, 35°C vs. thermoneutral condition [TN], 24°C) and fed 3 diets (control, PFA-C 250 ppm, PFA-C 400 ppm) in a 2 × 3 factorial design. After 21 d of cyclic HS, blood samples were collected for target gene expression analysis. HS upregulated the expression of superoxide dismutase 1 (SOD1) and downregulated glutathione peroxidase-3 (GPX-3), and there was diet × temperature interaction for SOD2, GPX-1, and GPX-3, where gene expression was increased by PFA-C250 during HS but was unchanged for PFA-C400. Plasma total antioxidant capacity (TAC) and malondialdehyde (MDA) content were increased by HS. Gene expression of interleukin-18 (IL-18) was decreased by HS, without further effect of PFA. HS increased tumor necrosis factor α (TNFα), but this effect was mitigated by PFA-C400. C-C motif chemokine ligands 4 and 20 (CCL4 and CCL20) showed a similar pattern to TNFα, with PFA-C400 ameliorating the negative effect of HS. The nucleotide-binding, leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome was decreased by HS and further lowered by PFA-C400, but the nucleotide-binding oligomerization domain, leucine-rich repeat, and CARD domain containing 3 (NLRC3) and nucleotide-binding, leucine-rich repeat containing X1 (NLRX1) inflammasomes were increased by PFA under TN conditions, with no effects of HS. Heat shock proteins (HSP) and heat shock factors (HSF) were unaffected by PFA or HS. Together these data indicate that gene expression of circulating inflammatory factors are dysregulated during HS, and supplemental dietary PFA may be protective.


Assuntos
Galinhas , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Resposta ao Choque Térmico , Inflamassomos , Extratos Vegetais , Animais , Antioxidantes/farmacologia , Galinhas/sangue , Galinhas/genética , Galinhas/imunologia , Dieta/veterinária , Inflamassomos/sangue , Inflamassomos/genética , Masculino , Extratos Vegetais/farmacologia , Distribuição Aleatória , Transcriptoma
7.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429941

RESUMO

The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.


Assuntos
Proteínas de Ligação a DNA/genética , Inflamação/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Evolução Clonal , Humanos , Inflamassomos/genética , Inflamação/patologia , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia
8.
Mol Immunol ; 131: 191-200, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33446392

RESUMO

Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are involved in various pathophysiological processes of disease, such as cancer occurrence, viral invasion, and inflammatory damage. The main inflammatory body component, nod-like receptor protein 3 (NLRP3), is the trigger point of inflammatory reactions and inflammation-related diseases and coordinates the body's response to inflammation. At present, increasing evidence shows that the interaction of lncRNAs and the NLRP3 inflammasome plays an important role in the inflammatory response and different diseases. This may be involved in the development and progression of various diseases by activating signalling pathways and a variety of molecular regulatory mechanisms-this article reviews progress in research on the relationship between lncRNAs and the NLRP3 inflammasome under different conditions.


Assuntos
Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , RNA Longo não Codificante/genética , Animais , Humanos , Inflamação/genética , Transdução de Sinais/genética
9.
Nat Commun ; 12(1): 188, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420028

RESUMO

Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells-a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Inflamassomos/química , Inflamassomos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Caspase 1/metabolismo , Microscopia Crioeletrônica , Células HEK293 , Humanos , Inflamassomos/genética , Inflamação , Simulação de Acoplamento Molecular , Mutação , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Transdução de Sinais
10.
Mol Med Rep ; 23(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33300067

RESUMO

Inflammation may be responsible for the development of premature rupture of membranes (PROM) including preterm PROM (PPROM) and mature PROM (MPROM). A total of four classic receptor proteins have been confirmed to assemble inflammasomes: NLR family pyrin domain containing (NLRP)1, NLRP3 and NLR family CARD­domain containing 4 (NLRC4) and absent in melanoma 2 (AIM2). The activation and expression of these receptor­modulated inflammasomes in placenta and fetal membrane of PROM pregnancies requires investigation. In addition, a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) is a risk factor for PROM, but whether its expression is associated with inflammasome activation remains to be elucidated. In the present study, the placenta and fetal membrane tissues of patients who had suffered PPROM and MPROM and healthy pregnancies were investigated. Reverse transcription­quantitative PCR was used to determine the mRNA expression of inflammasomes and ADAMTS4. Western blotting, immunohistochemistry and ELISA were used to investigate the protein expression levels of inflammasomes and ADAMTS4. The results demonstrated that all four inflammasomes were elevated in placenta and fetal membrane of PPROMs as were mRNA and protein expression levels of IL­18 and IL­1ß (compared with controls). A further increase of inflammasomes and interleukins was observed in MPROMs compared with controls. Similar results were also observed in ADAMTS4 expression in PPROM and MPROM groups. However, immunohistochemistry results revealed no significant difference of inflammasome receptor expression in PPROMs compared with controls. Finally, a general positive correlation between ADAMTS4 and all four inflammasome receptors in placenta and fetal membrane of PPROMs and MPROMs was observed. The present study revealed that NLRP1, NLRP3, AIM2 and NLRC4 inflammasome activation in PROM was increased. Promoted ADAMTS4 level was further observed in PROM group and was significantly correlated with inflammasome expression. Inhibition of inflammasome activation may provide a therapeutic target for clinical PROM treatment.


Assuntos
Proteínas ADAMTS/biossíntese , Ruptura Prematura de Membranas Fetais/enzimologia , Regulação Enzimológica da Expressão Gênica , Inflamassomos/metabolismo , Placenta/enzimologia , Proteínas ADAMTS/genética , Adulto , Feminino , Ruptura Prematura de Membranas Fetais/genética , Ruptura Prematura de Membranas Fetais/patologia , Humanos , Inflamassomos/genética , Placenta/patologia , Gravidez
11.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(12): 1076-1082, 2020 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-33325360

RESUMO

Objective To study the mechanism of community-acquired respiratory distress syndrome (CARDS) toxin of Mycoplasma pneumoniae (Mp) inducing THP-1 cell autophagy and the activation of pyrin domain containing the nucleotide-binding oligomerization domain-like receptor family 3 (NLRP3). Methods The recombinant CARDS (rCARDS) Mp toxin was obtained by Escherichia coli expression system, and THP-1 cells were treated with the toxin at the concentrations of 5 and 10 µg/mL for 20, 40 minutes, 1, 2 and 3 hours. The expression of autophagy-related proteins beclin-1, LC3II and P62 of THP-1 cells were determined by Western blot; the gene expression of NLRP3, caspase-1 and interleukin 1ß (IL-1ß) were detected by real-time quantitative PCR; and the level of reactive oxygen species (ROS) of THP-1 cells was tested by DCFH-DA staining. Results Compared with the control group, when treated with rCARDS toxin for 1 hour, the expression of beclin-1, LC3 and P62 significant increased. When treated with rCARDS toxin for 2 and 3 hours, the expression of beclin-1, LC3 and P62 significant decreased. When treated with rCARDS toxin for 20 and 40 minutes, the NLRP3 gene expression had no significant difference between the groups treated with the concentration of 5 and 10 µg/mL rCARDS toxin. NLRP3 gene expression in the groups treated with rCARDS toxin was higher than that in the control group in the whole experiment. When treated with rCARDS toxin for 1 hour and 2 hours, the NLRP3 gene expression of the 10 µg/mL group was significant higher than that in the 5 µg/mL group. When treated with rCARDS toxin for 3 hours, the NLRP3 gene expression of the 10 µg/mL group and 5 µg/mL group was lower than that in the groups treated for 2 hours. When treated with rCARDS toxin for 40 minutes, 1 hour and 2 hours, the caspase-1 mRNA expression of rCARDS toxin groups was higher than that in the control group. When treated for 40 minutes, 1, 2 and 3 hours, the caspase-1 gene expression of the 10 µg/mL group was significantly higher than that in the 5 µg/mL group. Compared to the control group, when treated with rCARDS toxin for 20 and 40 minutes, IL-1ß gene expression had no significant difference. When the time prolonged to 1 hour and 3 hours, the levels of IL-1ß mRNA expression and ROS had a significant increase in a dose-dependent manner in all groups. Conclusion CARDS Mp toxin can activate NLRP3 inflammasomes and induce cell autophagy in THP-1 cells.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Autofagia , Caspase 1/genética , Humanos , Inflamassomos/genética , Interleucina-1beta/genética , Mycoplasma pneumoniae/genética , Células THP-1
12.
Int J Mol Sci ; 21(24)2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33317034

RESUMO

Among the causes of global death and disability, ischemic stroke (also known as cerebral ischemia) plays a pivotal role, by determining the highest number of worldwide mortality, behind cardiomyopathies, affecting 30 million people. The etiopathogenetic burden of a cerebrovascular accident could be brain ischemia (~80%) or intracranial hemorrhage (~20%). The most common site when ischemia occurs is the one is perfused by middle cerebral arteries. Worse prognosis and disablement consequent to brain damage occur in elderly patients or affected by neurological impairment, hypertension, dyslipidemia, and diabetes. Since, in the coming years, estimates predict an exponential increase of people who have diabetes, the disease mentioned above constitutes together with stroke a severe social and economic burden. In diabetic patients after an ischemic stroke, an exorbitant activation of inflammatory molecular pathways and ongoing inflammation is responsible for more severe brain injury and impairment, promoting the advancement of ischemic stroke and diabetes. Considering that the ominous prognosis of ischemic brain damage could by partially clarified by way of already known risk factors the auspice would be modifying poor outcome in the post-stroke phase detecting novel biomolecules associated with poor prognosis and targeting them for revolutionary therapeutic strategies.


Assuntos
Aterosclerose/imunologia , /imunologia , Animais , Aterosclerose/complicações , Aterosclerose/genética , Barreira Hematoencefálica/metabolismo , Humanos , Imunidade Inata , Inflamassomos/genética , Inflamassomos/metabolismo , /genética , MicroRNAs/genética , MicroRNAs/metabolismo
13.
J Toxicol Sci ; 45(10): 625-637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33012731

RESUMO

NOD-like receptor protein 3 (NLRP3) is involved in acute lung injury (ALI), but its exact role in phosgene-induced ALI is not clearly understood. The aim of the study is to explore the potential therapeutic effect of NLRP3 inflammasome modulation in the management of phosgene-induced ALI. ALI was induced in rats by phosgene exposure at 8.33 g/m3 for 5 min, 30 hr before intravenous injection of adenovirus-NLRP3 shRNA (Ad/NLRP3-shRNA). The histological changes in the lung were evaluated. Bronchoalveolar lavage fluid (BALF) neutrophils were counted (smear), and protein content was measured using the BCA assay. The wet/dry ratio of lung tissue (W/D) was measured. TUNEL staining for DNA damage was used to indirectly assess pyroptosis. NLRP3 inflammasome was assessed by immunohistochemistry, RT-PCR, western blotting. Cytokines were measured by ELISA. Histological analyses revealed reduced severity in phosgene-induced ALI with Ad/NLRP3-shRNA pretreatment. TUNEL staining indicated decreased pyroptosis in Psg-Ad/NLRP3-shRNA rats. Decreased mRNA and protein levels of NLRP3 and caspase-1 (all P < 0.05), but not ASC (P > 0.05), were found in Psg-Ad/NLRP3-shRNA rats. Immunohistochemistry revealed that Ad/NLRP3-shRNA pretreatment inhibited NLRP3 inflammasome activation. Reduced level of pro-inflammatory interleukin (IL)-1ß, IL-18, IL-33, and tumor necrosis factor (TNF)-α (all P < 0.05), but not of anti-inflammatory IL-4 and IL-10 (all P > 0.05), were found in serum and BALF from Ad/NLRP3-shRNA rats. NLRP3 gene silencing exerts beneficial effects on phosgene-induced lung injury by inhibiting NLRP3 inflammasome activation and pro-inflammatory factors, but not anti-inflammatory factors. Disruption of NLRP3 inflammasome activation might be used as a therapeutic modality for the treatment of phosgene-induced ALI.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/terapia , Inativação Gênica , Terapia Genética/métodos , Inflamassomos/genética , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosgênio/envenenamento , RNA Interferente Pequeno/administração & dosagem , Lesão Pulmonar Aguda/diagnóstico , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intravenosas , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Masculino , Ratos Sprague-Dawley
14.
Virus Res ; 289: 198163, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32918943

RESUMO

BACKGROUND: Susceptibility to severe viral infections was reported to be associated with genetic variants in immune response genes using case reports and GWAS studies. SARS-CoV-2 is an emergent viral disease that caused millions of COVID-19 cases all over the world. Around 15 % of cases are severe and some of them are accompanied by dysregulated immune system and cytokine storm. There is increasing evidence that severe manifestations of COVID-19 might be attributed to human genetic variants in genes related to immune deficiency and or inflammasome activation (cytokine storm). OBJECTIVE: Identify the candidate genes that are likely to aid in explaining severe COVID-19 and provide insights to understand the pathogenesis of severe COVID-19. METHODS: In this article, we systematically reviewed genes related to viral susceptibility that were reported in human genetic studies (Case-reports and GWAS) to understand the role of host viral interactions and to provide insights into the pathogenesis of severe COVID-19. RESULTS: We found 40 genes associated with viral susceptibility and 21 of them were associated with severe SARS-CoV disease and severe COVID-19. Some of those genes were implicated in TLR pathways, others in C-lectin pathways, and others were related to inflammasome activation (cytokine storm). CONCLUSION: This compilation represents a list of candidate genes that are likely to aid in explaining severe COVID-19 which are worthy of inclusion in gene panels and during meta-analysis of different variants in host genetics studies of COVID-19. In addition, we provide several hypotheses for severe COVID-19 and possible therapeutic targets.


Assuntos
Betacoronavirus , Infecções por Coronavirus/genética , Pandemias , Pneumonia Viral/genética , Adolescente , Adulto , Fatores Etários , Alelos , Infecções por Coronavirus/tratamento farmacológico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno/genética , Humanos , Inflamassomos/genética , Lectinas/genética , Pessoa de Meia-Idade , Modelos Genéticos , Terapia de Alvo Molecular , Mutação , Polimorfismo de Nucleotídeo Único , Síndrome Respiratória Aguda Grave/genética , Transdução de Sinais/genética , Receptor 3 Toll-Like/genética , Receptores Toll-Like/genética , Viroses/genética , Adulto Jovem
15.
PLoS One ; 15(8): e0237752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817626

RESUMO

Pseudomonas aeruginosa remains a leading cause of nosocomial and serious life-threatening infections, and contributes to increased mortality in immunocompromised individuals. P. aeruginosa infection triggers host immune response and often provokes potent inflammatory mediators, which do not necessarily eradicate the causative pathogen. On the other hand, it causes severe airway damage and eventually decreased lung function. Such unfavorable outcomes of inflammatory injury have necessitated the development of novel effective agents that can combat with P. aeruginosa-mediated inflammation. Herein, we investigated the potential of quercetin in regulating P. aeruginosa-induced inflammation, with particular emphasized on the interleukin-1ß (IL-1ß). Our results showed that quercetin exerted the potent inhibitory activity against the production of IL-1ß in macrophages infected by live P. aeruginosa PAO1, without exhibiting cytotoxicity. According to our settings, such the potent inhibitory activity of quercetin was clearly demonstrated through its ability to efficiently inhibit IL-1ß during P. aeruginosa infection, pre- or even post-infection. In addition, quercetin strongly suppressed MAPK signaling pathway by inhibiting phosphorylation of the p38 MAPK and JNK2, and molecular docking study supported well with this observation. Moreover, quercetin reduced the NLRP3 expression and inhibited the P. aeruginosa-mediated cleavage of caspase-1 as well as mature IL-1ß. These results thus indicated that quercetin inhibition of P. aeruginosa-induced IL-1ß production is mediated by suppressing the initial priming step and by inhibiting the NLRP3 inflammasome activation. Taken together, our findings demonstrated the promising regulatory activity of quercetin against IL-1ß production in P. aeruginosa-infected macrophages, and indicated that quercetin has the potential to be effective as a novel therapeutic agent for treatment of P. aeruginosa-induced inflammation.


Assuntos
Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Infecções por Pseudomonas/tratamento farmacológico , Quercetina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Infecções por Pseudomonas/genética , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Transdução de Sinais/efeitos dos fármacos
16.
PLoS Pathog ; 16(8): e1008752, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760121

RESUMO

Members of the family of pyrin and HIN domain containing (PYHIN) proteins play an emerging role in innate immunity. While absent in melanoma 2 (AIM2) acts a cytosolic sensor of non-self DNA and plays a key role in inflammasome assembly, the γ-interferon-inducible protein 16 (IFI16) restricts retroviral gene expression by sequestering the transcription factor Sp1. Here, we show that the remaining two human PYHIN proteins, i.e. myeloid cell nuclear differentiation antigen (MNDA) and pyrin and HIN domain family member 1 (PYHIN1 or IFIX) share this antiretroviral function of IFI16. On average, knock-down of each of these three nuclear PYHIN proteins increased infectious HIV-1 yield from human macrophages by more than an order of magnitude. Similarly, knock-down of IFI16 strongly increased virus transcription and production in primary CD4+ T cells. The N-terminal pyrin domain (PYD) plus linker region containing a nuclear localization signal (NLS) were generally required and sufficient for Sp1 sequestration and anti-HIV-1 activity of IFI16, MNDA and PYHIN1. Replacement of the linker region of AIM2 by the NLS-containing linker of IFI16 resulted in a predominantly nuclear localization and conferred direct antiviral activity to AIM2 while attenuating its ability to form inflammasomes. The reverse change caused nuclear-to-cytoplasmic relocalization of IFI16 and impaired its antiretroviral activity but did not result in inflammasome assembly. We further show that the Zn-finger domain of Sp1 is critical for the interaction with IFI16 supporting that pyrin domains compete with DNA for Sp1 binding. Finally, we found that human PYHIN proteins also inhibit Hepatitis B virus and simian vacuolating virus 40 as well as the LINE-1 retrotransposon. Altogether, our data show that IFI16, PYHIN1 and MNDA restrict HIV-1 and other viral pathogens by interfering with Sp1-dependent gene expression and support an important role of nuclear PYHIN proteins in innate antiviral immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Núcleo Celular/metabolismo , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Macrófagos/imunologia , Proteínas Nucleares/metabolismo , Fator de Transcrição Sp1/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Núcleo Celular/genética , DNA Viral/genética , Células HEK293 , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Células Hep G2 , Humanos , Imunidade Inata/imunologia , Inflamassomos/genética , Inflamassomos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Proteínas Nucleares/genética , Fator de Transcrição Sp1/genética , Replicação Viral
17.
Sci China Life Sci ; 63(9): 1-14, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32613490

RESUMO

NLRs constitute intracellular immune receptors in both plants and animals. Direct or indirect ligand recognition results in formation of oligomeric NLR complexes to mediate immune signaling. Over the past 20 years, rapid progress has been made in our understanding of NLR signaling. Structural and biochemical studies provide insight into molecular basis of autoinhibition, ligand recognition, and resistosome/inflammasome formation of several NLRs. In this review, we summarize these studies focusing on the structural aspect of NLRs. We also discuss the analogies and differences between plant and animal NLRs in their mechanisms of action and how the available knowledge may shed light on the signaling mechanisms of other NLRs.


Assuntos
Proteínas NLR/genética , Proteínas NLR/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Animais , Humanos , Imunidade Inata/genética , Inflamassomos/genética , Modelos Biológicos , Imunidade Vegetal/genética , Proteínas de Plantas/genética , Plantas , Conformação Proteica , Transdução de Sinais , Relação Estrutura-Atividade
18.
Proc Natl Acad Sci U S A ; 117(31): 18832-18839, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32709746

RESUMO

Plant and animal intracellular nucleotide-binding, leucine-rich repeat (NLR) immune receptors detect pathogen-derived molecules and activate defense. Plant NLRs can be divided into several classes based upon their N-terminal signaling domains, including TIR (Toll-like, Interleukin-1 receptor, Resistance protein)- and CC (coiled-coil)-NLRs. Upon ligand detection, mammalian NAIP and NLRC4 NLRs oligomerize, forming an inflammasome that induces proximity of its N-terminal signaling domains. Recently, a plant CC-NLR was revealed to form an inflammasome-like hetero-oligomer. To further investigate plant NLR signaling mechanisms, we fused the N-terminal TIR domain of several plant NLRs to the N terminus of NLRC4. Inflammasome-dependent induced proximity of the TIR domain in planta initiated defense signaling. Thus, induced proximity of a plant TIR domain imposed by oligomerization of a mammalian inflammasome is sufficient to activate authentic plant defense. Ligand detection and inflammasome formation is maintained when the known components of the NLRC4 inflammasome is transferred across kingdoms, indicating that NLRC4 complex can robustly function without any additional mammalian proteins. Additionally, we found NADase activity of a plant TIR domain is necessary for plant defense activation, but NADase activity of a mammalian or a bacterial TIR is not sufficient to activate defense in plants.


Assuntos
Proteínas NLR , Imunidade Vegetal , Proteínas de Plantas , Proteínas Recombinantes de Fusão , Transdução de Sinais , Animais , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Mamíferos , Proteínas NLR/química , Proteínas NLR/genética , Proteínas NLR/imunologia , Proteínas NLR/metabolismo , Imunidade Vegetal/genética , Imunidade Vegetal/imunologia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Domínios Proteicos/genética , Domínios Proteicos/fisiologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
19.
J Stroke Cerebrovasc Dis ; 29(8): 104874, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689633

RESUMO

INTRODUCTION: Previous studies have reported the involvement of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the inflammatory activation and pathophysiology of Ischemic Stroke (IS). Variations in genes encoding the constituent proteins of NLRP3 inflammasome can alter the risk of IS. OBJECTIVE: We investigated the role of the NLRP3 inflammasome in the pathogenesis of IS by establishing associations between combined polymorphisms of caspase recruitment domain-containing protein 8 (CARD8) rs2043211 and NLRP3 rs10754558 and the susceptibility to IS in a Chinese population. METHODS: Single nucleotide polymorphisms (SNPs) in CARD8 rs2043211 and NLRP3 rs10754558 were analyzed using TaqMan SNP genotyping assays in patients with IS (n=234) and healthy controls (n=115). Logistic regression analysis was carried out to evaluate potential interactions between CARD8 and NLRP3. RESULTS: Compared with healthy controls, there were no significant differences in the minor allele frequency (MAF) and the genotype frequency of NLRP3 rs10754558 or CARD8 rs2043211 in patients with IS(P>0.05). After stratification by gender, there was an increased risk for IS in men carrying heterozygous CARD8 rs2043211 when a co-dominant genetic model was applied (P=0.021, OR=3.83[1.22-12.03]). Logistic regression analysis indicated that men carrying both CARD8 rs2043211 AT and NLRP3 rs10754558 CG had a significantly higher risk of IS (P=0.046, OR=7.116[1.033-49.044]). CONCLUSIONS: Nucleotide variations in the genes encoding NLRP3 inflammasome proteins may be important to IS, and men carrying CARD8 rs2043211 and NLRP3 rs10754558, both heterozygous, confer a higher risk of IS.


Assuntos
Isquemia Encefálica/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etnologia , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene , Interação Gene-Ambiente , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Fatores Sexuais , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etnologia
20.
Clin Immunol ; 217: 108490, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32492478
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