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1.
Int J Biol Sci ; 20(7): 2658-2685, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725851

RESUMO

Mucosal epithelial death is an essential pathological characteristic of portal hypertensive gastropathy (PHG). FADDosome can regulate mucosal homeostasis by controlling mitochondrial status and cell death. However, it remains ill-defined whether and how the FADDosome is involved in the epithelial death of PHG. The FADDosome formation, mitochondrial dysfunction, glycolysis process and NLRP3 inflammasome activation in PHG from both human sections and mouse models were investigated. NLRP3 wild-type (NLRP3-WT) and NLRP3 knockout (NLRP3-KO) littermate models, critical element inhibitors and cell experiments were utilized. The mechanism underlying FADDosome-regulated mitochondrial dysfunction and epithelial death in PHG was explored. Here, we found that FADD recruited caspase-8 and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to form the FADDosome to promote Drp1-dependent mitochondrial fission and dysfunction in PHG. Also, FADDosome modulated NOX2 signaling to strengthen Drp1-dependent mitochondrial fission and alter glycolysis as well as enhance mitochondrial reactive oxygen species (mtROS) production. Moreover, due to the dysfunction of electron transport chain (ETC) and alteration of antioxidant enzymes activity, this altered glycolysis also contributed to mtROS production. Subsequently, the enhanced mtROS production induced NLRP3 inflammasome activation to result in the epithelial pyroptosis and mucosal injury in PHG. Thus, the FADDosome-regulated pathways may provide a potential therapeutic target for PHG.


Assuntos
Proteína de Domínio de Morte Associada a Fas , Mucosa Gástrica , Hipertensão Portal , Mitocôndrias , Animais , Camundongos , Mitocôndrias/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Hipertensão Portal/metabolismo , Hipertensão Portal/patologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Inflamassomos/metabolismo
2.
Braz J Med Biol Res ; 57: e13299, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716981

RESUMO

25-hydroxycholesterol (25-HC) plays a role in the regulation of cell survival and immunity. However, the effect of 25-HC on myocardial ischemia/reperfusion (MI/R) injury remains unknown. Our present study aimed to investigate whether 25-HC aggravated MI/R injury through NLRP3 inflammasome-mediated pyroptosis. The overlapping differentially expressed genes (DEGs) in MI/R were identified from the GSE775, GSE45818, GSE58486, and GSE46395 datasets in Gene Expression Omnibus (GEO) database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the database of Annotation, Visualization and Integration Discovery (DAVID). The protein-protein interaction (PPI) network of the overlapping DEGs was established using the Search Tool for the Retrieval of Interacting Genes (STRING) database. These bioinformatics analyses indicated that cholesterol 25-hydroxylase (CH25H) was one of the crucial genes in MI/R injury. The oxygen-glucose deprivation/reoxygenation (OGD/R) cell model was established to simulate MI/R injury. Western blot and RT-qPCR analysis demonstrated that CH25H was significantly upregulated in OGD/R-stimulated H9C2 cardiomyocytes. Moreover, knockdown of CH25H inhibited the OGD/R-induced pyroptosis and nod-like receptor protein 3 (NLRP3) inflammasome activation, as demonstrated by cell counting kit-8 (CCK8), lactate dehydrogenase (LDH), RT-qPCR, and western blotting assays. Conversely, 25-HC, which is synthesized by CH25H, promoted activation of NLRP3 inflammasome in OGD/R-stimulated H9C2 cardiomyocytes. In addition, the NLRP3 inhibitor BAY11-7082 attenuated 25-HC-induced H9C2 cell injury and pyroptosis under OGD/R condition. In conclusion, 25-HC could aggravate OGD/R-induced pyroptosis through promoting activation of NLRP3 inflammasome in H9C2 cells.


Assuntos
Glucose , Hidroxicolesteróis , Inflamassomos , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Animais , Ratos , Western Blotting , Glucose/metabolismo , Hidroxicolesteróis/metabolismo , Hidroxicolesteróis/farmacologia , Inflamassomos/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oxigênio/metabolismo , Piroptose/fisiologia
3.
J Cardiothorac Surg ; 19(1): 283, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730417

RESUMO

OBJECTIVE: Myocardial infarction (MI) -induced cardiac dysfunction can be attenuated by aerobic exercises. This study explored the mechanism of interval training (IT) regulating cardiac function in MI rats, providing some theoretical basis for clarifying MI pathogenesis and new ideas for clinically treating MI. METHODS: Rats were subjected to MI modeling, IT intervention, and treatments of the Transforming growth factor-ß1 (TGF-ß1) pathway or the nod-like receptor protein 3 (NLRP3) activators. Cardiac function and hemodynamic indicator alterations were observed. Myocardial pathological damage and fibrosis, reactive oxygen species (ROS) level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, MDA content, inflammasome-associated protein levels, and inflammatory factor levels were assessed. The binding between TGF-ß1 and receptor was detected. RESULTS: MI rats exhibited decreased left ventricle ejection fraction (LVEF), left ventricle fractional shortening  (LVFS), left ventricular systolic pressure  (LVSP), positive and negative derivates max/min (dP/dt max/min) and increased left ventricular end-systolic pressure (LVEDP), a large number of scar areas in myocardium, disordered cell arrangement and extensive fibrotic lesions, increased TGF-ß1 and receptor binding, elevated ROS level and MDA content and weakened SOD, CAT and GSH-Px activities, and up-regulated NLRP3, apoptosis-associated speck-like protein containing a CARD  (ASC) and cleaved-caspase-1 levels, while IT intervention caused ameliorated cardiac function. IT inactivated the TGF-ß1 pathway to decrease oxidative stress in myocardial tissues of MI rats and inhibit NLRP3 inflammasome activation. Activating NLRP3 partially reversed IT-mediated improvement on cardiac function in MI rats. CONCLUSION: IT diminished oxidative stress in myocardial tissues and suppressed NLRP3 inflammasome activation via inactivating the TGF-ß1 pathway, thus improving the cardiac function of MI rats.


Assuntos
Inflamassomos , Infarto do Miocárdio , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1 , Animais , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Inflamassomos/metabolismo , Masculino , Modelos Animais de Doenças , Transdução de Sinais/fisiologia , Condicionamento Físico Animal/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Função Ventricular Esquerda/fisiologia , Miocárdio/metabolismo , Miocárdio/patologia
4.
Int J Mol Sci ; 25(9)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38731826

RESUMO

Although Herpes simplex virus type 1 (HSV-1) has been deeply studied, significant gaps remain in the fundamental understanding of HSV-host interactions: our work focused on studying the Infected Cell Protein 27 (ICP27) as an inhibitor of the Absent-in-melanoma-2 (AIM 2) inflammasome pathway, leading to reduced pro-inflammatory cytokines that influence the activation of a protective innate immune response to infection. To assess the inhibition of the inflammasome by the ICP27, hTert-immortalized Retinal Pigment Epithelial cells (hTert-RPE 1) infected with HSV-1 wild type were compared to HSV-1 lacking functional ICP27 (HSV-1∆ICP27) infected cells. The activation of the inflammasome by HSV-1∆ICP27 was demonstrated by quantifying the gene and protein expression of the inflammasome constituents using real-time PCR and Western blot. The detection of the cleavage of the pro-caspase-1 into the active form was performed by using a bioluminescent assay, while the quantification of interleukins 1ß (IL-1ß) and 18 (IL-18)released in the supernatant was quantified using an ELISA assay. The data showed that the presence of the ICP27 expressed by HSV-1 induces, in contrast to HSV-1∆ICP27 vector, a significant downregulation of AIM 2 inflammasome constituent proteins and, consequently, the release of pro-inflammatory interleukins into the extracellular environment reducing an effective response in counteracting infection.


Assuntos
Citocinas , Herpesvirus Humano 1 , Proteínas Imediatamente Precoces , Inflamassomos , Epitélio Pigmentado da Retina , Humanos , Inflamassomos/metabolismo , Herpesvirus Humano 1/fisiologia , Citocinas/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Proteínas Imediatamente Precoces/genética , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/virologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Linhagem Celular , Herpes Simples/imunologia , Herpes Simples/metabolismo , Herpes Simples/virologia , Proteínas de Ligação a DNA
5.
Arch Dermatol Res ; 316(5): 156, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734816

RESUMO

Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus, and chronic skin colonization by Staphylococcus aureus. To understand the inflammatory status in AD, we investigated the inflammasome complex, that activates ASC (Apoptosis-associated speck-like protein containing a CARD), caspase-1 and GSDMD (gasdermin-D), and production of IL-1ß and IL-18. We aimed to evaluate the expression of the inflammasome pathway in the skin of adults with AD. Thirty patients with moderate to severe AD and 20 healthy controls were enrolled in the study. We performed the analysis of the inflammasome components NLRP1, NLRP3, AIM-2, IL-1ß, IL-18, Caspase-1, ASC, GSDMD, and CD68 expression (macrophage marker) by immunohistochemistry and immunofluorescence. The main findings included increased expression of NLRP3, NLRP1 and AIM-2 at dermal level of severe AD; augmented IL-18 and IL-1ß expression at epidermis of moderate and severe patients, and in the dermis of severe AD; augmented expression of ASC, caspase-1 and GSDMD in both epidermis and dermis of moderate and severe AD. We detected positive correlation between caspase-1, GSDMD and IL-1ß (epidermis) and caspase-1 (dermis) and AD severity; NLRP3, AIM-2 and IL-1ß, and NLRP3 with IL-18 in the epidermis; ASC, GSDMD and IL-1ß, and NLRP3, AIM-2, caspase-1, and IL-18 in the dermis. We also evidenced the presence of CD68+ macrophages secreting GSDMD, ASC and IL-1ß in moderate and severe AD. Cutaneous macrophages, early detected in moderate AD, have its role in the disease inflammatory mechanisms. Our study indicates a canonical activation pathway of inflammasomes, reinforced by the chronic status of inflammation in AD. The analysis of the inflammasome complex evidenced an imbalance in its regulation, with increased expression of the evaluated components, which is remarkably in severe AD, emphasizing its relevance as potential disease biomarkers and targets for immunomodulatory interventions.


Assuntos
Proteínas Adaptadoras de Sinalização CARD , Caspase 1 , Dermatite Atópica , Inflamassomos , Interleucina-18 , Interleucina-1beta , Peptídeos e Proteínas de Sinalização Intracelular , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas de Ligação a Fosfato , Humanos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Macrófagos/metabolismo , Macrófagos/imunologia , Interleucina-1beta/metabolismo , Masculino , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Adulto , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18/metabolismo , Caspase 1/metabolismo , Pele/patologia , Pele/imunologia , Pele/metabolismo , Índice de Gravidade de Doença , Pessoa de Meia-Idade , Antígenos de Diferenciação Mielomonocítica/metabolismo , Adulto Jovem , Proteínas Reguladoras de Apoptose/metabolismo , Antígenos CD/metabolismo , Proteínas NLR/metabolismo , Estudos de Casos e Controles , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologia , Gasderminas , Molécula CD68 , Proteínas de Ligação a DNA
6.
Aging Dis ; 15(3): 1006-1028, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38722788

RESUMO

While classical NOD-like receptor pyrin domain containing protein 1 (NLRP1) and NLRP3 inflammasomal proteins have been extensively investigated, the contribution of NLRP2 is still ill-defined in the nervous system. Given the putative significance of NLRP2 in orchestrating neuroinflammation, further inquiry is needed to gain a better understanding of its connectome, hence its specific targeting may hold a promising therapeutic implication. Therefore, bioinformatical approach for extracting information, specifically in the context of neuropathologies, is also undoubtedly preferred. To the best of our knowledge, there is no review study selectively targeting only NLRP2. Increasing, but still fragmentary evidence should encourage researchers to thoroughly investigate this inflammasome in various animal- and human models. Taken together, herein we aimed to review the current literature focusing on the role of NLRP2 inflammasome in the nervous system and more importantly, we provide an algorithm-based protein network of human NLRP2 for elucidating potentially valuable molecular partnerships that can be the beginning of a new discourse and future therapeutic considerations.


Assuntos
Proteínas Reguladoras de Apoptose , Inflamassomos , Humanos , Inflamassomos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sistema Nervoso/metabolismo
7.
J Cell Mol Med ; 28(9): e18286, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38742843

RESUMO

Osteosarcoma, the primary bone cancer in adolescents and young adults, is notorious for its aggressive growth and metastatic potential. Our study delved into the prognostic impact of inflammasome-related gene signatures in osteosarcoma patients, employing comprehensive genetic profiling to uncover signatures linked with patient outcomes. We identified three patient subgroups through consensus clustering, with one showing worse survival rates correlated with high FGFR3 and RARB expressions. Immune profiling revealed significant immune cell infiltration differences among these subgroups, affecting survival. Utilising advanced machine learning, including StepCox and gradient boosting machine algorithms, we developed a prognostic model with a notable c-index of 0.706, highlighting CD36 and MYD88 as key genes. Higher inflammasome risk scores from our model were associated with poorer survival, corroborated across datasets. In vitro experiments validated CD36 and MYD88's roles in promoting osteosarcoma cell proliferation, invasion and migration, emphasising their therapeutic potential. This research offers new insights into inflammasomes' role in osteosarcoma, introducing novel biomarkers for risk assessment and potential therapeutic targets. Our findings suggest a pathway towards personalised treatment strategies, potentially improving patient outcomes in osteosarcoma.


Assuntos
Biomarcadores Tumorais , Neoplasias Ósseas , Regulação Neoplásica da Expressão Gênica , Inflamassomos , Osteossarcoma , Humanos , Osteossarcoma/genética , Osteossarcoma/patologia , Osteossarcoma/imunologia , Osteossarcoma/mortalidade , Inflamassomos/metabolismo , Inflamassomos/genética , Biomarcadores Tumorais/genética , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/diagnóstico , Perfilação da Expressão Gênica , Feminino , Masculino , Transcriptoma/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Adolescente , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo
8.
Gut Microbes ; 16(1): 2351532, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38727248

RESUMO

Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.


Assuntos
Microbioma Gastrointestinal , Lipopolissacarídeos , NF-kappa B , Prevotella , Insuficiência Renal Crônica , Transdução de Sinais , Receptor 4 Toll-Like , Calcificação Vascular , Animais , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , NF-kappa B/metabolismo , Lipopolissacarídeos/metabolismo , Ratos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/microbiologia , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Humanos , Masculino , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Prevotella/metabolismo , Ratos Sprague-Dawley , Miócitos de Músculo Liso/metabolismo , Osteogênese/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fezes/microbiologia , Inflamassomos/metabolismo
9.
Nat Commun ; 15(1): 4025, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38740804

RESUMO

Intracellular membranes composing organelles of eukaryotes include membrane proteins playing crucial roles in physiological functions. However, a comprehensive understanding of the cellular responses triggered by intracellular membrane-focused oxidative stress remains elusive. Herein, we report an amphiphilic photocatalyst localised in intracellular membranes to damage membrane proteins oxidatively, resulting in non-canonical pyroptosis. Our developed photocatalysis generates hydroxyl radicals and hydrogen peroxides via water oxidation, which is accelerated under hypoxia. Single-molecule magnetic tweezers reveal that photocatalysis-induced oxidation markedly destabilised membrane protein folding. In cell environment, label-free quantification reveals that oxidative damage occurs primarily in membrane proteins related to protein quality control, thereby aggravating mitochondrial and endoplasmic reticulum stress and inducing lytic cell death. Notably, the photocatalysis activates non-canonical inflammasome caspases, resulting in gasdermin D cleavage to its pore-forming fragment and subsequent pyroptosis. These findings suggest that the oxidation of intracellular membrane proteins triggers non-canonical pyroptosis.


Assuntos
Inflamassomos , Proteínas de Membrana , Oxirredução , Piroptose , Humanos , Inflamassomos/metabolismo , Proteínas de Membrana/metabolismo , Estresse Oxidativo , Catálise , Estresse do Retículo Endoplasmático , Peróxido de Hidrogênio/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Radical Hidroxila/metabolismo , Mitocôndrias/metabolismo , Membranas Intracelulares/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Animais , Processos Fotoquímicos , Dobramento de Proteína , Caspases/metabolismo , Gasderminas
10.
Front Immunol ; 15: 1298275, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38707903

RESUMO

Background: Innate immune responses against infectious agents can act as triggers of inflammatory diseases. On the other hand, various pathogens have developed mechanisms for the evasion of the immune response, based on an inhibition of innate immunity and inflammatory responses. Inflammatory diseases could thus be controlled through the administration of pathogens or pathogen-derived molecules, capable of interfering with the mechanisms at the basis of inflammation. In this framework, the NLRP3 inflammasome is an important component in innate antimicrobial responses and a major player in the inflammatory disease. Parasites of the genus Leishmania are master manipulators of innate immune mechanisms, and different species have been shown to inhibit inflammasome formation. However, the exploitation of pathogenic Leishmania species as blockers of NLRP3-based inflammatory diseases poses safety concerns. Methods: To circumvent safety issues associated with pathogenic parasites, we focused on Leishmania tarentolae, a species of Leishmania that is not infectious to humans. Because NLRP3 typically develops in macrophages, in response to the detection and engulfment microorganisms, we performed our experiments on a monocyte-macrophage cell line (THP-1), either wild type or knockout for ASC, a key component of NLRP3 formation, with determination of cytokines and other markers of inflammation. Results: L. tarentolae was shown to possess the capability of dampening the formation of NLRP3 inflammasome and the consequent expression of pro-inflammatory molecules, with minor differences compared to effects of pathogenic Leishmania species. Conclusion: The non-pathogenic L. tarentolae appears a promising pro-biotic microbe with anti-inflammatory properties or a source of immune modulating cellular fractions or molecules, capable of interfering with the formation of the NLRP3 inflammasome.


Assuntos
Inflamassomos , Inflamação , Leishmania , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Humanos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Leishmania/imunologia , Inflamação/imunologia , Células THP-1 , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Imunidade Inata , Citocinas/metabolismo
11.
Exp Biol Med (Maywood) ; 249: 10104, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38708425

RESUMO

Seawater-drowning-induced acute lung injury (SD-ALI) is a life-threatening disorder characterized by increased alveolar-capillary permeability, an excessive inflammatory response, and refractory hypoxemia. Perfluorocarbons (PFCs) are biocompatible compounds that are chemically and biologically inert and lack toxicity as oxygen carriers, which could reduce lung injury in vitro and in vivo. The aim of our study was to explore whether the vaporization of PFCs could reduce the severity of SD-ALI in canines and investigate the underlying mechanisms. Eighteen beagle dogs were randomly divided into three groups: the seawater drowning (SW), perfluorocarbon (PFC), and control groups. The dogs in the SW group were intratracheally administered seawater to establish the animal model. The dogs in the PFC group were treated with vaporized PFCs. Probe-based confocal laser endomicroscopy (pCLE) was performed at 3 h. The blood gas, volume air index (VAI), pathological changes, and wet-to-dry (W/D) lung tissue ratios were assessed. The expression of heme oxygenase-1 (HO-1), nuclear respiratory factor-1 (NRF1), and NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasomes was determined by means of quantitative real-time polymerase chain reaction (qRT-PCR) and immunological histological chemistry. The SW group showed higher lung injury scores and W/D ratios, and lower VAI compared to the control group, and treatment with PFCs could reverse the change of lung injury score, W/D ratio and VAI. PFCs deactivated NLRP3 inflammasomes and reduced the release of caspase-1, interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) by enhancing the expression of HO-1 and NRF1. Our results suggest that the vaporization of PFCs could attenuate SD-ALI by deactivating NLRP3 inflammasomes via the HO-1/NRF1 pathway.


Assuntos
Lesão Pulmonar Aguda , Fluorocarbonos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Fluorocarbonos/farmacologia , Cães , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Água do Mar , Masculino , Afogamento/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Pulmão/metabolismo , Pulmão/efeitos dos fármacos
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 40(4): 327-332, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38710517

RESUMO

Objective To investigate the liver injury induced by chronic intermittent hypoxia (CIH) activation of NOD-like receptor pyrin domain containing protein 1 (NLRP1) inflammasome. Methods C57BL/6 male mice were randomly divided into control group and CIH group. Mice in CIH group were put into CIH chamber for molding (8 hours a day for 4 weeks). After 4 weeks of molding, liver tissue cells was observed by HE staining, and the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of mice were detected by kit. The levels of reactive oxygen species (ROS) in liver tissue were detected by dihydroethidine (DHE). The expression and localization of NLRP1, apoptosis speck-like protein containing a caspase activation and recruiting domain (ASC) and caspase-1 were detected by immunohistochemical staining. The protein expressions of NLRP1, ASC, caspase-1, interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were detected by Western blot analysis. The serum levels of IL-1ß and TNF-α were detected by ELISA. Results Compared with the control group, the CIH group exhibited significant pathological changes in hepatocytes. Hepatocytes showed signs of rupture and necrosis, accompanied by inflammatory cell aggregation. Furthermore, the levels of ALT, AST, ROS, IL-1ß and TNF-α were elevated, along with increased protein expressions of NLRP1, ASC, caspase-1, IL-1ß and TNF-α. Conclusion CIH causes liver injury by activating NLRP1 inflammasome.


Assuntos
Caspase 1 , Hipóxia , Inflamassomos , Interleucina-1beta , Fígado , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio , Animais , Masculino , Inflamassomos/metabolismo , Hipóxia/metabolismo , Hipóxia/complicações , Espécies Reativas de Oxigênio/metabolismo , Fígado/metabolismo , Fígado/patologia , Caspase 1/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Alanina Transaminase/sangue , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Aspartato Aminotransferases/sangue , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia
13.
Cardiovasc Diabetol ; 23(1): 160, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715043

RESUMO

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.


Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Fibrose , Fatores de Diferenciação de Crescimento , Inflamassomos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Piroptose , Transdução de Sinais , Animais , Piroptose/efeitos dos fármacos , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Linhagem Celular , Inflamassomos/metabolismo , Masculino , Fatores de Diferenciação de Crescimento/metabolismo , Ratos , Glicemia/metabolismo , Camundongos , Glucose/metabolismo , Glucose/toxicidade , Proteínas Morfogenéticas Ósseas , PPAR alfa
14.
Front Immunol ; 15: 1248907, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720893

RESUMO

Introduction: Sepsis remains a major cause of death in Intensive Care Units. Sepsis is a life-threatening multi-organ dysfunction caused by a dysregulated systemic inflammatory response. Pattern recognition receptors, such as TLRs and NLRs contribute to innate immune responses. Upon activation, some NLRs form multimeric protein complexes in the cytoplasm termed "inflammasomes" which induce gasdermin d-mediated pyroptotic cell death and the release of mature forms of IL-1ß and IL-18. The NLRP6 inflammasome is documented to be both a positive and a negative regulator of host defense in distinct infectious diseases. However, the role of NLRP6 in polymicrobial sepsis remains elusive. Methods: We have used NLRP6 KO mice and human septic spleen samples to examine the role of NLRP6 in host defense in sepsis. Results: NLRP6 KO mice display enhanced survival, reduced bacterial burden in the organs, and reduced cytokine/chemokine production. Co-housed WT and KO mice following sepsis show decreased bacterial burden in the KO mice as observed in singly housed groups. NLRP6 is upregulated in CD3, CD4, and CD8 cells of septic patients and septic mice. The KO mice showed a higher number of CD3, CD4, and CD8 positive T cell subsets and reduced T cell death in the spleen following sepsis. Furthermore, administration of recombinant IL-18, but not IL-1ß, elicited excessive inflammation and reversed the survival advantages observed in NLRP6 KO mice. Conclusion: These results unveil NLRP6 as a negative regulator of host defense during sepsis and offer novel insights for the development of new treatment strategies for sepsis.


Assuntos
Camundongos Knockout , Sepse , Animais , Sepse/imunologia , Sepse/microbiologia , Humanos , Camundongos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Camundongos Endogâmicos C57BL , Masculino , Citocinas/metabolismo , Feminino , Imunidade Inata , Modelos Animais de Doenças , Baço/imunologia , Receptores de Superfície Celular , Peptídeos e Proteínas de Sinalização Intracelular
15.
Front Immunol ; 15: 1342350, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38720901

RESUMO

Dyslipidemia is the most prevalent independent risk factor for patients with chronic kidney disease (CKD). Lipid-induced NLRP3 inflammasome activation in kidney-resident cells exacerbates renal injury by causing sterile inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox balance; however, the exact role of Nrf2 signaling and its regulation of the NLRP3 inflammasome in hyperlipidemia-induced kidney injury are poorly understood. In this study, we demonstrated that activation of the mtROS-NLRP3 inflammasome pathway is a critical contributor to renal tubular epithelial cell (RTEC) apoptosis under hyperlipidemia. In addition, the Nrf2/ARE signaling pathway is activated in renal tubular epithelial cells under hyperlipidemia conditions both in vivo and in vitro, and Nrf2 silencing accelerated palmitic acid (PA)-induced mtROS production, mitochondrial injury, and NLRP3 inflammasome activation. However, the activation of Nrf2 with tBHQ ameliorated mtROS production, mitochondrial injury, NLRP3 inflammasome activation, and cell apoptosis in PA-induced HK-2 cells and in the kidneys of HFD-induced obese rats. Furthermore, mechanistic studies showed that the potential mechanism of Nrf2-induced NLRP3 inflammasome inhibition involved reducing mtROS generation. Taken together, our results demonstrate that the Nrf2/ARE signaling pathway attenuates hyperlipidemia-induced renal injury through its antioxidative and anti-inflammatory effects through the downregulation of mtROS-mediated NLRP3 inflammasome activation.


Assuntos
Células Epiteliais , Hiperlipidemias , Inflamassomos , Túbulos Renais , Fator 2 Relacionado a NF-E2 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Hiperlipidemias/metabolismo , Hiperlipidemias/complicações , Hiperlipidemias/imunologia , Células Epiteliais/metabolismo , Ratos , Humanos , Túbulos Renais/patologia , Túbulos Renais/metabolismo , Masculino , Linhagem Celular , Apoptose , Elementos de Resposta Antioxidante , Mitocôndrias/metabolismo , Modelos Animais de Doenças , Ratos Sprague-Dawley
16.
Sci Rep ; 14(1): 10178, 2024 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702410

RESUMO

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been associated with worse outcomes from severe traumatic brain injury (TBI). The NLRP3 inflammasome is also strongly associated with other pro-inflammatory conditions, such as obesity. Little is known about the potential effect of mild TBI (mTBI) on the NLRP3 inflammasome and the extent to which modifying factors, such as obesity, may augment the inflammatory response to mTBI. The purpose of this study was to evaluate the association of NLRP3 inflammasome proteins with obese body mass index (BMI ≥ 30) within 24 h of mTBI after presenting to a level 1 trauma center emergency department. This is a secondary analysis of prospectively enrolled patients with mTBI who presented to the emergency department of one U.S. Level 1 trauma center from 2013 to 2018 (n = 243). A series of regression models were built to evaluate the association of NLRP3 proteins obtained from blood plasma within 24 h of injury and BMI as well as the potential interaction effect of higher BMI with NLRP3 proteins (n = 243). A logistic regression model revealed a significant association between IL-18 (p < 0.001) in mTBI patients with obese BMI compared to mTBI patients with non-obese BMI (< 30). Moderation analyses revealed statistically significant interaction effects between apoptotic speck-like protein (ASC), caspase-1, IL-18, IL-1ß and obese BMI which worsened symptom burden, quality of life, and physical function at 2 weeks and 6 months post-injury. Higher acute concentrations of IL-1ß in the overall cohort predicted higher symptoms at 6-months and worse physical function at 2-weeks and 6-months. Higher acute concentrations of IL-18 in the overall cohort predicted worse physical function at 6-months. In this single center mTBI cohort, obese BMI interacted with higher acute concentrations of NLRP3 inflammasome proteins and worsened short- and long-term clinical outcomes.


Assuntos
Índice de Massa Corporal , Concussão Encefálica , Inflamassomos , Interleucina-18 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Obesidade , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Masculino , Feminino , Obesidade/complicações , Inflamassomos/metabolismo , Adulto , Pessoa de Meia-Idade , Concussão Encefálica/complicações , Concussão Encefálica/sangue , Interleucina-18/sangue , Interleucina-18/metabolismo , Estudos Prospectivos , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Caspase 1/metabolismo
17.
Front Immunol ; 15: 1344098, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38711511

RESUMO

Inflammatory responses, especially chronic inflammation, are closely associated with many systemic diseases. There are many ways to treat and alleviate inflammation, but how to solve this problem at the molecular level has always been a hot topic in research. The use of nanoparticles (NPs) as anti-inflammatory agents is a potential treatment method. We synthesized new hollow cerium oxide nanomaterials (hCeO2 NPs) doped with different concentrations of Cu5.4O NPs [the molar ratio of Cu/(Ce + Cu) was 50%, 67%, and 83%, respectively], characterized their surface morphology and physicochemical properties, and screened the safe concentration of hCeO2@Cu5.4O using the CCK8 method. Macrophages were cultured, and P.g-lipopolysaccharide-stimulated was used as a model of inflammation and co-cultured with hCeO2@Cu5.4O NPs. We then observe the effect of the transcription levels of CTSB, NLRP3, caspase-1, ASC, IL-18, and IL-1ß by PCR and detect its effect on the expression level of CTSB protein by Western blot. The levels of IL-18 and IL-1ß in the cell supernatant were measured by enzyme-linked immunosorbent assay. Our results indicated that hCeO2@Cu5.4O NPs could reduce the production of reactive oxygen species and inhibit CTSB and NLRP3 to alleviate the damage caused by the inflammatory response to cells. More importantly, hCeO2@Cu5.4O NPs showed stronger anti-inflammatory effects as Cu5.4O NP doping increased. Therefore, the development of the novel nanomaterial hCeO2@Cu5.4O NPs provides a possible new approach for the treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios , Cério , Cobre , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cério/farmacologia , Cério/química , Transdução de Sinais/efeitos dos fármacos , Animais , Camundongos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Anti-Inflamatórios/farmacologia , Nanopartículas , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
18.
J Med Virol ; 96(5): e29643, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38695269

RESUMO

Severe pneumonia caused by respiratory viruses has become a major threat to humans, especially with the SARS-CoV-2 outbreak and epidemic. The aim of this study was to investigate the universal molecular mechanism of severe pneumonia induced by multiple respiratory viruses and to search for therapeutic strategies targeting this universal molecular mechanism. The common differential genes of four respiratory viruses, including respiratory syncytial virus (RSV), rhinovirus, influenza, and SARS-CoV-2, were screened by GEO database, and the hub gene was obtained by Sytohubba in Cytoscape. Then, the effect of hub genes on inflammasome and pyrodeath was investigated in the model of RSV infection in vitro and in vivo. Finally, through virtual screening, drugs targeting the hub gene were obtained, which could alleviate severe viral pneumonia in vitro and in vivo. The results showed that CMPK2 is one of the hub genes after infection by four respiratory viruses. CMPK2 activates the inflammasome by activating NLRP3, and promotes the releases of inflammatory factors interleukin (IL)-1ß and IL-18 to induce severe viral pneumonia. Z25 and Z08 can reduce the expression level of CMPK2 mRNA and protein, thereby inhibiting NLRP3 and alleviating the development of severe viral pneumonia. In conclusion, the inflammatory response mediated by CMPK2 is the common molecular mechanism of severe pneumonia induced by viral infection, and Z25 and Z08 can effectively alleviate viral infection and severe pneumonia through this mechanism.


Assuntos
Inflamassomos , Piroptose , Piroptose/efeitos dos fármacos , Humanos , Animais , Inflamassomos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Interleucina-18/metabolismo , Interleucina-18/genética , SARS-CoV-2 , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia
19.
Int J Mol Sci ; 25(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38732221

RESUMO

Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years. At present, there is no other effective intervention except surgical treatment for AAA. With the aging of the human population, its incidence is increasing year by year, posing a serious threat to human health. Modern studies suggest that vascular chronic inflammatory response is the core process in AAA occurrence and development. Inflammasome, a multiprotein complex located in the cytoplasm, mediates the expression of various inflammatory cytokines like interleukin (IL)-1ß and IL-18, and thus plays a pivotal role in inflammation regulation. Therefore, inflammasome may exert a crucial influence on the progression of AAA. This article reviews some mechanism studies to investigate the role of inflammasome in AAA and then summarizes several potential drugs targeting inflammasome for the treatment of AAA, aiming to provide new ideas for the clinical prevention and treatment of AAA beyond surgical methods.


Assuntos
Aneurisma da Aorta Abdominal , Inflamassomos , Aneurisma da Aorta Abdominal/metabolismo , Humanos , Inflamassomos/metabolismo , Animais , Inflamação/metabolismo
20.
Rev Int Androl ; 22(1): 44-52, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38735877

RESUMO

Whether chronic inflammation in the genital tract induced by obesity shares in spermatogenic dysfunction is not clearly known. We aimed to study the effect of high fat diet (HFD) on spermatogenesis, seminal oxidative stress (malondialdehyde (MDA)) and inflammatory markers (high mobility group box 1 (HMGB1), nucleotide-binding oligomerization domain, leucine rich repeat and pyrin-3 domain containing (NLRP3)) in the rat testes and the role of zinc on testicular dysfunction and chronic inflammation in high fat diet (HFD) fed rat testes. This parallel group comparative experimental study included 36 male wistar rats divided into 3 groups: group A (fed on normal control diet); group B (fed on high fat diet (HFD) only); and group C (fed on HFD with zinc supplementation 3.2 mg/kg/day orally). At the end of the 12th week, sperm count, viability and motility were assessed by computer-assisted seemen analysis (CASA), seminal malondialdehyde measured by calorimetry and histopathological examination of testicular sections was done. Immunohistochemical staining was done for HMGB1 and NLRP3 evaluation. Sperm count was lowest in group B. Groups A and C showed statistically significant higher mean sperm vitality, total and progressive motility scores (p < 0.001), while no difference was found between the groups A and C (p > 0.05). Seminal malondialdehyde level was significantly highest in group B. Tubular diameter, epithelial height and Johnsen score were significantly lowest in group B. Significantly higher HMGB1 and NLRP3 levels were demonstrated in group B (p < 0.001). Obesity is associated with testicular dysfunction, testicular oxidative stress and increased testicular HMGB1 and NLRP3. We suggest a beneficial effect of zinc on testicular function in HFD-rats.


Assuntos
Dieta Hiperlipídica , Proteína HMGB1 , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo , Ratos Wistar , Espermatogênese , Testículo , Zinco , Animais , Masculino , Proteína HMGB1/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ratos , Espermatogênese/efeitos dos fármacos , Zinco/administração & dosagem , Testículo/efeitos dos fármacos , Testículo/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Malondialdeído/metabolismo , Malondialdeído/análise , Inflamação/etiologia , Inflamação/metabolismo , Espermatozoides/efeitos dos fármacos , Obesidade/metabolismo
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