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1.
Nutrients ; 15(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36615880

RESUMO

Alcoholic liver disease (ALD) is caused by chronic excessive alcohol consumption, which leads to inflammation, oxidative stress, lipid accumulation, liver fibrosis/cirrhosis, and even liver cancer. However, there are currently no effective drugs for ALD. Herein, we report that a natural phytosterol Daucosterol (DAU) can effectively protect against liver injury caused by alcohol, which plays anti-inflammatory and antioxidative roles in many chronic inflammatory diseases. Our results demonstrate that DAU ameliorates liver inflammation induced by alcohol through p38/nuclear factor kappa B (NF-κB)/NOD-like receptor protein-3 (NLRP3) inflammasome pathway. Briefly, DAU decreases NF-κB nuclear translocation and inhibits NLRP3 activation by decreasing p38 phosphorylation. At the same time, DAU also protects against hepatic oxidative stress and lipid accumulation. In conclusion, our research provides a new clue about the protective effects of naturally active substances on ALD.


Assuntos
Inflamassomos , NF-kappa B , Humanos , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR , Transdução de Sinais , Sitosteroides/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Etanol/farmacologia , Cirrose Hepática
2.
Curr Biol ; 33(1): R33-R36, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36626862

RESUMO

A new study reveals how Mycobacterium tuberculosis evades anti-bacterial immunity by modifying the plasma membrane phospholipid composition of infected macrophages, thereby blocking the host's pyroptosis response and supporting chronic infection.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Inflamassomos/metabolismo , Tuberculose/metabolismo , Tuberculose/microbiologia , Macrófagos/metabolismo
3.
Biomed Pharmacother ; 158: 114175, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36587556

RESUMO

Gout is a metabolic disease affected by monosodium urate (MSU) deposition, which is directly related to hyperuricemia. Recent reports on the prevalence and incidence of gout have been widely circulated worldwide. Currently, the anti-gout drugs in clinical practice are mainly small-molecule synthetic drugs, and the effectiveness and safety are limited. Reducing uric acid and inhibiting inflammation are the focused areas of drug research and development on gout. Rutin, a natural flavonoid, has been reported to alleviate inflammation in various diseases. However, whether rutin exerts protective effects on gout remains to be elucidated. This study used quails without urate oxidase as experimental animals to induce endogenous gout models through a high purine diet. We confirmed that quail in the model group developed gout symptoms at 30 days of the experiment. And the targets of uric acid metabolism, oxidative stress level, and NLRP3 inflammasome were dysregulated in quails. Rutin treatment improves gout and reduces inflammatory expression in quail. We further confirmed that rutin treatment reduced XOD activity and uric acid levels in quail. And rutin inhibited ROS production, restored oxidative stress balance, inhibited NLRP3 inflammasome activation, and exerted anti-inflammatory effects. We extracted and identified the fibroblast-like synoviocytes (FLS) for the first time. The results showed that rutin could reduce ROS production and NLRP3 inflammasome activation of FLS after uric acid stimulation. In conclusion, our findings underscore that rutin may be a gout protective agent by reducing XOD activity, inhibiting ROS production and NLRP3 inflammasome activation. Meanwhile, this study also provides an available animal model for the research drugs of gout.


Assuntos
Gota , Inflamassomos , Espécies Reativas de Oxigênio , Rutina , Animais , Gota/tratamento farmacológico , Gota/metabolismo , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rutina/farmacologia , Ácido Úrico/farmacologia , Codorniz
4.
Respir Res ; 24(1): 25, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694200

RESUMO

BACKGROUND: Radiation-induced lung injury (RILI) is the most common and serious complication of chest radiotherapy. However, reported radioprotective agents usually lead to radiation resistance in tumor cells. The key to solving this problem is to distinguish between the response of tumor cells and normal lung epithelial cells to radiation damage. METHODS: RNA-Seq was used to recognize potential target of alleviating the progression of RILI as well as inhibiting tumor growth. The activation of NLRP3 inflammasome in lung epithelial cells was screened by qRT-PCR, western blotting, immunofluorescence, and ELISA. An in vivo model of RILI and in vitro conditioned culture model were constructed to evaluate the effect of NLRP3/interleukin-1ß on fibroblasts activation. ROS, ATP, and (NADP)+/NADP(H) level in lung epithelial cells was detected to explore the mechanism of NLRP3 inflammasome activation. The lung macrophages of the mice were deleted to evaluate the role of lung epithelial cells in RILI. Moreover, primary cells were extracted to validate the results obtained from cell lines. RESULTS: NLRP3 activation in epithelial cells after radiation depends on glycolysis-related reactive oxygen species accumulation. DPYSL4 is activated and acts as a negative regulator of this process. The NLRP3 inflammasome triggers interleukin-1ß secretion, which directly affects fibroblast activation, proliferation, and migration, eventually leading to lung fibrosis. CONCLUSIONS: Our study suggests that NLRP3 inflammasome activation in lung epithelial cells is essential for radiation-induced lung injury. These data strongly indicate that targeting NLRP3 may be effective in reducing radiation-induced lung injury in clinical settings.


Assuntos
Inflamassomos , Lesão Pulmonar , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-1beta/metabolismo , Lesão Pulmonar/metabolismo , NADP/metabolismo , NADP/farmacologia , Pulmão/metabolismo , Células Epiteliais/metabolismo , Espécies Reativas de Oxigênio/metabolismo
5.
Allergol Immunopathol (Madr) ; 51(1): 177-186, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36617838

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of impaired vision as well as some earlier effects, such as reading and face recognition. Oxidative damage and inflammation of retinal pigment epithelial (RPE) cells are major causes of AMD. Additionally, autophagy in RPE cells can lead to cellular homeostasis under oxidative stress. Nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) is a mysterious modulator of the immune system function which inhibits inflammatory response, attenuates reactive oxygen species (ROS) production, and regulates autophagy. This study attempted to explore the role of NLRX1 in oxidative stress, inflammation, and autophagy in AMD. METHODS: An in vitro model of AMD was built in human retinal pigment epithelial cell line 19 (ARPE-19) treated with H2O2. The cell viability, NLRX1 expressions, levels of superoxide dismutase (SOD), glutathione (GHS), and ROS, concentrations of interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), IL-6, and monocyte chemoattractant protein-1 (MCP-1), expressions of NLRX1, p62, LC3-II/LC3-I, FUNDC1, and NOD-like receptor protein 3 (NLRP3) inflammasome were expounded by cell counting kit-8, colorimetric, enzyme-linked immunosorbent serologic assay (ELISA), and Western blot assay. RESULTS: H2O2 treatment notably reduced the relative protein expression of NLRX1. Meanwhile, H2O2 incubation decreased cell viability, diminished SOD and GSH concentrations, accompanied with the increased level of ROS, enhanced IL-1ß, TNF-α, IL-6, and MCP-1 concentrations, and aggrandized the relative protein expression of p62 with reduced LC3-II/LC3-I ratio. Moreover, these results were further promoted with knockdown of NLRX1 and reversed with overexpression. Mechanically, silencing of NLRX1 further observably enhanced the relative levels of -phosphorylated FUNDC1/FUNDC1, and NLRP3 inflammasome-related proteins, while overexpression of NLRX1 exhibited inverse results in the H2O2-induced ARPE-19 cells. CONCLUSION: NLRX1 suppressed H2O2-induced oxidative stress and inflammation, and facilitated autophagy by suppressing FUNDC1 phosphorylation and NLRP3 activation in ARPE-19 cells.


Assuntos
Degeneração Macular , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Inflamassomos/farmacologia , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Fosforilação , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Estresse Oxidativo , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Proteínas de Transporte , Inflamação/patologia , Autofagia , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia
6.
Sci Signal ; 16(768): eabh1083, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36649377

RESUMO

Inflammasomes are intracellular protein complexes that promote an inflammatory host defense in response to pathogens and damaged or neoplastic tissues and are implicated in inflammatory disorders and therapeutic-induced toxicity. We investigated the mechanisms of activation for inflammasomes nucleated by NOD-like receptor (NLR) protiens. A screen of a small-molecule library revealed that several tyrosine kinase inhibitors (TKIs)-including those that are clinically approved (such as imatinib and crizotinib) or are in clinical trials (such as masitinib)-activated the NLRP3 inflammasome. Furthermore, imatinib and masitinib caused lysosomal swelling and damage independently of their kinase target, leading to cathepsin-mediated destabilization of myeloid cell membranes and, ultimately, cell lysis that was accompanied by potassium (K+) efflux, which activated NLRP3. This effect was specific to primary myeloid cells (such as peripheral blood mononuclear cells and mouse bone marrow-derived dendritic cells) and did not occur in other primary cell types or various cell lines. TKI-induced lytic cell death and NLRP3 activation, but not lysosomal damage, were prevented by stabilizing cell membranes. Our findings reveal a potential immunological off-target of some TKIs that may contribute to their clinical efficacy or to their adverse effects.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mesilato de Imatinib , Leucócitos Mononucleares/metabolismo , Morte Celular , Células Mieloides/metabolismo , Interleucina-1beta/metabolismo
7.
PLoS One ; 18(1): e0279028, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662875

RESUMO

Nod-Like Receptor Pyrin domain-containing protein 6 (NLRP6), a member of the Nucleotide-oligomerization domain-Like Receptor (NLR) family of proteins, assembles together with the ASC protein to form an inflammasome upon stimulation by bacterial lipoteichoic acid and double-stranded DNA. Besides its expression in myeloid cells, NLRP6 is also expressed in intestinal epithelial cells where it may contribute to the maintenance of gut homeostasis and negatively controls colorectal tumorigenesis. Here, we report that NLRP6 is very faintly expressed in several colon cancer cell lines, detected only in cytoplasmic small dots were it colocalizes with ASC. Consequently, it is very hardly detected by standard western-blotting techniques by several presently available commercial antibodies which, in contrast, highly cross-react with a protein of 90kDa that we demonstrate to be unrelated to NLRP6. We report here these results to caution the community not to confuse the 90kDa protein with the endogenous human NLRP6.


Assuntos
Inflamassomos , Neoplasias , Humanos , Inflamassomos/metabolismo , Homeostase , Células Epiteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular
8.
Cells ; 12(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36672229

RESUMO

The NLRP3 inflammasome is a multimolecular complex that processes inactive IL-1ß and IL-18 into proinflammatory cytokines. OLT1177 is an orally active small compound that specifically inhibits NLRP3. Here, B16F10 melanoma were implanted in mice and treated with OLT1177 as well as combined with the glucocorticoid dexamethasone. At sacrifice, OLT1177 treated mice had significantly smaller tumors compared to tumor-bearing mice treated with vehicle. However, the combined treatment of OLT1177 plus dexamethasone revealed a greater suppression of tumor growth. This reduction was accompanied by a downregulation of nuclear and mitochondrial STAT3-dependent gene transcription and by a significant reduction of STAT3 Y705 and S727 phosphorylations in the tumors. In vitro, the human melanoma cell line 1205Lu, stimulated with IL-1α, exhibited significantly lower levels of STAT3 Y705 phosphorylation by the combination treatment, thus affecting the nuclear functions of STAT3. In the same cells, STAT3 serine 727 phosphorylation was also lower, affecting the mitochondrial functions of STAT3. In addition, metabolic analyses revealed a marked reduction of ATP production rate and glycolytic reserve in cells treated with the combination of OLT1177 plus dexamethasone. These findings demonstrate that the combination of OLT1177 and dexamethasone reduces tumor growth by targeting nuclear as well as mitochondrial functions of STAT3.


Assuntos
Melanoma , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Animais , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Melanoma/tratamento farmacológico , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Fator de Transcrição STAT3/metabolismo
9.
Life Sci ; 314: 121352, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36592789

RESUMO

Traumatic brain injury (TBI), an acquired brain injury imparted by a mechanical trauma to the head, has significant ramifications in terms of long-term disability and cost of healthcare. TBI is characterized by an initial phase of cell death owing to direct mechanical injury, followed by a secondary phase in which neuroinflammation plays a pivotal role. Activation of inflammasome complexes triggers a cascade that leads to activation of inflammatory mediators such as caspase-1, Interleukin (IL)-18, and IL-1ß, eventually causing pyroptosis. NLRP3 inflammasome, a component of the innate immune response, has been implicated in a number of neurodegenerative diseases, including TBI. Recent findings indicate that NLRP3 inhibitors can potentially ameliorate neuroinflammation and improve cognition and motor function in TBI. The NLRP3 inflammasome also holds potential as a predictive biomarker for the long-term sequelae following TBI. Although several therapeutic agents have shown promising results in pre-clinical studies, none of them have been effective in human trials for TBI, to date. Thus, it is imperative that such promising therapeutic candidates are evaluated in clinical trials to assess their efficacy in alleviating neurological impairments in TBI. This review offers an insight into the pathophysiology of TBI, with an emphasis on neuroinflammation in the aftermath of TBI. We highlight the NLRP3 inflammasome and explore its role in the neuroinflammatory cascade in TBI. We also shed light on its potential as a prospective biomarker and therapeutic target for TBI management.


Assuntos
Lesões Encefálicas Traumáticas , Inflamassomos , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doenças Neuroinflamatórias , Lesões Encefálicas Traumáticas/metabolismo , Biomarcadores , Interleucina-1beta/metabolismo
10.
Food Chem Toxicol ; 172: 113601, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36610472

RESUMO

Cadmium accumulates in the kidney and causes inflammation. The NLRP3 inflammasome has been linked to the pathogenesis of inflammation. Hyperoside (HYP) possesses potent nephroprotective properties against of kidney injury. This study aimed to research the effects and related mechanism of HYP on Cd-induced kidney damage. Wide-type and NLRP3-/- mice were used to determine the role of NLRP3 inflammasome in Cd-induced renal dysfunction. Female C57BL/6 were treated with Cd (50 m,g/L) and HYP (25, 50 mg/kg) for 12 weeks. In vitro experiments, the human renal proximal-tubule epithelial cells (RPTEC/TERT1) were pretreated with HYP (50-200 µM) before exposure to Cd. NLRP3 deficiency attenuated Cd-induced NLRP3 activation, inflammation and kidney injury in mice. HYP treatment significantly alleviated Cd-induced kidney injury by decreasing indexes of kidney function, reducing pro-inflammatory cytokines release, decreasing ROS production and suppressing NLRP3 inflammasome activation. Moreover, treatment with siRNA targeting NLRP3 blocked the anti-inflammatory protective effect of HYP in Cd-treated cells. Additionally, HYP markedly inhibited Cd-induced MAPK/NF-κB pathway stimulation in vitro and in vivo. The findings indicated HYP conferred protection against Cd-induced kidney inflammation via suppression of NLRP3 inflammasome mediated by ROS/MAPK/NF-κB signaling. Our results thus support the notion of developing HYP as promising therapeutic candidate for Cd-induced kidney injury.


Assuntos
Inflamassomos , NF-kappa B , Humanos , Feminino , Camundongos , Animais , NF-kappa B/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Rim , Inflamação/metabolismo
11.
Theranostics ; 13(1): 374-390, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593964

RESUMO

Rationale: The inflammasome has been widely reported to be involved in various myopathies, but little is known about its role in denervated muscle. Here, we explored the role of NLRP3 inflammasome activation in experimental models of denervation in vitro and in vivo. Methods: Employing muscular NLRP3 specific knock-out (NLRP3 cKO) mice, we evaluated the effects of the NLRP3 inflammasome on muscle atrophy in vivo in muscle-specific NLRP3 conditional knockout (cKO) mice subjected to sciatic nerve transection and in vitro in cells incubated with NLRP3 inflammasome activator (NIA). To evaluate the underlying mechanisms, samples were collected at different time points for RNA-sequencing (RNA-seq), and the interacting molecules were comprehensively analysed. Results : In the experimental model, NLRP3 inflammasome activation after denervation led to pyroptosis and upregulation of MuRF1 and Atrogin-1 expression, facilitating ubiquitin-proteasome system (UPS) activation, which was responsible for muscle proteolysis. Conversely, genetic knockout of NLRP3 in muscle inhibited pyroptosis-associated protein expression and significantly ameliorated muscle atrophy. Furthermore, cotreatment with shRNA-NLRP3 markedly attenuated NIA-induced C2C12 myotube pyroptosis and atrophy. Intriguingly, inhibition of NLRP3 inflammasome activation significantly suppressed apoptosis. Conclusions: These in vivo and in vitro findings demonstrate that during denervation, the NLRP3 inflammasome is activated and stimulates muscle atrophy via pyroptosis, proteolysis and apoptosis, suggesting that it may contribute to the pathogenesis of neuromuscular diseases.


Assuntos
Inflamassomos , Piroptose , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteólise , Apoptose , Atrofia Muscular/metabolismo , Denervação
12.
Int J Biol Sci ; 19(1): 242-257, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36594089

RESUMO

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pro-inflammatory immune receptor potentiating acute lung injury (ALI). However, the mechanism of TREM-1-triggered inflammation response remains poorly understood. Here, we showed that TREM-1 blocking attenuated NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome activation and glycolysis in LPS-induced ALI mice. Then, we observed that TREM-1 activation enhanced glucose consumption, induced glycolysis, and inhibited oxidative phosphorylation in macrophages. Specifically, inhibition of glycolysis with 2-deoxyglucose diminished NLRP3 inflammasome activation of macrophages triggered by TREM-1. Hypoxia-inducible factor-1α (HIF-1α) is a critical transcriptional regulator of glycolysis. We further found that TREM-1 activation facilitated HIF-1α accumulation and translocation to the nucleus via the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Inhibiting mTOR or HIF-1α also suppressed TREM-1-induced metabolic reprogramming and NLRP3/caspase-1 activation. Overall, the mTOR/HIF-1α/glycolysis pathway is a novel mechanism underlying TREM-1-governed NLRP3 inflammasome activation. Therapeutic targeting of the mTOR/HIF-1α/glycolysis pathway in TREM-1-activated macrophages could be beneficial for treating or preventing inflammatory diseases, such as ALI.


Assuntos
Lesão Pulmonar Aguda , Inflamassomos , Animais , Camundongos , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos NOD , Macrófagos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Glicólise , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Mamíferos/metabolismo
13.
Cell Commun Signal ; 21(1): 1, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597090

RESUMO

BACKGROUND: The NLRP3 inflammasome activation is the molecular basis of Helicobacter pylori (Hp)-associated gastritis. Tripartite motif (TRIM) 31 is involved in diverse pathological events. However, whether TRIM31 plays a role in the activation of NLRP3 inflammasome in Hp infection is not clarified. METHODS: A mouse model of chronic Hp infection was established, and the gastric tissues were subjected to the polymerase chain reaction, western blotting, histopathological analysis, and RNA sequencing. The mitochondrial membrane potential and ROS in the human gastric epithelium GES-1 cells with or without Hp infection were measured by flow cytometry. GES-1 cells with or without TRIM31 knockdown were transfected with mCherry-EGFP-LC3 adenovirus. After rapamycin and bafilomycin A1 stimulation, autophagy flux in the above primed GES-1 cells was assessed by laser confocal microscope. Lysosomal acidification and expression levels of cathepsin B and cathepsin D in GES-1 cells with Hp infection were measured. RESULTS: NLRP3 inflammasome was activated in the gastric tissues of mice with chronic Hp infection in vivo and the GES-1 cells with Hp infection in vitro. TRIM31 was downregulated in Hp infection. TRIM31 negatively regulated the NLRP3 inflammasome activation. Enhanced ROS, impaired autophagy flux, and decreased expression of lysosomal cathepsin B and cathepsin D were observed in TRIM31-deficient GES-1 cells with Hp infection. In turn, inhibition of ROS led to the decreased expression of NLRP3 inflammasome. CONCLUSIONS: Together, our data identified that TRIM31 negatively regulated the activation of NLRP3 inflammasome in Hp-associated gastritis by affecting ROS and autophagy of gastric epithelial cells. Video abstract.


Assuntos
Gastrite , Helicobacter pylori , Camundongos , Humanos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ubiquitina-Proteína Ligases , Espécies Reativas de Oxigênio/metabolismo , Catepsina B , Helicobacter pylori/metabolismo , Catepsina D , Autofagia , Proteínas com Motivo Tripartido
14.
Intern Med ; 62(1): 43-50, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36596474

RESUMO

Autoinflammatory diseases are systemic disorders caused by genetic or acquired abnormalities in certain signaling pathways of the innate immune system. Dysregulated activation of the inflammasome, i.e. molecular platforms responsible for the activation of caspase-1 and production of interleukin-1ß, causes autoinflammation. Familial Mediterranean fever (FMF), the most common genetic autoinflammatory disease, is characterized by a periodic fever and serositis. The complex and heterogeneous genetic background of Japanese FMF patients, accompanied by potential overlap with other rheumatic diseases, suggests crosstalk between genetic and environmental factors. Recently, FMF has been recognized as being part of a spectrum of autoinflammatory syndromes named pyrin-associated autoinflammatory diseases. The discovery of a new monogenic autoinflammatory disease, A20 haploinsufficiency, may provide novel insights into early-onset Behçet's-like diseases. In contrast, adult-onset Still's disease and Schnitzler's syndrome are acquired autoinflammatory diseases without a monogenic abnormality. Although the concept of autoinflammatory diseases originally applied to monogenic hereditary recurrent fevers, it has been expanded to include non-genetic complex autoinflammatory diseases. Information concerning monogenic autoinflammatory diseases may prove useful for elucidating the molecular mechanisms underlying non-genetic autoinflammatory diseases.


Assuntos
Síndrome de Behçet , Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Adulto , Humanos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Inflamassomos , Febre , Síndrome de Behçet/genética
16.
Invest Ophthalmol Vis Sci ; 64(1): 4, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36626177

RESUMO

Purpose: The pathogenesis of the lacrimal glands (LGs) is facilitated by inflammation mediated by the NACHT, LRR, and NLRP3 inflammasomes in dry eye disease. This research aimed to explore the protective effects of Aquaporin 5 (AQP5) on LGs by inhibiting reactive oxygen species (ROS) and the NLRP3 inflammasome. Methods: AQP5 knockout (AQP5-/-) mice were used to evaluate pathological changes in LGs. ROS generation was detected with a dichlorodihydro-fluorescein diacetate assay. Lipid metabolism was assessed by Oil Red O staining. The reversal of the mitochondrial membrane potential was detected using a JC-1 fluorescent probe kit. The effect of AQP5 on NLRP3/caspase-1/Gasdermin-D (GSDMD)-mediated pyroptosis was examined using pharmacological treatment of N-acetyl L-cysteine or MCC950. Results: AQP5 loss significantly increased ROS generation, lipid metabolism disorders, TUNEL-positive cells, and reversal of the mitochondrial membrane potential in the AQP5-/- LGs. NLRP3 upregulation, increased caspase-1 and GSDMD activity, and enhanced IL-1ß release were detected in the AQP5-/- mouse LGs and primary LG epithelial cells. MCC950 significantly suppressed NLRP3 inflammasome-related pyroptosis induced by AQP5 deficiency in LGs and primary LG epithelial cells. Furthermore, we discovered that prestimulating the AQP5-/- primary LG epithelial cells with N-acetyl L-cysteine decreased NLRP3 expression, caspase-1 and GSDMD activity levels, and IL-1ß release. Conclusions: Our results revealed that AQP5 loss promoted NLRP3 inflammasome activation through ROS generation. Inhibiting the ROS or NLRP3 inflammasome significantly alleviated the damage and pyroptosis of AQP5-deficient LG epithelial cells, which could provide new insights into dry eye disease.


Assuntos
Síndromes do Olho Seco , Aparelho Lacrimal , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Piroptose , Aparelho Lacrimal/metabolismo , Linhagem Celular , Caspase 1/metabolismo , Acetilcisteína/farmacologia , Síndromes do Olho Seco/metabolismo
17.
BMC Cardiovasc Disord ; 23(1): 10, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627567

RESUMO

Cardiomyocytes injury has been considered as a key contributor for myocardial infarction (MI). Uric acid (UA) can induce cardiomyocytes injury, which is closely related to NLRP3 activation and inflammatory factor generation. However, the mechanism how UA modulates cardiomyocytes remains elusive. Western blotting and qRT-PCR were applied for measuring protein and mRNA expression, respectively. ROS production and Ca2+ influx were measured by flow cytometry. Patch clamp technique was used for measuring transient receptor potential melastatin 2 (TRPM2) channel. Ligation of left anterior descending for 2 h was performed to induce MI animal model. The rats were treated by different concentration of uric acid. The artery tissues were stained by HE and collected for measurement of NLRP3 and inflammatory factors. Supplementation of UA significantly promoted apoptosis, and augmented the expression of intercellular adhesion molecule-1, chemoattractant protein-1, vascular cell adhesion molecule-1, and NLRP3 inflammasome. Knockdown of NLRP3 reversed the influence of UA on MI by decreasing collagen deposition, fibrotic area, apoptosis. The expression of NLRP3 inflammasome increased markedly after treatment of UA. UA activated ROS/TRPM2/Ca2+ pathway through targeting NLRP3. UA activated NLRP3 inflammasome and augments inflammatory factor production, which in turn exacerbates cardiomyocytes injury. Knockdown of NLRP3 reversed the influence of UA on apoptosis and cell cycle. UA may promote cardiomyocytes injury through activating NLRP3 inflammasome and ROS/TRPM2 channel/Ca2+ pathway.


Assuntos
Infarto do Miocárdio , Canais de Cátion TRPM , Ratos , Animais , Inflamassomos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Úrico/farmacologia , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Domínio Pirina , Proteínas de Transporte , Infarto do Miocárdio/genética
18.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 39(1): 34-40, 2023 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-36631013

RESUMO

Objective To examine the effects of Coxsackie virus B3 (CVB3) on the NLR family, pyrin domain containing protein 3 (NLPR3) of mouse macrophages and its mechanisms. Methods RAW264.7 cells, primary mouse macrophages (bone marrow-derived macrophages or peritoneal macrophages), and short hairpin RNA (shRNA)-NLRP3 lentivirus infected RAW264.7 cells were stimulated by different dosages of CVB3. The transcript levels of NLRP3 and IL-1ß were measured by quantitative real-time PCR. IL-1ß in the supernatants of cell cultures was determined by ELISA. The protein level of NLRP3 was tested by Western blot analysis and the interacting proteins of NLRP3 were detected by co-immunoprecipitation (Co-IP). Results The transcript levels of NLRP3 and IL-1ß were significantly up-regulated in the CVB3 stimulated RAW264.7 cells and primary mouse macrophages (bone marrow-derived macrophages or peritoneal macrophages). The expression level of NLRP3 presented CVB3-dose dependence and demonstrated the highest expression level at 6 hours after CVB3 treatment. The transcript level of IL-1ß significantly increased the most at 6 hours after CVB3 treatment, while the protein level of IL-1ß peaked at 24 hours after CVB3 treatment. In the GFP-shRNA-NLRP3 lentivirus infected RAW264.7 cells, NLRP3 was obviously inhibited, and with CVB3 stimulation, IL-1ß in the supernatants of cell cultures decreased significantly. Moreover, NLRP3 antibody was used for Co-IP experiment, in which the resultant protein complex was then stained with silver nitrate. The differential protein band between different groups was identified as nicotinamide adenine dinucleotide kinase 2 (NADK2) by mass spectrometry. This result demonstrated that CVB3 induced the interaction between NADK2 and NLRP3. Conclusion CVB3 stimulation promotes the activation of NLRP3 in macrophages, thereby enhancing the expression and secretion of pro-inflammatory cytokine IL-1ß by activating NADK2.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , NAD/metabolismo , NAD/farmacologia , Macrófagos/metabolismo , RNA Interferente Pequeno/metabolismo , Interleucina-1beta/metabolismo
19.
Int J Biol Sci ; 19(2): 593-609, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632449

RESUMO

Septic acute kidney injury (AKI) is characterized by inflammation. Pyroptosis often occurs during AKI and is associated with the development of septic AKI. This study found that induction of insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to a higher level can induce pyroptosis in renal tubular cells. Meanwhile, macrophage migration inhibitory factor (MIF), a subunit of NLRP3 inflammasomes, was essential for IGF2BP1-induced pyroptosis. A putative m6A recognition site was identified at the 3'-UTR region of E2F transcription factor 1 (E2F1) mRNA via bioinformatics analyses and validated using mutation and luciferase experiments. Further actinomycin D (Act D) chase experiments showed that IGF2BP1 stabilized E2F1 mRNA dependent on m6A. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) indicated that E2F1 acted as a transcription factor to promote MIF expression. Thus, IGF2BP1 upregulated MIF through directly upregulating E2F1 expression via m6A modification. Experiments on mice with cecum ligation puncture (CLP) surgery verified the relationships between IGF2BP1, E2F1, and MIF and demonstrated the significance of IGF2BP1 in MIF-associated pyroptosis in vivo. In conclusion, IGF2BP1 was a potent pyroptosis inducer in septic AKI through targeting the MIF component of NLRP3 inflammasomes. Inhibiting IGF2BP1 could be an alternate pyroptosis-based treatment for septic AKI.


Assuntos
Injúria Renal Aguda , Fatores Inibidores da Migração de Macrófagos , Animais , Camundongos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Rim/metabolismo , Injúria Renal Aguda/metabolismo , Inflamação , RNA Mensageiro
20.
Invest Ophthalmol Vis Sci ; 64(1): 1, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36595275

RESUMO

Purpose: Pyroptosis, a novel proinflammatory programmed cell death, has been implicated in some ocular diseases. Of special note is the noncanonical pyroptosis that has recently been recognized to play a critical role in microbial keratitis. We previously discovered a new potent small molecular pyroptosis inhibitor, J114. In this investigation, we will explore whether J114 is able to inhibit the noncanonical pyroptosis and the underlying mechanism. Then a lipopolysaccharide (LPS)-induced keratitis mouse model will be used to evaluate the therapeutic effect of J114 in vivo. Methods: In vitro, macrophages originating from humans or mice were stimulated with intracellular LPS to induce noncanonical pyroptosis activation. in vivo, acute keratitis in mouse was induced by LPS intrastromal injection. We verified the protective effect of J114 on noncanonical pyroptosis. Clinical scoring, histological observation, macrophage localization, and quantification of pyroptotic markers in the cornea were used to characterize the therapeutic effects. Results: J114 substantially inhibited the noncanonical pyroptosis and the release of inflammatory cytokines by suppressing the activation of caspase-4/5/11 and the noncanonical NLRP3 inflammasome through blocking the NLRP3-ASC interaction. in vivo, J114 protected against LPS-induced noncanonical pyroptosis of acute keratitis, as manifested by alleviated clinical manifestations and histological disorders, and relieved inflammatory reactions. Conclusions: In this study, we found that J114 could efficiently inhibit LPS-induced noncanonical pyroptosis and revealed the underlying mechanism. This compound displayed significant anti-inflammatory activity in the LPS-induced keratitis mouse model. All the findings indicated that J114 could be a potential lead compound for drug development against inflammatory ocular surface diseases.


Assuntos
Ceratite , Piroptose , Humanos , Camundongos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipopolissacarídeos/toxicidade , Inflamassomos/metabolismo , Inflamação , Ceratite/induzido quimicamente , Ceratite/tratamento farmacológico
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