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1.
Microbiologyopen ; 13(3): e23, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38867416

RESUMO

The G protein-coupled estrogen receptor, also known as GPER1 or originally GPR30, is found in various tissues, indicating its diverse functions. It is typically present in immune cells, suggesting its role in regulating immune responses to infectious diseases. Our previous studies have shown that G-1, a selective GPER agonist, can limit the pathogenesis mediated by Staphylococcus aureus alpha-hemolysin (Hla). It aids in clearing bacteria in a mouse skin infection model and restricts the surface display of the Hla receptor, ADAM10 (a disintegrin and metalloprotease 10) in HaCaT keratinocytes. In this report, we delve into the modulation of GPER in human immune cells in relation to the NLRP3 inflammasome. We used macrophage-like differentiated THP-1 cells for our study. We found that treating these cells with G-1 reduces ATP release, decreases the activity of the caspase-1 enzyme, and lessens cell death following Hla intoxication. This is likely due to the reduced levels of ADAM10 and NLRP3 proteins, as well as the decreased display of the ADAM10 receptor in the G-1-treated THP-1 cells. Our studies, along with our previous work, suggest the potential therapeutic use of G-1 in reducing Hla susceptibility in humans. This highlights the importance of GPER in immune regulation and its potential as a therapeutic target.


Assuntos
Proteína ADAM10 , Secretases da Proteína Precursora do Amiloide , Toxinas Bacterianas , Proteínas Hemolisinas , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Staphylococcus aureus , Proteína ADAM10/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Humanos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Hemolisinas/metabolismo , Inflamassomos/metabolismo , Toxinas Bacterianas/metabolismo , Células THP-1 , Receptores de Estrogênio/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/agonistas , Caspase 1/metabolismo , Trifosfato de Adenosina/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/microbiologia , Dipeptídeos , Ácidos Hidroxâmicos
2.
Immun Inflamm Dis ; 12(6): e1309, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38860765

RESUMO

BACKGROUND: Astragaloside IV (AS-IV) is the most active monomer in the traditional Chinese herbal medicine Radix Astragali, which has a wide range of antiviral, anti-inflammatory, and antifibrosis pharmacological effects, and shows protective effects in acute lung injury. METHODS: This study utilized the immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, western blot, and hematoxylin and eosin staining methods to investigate the mechanism of AS-IV in reducing viral pneumonia caused by influenza A virus in A549 cells and BALB/c mice. RESULTS: The results showed that AS-IV suppressed reactive oxygen species production in influenza virus-infected A549 cells in a dose-dependent manner, and subsequently inhibited the activation of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 inflammasome and Caspase-1, decreased interleukin (IL) -1ß and IL-18 secretion. In BALB/c mice infected with Poly (I:C), oral administration of AS-IV can significantly reduce Poly (I:C)-induced acute pneumonia and lung pathological injury. CONCLUSIONS: AS-IV alleviates the inflammatory response induced by influenza virus in vitro and lung flammation and structural damage caused by poly (I:C) in vivo.


Assuntos
Caspase 1 , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR , Infecções por Orthomyxoviridae , Espécies Reativas de Oxigênio , Saponinas , Transdução de Sinais , Triterpenos , Animais , Saponinas/farmacologia , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Camundongos , Transdução de Sinais/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Caspase 1/metabolismo , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamação/tratamento farmacológico , Vírus da Influenza A/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
3.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(5): 810-817, 2024 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-38862438

RESUMO

OBJECTIVE: To explore the neuroprotective effect of coenzyme Q10 and its possible mechanism in mice with chronic restraint stress (CRS). METHODS: Mouse models of CRS were treated with intraperitoneal injections of coenzyme Q10 at low, moderate and high doses (50, 100 and 200 mg/kg, respectively, n=8), VX765 (a caspase-1 specific inhibitor, 50 mg/kg, n=8), or fluoxetine (10 mg/kg, n=8) on a daily basis for 4 weeks, and the changes in depression-like behaviors of the mice were assessed by sugar water preference test, forced swimming test and tail suspension test. The expression of glial fibrillary acidic protein (GFAP) in the hippocampus of the mice was detected using immunohistochemistry, and the number of synaptic spines was determined with Golgi staining. Western blotting was performed to detect the changes in the expressions of GFAP and pyroptosis-related proteins in the hippocampus, and the colocalization of neurons and caspase-1 p10 was examined with immunofluorescence assay. RESULTS: Compared with the normal control mice, the mouse models of CRS showed significantly reduced sugar water preference and increased immobility time in forced swimming and tail suspension tests (P < 0.05), and these depression-like behaviors were obviously improved by treatment with coenzyme Q10, VX765 or FLX. The mouse models showed a significantly decreased positive rate of GFAP and lowered GFAP protein expression in the hippocampus with obviously decreased synaptic spines, enhanced expressions of GSDMD-N, caspase-1 and IL-1ß, and increased colocalization of neurons and caspase-1 p10 (all P < 0.05). All these changes were significantly ameliorated in the mouse models after treatment with Q10. CONCLUSION: Coenzyme Q10 can alleviate depression-like behaviors in mice with CRS by down-regulating the pyroptosis signaling pathway.


Assuntos
Depressão , Modelos Animais de Doenças , Hipocampo , Piroptose , Restrição Física , Transdução de Sinais , Estresse Psicológico , Ubiquinona , Animais , Camundongos , Piroptose/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Caspase 1/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Comportamento Animal/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
4.
Mol Med Rep ; 30(2)2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38873985

RESUMO

Macrophage pyroptosis mediates vascular inflammation and atherosclerosis (AS). Hydrogen sulfide (H2S) exerts a protective role in preventing inflammation and AS. However, its molecular mechanisms of regulating the pyroptosis signaling pathway and inhibiting macrophage pyroptosis remain unexplored. The present study aimed to determine whether H2S mitigates macrophage pyroptosis by downregulating the pyroptosis signaling pathway and S­sulfhydrating caspase­1 under the stimulation of oxidized low­density lipoprotein (ox­LDL), a pro­atherosclerotic factor. Macrophages derived from THP­1 monocytes were pre­treated using exogenous H2S donors sodium hydrosulfide (NaHS) and D,L­propargylglycine (PAG), a pharmacological inhibitor of endogenous H2S­producing enzymes, alone or in combination. Subsequently, cells were stimulated with ox­LDL or the desulfhydration reagent dithiothreitol (DTT) in the presence or absence of NaHS and/or PAG. Following treatment, the levels of H2S in THP­1 derived macrophages were measured by a methylene blue colorimetric assay. The pyroptotic phenotype of THP­1 cells was observed and evaluated by light microscopy, Hoechst 33342/propidium iodide fluorescent staining and lactate dehydrogenase (LDH) release assay. Caspase­1 activity in THP­1 cells was assayed by caspase­1 activity assay kit. Immunofluorescence staining was used to assess the accumulation of active caspase­1. Western blotting and ELISA were performed to determine the expression of pyroptosis­specific markers (NLRP3, pro­caspase­1, caspase­1, GSDMD and GSDMD­N) in cells and the secretion of pyroptosis­related cytokines [interleukin (IL)­1ß and IL­18] in the cell­free media, respectively. The S­sulfhydration of pro­caspase­1 in cells was assessed using a biotin switch assay. ox­LDL significantly induced macrophage pyroptosis by activating the pyroptosis signaling pathway. Inhibition of endogenous H2S synthesis by PAG augmented the pro­pyroptotic effects of ox­LDL. Conversely, exogenous H2S (NaHS) ameliorated ox­LDL­and ox­LDL + PAG­induced macrophage pyroptosis by suppressing the activation of the pyroptosis signaling pathway. Mechanistically, ox­LDL and the DTT increased caspase­1 activity and downstream events (IL­1ß and IL­18 secretion) of the caspase­1­dependent pyroptosis pathway by reducing S­sulfhydration of pro­caspase­1. Conversely, NaHS increased S­sulfhydration of pro­caspase­1, reducing caspase­1 activity and caspase­1­dependent macrophage pyroptosis. The present study demonstrated the molecular mechanism by which H2S ameliorates macrophage pyroptosis by suppressing the pyroptosis signaling pathway and S­sulfhydration of pro­caspase­1, thereby suppressing the generation of active caspase-1 and activity of caspase-1.


Assuntos
Caspase 1 , Sulfeto de Hidrogênio , Lipoproteínas LDL , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas de Ligação a Fosfato , Piroptose , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Piroptose/efeitos dos fármacos , Humanos , Caspase 1/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , Proteínas de Ligação a Fosfato/metabolismo , Células THP-1 , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Gasderminas , Alcinos , Glicina/análogos & derivados , Sulfetos
5.
Folia Biol (Praha) ; 70(1): 74-83, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38830125

RESUMO

Chlamydia psittaci pneumonia (CPP) is a lung disease caused by the infection with the Chla-mydia psittaci bacterium, which can lead to severe acute respiratory distress syndrome and systemic symptoms. This study explored the specific mechanisms underlying the impact of reactive oxygen species (ROS) on the Th17/Treg balance in CPP. The levels of ROS and the differentiation ratio of Th17/Treg in the peripheral blood of healthy individuals and CPP patients were measured using ELISA and flow cytometry, respectively. The association between the ROS levels and Th17/Treg was assessed using Pearson correlation analysis. The ROS levels and the Th17/Treg ratio were measured in CD4+ T cells following H2O2 treatment and NLRP3 inhibition. The effects of H2O2 treatment and NLRP3 inhibition on the NLRP3/IL-1ß/caspase-1 pathway were observed using immunoblotting. Compared to the healthy group, the CPP group exhibited increased levels of ROS in the peripheral blood, an elevated ratio of Th17 differentiation, and a decreased ratio of Treg differentiation. ROS levels were positively correlated with the Th17 cell proportion but negatively correlated with the Treg cell proportion. The ROS levels and NLRP3/IL-1ß/caspase-1 expression were up-regulated in CD4+ T cells after H2O2 treatment. Furthermore, there was an increase in Th17 differentiation and a decrease in Treg differentiation. Conversely, the NLRP3/IL-1ß/caspase-1 pathway inhibition reversed the effects of H2O2 treatment, with no significant change in the ROS levels. ROS regulates the Th17/Treg balance in CPP, possibly through the NLRP3/IL-1ß/caspase-1 pathway. This study provides a new perspective on the development of immunotherapy for CPP.


Assuntos
Caspase 1 , Diferenciação Celular , Chlamydophila psittaci , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , Espécies Reativas de Oxigênio , Linfócitos T Reguladores , Células Th17 , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Reguladores/imunologia , Caspase 1/metabolismo , Diferenciação Celular/efeitos dos fármacos , Interleucina-1beta/metabolismo , Transdução de Sinais , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Peróxido de Hidrogênio/metabolismo , Psitacose
6.
J Neuroinflammation ; 21(1): 151, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840215

RESUMO

BACKGROUND: Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes. METHODS: 5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated. RESULTS: The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established. CONCLUSIONS: Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.


Assuntos
Caspase 1 , Dieta Cetogênica , Camundongos Transgênicos , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Caspase 1/metabolismo , Dieta Cetogênica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Carboidratos da Dieta/farmacologia , Sistema Nervoso Central/metabolismo , Microbioma Gastrointestinal/fisiologia , Camundongos Endogâmicos C57BL
7.
Pestic Biochem Physiol ; 202: 105930, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38879323

RESUMO

Due to the widespread use of metolachlor (MET), the accumulation of MET and its metabolites in the environment has brought serious health problems to aquatic organisms. At present, the toxicity of MET on the physiological metabolism of aquatic animals mainly focused on the role of enzymes. There is still a lack of research on the molecular mechanisms of MET hepatotoxicity, especially on antagonizing MET toxicity. Therefore, this study focuses on grass carp hepatocytes (L8824 cells) closely related to toxin accumulation. By establishing a MET exposed L8824 cells model, it is determined that MET exposure induces pyrolytic inflammation of L8824 cells. Subsequent mechanistic studies found that MET exposure induces pyroptosis in L8824 cells through mitochondrial dysfunction, and siCaspase-1 inhibits the MET induced ROS production, suggesting a regulation of ROS-NLRP3- Caspase-1 pyroptotic inflammation cycling center in MET induced injury to L8824 cells. Molecular docking revealed a strong binding energy between melatonin (MT) and Caspase-1. Finally, a model of L8824 cells with MT intervention in MET exposure was established. MT can antagonize the pyroptosis induced by MET exposure in L8824 cells by targeting Caspase-1, thereby restoring mitochondrial function and inhibiting the ROS-pyroptosis cycle. This study discovered targets and mechanisms of MT regulating pyroptosis in MET exposed-L8824 cells, and the results are helpful to provide new targets for the design of MET antidotes.


Assuntos
Acetamidas , Carpas , Hepatócitos , Melatonina , Simulação de Acoplamento Molecular , Animais , Carpas/metabolismo , Melatonina/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Acetamidas/toxicidade , Acetamidas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular , Piroptose/efeitos dos fármacos , Caspase 1/metabolismo , Herbicidas/toxicidade , Simulação por Computador , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
8.
Environ Res ; 255: 119210, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38795947

RESUMO

Chronic lead (Pb) exposure causes neurodysfunction and contributes to the development of neurodegenerative disease. However, the mechanism of Pb-induced neurological dysfunction have yet to be fully elucidated. This study determined the role pyroptosis plays in Pb-induced neurodysfunction in neurons. We used both in vitro and in vivo approaches to explore whether Pb exposure induces caspase-1-mediated pyroptosis in neurons and its relationship to Pb-induced neurological disorders. Our findings showed that caspase-1-mediated pyroptosis in Pb-exposed neurons activated glycogen synthase kinase 3 protease activity by disrupting Ca2+/calmodulin-dependent protein kinase II/cAMP-response element binding protein pathway, leading to neurological disorders. Moreover, the caspase-1 inhibition VX-765 or the non-steroidal anti-inflammatory drug sodium para-aminosalicylic acid (PAS-Na) attenuated the Pb-induced neurological disorders by alleviating caspase-1 mediated neuronal pyroptosis. Our novel studies suggest that caspase-1-mediated pyroptosis in neurons represents a potential mechanism for Pb-induced neurodysfunction, identifying a putative target for attenuating the neurodegenerative effects induced by this metal.


Assuntos
Caspase 1 , Chumbo , Neurônios , Piroptose , Piroptose/efeitos dos fármacos , Animais , Caspase 1/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Chumbo/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Masculino , Dipeptídeos , para-Aminobenzoatos
9.
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
10.
Biomed Pharmacother ; 175: 116797, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38776675

RESUMO

Cisplatin (CIS) stands as one of the most effective chemotherapy drugs currently available. Despite its anticancer properties, the clinical application of CIS is restricted due to nephrotoxicity. Our research aimed to specify the impact of ketotifen fumarate (KET) against nephrotoxicity induced by CIS in mice. Male NMRI mice were treated with KET (0.4, 0.8, and 1.6 mg/kg, ip) for seven days. On the fourth day of the study, a single dose of CIS (13 mg/kg, ip) was administered, and the mice were sacrificed on the eighth day. The results indicated that administration of KET attenuated CIS-induced elevation of BUN and Cr in the serum, as well as renal KIM-1 levels. This improvement was accompanied by a significant reduction in kidney tissue damage, which was supported by histopathological examinations. Likewise, the decrease in the ratio of GSH to GSSG and antioxidant enzyme activities (CAT, SOD, and GPx), and the increase in lipid peroxidation marker (TBARS) were reversed in KET-treated mice. The ELISA results revealed that KET-treated mice ameliorated CIS-induced elevation in the renal levels of TNF-α, IL-1ß, and IL-18. Western blot analysis exhibited that KET suppressed the activation of the transcription factor NF-κB and the NLRP3 inflammasome in the kidney of CIS-treated mice. Moreover, KET treatment reversed the changes in the protein expression of markers related to apoptosis (Bax, Bcl2, Caspase-3, and p53). Interestingly, KET significantly enhanced the cytotoxicity of CIS in HeLa cells. In conclusion, this study provides valuable insights into the promising effects of KET in mitigating CIS-induced nephrotoxicity.


Assuntos
Injúria Renal Aguda , Caspase 1 , Caspase 3 , Cisplatino , Cetotifeno , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais , Proteína X Associada a bcl-2 , Animais , Cisplatino/toxicidade , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Caspase 1/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Caspase 3/metabolismo , Humanos , Cetotifeno/farmacologia , Proteína X Associada a bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Células HeLa , Estresse Oxidativo/efeitos dos fármacos
11.
Biochem Biophys Res Commun ; 717: 149978, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38718564

RESUMO

Caspase-1 is one of the main mediators of inflammatory caspases and has become a correspondent with inflammation, cell death, and several inflammatory diseases. In this review, we systematically summarize both original and recent advances in caspase-1 to provide references for a better understanding of the molecular mechanisms in its activation and functions. This study investigates and summarizes the published articles concerning caspase-1, inflammation, pyroptosis, apoptosis, and cell death by searching academic search systems, including the PubMed, Web of Science, and Google Scholar. Caspase-1 is one of the main mediators of inflammatory caspases and has become a correspondent with inflammation and cell death. In cell death, caspase-1 was originally found to cause apoptosis in fibroblasts. Importantly, caspase-1 was later reported to execute programmed cell death, including pyroptosis and apoptosis, in many immune cells in response to diverse stimuli. It is widely established that different pathways can activate caspase-1 and subsequently mediate cell death and inflammation. It has become increasingly clear that caspase-1 is responsible for the initiation and control of pyroptosis, apoptosis, and inflammation in addition to its well-known function in cleaving IL-1ß. The significant advancement in the understanding of caspase-1-controlled cell death and novel substrates inspires new therapeutic approaches in the future.


Assuntos
Apoptose , Caspase 1 , Piroptose , Caspase 1/metabolismo , Humanos , Animais , Ativação Enzimática , Inflamação/metabolismo , Inflamação/patologia , Transdução de Sinais
12.
Artigo em Chinês | MEDLINE | ID: mdl-38802305

RESUMO

Objective: To explore the effect of the absent in melanoma 2 (AIM2) -mediated neuroinflammation in noise-induced cognitive dysfunction in rats. Methods: In April 2023, sixteen male Wistar rats were randomly divided into control group and noise group, with 8 rats in each group. The rats in the noise group were placed in 50 cm×50 cm×40 cm transparent boxes and exposed to 100 dB (A) white noise with a sound pressure level of 100 dB (A) (4 h/d for 30 d) . At the same time, rats in the control group were kept in similar boxes with environmental noise less than 60 dB (A) . After 30 days of noise exposure, the Morris water maze experiment was applied to test the learning and memory abilities of the rats; the pathological morphology of hippocampal tissues was observed by Hematoxylin-Eosin (HE) staining. Western blot was used to detect the protein expression levels of AIM2, cysteinyl aspartate specific proteinase-1 (caspase-1) , apoptosis-associated speck-like protein (ASC) , interleukin-1ß (IL-1ß) , IL-18, ionic calcium-binding articulation molecule-1 (Iba-1) , and glial fibrillary acidic protein (GFAP) . The expression of both Iba-1 and GFAP in hippocampal tissue was assessed by immunohistochemical staining. The co-localization of AIM2 with Iba-1 or GFAP was determined by immunofluorescence double staining. Results: Compared with the control group, the escape latency of rats in the noise group was increased by 16.29 s, 17.71 s, and 20.26 s on days 3, 4, and 5, respectively. On day 6, the noise-exposed rats spent shorter time in the target quadrant and had fewer times in crossing the platform[ (7.25±2.27) s and (1.13±0.64) times] than the control group[ (15.64±3.99) s and (4.25±2.12) times] (P<0.05) . After noise exposure, hippocampal neurons of rats displayed marked nuclear hyperchromatic and pyknosis phenomenon. The noise-exposed rats had higher numbers of both microglia and astrocytes (27.00±2.65 and 43.33±5.51) in the DG area of the hippocampus relative to the control group (14.67±3.06 and 20.00±4.58) (P<0.05) . Moreover, the glial cells in the noise group had larger cell cytosol with more and thicker branches. The protein expression levels of inflammatory cytokines Cleaved-IL-1ß and Cleaved-IL-18 in the hippocampus of rats in the noise group (1.55±0.19 and 1.74±0.12) were significantly higher than the control group (1.00±0.11 and 1.00±0.13) (P<0.05) . After noise exposure, the protein expression levels of AIM2, Cleaved-Caspase-1 and ASC (1.19±0.09, 1.34±0.07 and 1.14±0.01) were higher than the control group (1.00±0.07, 1.00±0.14 and 1.00±0.06) and differences between the two groups were statistically significant (P<0.05) . A significant increase in the number of cells co-localizing AIM2 with Iba-1 or GFAP in the noise group (28.67±4.04 and 40.67±5.13) compared with the control group (15.67±4.04 and 17.67±3.79) , and statistically significant differences were observed between the two groups (P<0.05) . Conclusion: Noise exposure may activate the AIM2 inflammasome in hippocampal glial cells of rats, releasing excessive inflammatory cytokines and causing neuroinflammation that damages neurons.


Assuntos
Disfunção Cognitiva , Hipocampo , Inflamassomos , Interleucina-18 , Ruído , Ratos Wistar , Animais , Ratos , Masculino , Ruído/efeitos adversos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/etiologia , Inflamassomos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Proteínas de Ligação a DNA/metabolismo , Caspase 1/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Aprendizagem em Labirinto
13.
Chem Biol Interact ; 397: 111083, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38821455

RESUMO

Lung cancer stem cells (CSCs) drive continuous cancer growth and metastatic dissemination; thus, there is an urgent requirement to acquire effective therapeutic strategies for targeting lung CSCs. Diallyl trisulfide (DATS), a garlic organosulfide, possesses suppressive potential in lung cancer; however, its underlying mechanism is still unclear. In this study, we identified DATS as a pyroptosis inducer in lung cancer cells. DATS-treated A549 and H460 cells exhibited pyroptotic cell death, with characteristic large bubbles appearing on their plasma membrane and LDH release. DATS induced cell death, arrested the cell cycle at the G2/M phase, and inhibited colony formation in lung cancer cells. Meanwhile, we found that DATS significantly suppressed the malignant features by impairing lung CSC-like properties, including sphere formation ability, CD133 positive cell number, and lung CSCs marker expression. Mechanistically, DATS induced cell pyroptosis via increasing the expression of NLRP3, ASC, Pro Caspase 1, Cleaved Caspase 1, GSDMD, GSDMD-N, and IL-1ß. The verification experiments showed that the effects of DATS on pyroptosis and lung CSC-like properties were weakened after Caspase 1 inhibitor VX-765 treatment, indicating that DATS activated NLRP3 inflammasome-mediated pyroptosis by targeting Caspase 1 in lung cancer cells. Moreover, DATS increased ROS overproduction and mitochondrial dysfunction, which contributed to DATS-induced pyroptosis of lung cancer cells. NAC treatment reversed the effects of DATS on pyroptosis and CSC-like properties. In vivo experiment further confirmed that DATS restrained tumor growth. Together, our results suggest that DATS promotes pyroptosis and impairs lung CSC-like properties by activating ROS/Caspase 1 signaling pathway, thereby retarding lung cancer progression.


Assuntos
Compostos Alílicos , Caspase 1 , Neoplasias Pulmonares , Células-Tronco Neoplásicas , Piroptose , Espécies Reativas de Oxigênio , Transdução de Sinais , Sulfetos , Piroptose/efeitos dos fármacos , Compostos Alílicos/farmacologia , Sulfetos/farmacologia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Caspase 1/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Transdução de Sinais/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células A549
14.
Mol Biol Rep ; 51(1): 655, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38739285

RESUMO

BACKGROUND: There is limited data regarding the hazardous effect of gentamicin (GM) on the uterus and whether or not vinpocetine (Vinpo) ameliorates it. The present study aimed to identify the possible protective effect of Vinpo in GM-induced uterine injury in rats. METHODS: Female rats were assorted in control-group, Vinpo-group, GM-group, and Vinpo plus GM group. Serum and uterine GM concentration were measured. Uterine oxidative stress parameters besides inflammatory and apoptotic biomarkers were evaluated. Uterine histopathological examination and interlukin-1beta (IL-1ß) immune-histochemical study were detected. RESULTS: GM significantly increased uterine oxidative stress, inflammatory and apoptotic biomarkers. Histopathological picture of uterine damage and increased IL-1ß immunoexpression were detected. Vinpo significantly ameliorated the distributed GM concentration, oxidative stress, inflammatory and apoptotic biomarkers with a prompt improvement in histopathological picture and a decrease in IL-1ß immunoexpression. CONCLUSION: Vinpo protective effect against GM-induced uterine injury involves modulation of inflammasome/caspase-1/IL-1ß signaling pathway.


Assuntos
Caspase 1 , Gentamicinas , Inflamassomos , Interleucina-1beta , Estresse Oxidativo , Transdução de Sinais , Útero , Alcaloides de Vinca , Animais , Feminino , Interleucina-1beta/metabolismo , Alcaloides de Vinca/farmacologia , Ratos , Caspase 1/metabolismo , Gentamicinas/efeitos adversos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos
15.
Int J Nanomedicine ; 19: 4007-4019, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715701

RESUMO

Introduction: Nanosized outer membrane vesicles (OMVs) from Gram-negative bacteria have attracted increasing interest because of their antitumor activity. However, the antitumor effects of MVs isolated from Gram-positive bacteria have rarely been investigated. Methods: MVs of Staphylococcus aureus USA300 were prepared and their antitumor efficacy was evaluated using tumor-bearing mouse models. A gene knock-in assay was performed to generate luciferase Antares2-MVs for bioluminescent detection. Cell counting kit-8 and lactic dehydrogenase release assays were used to detect the toxicity of the MVs against tumor cells in vitro. Active caspase-1 and gasdermin D (GSDMD) levels were determined using Western blot, and the tumor inhibition ability of MVs was determined in B16F10 cells treated with a caspase-1 inhibitor. Results: The vesicular particles of S. aureus USA300 MVs were 55.23 ± 8.17 nm in diameter, and 5 µg of MVs remarkably inhibited the growth of B16F10 melanoma in C57BL/6 mice and CT26 colon adenocarcinoma in BALB/c mice. The bioluminescent signals correlated well with the concentrations of the engineered Antares2-MVs (R2 = 0.999), and the sensitivity for bioluminescence imaging was 4 × 10-3 µg. Antares2-MVs can directly target tumor tissues in vivo, and 20 µg/mL Antares2-MVs considerably reduced the growth of B16F10 and CT26 tumor cells, but not non-carcinomatous bEnd.3 cells. MV treatment substantially increased the level of active caspase-1, which processes GSDMD to trigger pyroptosis in tumor cells. Blocking caspase-1 activation with VX-765 significantly protected tumor cells from MV killing in vitro and in vivo. Conclusion: S. aureus MVs can kill tumor cells by activating the pyroptosis pathway, and the induction of pyroptosis in tumor cells is a promising strategy for cancer treatment.


Assuntos
Caspase 1 , Piroptose , Staphylococcus aureus , Animais , Feminino , Camundongos , Antineoplásicos , Membrana Externa Bacteriana , Caspase 1/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo , Melanoma Experimental/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas de Ligação a Fosfato/metabolismo , Staphylococcus aureus/metabolismo
16.
Arch Oral Biol ; 164: 105987, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38723420

RESUMO

OBJECTIVE: The purpose of this study was to investigate interleukin (IL)-1ß, IL-18, nod-like receptor pyrin domain-containing protein 3 (NLRP3), apoptosis-related speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 levels in saliva and serum in different periodontal diseases and to evaluate the changes after non-surgical periodontal treatment (NSPT). DESIGN: A total of 45 participants, 15 healthy, 15 gingivitis, and 15 stage III grade C (SIIIGC) periodontitis patients, were included in the study. Periodontal parameters were assessed, and salivary and serum samples were collected at baseline in all groups and one and three months after NSPT in gingivitis and periodontitis groups. An enzyme-linked immunosorbent assay was used to analyse IL-1ß, IL-18, NLRP3, ASC, and caspase-1 levels. RESULTS: After NSPT, improvement was observed in all clinical parameters, along with periodontal inflamed surface area (PISA) in gingivitis and periodontitis groups. PISA scores were positively correlated with IL-1ß, NLRP3, and caspase-1 at baseline (p < 0.05). Salivary and serum IL-1ß, NLRP3 levels were higher in periodontitis compared to healthy controls at baseline and reduced after treatment (p < 0.05). Receiver operating characteristic analysis revealed that salivary IL-1ß, NLRP3, and caspase-1 had the ability to discriminate SIIIGC periodontitis patients from healthy subjects (p < 0.05). CONCLUSION: In conclusion, salivary IL-1ß, NLRP3, and caspase-1 are at aberrantly high levels in SIIIGC periodontitis and are remarkably decreased following NSPT; these inflammasome biomarkers may show potential utility in diagnosing and monitoring periodontitis.


Assuntos
Biomarcadores , Caspase 1 , Ensaio de Imunoadsorção Enzimática , Gengivite , Inflamassomos , Interleucina-18 , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , Saliva , Humanos , Feminino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Masculino , Biomarcadores/sangue , Caspase 1/sangue , Caspase 1/metabolismo , Saliva/metabolismo , Saliva/química , Interleucina-18/sangue , Interleucina-18/metabolismo , Interleucina-18/análise , Inflamassomos/metabolismo , Adulto , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Gengivite/terapia , Gengivite/metabolismo , Gengivite/sangue , Pessoa de Meia-Idade , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Periodontite/terapia , Periodontite/metabolismo , Periodontite/sangue
17.
J Agric Food Chem ; 72(22): 12775-12787, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38776285

RESUMO

Excessive intake of fat and fructose in Western diets has been confirmed to induce renal lipotoxicity, thereby driving the progression of chronic kidney disease (CKD). This study was conducted to evaluate the efficacy of magnoflorine in a CKD mouse model subjected to high-fat and high-fructose diets. Our results demonstrated that magnoflorine treatment ameliorated abnormal renal function indices (serum creatinine, urea nitrogen, uric acid, and urine protein) in high-fat- and high-fructose-fed mice. Histologically, renal tubular cell steatosis, lipid deposition, tubular dilatation, and glomerular fibrosis were significantly reduced by the magnoflorine treatment in these mice. Mechanistically, magnoflorine promotes Parkin/PINK1-mediated mitophagy, thereby inhibiting NLRP3/Caspase-1-mediated pyroptosis. Consistent findings were observed in the palmitic acid-incubated HK-2 cell model. Notably, both silencing of Parkin and the use of a mitophagy inhibitor reversed the inhibitory effect of magnoflorine on NLRP3 inflammasome activation in vitro. Therefore, the present study provides compelling evidence that magnoflorine improves renal injury in high-fat- and high-fructose-fed mice by promoting Parkin/PINK1-dependent mitophagy to inhibit NLRP3 inflammasome activation and pyroptosis. Our findings suggest that dietary supplementation with magnoflorine and magnoflorine-rich foods (such as magnolia) might be an effective strategy for the prevention of CKD.


Assuntos
Caspase 1 , Dieta Hiperlipídica , Frutose , Camundongos Endogâmicos C57BL , Mitofagia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas Quinases , Piroptose , Insuficiência Renal Crônica , Ubiquitina-Proteína Ligases , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Camundongos , Piroptose/efeitos dos fármacos , Frutose/efeitos adversos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Masculino , Mitofagia/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Humanos , Proteínas Quinases/metabolismo , Proteínas Quinases/genética , Caspase 1/metabolismo , Caspase 1/genética , Aporfinas/farmacologia , Inflamassomos/metabolismo
18.
Int Immunopharmacol ; 135: 112314, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38788450

RESUMO

We previously reported that rosmarinic acid (RA) ameliorated renal fibrosis in a unilateral ureteral obstruction (UUO) murine model of chronic kidney disease. This study aimed to determine whether RA attenuates indoxyl sulfate (IS)-induced renal fibrosis by regulating the activation of the NLRP3 inflammasome/IL-1ß/Smad circuit. We discovered the NLRP3 inflammasome was activated in the IS treatment group and downregulated in the RA-treated group in a dose-dependent manner. Additionally, the downstream effectors of the NLRP3 inflammasome, cleaved-caspase-1 and cleaved-IL-1ß showed similar trends in different groups. Moreover, RA administration significantly decreased the ROS levels of reactive oxygen species in IS-treated cells. Our data showed that RA treatment significantly inhibited Smad-2/3 phosphorylation. Notably, the effects of RA on NLRP3 inflammasome/IL-1ß/Smad and fibrosis signaling were reversed by the siRNA-mediated knockdown of NLRP3 or caspase-1 in NRK-52E cells. In vivo, we demonstrated that expression levels of NLRP3, c-caspase-1, c-IL-1ß, collagen I, fibronectin and α-SMA, and TGF- ß 1 were downregulated after treatment of UUO mice with RA or RA + MCC950. Our findings suggested RA and MCC950 synergistically inhibited UUO-induced NLRP3 signaling activation, revealing their renoprotective properties and the potential for combinatory treatment of renal fibrosis and chronic kidney inflammation.


Assuntos
Cinamatos , Depsídeos , Fibrose , Indicã , Inflamassomos , Rim , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ácido Rosmarínico , Transdução de Sinais , Animais , Depsídeos/farmacologia , Depsídeos/uso terapêutico , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Linhagem Celular , Camundongos , Interleucina-1beta/metabolismo , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia , Espécies Reativas de Oxigênio/metabolismo , Modelos Animais de Doenças , Proteína Smad2/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Proteína Smad3/metabolismo , Caspase 1/metabolismo , Nefropatias/tratamento farmacológico , Nefropatias/induzido quimicamente , Nefropatias/patologia
19.
Int Immunopharmacol ; 135: 112281, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38762925

RESUMO

The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause significant intestinal alteration and inflammation and lead to the occurrence of inflammatory diseases resembling duodenal ulcers. Astragaloside IV (AS-IV) is a glycoside of cycloartane-type triterpene isolated from the dried root of Astragalus membranaceus (Fisch.) Bge. (family Fabaceae), and has been used for ameliorating the NSAID-induced inflammation in the small intestine. The present study aimed to investigate the effects of AS-IV on indomethacin (IND)-induced inflammation in the small intestine of rats and its underlying mechanisms. Hematoxylin-eosin (H&E) staining, transmission and scanning electron microscopy were carried out to observe the surface morphology and ultrastructure of the small intestinal mucosa. Immunofluorescence and ELISA tests were employed to detect the expressions of NLRP3, ASC, caspase-1, and NF-κB proteins, as well as inflammatory factors IL-1ß and IL-18, to uncover potential molecular mechanisms responsible for mitigating small intestinal inflammation. The results demonstrated that AS-IV significantly decreased the ulcer index, improved the surface morphology and microstructure of the small intestinal mucosa, and increased mucosal blood flow. Molecular docking revealed a strong and stable binding capacity of AS-IV to NLRP3, ASC, caspase-1, and NF-κB proteins. Further experimental validation exhibited that AS-IV markedly decreased levels of IL-1ß and IL-18, and inhibited the protein expression of NLRP3, ASC, caspase-1, and NF-κB. Our data demonstrate that AS-IV ameliorates IND-induced intestinal inflammation in rats by inhibiting the activation of NLRP3 inflammasome and reducing the release of IL-1ß and IL-18, thereby representing a promising therapy for IND-induced intestinal inflammation.


Assuntos
Indometacina , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Sprague-Dawley , Saponinas , Triterpenos , Animais , Saponinas/farmacologia , Saponinas/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Masculino , Ratos , Anti-Inflamatórios não Esteroides/farmacologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Intestino Delgado/metabolismo , Intestino Delgado/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , NF-kappa B/metabolismo , Interleucina-1beta/metabolismo , Simulação de Acoplamento Molecular , Caspase 1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente
20.
Mol Med Rep ; 30(1)2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38785157

RESUMO

Tributyltin chloride (TBTC) is known to have effects and mechanisms in various diseases; however, whether TBTC is detrimental to joints and causes osteoarthritis (OA), as well as its underlying mechanism, has not yet been fully elucidated. The present study explored the effects of TBTC on rat chondrocytes, as well as on mouse OA. The toxicity of TBTC toward rat chondrocytes was detected using a lactate dehydrogenase (LDH) leakage assay and cell viability was evaluated using the Cell Counting Kit­8 assay. The results showed that TBTC decreased the viability of rat chondrocytes and increased the LDH leakage rate in a concentration­dependent manner. Moreover, compared with in the control group, TBTC increased the expression levels of interleukin (IL)­1ß, IL­18, matrix metalloproteinase (MMP)­1, MMP­13, NLR family pyrin domain containing 3 (NLRP3), caspase­1, PYD and CARD domain containing, and gasdermin D in chondrocytes. Furthermore, knockdown of NLRP3 reversed the TBTC­induced increases in LDH leakage and NLRP3 inflammasome­associated protein levels. In vivo, TBTC exacerbated cartilage tissue damage in mice from the OA group, as evidenced by the attenuation of safranin O staining. In conclusion, TBTC may aggravate OA in mice by promoting chondrocyte damage and inducing pyroptosis through the activation of NLRP3 and caspase­1 signaling. The present study demonstrated that TBTC can cause significant damage to the articular cartilage; therefore, TBTC contamination should be strictly monitored.


Assuntos
Condrócitos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Osteoartrite , Piroptose , Compostos de Trialquitina , Animais , Condrócitos/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose/efeitos dos fármacos , Camundongos , Ratos , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoartrite/etiologia , Masculino , Inflamação/metabolismo , Inflamação/patologia , Inflamação/induzido quimicamente , Caspase 1/metabolismo , Inflamassomos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Interleucina-1beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
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