Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 357
Filtrar
1.
Molecules ; 26(20)2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34684819

RESUMO

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


Assuntos
Berberina/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Humanos , Inflamassomos/química , Inflamação/metabolismo , Doenças Metabólicas/tratamento farmacológico , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/química , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Compostos Fitoquímicos/farmacologia , Fitoterapia , Transdução de Sinais/efeitos dos fármacos
2.
Molecules ; 26(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684784

RESUMO

This work investigated the preparation, characterization, antioxidant, and anti-inflammation capacities of Flammulina velutipes polyphenols (FVP) and fermented FVP (FFVP). The results revealed that the new syringic acid, accounting for 22.22%, was obtained after fermentation (FFVP). FFVP exhibits higher antioxidant and anti-inflammation activities than FVP, enhancing cell viability and phagocytosis, inhibiting the secretion of NO and ROS, and reducing the inflammatory response of RAW264.7 cells. This study revealed that FFVP provides a theoretical reference for in-depth study of its regulatory mechanisms and further development of functional antioxidants that are applicable in the food and health industry.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Flammulina/química , Polifenóis/química , Polifenóis/farmacologia , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Fermentação , Inflamassomos/antagonistas & inibidores , Camundongos , Microscopia Eletrônica de Varredura , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Life Sci ; 285: 119974, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34560082

RESUMO

AIMS: Chemical renal toxicity is common and has limited therapeutic interventions. The NLRP3 inhibitor dapansutrile (DAPA) undergoes clinical phase II trials and it shows promising beneficial effects in various inflammatory diseases. The current study aims at evaluating the effect of DAPA on folic acid (FA) induced acute kidney injury (AKI) and its possible transition to chronic injury. MATERIALS AND METHODS: Two treatment protocols were studied depending on DAPA injection timing. A prophylactic protocol involving the injection of DAPA (0.2 mg/kg) daily for seven days before FA challenge and a therapeutic protocol where DAPA was injected after FA. Each protocol included four groups of rats: control group, DAPA group, FA group and DAPA+FA group. Serum creatinine, urea and uric acid were measured. Also, kidney injury, necrosis and fibrosis percentage in addition to infiltration of CD68 positive cells were evaluated. Activation markers of inflammasome and the expression of Ki-67 and LC-3 were measured. KEY FINDINGS: Results showed an improvement in renal tissue integrity and a significant decrease in kidney function biomarkers, caspase-1, IL-1ß and IL-18 by DAPA injection (p < 0.05). In addition, DAPA decreased the proliferation marker Ki-67 and the autophagic marker LC-3 (p < 0.01). SIGNIFICANCE: DAPA potentially alleviates FA induced nephrotoxicity through targeting inflammasome/caspase-1/IL axis. Moreover, it shows a regulatory effect on renal regeneration and autophagy.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Caspase 1/metabolismo , Ácido Fólico/toxicidade , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Nitrilas/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Animais , Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Biomarcadores , Proliferação de Células , Interleucina-18/antagonistas & inibidores , Interleucina-18/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Antígeno Ki-67/metabolismo , Rim/efeitos dos fármacos , Masculino , Nitrilas/farmacologia , Ratos , Ratos Sprague-Dawley
4.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443594

RESUMO

Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are conserved cytosolic pattern recognition receptors (PRRs) that track the intracellular milieu for the existence of infection, disease-causing microbes, as well as metabolic distresses. The NLRP3 inflammasome agglomerates are consequent to sensing a wide spectrum of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Certain members of the NLR family have been documented to lump into multimolecular conglomerates called inflammasomes, which are inherently linked to stimulation of the cysteine protease caspase-1. Following activation, caspase-1 severs the proinflammatory cytokines interleukin (IL)-1ß and IL-18 to their biologically active forms, with consequent commencement of caspase-1-associated pyroptosis. This type of cell death by pyroptosis epitomizes a leading pathway of inflammation. Accumulating scientific documentation has recorded overstimulation of NLRP3 (NOD-like receptor protein 3) inflammasome involvement in a wide array of inflammatory conditions. IL-1ß is an archetypic inflammatory cytokine implicated in multiple types of inflammatory maladies. Approaches to impede IL-1ß's actions are possible, and their therapeutic effects have been clinically demonstrated; nevertheless, such strategies are associated with certain constraints. For instance, treatments that focus on systemically negating IL-1ß (i.e., anakinra, rilonacept, and canakinumab) have been reported to result in an escalated peril of infections. Therefore, given the therapeutic promise of an NLRP3 inhibitor, the concerted escalated venture of the scientific sorority in the advancement of small molecules focusing on direct NLRP3 inflammasome inhibition is quite predictable.


Assuntos
Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Humanos
5.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207886

RESUMO

Interleukin-1ß (IL-1ß), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve ß-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.


Assuntos
Infarto Miocárdico de Parede Anterior/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Nitrilas/farmacologia , Animais , Infarto Miocárdico de Parede Anterior/metabolismo , Infarto Miocárdico de Parede Anterior/patologia , Anti-Inflamatórios/farmacologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Diástole , Modelos Animais de Doenças , Inflamassomos/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos ICR , Contração Miocárdica , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia
6.
Ann Neurol ; 90(2): 177-188, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34219266

RESUMO

Inflammasomes are multimeric protein complexes that can sense a plethora of microbe- and damage-associated molecular signals. They play important roles in innate immunity and are key regulators of inflammation in health and disease. Inflammasome-mediated processing and secretion of proinflammatory cytokines such as interleukin (IL) 1ß and IL-18 and induction of pyroptosis, a proinflammatory form of cell death, have been associated with the development and progression of common immune-mediated and degenerative central nervous system (CNS) diseases such as Alzheimer disease, multiple sclerosis, brain injury, stroke, epilepsy, Parkinson disease, and amyotrophic lateral sclerosis. A growing number of pharmacological compounds inhibiting inflammasome activation and signaling show therapeutic efficacy in preclinical models of the aforementioned disease conditions. Here, we illustrate regulatory mechanisms of inflammasome activation during CNS homeostasis and tissue injury. We highlight the evidence for inflammasome activation as a mechanistic underpinning in a wide range of CNS diseases and critically discuss the promise and potential limitations of therapeutic strategies that aim to inhibit the inflammasome components in neurological disorders. ANN NEUROL 2021;90:177-188.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Inflamassomos/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Doenças do Sistema Nervoso/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Sistemas de Liberação de Medicamentos/tendências , Humanos , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Doenças do Sistema Nervoso/metabolismo , Resultado do Tratamento
7.
Life Sci ; 280: 119743, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166711

RESUMO

AIMS: Saxagliptin, a selective/potent dipeptidyl peptidase-4 inhibitor, has revealed remarkable anti-inflammatory features in murine models of nephrotoxicity, hepatic injury, and neuroinflammation. However, its potential effect on ethanol-induced gastric mucosal injury has not been examined. Hence, the present work investigated the prospect of saxagliptin to attenuate ethanol-evoked gastric injury, with emphasis on the AMPK/mTOR-driven autophagy and NLRP3/ASC/caspase-1 pathway. MATERIALS AND METHODS: In ethanol-induced gastropathy, the gastric tissues were examined by immunohistochemistry, immunoblotting, histopathology, and ELISA. KEY FINDINGS: The results demonstrated that saxagliptin (10 mg/kg; by gavage) suppressed the gastric pathological signs (area of gastric ulcer and ulcer index scores), histopathologic aberrations/damage scores, without provoking hypoglycemia in rats. These protective features were attributed to the enhancement of gastric mucosal autophagy flux, as proven with increased expression of LC3-II and Beclin 1, decreased accumulation of p62 SQSTM1, and activation of the autophagy-linked AMPK/mTOR pathway by increasing the expression of p-AMPK/AMPK and decreasing the expression of the autophagy suppressor p-mTOR/mTOR signal. In tandem, saxagliptin counteracted the ethanol-induced pro-apoptotic events by downregulating Bax, upregulating Bcl2 protein, and lowering the Bax/Bcl2 ratio. Equally important, saxagliptin suppressed the NLRP3 inflammasome in the gastric tissue by lowering the expression of NLRP3, ASC, and nuclear NF-κBp65, decreasing the activity of caspase-1, and diminishing the IL-1ß levels. In the same regard, saxagliptin suppressed the mucosal oxidative stress by lowering lipid peroxide levels, increasing GSH and GPx antioxidants, and activating Nrf2/HO-1 pathway. SIGNIFICANCE: Saxagliptin may be a promising intervention against ethanol-evoked gastropathy by activating AMPK/mTOR-driven autophagy and inhibiting NLRP3 inflammasome.


Assuntos
Adamantano/análogos & derivados , Autofagia/efeitos dos fármacos , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Etanol/efeitos adversos , Gastropatias/induzido quimicamente , Gastropatias/tratamento farmacológico , Adamantano/uso terapêutico , Animais , Inflamassomos/antagonistas & inibidores , Inflamassomos/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 , Proteínas Quinases/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Gastropatias/patologia , Serina-Treonina Quinases TOR/metabolismo
8.
Phytother Res ; 35(9): 5203-5213, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34131970

RESUMO

Myocardial injury and cardiovascular dysfunction are serious consequences of sepsis and contribute to high mortality. Currently, the pathogenesis of myocardial injury in sepsis is still unclear, and therapeutic approaches are limited. In this study, we investigated the protective effect of emodin on septic myocardial injury and the underlying mechanism. Lipopolysaccharide (LPS)-induced C57BL/6 mice and cardiomyocytes were used as models of sepsis in vivo and in vitro, respectively. The results showed that emodin alleviated cardiac dysfunction, myocardial injury and improved survival rate in LPS-induced septic mice. Emodin attenuated the levels of inflammatory cytokines and cardiac inflammation induced by LPS. Emodin reduced NOD-like receptor protein 3 (NLRP3) and Gasdermin D (GSDMD) expression in the heart tissue of LPS-induced septic mice. In vitro, emodin alleviated LPS-induced cell injury and inflammation in cardiomyocytes by inhibiting NLRP3 inflammasome activation. In addition, an NLRP3 inhibitor was used to further confirm the function of the NLRP3 inflammasome in LPS-induced myocardial injury. Taken together, our findings suggest that emodin improves LPS-induced myocardial injury and cardiac dysfunction by alleviating the inflammatory response and cardiomyocyte pyroptosis by inhibiting NLRP3 inflammasome activation, which provides a feasible strategy for preventing and treating myocardial injury in sepsis.


Assuntos
Emodina , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sepse/tratamento farmacológico , Animais , Emodina/farmacologia , Coração/efeitos dos fármacos , Inflamassomos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Proteínas NLR
9.
Adv Drug Deliv Rev ; 178: 113848, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34182016

RESUMO

The emergence of SARS-CoV-2, and the ensuing global pandemic, has resulted in an unprecedented response to identify therapies that can limit uncontrolled inflammation observed in patients with moderate to severe COVID-19. The immune pathology behind COVID-19 is complex and involves the activation and interaction of multiple systems including, but not limited to, complement, inflammasomes, endothelial as well as innate and adaptive immune cells to bring about a convoluted profile of inflammation, coagulation and tissue damage. To date, therapeutic approaches have focussed on inhibition of coagulation, untargeted immune suppression and/or cytokine-directed blocking agents. Regardless of recently achieved improvements in individual patient outcomes and survival rates, improved and focussed approaches targeting individual systems involved is needed to further improve prognosis and wellbeing. This review summarizes the current understanding of molecular and cellular systems involved in the pathophysiology of COVID-19, and their contribution to pathogen clearance and damage to then discuss possible therapeutic options involving immunomodulatory drug delivery systems as well as summarising the complex interplay between them.


Assuntos
Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Fatores Imunológicos/administração & dosagem , Inflamassomos/antagonistas & inibidores , Adjuvantes Imunológicos/administração & dosagem , Animais , Antivirais/imunologia , COVID-19/imunologia , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/imunologia , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Sistemas de Liberação de Medicamentos/tendências , Humanos , Fatores Imunológicos/imunologia , Inflamassomos/imunologia
10.
Toxicol Lett ; 349: 1-11, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34052309

RESUMO

Pesticides exposure can lead to damage of dopaminergic neurons, which are associated with increased risk of Parkinson's disease (PD). However, the etiology of PD remains poorly understood and no therapeutic strategy is available. Previous studies suggested the involvement of NLRP3 inflammasome in the onset of PD. This study was designed to investigate whether glibenclamide, an inhibitor of NLRP3 inflammasome, could offer a reliable protective strategy for PD in a mouse PD model induced by paraquat and maneb. We found that glibenclamide exerted potent neuroprotection against paraquat and maneb-induced upregulation of α-synuclein, dopaminergic neurodegeneration and motor impairment in brain of mice. Mechanistically, glibenclamide treatment blocked NLRP3 inflammasome activation evidenced by reduced expressions of NLRP3, activated caspase-1 and mature interleukin-1ß in glibenclamide co-treated mice compared with those in paraquat and maneb group mice. Furthermore, glibenclamide treatment mitigated paraquat and maneb-induced microglial M1 proinflammatory response and nuclear factor-κB activation in mice. Finally, the increased superoxide production, lipid peroxidation, protein levels of NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) induced by paraquat and maneb were all attenuated by glibenclamide. Overall, our findings demonstrated that glibenclamide protected dopaminergic neurons in a mouse PD model induced by combined exposures of paraquat and maneb through suppression of NLRP3 inflammasome activation, microglial M1 polarization and oxidative stress.


Assuntos
Antiparkinsonianos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Glibureto/farmacologia , Inflamassomos/antagonistas & inibidores , Atividade Motora/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Degeneração Neural , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Inflamassomos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Maneb , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , NADPH Oxidase 2/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia
11.
ACS Chem Biol ; 16(6): 982-990, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34003636

RESUMO

Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonamidas/farmacologia , Anidrase Carbônica II/metabolismo , Linhagem Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Furanos/química , Humanos , Indenos/química , Inflamassomos/metabolismo , Macrófagos/metabolismo , Modelos Moleculares , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteômica , Sulfonamidas/química
12.
Biochem Biophys Res Commun ; 561: 7-13, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33992835

RESUMO

Doxorubicin (DOX) is a broad-spectrum antineoplastic drug; however, its serious cardiotoxic side effects in inflammatory responses limit its use in clinical applications. Dopamine D1 receptor (DRD1), a G protein-coupled receptor, is crucial for the development and function of the nervous system; additionally, it also play a role in immune regulation. However, the specific role of DRD1 in DOX-induced cardiac inflammation has not yet been clarified. Here, we discovered that DRD1 expression was induced by DOX treatment in H9C2 cardiomyocytes. DRD1 activation by A-68930, a DRD1-specific agonist, decreased DOX-induced nucleotide-binding domain-like receptor protein 3 (NLRP3) expression, caspase-1 activation, and IL-1ß maturation in H9C2 cells. Expression of the cytokines IL-1ß and IL-18 in the supernatants was also inhibited by A-68930 treatment. DRD1 knockdown, using siRNA, abolished the effects of A-68930 on the DOX-induced NLRP3 inflammasome. Furthermore, we found that DRD1 signaling downregulated the NLRP3 inflammasome in H9C2 cells through cyclic adenosine monophosphate (cAMP). Moreover, application of A-68930 to activate DRD1 reduced cardiac injury and fibrosis in a DOX-treated mouse model by suppressing the NLRP3 inflammasome in the heart. These findings indicate that DRD1 signaling may protect against DOX-induced cardiac injury by inhibiting the NLRP3 inflammasome-mediated inflammation.


Assuntos
Cardiotoxicidade/prevenção & controle , Cromanos/farmacologia , Doxorrubicina/toxicidade , Inflamassomos/antagonistas & inibidores , Miócitos Cardíacos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Receptores de Dopamina D1/agonistas , Animais , Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Células Cultivadas , Citocinas/metabolismo , Agonistas de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Receptores de Dopamina D1/metabolismo , Transdução de Sinais , Inibidores da Topoisomerase II/toxicidade
13.
Eur J Pharmacol ; 904: 174166, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33979651

RESUMO

Pyroptosis has recently been established as a term of programmed-inflammatory cell death. Pyroptosis is mainly divided into two molecular signaling pathways, including caspase-1-dependent canonical and caspase-4/5/11-dependent non-canonical inflammasome pathways. Extensive investigations have reported inflammasome activation facilitates the maturation and secretion of the inflammatory factors interleukin-1ß/18 (IL-1ß/18), cleavage of gasdermin D (GSDMD), and leading to the stimulation of pyroptosis-mediated cell death. Furthermore, accumulating studies report NLRP3 inflammasome activation plays a significant role in triggering the pyroptosis-mediated cell death and promotes the pathogenesis of diabetic retinopathy (DR). Our current review elaborates on the molecular mechanisms of pyroptosis-signaling pathways and their potential roles in the pathogenesis and impact of DR development. We also emphasize several investigational molecules regulating key steps in pyroptotic-cell death to create new comprehensions and findings to explore the pathogenesis of DR advancement. Our narrative review concisely suggests these potential pharmacological agents could be promising therapies to treat and manage DR in the future.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/etiologia , Piroptose , Animais , Caspase 1/metabolismo , Retinopatia Diabética/fisiopatologia , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Piroptose/efeitos dos fármacos
14.
Nutrients ; 13(3)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807927

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is becoming one of the most common chronic liver diseases in the world. One of the features of NAFLD is hepatic fat accumulation, which further causes hepatic steatosis, fibrosis, and inflammation. Saponins, the major pharmacologically active ingredients isolated from Panax notoginseng, contain several ginsenosides, which have various pharmacological and therapeutic functions. However, the ginsenoside-specific molecular mechanism of saponins in NAFLD remains unknown. This study aimed to elucidate the effects of ginseng saponin extract and its ginsenosides on hepatic steatosis, fibrosis, and inflammation and their underlying action mechanism in NAFLD. Mice were fed a fast food diet (FFD) for 16 weeks to induce NAFLD and then treated with saponin extract (50 or 150 mg/kg) for the remaining nine weeks to determine the effects of saponin on NAFLD. Saponin extract administration significantly alleviated FFD-induced hepatic steatosis, fibrosis, and inflammation. Particularly, saponin extract, compared with conventional red ginseng, contained significantly increased amounts of ginsenosides (Rh1 (10.34-fold) and Rg2 (7.1-fold)). In vitro Rh1 and Rg2 treatments exerted an anti-steatotic effect in primary hepatocytes, an antifibrotic effect in hepatic stellate cells, and anti-inflammatory and pro-mitophagy effects in immortalized mouse Kupffer cells. Mechanistically, saponin extract alleviated lipopolysaccharide-induced NLRP3 inflammasome activation by promoting mitophagy. In conclusion, saponin extract inhibited inflammation-mediated pathological inflammasome activation in macrophages, thereby preventing NAFLD development. Thus, saponin extract administration may be an alternative method for NAFLD prevention.


Assuntos
Ginsenosídeos/farmacologia , Inflamassomos/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Panax/química , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Animais , Modelos Animais de Doenças , Fast Foods/efeitos adversos , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia
15.
Life Sci ; 278: 119542, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915128

RESUMO

AIM: Currently, drugs for the treatment of diabetic nephropathy (DN) are lacking. This study aimed to explore the protective effect of crocin on DN. MAIN METHODS: Diabetes was induced in rats by streptozotocin (STZ), and changes in metabolism and renal parameters after crocin treatment were measured. Dihydroethidium (DHE) fluorescence and superoxide generation were used to detect the levels of reactive oxygen species (ROS) in rat renal tissues. Enzyme-linked immunosorbent assay was used to measure changes inflammation-related factors with crocin treatment. In addition, the expression of Nod-like receptor family pyrin domain-containing 3 (NLRP3) signaling pathway components was detected by western blot analysis, qRT-PCR, and immunohistochemistry. KEY FINDINGS: Crocin lowered blood sugar, increased serum insulin levels, and improved diabetes-related symptoms, including kidney dysfunction. Masson trichrome staining revealed that crocin could improve renal tissue fibrosis caused by hyperglycemia. Moreover, crocin inhibited ROS production in renal tissues and generally inhibited the production of the proinflammatory factors TNF-α, IL-1ß, and IL-18. Crocin exerted these functions by inhibiting the expression of the NLRP3 inflammasome in DN rats. SIGNIFICANCE: Crocin alleviates DN related oxidative stress and inflammation by inhibiting NLRP3 inflammasomes. Our results provide a new target for the treatment of DN.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Carotenoides/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Animais , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Inflamação/complicações , Inflamação/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos Sprague-Dawley
16.
Phytother Res ; 35(9): 4804-4833, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33856730

RESUMO

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that induces caspase-1 activation and the downstream substrates involved with the processing and secretion of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 and tumor necrosis factor-α (TNF- α). The NLRP3 inflammasome is activated by a wide range of danger signals that derive from metabolic dysregulation. Activation of this complex often involves the adaptor ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. It has been shown that nutraceuticals and medicinal plants have antiinflammatory properties and could be used as complementary therapy in the treatment of several chronic diseases that are related to inflammation, for example, cardiovascular diseases and diabetes mellitus. Herb-based medicine has demonstrated protective effects against NLRP3 inflammasome activation. Therefore, this review focuses on the effects of nutraceuticals and bioactive compounds derived from medicinal plants on NLRP3 inflammasome activation and the possible mechanisms of action of these natural products. Thus, herb-based, natural products/compounds can be considered novel, practical, and accessible agents in chronic inflammatory diseases by inhibiting NLRP3 inflammasome activation.


Assuntos
Produtos Biológicos , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Plantas Medicinais , Produtos Biológicos/farmacologia , Caspase 1 , Citocinas , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química
17.
Viruses ; 13(4)2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923693

RESUMO

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1ß production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3-/-) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1ß, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-ß. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.


Assuntos
Inflamassomos/antagonistas & inibidores , Pulmão/imunologia , Pulmão/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Doenças Respiratórias/prevenção & controle , Animais , Animais Recém-Nascidos , Citocinas/imunologia , Feminino , Furanos/administração & dosagem , Indenos/administração & dosagem , Inflamassomos/genética , Inflamassomos/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Vírus Sincicial Respiratório Humano/imunologia , Doenças Respiratórias/imunologia , Doenças Respiratórias/virologia , Sulfonamidas/administração & dosagem
18.
Life Sci ; 273: 119286, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33662429

RESUMO

AIMS: Hepatic ischemia/reperfusion (I/R) injury is a critical factor affecting the prognosis of liver surgery. The aim of this study is to explore the effects of SET8 on hepatic I/R injury and the putative mechanisms. MAIN METHODS: The expression of SET8 and MARK4 in I/R group and sham group were detected both in vivo and in vitro. In addition, mouse and RAW 264.7 cells were transfected with MARK4 siRNA and SET8 siRNA knockdown of MARK4 and SET8, respectively. The expression of SET8, MARK4 and NLRP3-associated proteins were detected after different treatments. The pathology of liver and the serologic detection were detected after different treatments. KEY FINDINGS: Our present study identified SET domain-containing protein 8 (SET8) as an efficient protein, which can negatively regulate hepatic I/R-mediated inflammatory response and ameliorate hepatic I/R injury by suppressing microtubule affinity-regulating kinase 4 (MARK4)/ NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway. The data showed that MARK4 deficiency inhibited hypoxia/reoxygenation (H/R)-induced NLRP3 inflammasome activation, while SET8 deficiency showed the opposite effect. We further demonstrated that SET8 restrained NLRP3 inflammasome activation by inhibiting MARK4. Moreover, we verified SET8 made protective effect on hepatic I/R injury. SIGNIFICANCE: SET8 plays an essential role in hepatic ischemia/reperfusion injury in mice by suppressing MARK4/NLRP3 inflammasome pathway. Our results may offer a new strategy to mitigate hepatic I/R injury.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Histona-Lisina N-Metiltransferase/metabolismo , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Células Cultivadas , Histona-Lisina N-Metiltransferase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
19.
Int Immunopharmacol ; 95: 107576, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33770730

RESUMO

Inflammation is involved in noise-induced hearing loss (NIHL), but the mechanism is still unknown. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which triggers the inflammatory cascade, has been implicated in several inflammatory diseases in response to oxidative stress. However, whether the NLRP3 inflammasome is a key factor for permanent NIHL is still unknown. In this study, quantitative real-time polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assays (ELISAs) demonstrated that the expression levels of activated caspase-1, interleukin (IL)-1ß, IL-18, and NLRP3 were significantly increased in the cochleae of mice exposed to broadband noise (120 dB) for 4 h, compared with the control group. These results indicate that the activation of inflammasomes in the cochleae of mice during the pathological process of NIHL as well as NLRP3, a sensor protein of reactive oxygen species (ROS), may be key factors for inflammasome assembly and subsequent inflammation in cochleae. Moreover, many recent studies have revealed that NEK7 is an important component and regulator of NLRP3 inflammasomes by interacting with NLRP3 directly and that these interactions can be interrupted by oridonin. Here, we further determined that treatment with oridonin could indeed interrupt the interaction between NLRP3 and NEK7 as well as inhibit the downstream inflammasome activation in mouse cochleae after noise exposure. Furthermore, we tested anakinra, another inflammatory inhibitor, and it was shown to partially alleviate the degree of hearing impairment in some frequencies in an NIHL mouse model. These discoveries suggest that inhibiting NLRP3 inflammasomes and the downstream signaling pathway may provide a new strategy for the clinical treatment of NIHL.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diterpenos do Tipo Caurano/uso terapêutico , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Cóclea/efeitos dos fármacos , Cóclea/imunologia , Citocinas/imunologia , Diterpenos do Tipo Caurano/farmacologia , Perda Auditiva Provocada por Ruído/imunologia , Inflamassomos/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Camundongos Endogâmicos C57BL , Quinases Relacionadas a NIMA/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia
20.
Int Immunopharmacol ; 95: 107529, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33744777

RESUMO

Sepsis is a systemic inflammatory response syndrome resulted from severe infection. Excessive inflammation response plays an important role in sepsis-induced acute lung injury (ALI). Loganin is an iridoid glycoside isolated from Corni fructus and exerts an anti-inflammatory effect in multiple inflammatory diseases; however, the role of loganin in sepsis-induced ALI remains unknown. In the current study, the cecal ligation and puncture (CLP)-induced murine sepsis model was constructed to investigate the anti-inflammatory property of loganin in sepsis-induced ALI. Lipopolysaccharide (LPS)-treated Raw 264.7 cells and primary murine peritoneal macrophages were established to further explore underlying mechanism of loganin. Results showed that intragastrical administration of loganin significantly increased murine survival, reduced the alveolar structure damage and inflammatory cell infiltration. Loganin suppressed the release of the M1 macrophage-associated pro-inflammatory cytokines and induced the activation of M2-type anti-inflammatory cytokines. Besides, loganin dramatically inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent IL-1ß secretion. Further in vitro studies confirmed that loganin efficiently inhibited M1 macrophage polarization and NLRP3 inflammasome activation by blocking the extra-cellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways. Taken together, the anti-inflammatory effect of loganin in sepsis-induced ALI was associated with the ERK and NF-κB pathway-mediated macrophage polarization and NLRP3 inflammasome activation. Our study offers a favorable mechanistic basis to support the therapeutic potential of loganin in anti-inflammatory diseases, such as sepsis-induced ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Inflamassomos/antagonistas & inibidores , Iridoides/uso terapêutico , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Caspase 1/imunologia , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Iridoides/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Células RAW 264.7 , Sepse/complicações , Sepse/imunologia , Sepse/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...