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1.
BMC Complement Altern Med ; 19(1): 216, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412862

RESUMO

BACKGROUND: Breast cancer is still the most common malignant tumor that threatens the female's life in the world, especially triple-negative breast cancer (TNBC), one of the most difficult subtypes. Lack of targeted therapies brings about urgent demand for novel treatments. In this study we aim to investigate the anti-tumor activity of Berberine (BBR), a Chinese plant-derived alkaloid, against the TNBC cell line MDA-MB-231 and elucidate its mechanism referring to anti-inflammation. METHODS: Cell inhibition rate was measured by Cell Proliferation Assay, the cytotoxic effects was detected by Lactate dehydrogenase (LDH) leakage assay, the colony formation and migration potential were evaluated by colony formation assay and wound healing assay, the release of inflammatory cytokines was detected by EMD multifactor detection, and alterations of proteins and genes related to the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway were analyzed using western blotting and real-time Polymerase Chain Reaction (PCR). RESULTS: BBR reduce the viability of MDA-MB-231 cells and increased the release of LDH from the cells in a dose-dependent manner, with and inhibition of colony formation potential and migration of the cells. BBR also caused a marked reduction in the secretion of proinflammatory cytokines, Interleukin-1α (IL-1α), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Besides, a down-regulated behavior was observed with the expression of P2X purinoceptor 7 (P2X7), NLRP3, pro-caspase-1, apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1 p20, Interleukin-18 (IL-18), IL-1ß proteins and NLRP3, Caspase-1 and ASC mRNAs in the NLRP3 inflammasome cascade. CONCLUSIONS: Our results confirmed that BBR can effectively affect both tumor outgrowth and spontaneous metastasis in TNBC, and that we identified a new mechanism associated with inhibition the NLRP3 inflammasome pathway, suggesting its potential therapeutic relevance in clinical use.


Assuntos
Berberina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Apoptose/efeitos dos fármacos , Caspase 1/genética , Caspase 1/imunologia , Feminino , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/fisiopatologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
2.
Cell Physiol Biochem ; 53(2): 355-365, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31385664

RESUMO

BACKGROUND/AIMS: NLRP3 inflammasome activation has been reported to be an early mechanism responsible for glomerular inflammation and injury in obese mice. However, the precise mechanism of obesity-induced NLRP3 inflammasome activation remains unknown. The present study explored whether adipokine visfatin mediates obesity-induced NLRP3 inflammasome activation and consequent podocyte injury. METHODS: Inflammasome formation and immunofluorescence expressions were quantified by confocal microscopy. Caspase-activity, IL-1ß production and VEGF concentrations were measured by ELISA. RESULTS: Confocal microscopic analysis showed that visfatin treatment increased the colocalization of Nlrp3 with Asc or Nlrp3 with caspase-1 in podocytes indicating the formation of NLRP3 inflammasomes. This visfatin-induced NLRP3 inflammasome formation was abolished by pretreatment of podocytes with Asc siRNA. Correspondingly, visfatin treatment significantly increased the caspase-1 activity and IL-1ß production in podocytes, which was significantly attenuated by Asc siRNA transfection. Further RT-PCR and confocal microscopic analysis demonstrated that visfatin treatment significantly decreased the podocin expression (podocyte damage). Podocytes pretreatment with Asc siRNA or caspase-1 inhibitor, WEHD attenuated this visfatin-induced podocin reduction. Furthermore, Asc siRNA transfection was found to preserve podocyte morphology by maintaining the distinct arrangement of F-actin fibers normally lost in response to visfatin. It also prevented podocyte dysfunction by restoring visfatin-induced suppression of VEGF production and secretion. CONCLUSION: Visfatin induces NLRP3 inflammasome activation in podocytes and thereby resulting in podocyte injury.


Assuntos
Adipocinas/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Nicotinamida Fosforribosiltransferase/imunologia , Podócitos/imunologia , Animais , Linhagem Celular , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Camundongos , Obesidade/imunologia , Obesidade/patologia , Podócitos/citologia , Podócitos/patologia , Fator A de Crescimento do Endotélio Vascular/imunologia
3.
Life Sci ; 234: 116773, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31422095

RESUMO

AIMS: NLRP3 inflammasome activation is essential for the development and prognosis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho is suggested to modulate tissue inflammatory responses. The aim of the present study was to examine the protective effects of Klotho on DCM. MAIN METHODS: A streptozotocin-induced diabetes mouse model was established to assess the effects of Klotho in vivo, which was administered for 12 weeks. The characteristics of type 1 DCM were evaluated by general status, echocardiography, and histopathology. The expression of associated factors was determined by RT-qPCR and western blotting. Parallel experiments to determine the molecular mechanism through which Klotho prevents DCM were performed using H9C2 cells exposed to high glucose (35 mM). KEY FINDINGS: Diabetes-induced increases in serum creatine kinase-muscle/brain and lactate dehydrogenase levels, cardiac fibrosis, cardiomyocyte apoptosis, and cardiac dysfunction were ameliorated by Klotho. Additionally, Klotho suppressed TXNIP expression, NLRP3 inflammasome activation, and expression of the inflammatory cytokines tumor necrosis factor ɑ, interleukin-1ß, and interleukin-18 in vivo. In high glucose-cultured cardiomyocytes, Klotho and N-acetylcysteine significantly downregulated intracellular reactive oxygen species generation and TXNIP/NLRP3 inflammasome activation. Pretreatment of H9C2 cells with NLRP3 siRNA or Klotho prevented high glucose-induced inflammation and apoptosis in H9C2 cells. SIGNIFICANCE: Our results demonstrate that the protective effect of Klotho on diabetes-induced cardiac injury is associated with inhibition of the NLRP3 inflammasome pathway, suggesting its therapeutic potential for DCM.


Assuntos
Diabetes Mellitus Experimental/imunologia , Cardiomiopatias Diabéticas/imunologia , Glucuronidase/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Cardiotônicos/imunologia , Cardiotônicos/uso terapêutico , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Glucuronidase/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Ratos , Espécies Reativas de Oxigênio/imunologia
4.
Mol Immunol ; 114: 41-48, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31336248

RESUMO

Viral myocarditis, mainly caused by enteroviruses specially coxsackievirus B3 (CVB3) infection, is a common clinical cardiovascular disease and characterized by cardiac massive inflammation. Our previous study showed that CVB3-induced myocardial NLRP3 contributed to the development of viral myocarditis. In this study, we found that beside of being up-regulated in myocardiocytes, NLPR3 was also obviously increased in the cardiac infiltrating macrophages. While whether this accumulated NLRP3 influences, macrophage inflammatory responses remains unknown. By adoptive transfer assays, we found that mice receiving NLRP3 up-regulated macrophages showed much more abundant cardiac IL-1ß production and more severe myocardial inflammation, while those receiving NLRP3 down-regulated macrophages showed much less IL-1ß production and milder myocarditis, indicating that NLRP3 up-regulated macrophages played a pathological role in CVB3-induced myocarditis. In addition, we further found that it was CVB3 capsid proteins VP1 (predominant) and VP2, but not viral RNAs, robustly triggered macrophage NLRP3 up-regulation and activation. Our study demonstrated macrophage NLRP3 inflammasome could be efficiently be activated by CVB3 capsid proteins, and contributed to the pathogenesis of viral myocarditis. It might provide some clues to the development of new therapeutic strategies based on macrophage NLRP3 modulation.


Assuntos
Proteínas do Capsídeo/imunologia , Infecções por Coxsackievirus/imunologia , Enterovirus/imunologia , Inflamassomos/imunologia , Macrófagos/imunologia , Miocardite/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Transferência Adotiva/métodos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Regulação para Baixo/imunologia , Células HeLa , Coração/virologia , Humanos , Inflamação/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/virologia , Miocárdio/imunologia , Células RAW 264.7 , Regulação para Cima/imunologia , Viroses/imunologia , Viroses/virologia
5.
Vet Res ; 50(1): 53, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300043

RESUMO

Our previous studies demonstrated that matrine directly acts on the replication process of porcine reproductive and respiratory syndrome virus (PRRSV). Matrine inhibits viral replication and is also associated with the NF-κB signalling pathway. These results suggest that matrine has antiviral and anti-inflammatory effects. However, the specific anti-inflammatory mechanism of matrine is still unclear. In this study, we investigated the anti-IL-1ß mechanism of matrine, as IL-1ß is a major inflammatory cytokine, in porcine alveolar macrophages (PAMs) stimulated with 4 µg PRRSV 5'-untranslated region (UTR) RNA and 1 µg/mL LPS. After 5'UTR RNA and LPS co-stimulation of PAMs for 12 h, the expression of IL-1ß, IL-6, IL-8 and TNF-α was significantly increased. The results also showed that co-stimulation induced the expression of MyD88, and activated the NF-κB signalling pathway and NLRP3 inflammasome. Furthermore, matrine treatment downregulated MyD88, NLRP3 and caspase-1 expression, inhibited ASC speck formation, suppressed IκBα phosphorylation, and interfered with the translocation of NF-κB from the cytoplasm to the nucleus. These results suggest that matrine plays an important role in PAMs co-stimulated with PRRSV 5'UTR RNA and LPS via its effect on NF-κB and the NLRP3 inflammasome. These findings lay the foundation for the exploration of the clinical application of matrine in PRRSV disease.


Assuntos
Alcaloides/farmacologia , Inflamassomos/imunologia , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , NF-kappa B/imunologia , Quinolizinas/farmacologia , Animais , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , RNA Viral/genética , Transdução de Sinais/imunologia , Sus scrofa , Transfecção/veterinária
6.
PLoS Pathog ; 15(6): e1007795, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170267

RESUMO

Infection with the Streptococcus suis (S. suis) epidemic strain can cause Streptococcal toxic shock-like syndrome (STSLS), which is characterized by a cytokine storm, dysfunction of multiple organs and a high incidence of mortality despite adequate treatment. Despite some progress concerning the contribution of the inflammatory response to STSLS, the precise mechanism underlying STSLS development remains elusive. Here, we use a murine model to demonstrate that caspase-1 activity is critical for STSLS development. Furthermore, we show that inflammasome activation by S. suis is mainly dependent on NLRP3 but not on NLRP1, AIM2 or NLRC4. The important role of NLRP3 activation in STSLS is further confirmed in vivo with the NLRP3 inhibitor MCC950 and nlrp3-knockout mice. By comparison of WT strain with isogenic strains with mutation of various virulence genes for inflammasome activation, Suilysin is essential for inflammasome activation, which is dependent on the membrane perforation activity to cause cytosolic K+ efflux. Moreover, the mutant strain msly (P353L) expressing mutagenic SLY without hemolytic activity was unable to activate the inflammasome and does not cause STSLS. In summary, we demonstrate that the high membrane perforation activity of the epidemic strain induces a high level of NLRP3 inflammasome activation, which is essential for the development of the cytokine storm and multi-organ dysfunction in STSLS and suggests NLRP3 inflammasome as an attractive target for the treatment of STSLS.


Assuntos
Citocinas/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Choque Séptico/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus suis/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Citocinas/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Inflamassomos/genética , Camundongos , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Choque Séptico/genética , Choque Séptico/patologia , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/patologia
7.
J Neuroinflammation ; 16(1): 121, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174550

RESUMO

The NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome is a member of the NLR family of innate immune cell sensors. These are crucial regulators of cytokine secretions, which promote ischemic cell death and insulin resistance. This review summarizes recent progress regarding the NLRP3 inflammasome as a potential treatment for ischemic stroke in patients with diabetes, two complicated diseases that often occur together. Stroke worsens glucose metabolism abnormalities, and the outcomes after stroke are more serious for diabetic patients compared with those without diabetes. Inflammation contributes to organ injury after ischemic stroke and diabetes. Recent research has focused on inhibiting the activation of inflammasomes and thus reducing the maturation of proinflammatory cytokines such as interleukin (IL)-1ß and IL-18. Studies suggest that inhibition of NLRP3 prevents or alleviates both ischemic stroke and diabetes. Targeting against the assembly and activity of the NLRP3 inflammasome is a potential and novel therapy for inflammasome-associated diseases, including ischemic stroke concomitant with diabetes.


Assuntos
Isquemia Encefálica/metabolismo , Complicações do Diabetes/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/imunologia , Complicações do Diabetes/imunologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/imunologia
8.
Free Radic Res ; 53(7): 780-790, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185753

RESUMO

Oxidative stress is a key mechanism underlying ozone-induced lung injury. Mitochondria can release mitochondrial reactive oxidative species (mtROS), which may lead to the activation of NLRP3 inflammasome. The goal of this study was to examine the roles of mtROS and NLRP3 inflammasome in acute ozone-induced airway inflammation and bronchial hyperresponsiveness (BHR). C57/BL6 mice (n = 8/group) were intraperitoneally treated with vehicle (phosphate buffered saline, PBS) or mitoTEMPO (mtROS inhibitor, 20 mg/kg), or orally treated with VX-765 (caspse-1 inhibitor, 100 mg/kg) 1 h before the ozone exposure (2.5 ppm, 3 h). Compared to the PBS-treated ozone-exposed mice, mitoTEMPO reduced the level of total malondialdehyde in bronchoalveolar lavage (BAL) fluid and increased the expression of mitochondrial complexes II and IV in the lung 24 h after single ozone exposure. VX-765 inhibited ozone-induced BHR, BAL total cells including neutrophils and eosinophils, and BAL inflammatory cytokines including IL-1α, IL-1ß, KC, and IL-6. Both mitoTEMPO and VX-765 reduced ozone-induced mtROS and inhibited capase-1 activity in lung tissue whilst VX-765 further inhibited DRP1 and MFF expression, increased MFN2 expression, and down-regulated caspase-1 expression in the lung tissue. These results indicate that acute ozone exposure induces mitochondrial dysfunction and NLRP3 inflammasome activation, while the latter has a critical role in the pathogenesis of ozone-induced airway inflammation and BHR.


Assuntos
Hiper-Reatividade Brônquica/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Hiper-Reatividade Brônquica/imunologia , Modelos Animais de Doenças , Inflamassomos/imunologia , Inflamação/imunologia , Masculino , Camundongos , Mitocôndrias/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Espécies Reativas de Oxigênio/imunologia
9.
PLoS Pathog ; 15(6): e1007880, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31211814

RESUMO

The largest ever recorded epidemic of the Chikungunya virus (CHIKV) broke out in 2004 and affected four continents. Acute symptomatic infections are typically associated with the onset of fever and often debilitating polyarthralgia/polyarthritis. In this study, a systems biology approach was adopted to analyze the blood transcriptomes of adults acutely infected with the CHIKV. Gene signatures that were associated with viral RNA levels and the onset of symptoms were identified. Among these genes, the putative role of the Eukaryotic Initiation Factor (eIF) family genes and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3A) in the CHIKV replication process were displayed. We further compared these signatures with signatures induced by the Dengue virus infection and rheumatoid arthritis. Finally, we demonstrated that the CHIKV in vitro infection of murine bone marrow-derived macrophages induced IL-1 beta production in a mechanism that is significantly dependent on the inflammasome NLRP3 activation. The observations provided valuable insights into virus-host interactions during the acute phase and can be instrumental in the investigation of new and effective therapeutic interventions.


Assuntos
Artrite/imunologia , Febre de Chikungunya/imunologia , Vírus Chikungunya/fisiologia , Citidina Desaminase/imunologia , Proteínas/imunologia , Replicação Viral/imunologia , Adulto , Animais , Artrite/patologia , Artrite/virologia , Febre de Chikungunya/patologia , Vírus da Dengue/imunologia , Vírus da Dengue/patogenicidade , Feminino , Febre/imunologia , Febre/patologia , Febre/virologia , Seguimentos , Humanos , Interleucina-1beta/imunologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia
10.
Nat Commun ; 10(1): 2711, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221993

RESUMO

Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.


Assuntos
Inflamassomos/imunologia , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Sepse/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Seguimentos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamassomos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/imunologia , Monócitos/citologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptores Purinérgicos P2X7/imunologia , Sepse/sangue , Sepse/microbiologia , Sepse/mortalidade , Regulação para Cima/imunologia
11.
Prostate ; 79(12): 1439-1449, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31233226

RESUMO

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent disease of the urogenital system. Alcohol has been reported to be closely related to CP/CPPS. Thus, we intended to verify the role of alcohol in CP/CPPS and determine the underlying mechanism. METHODS: We induced experimental autoimmune prostatitis (EAP) mouse model by intradermally injecting a mixture of prostate antigens (PAgs) and complete Freund's adjuvant on days 0 and 28. Mice were treated with alcohol (control-alcohol and EAP-alcohol groups) or vehicle (control-vehicle, and EAP-vehicle groups) from day 32 to 42. Forty-two days after PAg injection, the pathological appearance of the prostate tissues was evaluated, and histological analyses of the prostate were performed. Chronic pelvic pain was assessed by applying von Frey filaments to the lower abdomen. Proinflammatory cytokines were detected by enzyme-linked immunosorbent assay tests. Then, we explored the effects of the NLRP3 inhibitor MCC950 on chronic pelvic pain and prostatic inflammation in this model. RESULTS: Histological analyses showed diffuse inflammation in the stromal tissues that were characterized by severe infiltration of neutrophils and mononuclear cells in mice in the EAP-alcohol group compared with EAP-vehicle group. Chronic pain tests showed that the response frequency was significantly increased using a von Frey filament at forces of 0.4, 1.0, and 4.0 g in EAP-alcohol group compared with EAP-vehicle (P < .05). The levels of proinflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-17, and IL-1ß were all significantly elevated in EAP-alcohol group compared with the EAP-vehicle group (P < .05). However, between the control-alcohol and control-vehicle groups, chronic pain tests, histological assays, and cytokine determinations showed no differences. Furthermore, our results demonstrated that MCC950 could decrease the expression level of NLRP3 inflammasome-related proteins including NLRP3, ASC, and caspase-1. The chronic pain tests, histological assays, and cytokine determinations showed that MCC950 could attenuate the chronic pain and prostatic inflammation through the inhibition of the NLRP3 inflammasome. CONCLUSIONS: This study indicated that alcohol could aggravate the severity of prostatic inflammation in EAP model though activating the NLRP3 inflammasome. Furthermore, the role of MCC950 in inhibiting NLRP3 inflammasome and decreasing IL-1ß secretion to alleviate EAP severity may show that it is a promising therapeutic agent for CP/CPPS.


Assuntos
Doenças Autoimunes/imunologia , Etanol/farmacologia , Dor Pélvica/imunologia , Próstata/imunologia , Prostatite/imunologia , Álcoois/farmacologia , Animais , Doenças Autoimunes/patologia , Dor Crônica/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Furanos/farmacologia , Inflamassomos/imunologia , Inflamação/imunologia , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Próstata/efeitos dos fármacos , Próstata/patologia , Prostatite/patologia , Ratos , Ratos Wistar , Sulfonamidas/farmacologia
12.
PLoS Pathog ; 15(6): e1007887, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31233552

RESUMO

Leishmaniasis is a neglected tropical disease affecting millions of individuals worldwide. P2X7 receptor has been linked to the elimination of Leishmania amazonensis. Biological responses evoked by P2X7 receptor activation have been well-documented, including apoptosis, phagocytosis, cytokine release, such as IL-1ß. It was demonstrated that NLRP3 inflammasome activation and IL-1ß signaling participated in resistance against L. amazonensis. Furthermore, our group has shown that L. amazonensis elimination through P2X7 receptor activation depended on leukotriene B4 (LTB4) production and release. Therefore, we investigated whether L. amazonensis elimination by P2X7 receptor and LTB4 involved NLRP3 inflammasome activation and IL-1ß signaling. We showed that macrophages from NLRP3-/-, ASC-/-, Casp-1/11-/-, gp91phox-/- , and IL-1R-/- mice treated with ATP or LTB4 did not decrease parasitic load as was observed in WT mice. When ASC-/- macrophages were treated with exogenous IL-1ß, parasite killing was noted, however, we did not see parasitic load reduction in IL-1R-/- macrophages. Similarly, macrophages from P2X7 receptor-deficient mice treated with IL-1ß also showed decreased parasitic load. In addition, when we infected Casp-11-/- macrophages, neither ATP nor LTB4 were able to reduce parasitic load, and Casp-11-/- mice were more susceptible to L. amazonensis infection than were WT mice. Furthermore, P2X7-/- L. amazonensis-infected mice locally treated with exogenous LTB4 showed resistance to infection, characterized by lower parasite load and smaller lesions compared to untreated P2X7-/- mice. A similar observation was noted when infected P2X7-/- mice were treated with IL-1ß, i.e., lower parasite load and smaller lesions compared to P2X7-/- mice. These data suggested that L. amazonensis elimination mediated by P2X7 receptor and LTB4 was dependent on non-canonical NLRP3 inflammasome activation, ROS production, and IL-1ß signaling.


Assuntos
Inflamassomos/imunologia , Interleucina-1beta/imunologia , Leishmania/imunologia , Leishmaniose/imunologia , Leucotrieno B4/imunologia , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptores Purinérgicos P2X7/imunologia , Transdução de Sinais/imunologia , Animais , Inflamassomos/genética , Interleucina-1beta/genética , Leishmaniose/genética , Leishmaniose/patologia , Leucotrieno B4/genética , Macrófagos/parasitologia , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptores Purinérgicos P2X7/genética , Transdução de Sinais/genética
13.
Int Immunopharmacol ; 73: 312-320, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129418

RESUMO

Progressive lung injury and pulmonary inflammation can be induced by an intraperitoneal injection of lipopolysaccharide (LPS). Interleukin-1ß (IL-1ß) is a key pro-inflammatory cytokine that can further exaggerate inflammation, which is cleaved and activated by the NALP3 inflammasome. Although the nuclear receptor Rev-erbα attenuates the level of LPS-induced pulmonary inflammation, the mechanism remains unclear. In this study, we investigated the influence of LPS-induced production of IL-1ß and Rev-erbα on the development of lung inflammation. Herein, we demonstrate that Rev-erbα reduces IL-1ß production and lung injury following an intraperitoneal injection of LPS, which is dependent on the NF-κB/NALP3 pathway. Thus, Rev-erbα is able to decrease the extent of acute lung injury by regulating IL-1ß production. This mechanism may represent a potential novel therapeutic approach for lung injury.


Assuntos
Lesão Pulmonar Aguda/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Glicina/análogos & derivados , Glicina/farmacologia , Interleucina-1beta/imunologia , Isoquinolinas/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células RAW 264.7 , Transdução de Sinais , Tiofenos/farmacologia
14.
Inflamm Res ; 68(6): 511-523, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31037316

RESUMO

OBJECTIVE: Chicoric acid (CA) is a natural product with promising antioxidant and anti-inflammatory properties; however, its protective effect on methotrexate (MTX)-induced acute kidney injury (AKI) hasn't been reported. We investigated the effect of CA on MTX-induced AKI in rats, pointing to the role of NF-κB/NLRP3 inflammasome and Nrf2/ARE/HO-1 signaling. MATERIALS AND METHODS: Wistar rats received 25 mg/kg and 50 mg/kg CA for 15 days and a single injection of MTX at day 16. At day 19, the rats were killed, and samples were collected for analyses. RESULTS: MTX induced a significant increase in serum creatinine and urea, and kidney Kim-1, reactive oxygen species (ROS), malondialdehyde and nitric oxide levels. In addition, MTX-induced rats exhibited multiple histopathological alterations, diminished antioxidant defenses, and decreased expression of Nrf2, NQO-1 and HO-1. CA prevented histological alterations, ameliorated kidney function markers, attenuated ROS production and lipid peroxidation, and boosted antioxidant defenses. CA suppressed the expression of NF-κB p65, NLRP3, caspase-1 and IL-1ß in the kidney of MTX-induced rats. Furthermore, CA inhibited MTX-induced apoptosis as evidenced by the decreased expression of BAX and caspase-3, and increased Bcl-2 gene expression. CONCLUSIONS: CA prevented MTX-induced AKI through activation of Nrf2/ARE/HO-1 signaling, and attenuation of ROS-induced activation of NF-κB/NLRP3 inflammasome signaling.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/imunologia , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Succinatos/farmacologia , Succinatos/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Elementos de Resposta Antioxidante/imunologia , Apoptose/efeitos dos fármacos , Antagonistas do Ácido Fólico , Heme Oxigenase (Desciclizante)/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Masculino , Metotrexato , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ratos Wistar , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
15.
Immunopharmacol Immunotoxicol ; 41(2): 277-284, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31084401

RESUMO

Objectives: Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints, which is associated with the rise of serum urate content. This study aims to investigate the therapeutic effect of Madecassoside on gouty arthritis and hyperuricemia. Methods: DBA/1 mice were intradermally injected with MSU to stimulate joint inflammation or intraperitoneally injected with MSU to trigger peritonitis. Moreover, ICR mice were exposed to potassium oxonate to stimulate hyperuricemia. Results: Madecassoside repressed MSU-triggered pad swelling, joint 99mTc uptake, and joint inflammation in DBA/1 mice with gouty arthritis. Neutrophil infiltration and IL-1ß & IL-6 & MCP-1 secretion was also alleviated in lavage fluids from DBA/1 mice with peritonitis due to Madecassoside treatment. Furthermore, Madecassoside decreased MSU-induced neutrophil cytosolic factor 1, caspase-1 and NLRP3 expression in mice with peritoneal inflammation. In hyperuricemic mice, Madecassoside improved renal dysfunction. Serum uric acid, BUN, and creatinine were down-regulated by Madecassoside. Conclusion: These findings indicate that Madecassoside has potential to ameliorate inflammation in both acute gouty arthritis model and peritonitis model, probably via regulating IL-1ß and NLRP3 expression. Practical point: Madecassoside also exhibited a urate-lowering effect and a renal protective effect in hyperuricemic mice.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Gotosa/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Triterpenos/farmacologia , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/imunologia , Citocinas/imunologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/imunologia , Hiperuricemia/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos ICR , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Peritonite/induzido quimicamente , Peritonite/imunologia , Peritonite/patologia , Ácido Úrico/toxicidade , ômega-Cloroacetofenona
16.
Food Funct ; 10(5): 2970-2985, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31074472

RESUMO

Obesity-related renal disease is related to caloric excess promoting deleterious cellular responses. However, a full understanding of the molecular mechanisms involved in progressive kidney disease, as well as a therapeutic strategy, is still absent. Fisetin (FIS), as a natural flavonoid, possesses various bioactivities in a number of disease models. However, its role in obesity-associated kidney injury is still unclear and requires elucidation. In our study, an obesity animal model was established using C57BL/6 mice fed with a normal chow diet (NCD) or high fat diet (HFD) for 16 weeks with or without FIS administration (20, 40 or 80 mg kg-1). Our results indicated that chronic HFD feeding led to a significant body weight gain in mice compared to the normal control group, accompanied by a marked insulin resistance and glucose intolerance, whereas FIS treatment exerted prominently protective effects. In addition, FIS significantly attenuated HFD-induced histological alterations in renal tissue samples. Moreover, FIS treatment down-regulated expression of kidney injury molecule-1 (KIM-1), and up-regulated nephrin and podocin expression levels in the kidneys of HFD-fed mice, improving their renal dysfunction. After HFD feeding, mice treated with FIS exhibited a decrease in phosphorylated IRS1Ser307, and an increase in phosphorylated glycogen synthase kinase 1 (IRS1Tyr608), AKT, forkhead box protein O1 (FOXO1) and glycogen synthase kinase (GSK)-3ß. Furthermore, FIS administration markedly restrained the inflammatory response in the kidneys of HFD-challenged mice, as evidenced by the reduced pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-1ß and IL-18, which was attributed to the blockage of nuclear factor κB (NF-κB) signaling. Importantly, FIS-treated obese mice exerted a remarkable decrease in RIP3 expressions in the kidneys compared to obese mice in the absence of FIS, along with an evident reduction in the NOD-like receptor protein 3 (NLRP3), an apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1. The protective effects of FIS against HFD-induced renal injury were verified in vitro using palmitate (PAL)-treated HK2 cells, an immortalized proximal tubule epithelial cell line from the adult human kidney. In summary, our results supported the notion that FIS functions as a promising agent to improve insulin resistance and inflammatory response against metabolic stress-induced renal injury.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Flavonoides/administração & dosagem , Resistência à Insulina , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/imunologia , Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/imunologia , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 1 do Vírus da Hepatite A/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
17.
Int Immunopharmacol ; 73: 146-155, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100709

RESUMO

Activation of NOD-like receptor (NLR) family and pyrin domain containing 3 (NLRP3) inflammasome contributes to inflammation and may lead to atherosclerosis. The NLRP3 inflammasome as a molecular platform regulates the activation of ATP signaling, K+ efflux, cathepsin-B activity, lysosomal function and pro-inflammatory cytokines (i.e. IL-1ß and IL-18). Statins has been widely prescribed for the treatment of hyperlipidemia and cardiovascular diseases. In addition to lipid-lowering effect, statins have immunomodulatory, anti-inflammatory, antioxidant and antiapoptotic functions. An increasing number of studies indicated NLRP3 inflammasome and their downstream mediators as important targets for statin drugs in inflammatory diseases. In this review, we discussed different aspect of the NLRP3 inflammasome signaling pathways and focused on the effect of statin drugs on NLRP3 inflammasomes in association to atherosclerosis in order to elucidate possible targets for future research and clinical settings.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Humanos
18.
Inflamm Res ; 68(7): 597-611, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31119302

RESUMO

OBJECTIVE: The present study was undertaken to validate whether TNF-α and calreticulin (CRT) serve as dual signaling to activate nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and HUVECs. The effect of human antigen R (HuR) in NLRP3 inflammasome activation was also explored in RA FLS. METHODS: Immunofluorescence was used to determine the expression of NLRP3 and adaptor protein apoptosis associated speck-like protein containing a CARD (ASC) in RA synovial tissue and HuR location in RA FLS. Western blot and quantitative real-time PCR were employed to measure the priming effect of NLRP3 inflammasome in cells and HuR expression in synovial tissue. The concentrations of IL-1ß and IL-18 were detected by enzyme linked immunosorbent assay. Immunohistochemistry was used to visualize the expression of HuR in synovial tissue. HuR knockdown in RA FLS was achieved by siRNA-mediated gene silencing. RESULTS: Higher expression of NLRP3 and ASC in RA synovial tissue than those in osteoarthritis was detected. The staining of NLRP3, ASC and cleaved IL-1ß were observed in FLS and vascular endothelial cells in RA synovium. Expression of NLRP3 and pro-IL-1ß in RA FLS and HUVECs treated with TNF-α was increased. The pro-IL-18 expression was also enhanced in HUVECs, but not in RA FLS. TNF-α/CRT dual stimulation of cells gave rise to caspase-1 p20 expression and the secretion of IL-1ß. The secreted IL-18 was also elevated in HUVECs but not in RA FLS. HuR expression was significantly elevated in RA synovial tissue. TNF-α initiated the nucleocytoplasmic shuttling of HuR in both FLS and HUVECs. The knockdown of HuR in FLS incubated with TNF-α led to reduced caspase-1 p20 protein expression and further resulted in decreased secretion of IL-1ß in the presence of CRT. CONCLUSIONS: TNF-α/CRT dual signaling induced NLRP3 inflammasome activation, which could be suppressed by HuR knockdown presumably due to the block of HuR translocating from nucleus to cytoplasma.


Assuntos
Artrite Reumatoide/imunologia , Calreticulina/imunologia , Proteína Semelhante a ELAV 1/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fator de Necrose Tumoral alfa/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Transdução de Sinais , Membrana Sinovial/imunologia , Sinoviócitos/imunologia
19.
Curr Top Microbiol Immunol ; 421: 267-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123893

RESUMO

Inflammasome-controlled transcription and subsequent cleavage-mediated activation of mature IL-1ß and IL-18 cytokines exemplify a crucial innate immune mechanism to combat intruding pathogens. Helicobacter pylori represents a predominant persistent infection in humans, affecting approximately half of the population worldwide, and is associated with the development of chronic gastritis, peptic ulcer disease, and gastric cancer. Studies in knockout mice have demonstrated that the pro-inflammatory cytokine IL-1ß plays a central role in gastric tumorigenesis. Infection by H. pylori was recently reported to stimulate the inflammasome both in cells of the mouse and human immune systems. Using mouse models and in vitro cultured cell systems, the bacterial pathogenicity factors and molecular mechanisms of inflammasome activation have been analyzed. On the one hand, it appears that H. pylori-stimulated IL-1ß production is triggered by engagement of the immune receptors TLR2 and NLRP3, and caspase-1. On the other hand, microRNA hsa-miR-223-3p is induced by the bacteria, which controls the expression of NLRP3. This regulating effect by H. pylori on microRNA expression was also described for more than 60 additionally identified microRNAs, indicating a prominent role for inflammatory and other responses. Besides TLR2, TLR9 becomes activated by H. pylori DNA and further TLR10 stimulated by the bacteria induce the secretion of IL-8 and TNF, respectively. Interestingly, TLR-dependent pathways can accelerate both pro- and anti-inflammatory responses during H. pylori infection. Balancing from a pro-inflammation to anti-inflammation phenotype results in a reduction in immune attack, allowing H. pylori to persistently colonize and to survive in the gastric niche. In this chapter, we will pinpoint the role of H. pylori in TLR- and NLRP3 inflammasome-dependent signaling together with the differential functions of pro- and anti-inflammatory cytokines. Moreover, the impact of microRNAs on H. pylori-host interaction will be discussed, and its role in resolution of infection versus chronic infection, as well as in gastric disease development.


Assuntos
Infecções por Helicobacter/genética , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Inflamassomos/metabolismo , Inflamação/microbiologia , MicroRNAs/biossíntese , Animais , Caspase 1/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptor 2 Toll-Like/imunologia , Receptor 2 Toll-Like/metabolismo
20.
Int Immunopharmacol ; 73: 379-388, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132733

RESUMO

Previous studies reported that L-fucose had anti-inflammatory effects in respiratory and cutaneous system. However, the effect of L-fucose on colitis and the underlying mechanism is poorly understood. We studied the anti-inflammatory effects of L-fucose on Dextran sulfate sodium (DSS)-induced acute colitis in vivo and on LPS/ATP-induced bone marrow derived macrophages (BMDMs) damage in vitro. Our results show that L-fucose significantly alleviated weight loss and disease activity index (DAI) scores in colitis and reduced the infiltration of macrophages and neutrophils. In addition, L-fucose can inhibit macrophage M1 polarization, inactivate the NLRP3 inflammasome and reduce the release of TNFα, IL1ß, IL6 pro-inflammatory cytokines. In vitro studies showed that L-fucose ameliorated cell damage resulting from the administration of LPS with ATP in BMDMs, inhibited NLRP3 inflammasome activation and reduced the release of corresponding pro-inflammatory cytokines. Finally, L-fucose can inhibit the expression of p-NF-kB in vivo and in vitro. Overall, our results show that L-fucose can attenuate colitis by inhibiting macrophage M1 polarization, inhibiting NLRP3 inflammasome and NF-kB activation, and down-regulation of pro-inflammatory cytokines.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Fucose/uso terapêutico , Doença Aguda , Animais , Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Citocinas/genética , Citocinas/imunologia , Sulfato de Dextrana , Fucose/farmacologia , Inflamassomos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia
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