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1.
FASEB J ; 38(3): e23472, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38329323

RESUMO

Allergic asthma development and pathogenesis are influenced by airway epithelial cells in response to allergens. Heme oxygenase-1 (HO-1), an inducible enzyme responsible for the breakdown of heme, has been considered an appealing target for the treatment of chronic inflammatory diseases. Herein, we report that alleviation of allergic airway inflammation by HO-1-mediated suppression of pyroptosis in airway epithelial cells (AECs). Using house dust mite (HDM)-induced asthma models of mice, we found increased gasdermin D (GSDMD) in the airway epithelium. In vivo administration of disulfiram, a specific inhibitor of pore formation by GSDMD, decreased thymic stromal lymphopoietin (TSLP) release, T helper type 2 immune response, alleviated airway inflammation, and reduced airway hyperresponsiveness (AHR). HO-1 induction by hemin administration reversed these phenotypes. In vitro studies revealed that HO-1 restrained GSDMD-mediated pyroptosis and cytokine TSLP release in AECs by binding Nuclear Factor-Kappa B (NF-κB) p65 RHD domain and thus controlling NF-κB-dependent pyroptosis. These data provide new therapeutic indications for purposing HO-1 to counteract inflammation, which contributes to allergic inflammation control.


Assuntos
Asma , Heme Oxigenase-1 , NF-kappa B , Animais , Camundongos , Citocinas/metabolismo , Células Epiteliais/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , Piroptose , Linfopoietina do Estroma do Timo
2.
J Cardiothorac Surg ; 19(1): 58, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317168

RESUMO

BACKGROUND: This study examined the effect of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway on chronic obstructive pulmonary disease (COPD) and the potential molecular mechanism. METHODS: A COPD mouse model was established by cigarette smoke exposure and administered with either ML385 or dimethyl fumarate (DMF). Airway resistance of mice was detected. IL-1ß and IL-6 levels in mice alveolar lavage fluid were examined by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining and immunohistochemical of lung tissues were utilized to detect lung injury and NLRP3 expression. DMF was used to treat COPD cell model constructed by exposing normal human bronchial epithelial (NHBE) cells to cigarette smoke extract. NHBE cells were transfected by NLRP3-expression vectors. Expression of proteins was detected by Western blot. RESULTS: COPD mice showed the enhanced airway resistance, the inactivated Nrf2/HO-1 pathway and the overexpressed NLRP3, Caspase-1 and GSDMD-N proteins in lung tissues, and the increased IL-1ß and IL-6 levels in alveolar lavage fluid. ML385 treatment augmented these indicators and lung injury in COPD mice. However, DMF intervention attenuated these indicators and lung injury in COPD mice. Nrf2/HO-1 pathway inactivation and overexpression of NLRP3, Caspase-1 and GSDMD-N proteins were observed in COPD cells. DMF intervention activated Nrf2/HO-1 pathway and down-regulated NLRP3, Caspase-1 and GSDMD-N proteins in COPD cells. However, NLRP3 overexpression abolished the effect of DMF on COPD cells. CONCLUSION: Nrf2/HO-1 pathway activation may alleviate inflammation in COPD by suppressing the NLRP3-related pyroptosis. Activating the Nrf2/HO-1 pathway may be an effective method to treat COPD.


Assuntos
Fumar Cigarros , Lesão Pulmonar , Doença Pulmonar Obstrutiva Crônica , Humanos , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Piroptose , Interleucina-6 , Heme Oxigenase-1/metabolismo , Fumar Cigarros/efeitos adversos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Inflamação , Caspases
3.
Zhen Ci Yan Jiu ; 49(2): 110-118, 2024 Feb 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38413031

RESUMO

OBJECTIVES: To observe the effect of electroacupuncture (EA) stimulation of "Jiaji"(EX-B2) on motor function, histomorphology, and expression of NOD-like receptor protein 3 (NLRP3) and N-terminal domain of gasdermin D (GSDMD-N) in the spinal cord tissue of rats with spinal cord injury (SCI), so as to explore its mechanism underlying improvement of SCI. METHODS: Forty eight female SD rats were randomly divided into sham surgery (sham), SCI model (model), EA, and NLRP3 agonist (monosodium urate, MSU) combined with Jiaji EA (MSU+EA) groups, with 12 rats in each group which were further divided into 3 d and 7 d subgroups, with 6 rats at each time point. Two EA groups received EA stimulation of EX-B2 with a frequency of 100 Hz, electrical current of 1-2 mA for 30 min, once a day for 3 or 7 days. After 5 min, 6 h, and 24 h of modeling, rats of the MSU+EA group received intraperitoneal injection of MSU (200 µg/kg, 200 µg/mL) . The motor function was evaluated using Basso-Beattie-Bresnahan (BBB) scale, the morphological structure of rat spinal cord tissue was observed by H.E. staining. The expression of pyroptosis related factors NLRP3, cleaved Caspase-1 and GSDMD-N of the spinal cord was observed by using immunohistochemistry and Western blot separately, the expression and localization of Iba-1 and GSDMD-N in the spinal cord tissue were observed using immunofluorescence double staining method. RESULTS: Compared with the sham group, the BBB scores after modeling and on day 3 and 7 were decreased (P<0.05), while the average OD values (immunoactivity) and expression levels of NLRP3, cleaved Caspase-1 and GSDMD-N proteins, and the immunofluorescence intensity of Iba-1/GSDMD-N (co-expression) of the spinal cord tissues on day 3 and 7 were significantly increased in the model group (P<0.05). In comparison with the model group, the BBB scores on day 3 and 7 were obviously increased (P<0.05), while the immunoactivity and expression levels of NLRP3, cleaved Caspase-1 and GSDMD proteins, and the immunofluorescence intensity of Iba-1/GSDMD-N on day 3 and 7 significantly down-regulated in the EA group (P<0.05) but not in the MSU+EA group (P>0.05), suggesting an elimination of the effects of EA after administration of NLRP3 agonist (MSU). H.E. staining showed obvious bleeding area in the spinal cord tissue, loose tissue and inflammatory cell infiltration on day 3 after modeling, and basic absorption of the bleeding, loose tissue, obvious vacuolar changes of the white matter area, loss and contraction of neurons with infiltration of a large number of inflammatory cells, which was milder in the EA group but not in the MSU+EA group. CONCLUSIONS: EA of EX-B2 can improve the motor function of SCI rats, which may be related to its functions in inhibiting pyroptosis of microglia mediated by NLRP3/Caspase-1 signaling pathway.


Assuntos
Eletroacupuntura , Traumatismos da Medula Espinal , Animais , Feminino , Ratos , Caspase 1 , Caspases , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose , Ratos Sprague-Dawley , Medula Espinal , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/terapia
4.
J Transl Med ; 22(1): 194, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388913

RESUMO

BACKGROUND: Peripheral nerve injury (PNI) is commonly observed in clinical practice, yet the underlying mechanisms remain unclear. This study investigated the correlation between the expression of a Ras-related protein Rab32 and pyroptosis in rats following PNI, and potential mechanisms have been explored by which Rab32 may influence Schwann cells pyroptosis and ultimately peripheral nerve regeneration (PNR) through the regulation of Reactive oxygen species (ROS) levels. METHODS: The authors investigated the induction of Schwann cell pyroptosis and the elevated expression of Rab32 in a rat model of PNI. In vitro experiments revealed an upregulation of Rab32 during Schwann cell pyroptosis. Furthermore, the effect of Rab32 on the level of ROS in mitochondria in pyroptosis model has also been studied. Finally, the effects of knocking down the Rab32 gene on PNR were assessed, morphology, sensory and motor functions of sciatic nerves, electrophysiology and immunohistochemical analysis were conducted to assess the therapeutic efficacy. RESULTS: Silencing Rab32 attenuated PNI-induced Schwann cell pyroptosis and promoted peripheral nerve regeneration. Furthermore, our findings demonstrated that Rab32 induces significant oxidative stress by damaging the mitochondria of Schwann cells in the pyroptosis model in vitro. CONCLUSION: Rab32 exacerbated Schwann cell pyroptosis in PNI model, leading to delayed peripheral nerve regeneration. Rab32 can be a potential target for future therapeutic strategy in the treatment of peripheral nerve injuries.


Assuntos
Traumatismos dos Nervos Periféricos , Ratos , Animais , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/terapia , Espécies Reativas de Oxigênio/metabolismo , Piroptose , Ratos Sprague-Dawley , Proliferação de Células , Células de Schwann/metabolismo , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Regeneração Nervosa/fisiologia
5.
Int J Biol Sci ; 20(4): 1413-1435, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38385085

RESUMO

Caspase-11 detection of intracellular lipopolysaccharide mediates non-canonical pyroptosis, which could result in inflammatory damage and organ lesions in various diseases such as sepsis. Our research found that lactate from the microenvironment of acetaminophen-induced acute liver injury increased Caspase-11 levels, enhanced gasdermin D activation and accelerated macrophage pyroptosis, which lead to exacerbation of liver injury. Further experiments unveiled that lactate inhibits Caspase-11 ubiquitination by reducing its binding to NEDD4, a negative regulator of Caspase-11. We also identified that lactates regulated NEDD4 K33 lactylation, which inhibits protein interactions between Caspase-11 and NEDD4. Moreover, restraining lactylation reduces non-canonical pyroptosis in macrophages and ameliorates liver injury. Our work links lactate to the exquisite regulation of the non-canonical inflammasome, and provides a basis for targeting lactylation signaling to combat Caspase-11-mediated non-canonical pyroptosis and acetaminophen-induced liver injury.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Piroptose , Humanos , Acetaminofen/toxicidade , Caspases Iniciadoras/metabolismo , Caspases/metabolismo , Ácido Láctico
6.
Sci Rep ; 14(1): 3175, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326642

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the major causes of liver-related morbidity and mortality globally. It ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) characterized by ballooning and hepatic inflammation. In the past few years, pyroptosis has been shown as a type of programmed cell death that triggers inflammation and plays a role in the development of NASH. However, the roles of pyroptosis-related genes (PRGs) in NASH remained unclear. In this study, we studied the expression level of pyroptosis-related genes (PRGs) in NASH and healthy controls, developed a diagnostic model of NASH based on PRGs and explored the pathological mechanisms associated with pyroptosis. We further compared immune status between NASH and healthy controls, analyzed immune status in different subtypes of NASH. We identified altogether twenty PRGs that were differentially expressed between NASH and normal liver tissues. Then, a novel diagnostic model consisting of seven PRGs including CASP3, ELANE, GZMA, CASP4, CASP9, IL6 and TP63 for NASH was constructed with an area under the ROC curve (AUC) of 0.978 (CI 0.965-0.99). Obvious variations in immune status between healthy controls and NASH cases were detected. Subsequently, the consensus clustering method based on differentially expressed PRGs was constructed to divide all NASH cases into two distinct pyroptosis subtypes with different immune and biological characteristics. Pyroptosis-related genes may play an important role in NASH and can provide new insights into the diagnosis and underlying mechanisms of NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Piroptose/genética , Inflamação/patologia
7.
Front Biosci (Landmark Ed) ; 29(2): 58, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38420829

RESUMO

BACKGROUND: Pyroptosis is a critical form of cell death during the development of chronic kidney disease (CKD). Tripartite motif 6 (TRIM6) is an E3-ubiquitin ligase that participates in the progression renal fibrosis (RF). The aim of this study was to investigate the roles of TRIM6 and Glutathione peroxidase 3 (GPX3) in oxidative stress-induced inflammasome activation and pyroptosis in Ang-II treated renal tubular epithelial cells. METHODS: To study its role in RF, TRIM6 expression was either reduced or increased in human kidney-2 (HK2) cells using lentivirus, and Ang-II, NAC and BMS-986299 were served as reactive oxygen species (ROS) inducer, ROS scavenger and NLRP3 agonist respectively. Pyroptosis and mitochondrial ROS were measured by flow cytometry. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were determined using commercial kits, while the levels of IL-1ß, IL-18, IL-6, and tumor necrosis factor-α (TNF-α) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). Co-immunoprecipitation (Co-IP) assay was used to evaluate the interaction between TRIM6 and GPX3. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to measure mRNA and protein expression, respectively. RESULTS: Treatment with Angiotensin II (Ang II) increased the protein and mRNA levels of TRIM6 in HK2 cells. Ang II also increased mitochondrial ROS production and the malondialdehyde (MDA) level, but decreased the levels of GSH and SOD. In addition, Ang II enhanced HK2 cell pyroptosis, increased the levels of IL-1ß, IL-18, IL-6, and TNF-α, and promoted the expression of active IL-1ß, NLRP3, caspase-1, and GSDMD-N proteins. These effects were reversed by knockdown of TRIM6 and by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. BMS-986299, an NLRP3 agonist treatment, did not affect ROS production in HK2 cells exposed to Ang II combined with NAC, but cell pyroptosis and inflammation were aggravated. Moreover, the overexpression of TRIM6 in HK2 cells resulted in similar effects to Ang II. NAC and GPX3 overexpression in HK2 cells could reverse ROS production, inflammation, and pyroptosis induced by TRIM6 overexpression. TRIM6 overexpression decreased the GPX3 protein level by promoting its ubiquitination, without affecting the GPX3 mRNA level. Thus, TRIM6 facilitates GPX3 ubiquitination, contributing to increased ROS levels and pyroptosis in HK2 cells. CONCLUSIONS: TRIM6 increases oxidative stress and promotes the pyroptosis of HK2 cells by regulating GPX3 ubiquitination. These findings could contribute to the development of novel drugs for the treatment of RF.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Interleucina-18/metabolismo , Interleucina-18/farmacologia , Piroptose , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transdução de Sinais , Inflamação , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Superóxido Dismutase/metabolismo , Células Epiteliais/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/farmacologia , Ubiquitinação , Malondialdeído/metabolismo , RNA Mensageiro/metabolismo
8.
CNS Neurosci Ther ; 30(2): e14551, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38421089

RESUMO

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a major source of morbidity and mortality after stroke, but the pathological mechanisms remain unclear. Previous studies have demonstrated that the CX3CR1 receptor plays a crucial role in maintaining an early protective microenvironment after stroke, but whether it persistently influences cognitive dysfunction in the chronic phase requires further investigation. METHODS: Mouse was used to establish a middle cerebral artery occlusion (MCAO)/reperfusion model to study PSCI. Cognitive function was assessed by the Morris water maze (MWM) and the novel object recognition test. Neurogenesis was assessed by immunofluorescence staining with Nestin+ /Ki67+ and DCX+ /BrdU+ double-positive cells. The cerebral damage was monitored by [18 F]-DPA-714 positron emission tomography, Nissel, and TTC staining. The pyroptosis was histologically, biochemically, and electron microscopically examined. RESULTS: Upon MCAO, at 28 to 35 days, CX3CR1 knockout (CX3CR1-/- ) mice had better cognitive behavioral performance both in MWM and novel object recognition test than their CX3CR1+/- counterparts. Upon MCAO, at 7 days, CX3CR1-/- mice increased the numbers of Nestin+ /Ki67+ and DCX+ /BrdU+ cells, and meanwhile it decreased the protein expression of GSDMD, NLRP3 inflammasome subunit, caspase-1, mature IL-1ß/IL-18, and p-P65 in the hippocampus as compared with CX3CR1+/- mice. In addition, CX3CR1-/- mice could reverse infarct volume in the hippocampus region post-stroke. CONCLUSION: Our study demonstrated that CX3CR1 gene deletion was beneficial to PSCI recovery. The mechanism might lie in inhibited pyroptosis and enhanced neurogenesis. CX3CR1 receptor may serve as a therapeutic target for improving the PSCI.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Microglia/patologia , Nestina/metabolismo , AVC Isquêmico/patologia , Piroptose , Bromodesoxiuridina/metabolismo , Antígeno Ki-67/metabolismo , Acidente Vascular Cerebral/patologia , Cognição , Infarto da Artéria Cerebral Média/patologia
9.
Crit Rev Immunol ; 44(3): 53-65, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38421705

RESUMO

BACKGROUND: The present study investigated the roles and mechanisms of platelet-derived exosomes in sepsis-induced acute renal injury. METHODS: The blood samples of septic patients and healthy controls were collected for clinical examination. The plasma levels of miR-223-3p and NLRP3 mRNA were analyzed by qRT-PCR and the serum IL-1ß and creatinine levels were quantified by enzyme-linked immunosorbent assay (ELISA). C57BL/6 mice injected with LPS (lipopolysaccharide) were employed as the animal model for sepsis-induced acute renal injury. Human coronary artery endothelial cells (HCAECs) were treated with TNF-α as a cellular model for sepsis-induced endothelial damages. RESULTS: The number of PMP (platelet-derived microparticles) in patients with sepsis was increased. The level of miR-223-3p in the platelet exosomes isolated from the serum sample in patients with sepsis was significantly lower than that of the healthy controls. The level of miR-223-3p was also decreased in the platelet exosomes of mouse model with sepsis-induced acute renal injury. Downregulating miR-223-3p promoted sepsis-induced acute renal injury in mice model, while the administration of miR-223-3p reduced the inflammation in endothelial cells of sepsis-induced acute renal injury. NLRP3 (NLR Family Pyrin Domain Containing 3) was identified as one target of miR-223-3p in the platelet exosomes of sepsis-induced acute kidney injury. miR-223-3p attenuated NLRP3-induced pyroptosis in endothelial cell model of sepsis-induced acute kidney injury. CONCLUSION: Our data suggest that platelet exosome-derived miR-223-3p negatively regulates NLRP3-dependent inflammasome to suppress pyroptosis in endothelial cells. Decreased miR-223-3p expression promotes the inflammation in sepsis-induced acute renal injury. Targeting miR-223-3p may be developed into a therapeutic approach for sepsis-induced acute renal injury.


Assuntos
Injúria Renal Aguda , Micropartículas Derivadas de Células , Exossomos , MicroRNAs , Sepse , Camundongos , Animais , Humanos , Camundongos Endogâmicos C57BL , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR , Células Endoteliais , Sepse/complicações , Injúria Renal Aguda/etiologia , Modelos Animais de Doenças , Inflamação , Lipopolissacarídeos , MicroRNAs/genética
10.
J Cancer Res Clin Oncol ; 150(2): 85, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38334883

RESUMO

BACKGROUND: Nephroblastoma, also known as Wilms' tumor (WT), is an embryonic malignant tumor and one of the most common malignant tumors in the abdominal region of children. The exact role and underlying mechanisms of aquaporin-1 (AQP1) in the occurrence and development of nephroblastoma remain unclear. METHODS: After overexpression of AQP1, cell proliferation was assessed using the CCK-8 proliferation assay and EdU staining. Flow cytometry was employed to assess cell apoptosis, and Western blotting (WB) analysis was conducted to validate the expression of relevant protein markers. mRNA sequencing (mRNA-Seq) was performed on WT cells overexpressing AQP1 to predict and characterize the associated mechanisms. Transmission electron microscopy was utilized to observe changes in the ultrastructure of WT cells undergoing apoptosis and pyroptosis following AQP1 overexpression. Functional in vivo validation was conducted through animal experiments. RESULTS: We validated that overexpression of AQP1 inhibited cell proliferation and promoted cell apoptosis and pyroptosis both in vitro and in vivo. mRNA-Seq analysis of WT cells with AQP1 overexpression suggested that these effects might be mediated through the inhibition of the JAK-STAT signaling pathway. Additionally, we discovered that overexpression of AQP1 activated the classical pyroptosis signaling pathway dependent on caspase-1, thereby promoting pyroptosis in WT. CONCLUSION: These findings highlight the important functional role of AQP1 in the pathobiology of nephroblastoma, providing novel insights into the development of this disease. Moreover, these results offer new perspectives on the potential therapeutic targeting of AQP1 as a treatment strategy for nephroblastoma.


Assuntos
Aquaporina 1 , Neoplasias Renais , Tumor de Wilms , Animais , Humanos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Renais/genética , Neoplasias Renais/patologia , Piroptose/genética , RNA Mensageiro/genética , Tumor de Wilms/genética , Tumor de Wilms/patologia , Aquaporina 1/genética
11.
Clinics (Sao Paulo) ; 79: 100336, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38325020

RESUMO

BACKGROUND: Xuebijing (XBJ) is widely applied in the treatment of Acute Lung Injury (ALI). This study focused on the potential mechanism of XBJ in Lipopolysaccharide (LPS)-induced ALI. METHODS: The rat ALI model was established by injection of LPS (10 mg/kg) and pretreated with XBJ (4 mL/kg) three days before LPS injection. BEAS-2B cell line was stimulated with LPS (1 µg/mL) and ATP (5 mM) to induce pyroptosis, and XBJ (2 g/L) was pretreated 24h before induction. The improvement effects of XBJ on pulmonary edema, morphological changes, and apoptosis in ALI lung tissue were evaluated by lung wet/dry weight ratio, HE-staining, and TUNEL staining. Inflammatory cytokines in lung tissue and cell supernatant were determined by ELISA. pyroptosis was detected by flow cytometry. Meanwhile, the expressions of miR-181d-5p, SPP1, p-p65, NLRP3, ASC, caspase-1, p20, and GSDMD-N in tissues and cells were assessed by RT-qPCR and immunoblotting. The relationship between miR-181d-5p and SPP1 in experimental inflammation was reported by dual luciferase assay. RESULTS: XBJ could improve inflammation and pyroptosis of ALI by inhibiting contents of inflammatory cytokines, and levels of inflammation- and pyroptosis-related proteins. Mechanistically, XBJ could up-regulate miR-181d-5p and inhibit SPP1 in ALI. miR-181d-5p can target the regulation of SPP1. Depressing miR-181d-5p compensated for the ameliorative effect of XBJ on ALI, and overexpressing SPP1 suppressed the attenuating effect of XBJ on LPS-induced inflammation and pyroptosis. CONCLUSION: XBJ can regulate the miR-181d-5p/SPP1 axis to improve inflammatory response and pyroptosis in ALI.


Assuntos
Lesão Pulmonar Aguda , Medicamentos de Ervas Chinesas , MicroRNAs , Ratos , Animais , Piroptose , Lipopolissacarídeos , MicroRNAs/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Inflamação/tratamento farmacológico , Citocinas
12.
Mol Med Rep ; 29(4)2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38391117

RESUMO

Acetaminophen (APAP) overdose is the primary cause of drug­induced acute liver failure in numerous Western countries. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation serves a pivotal role in the pathogenesis of various forms of acute liver injury. However, the cellular source for NLRP3 induction and its involvement during APAP­induced hepatotoxicity have not been thoroughly investigated. In the present study, hematoxylin and eosin staining was performed to assess histopathological changes of liver tissue. Immunohistochemistry staining(NLRP3, Caspase­1, IL­1ß, GSDMD and Caspase­3), western blotting (NLRP3, Caspase­1, IL­1ß, GSDMD and Caspase­3) and RT­qPCR (NLRP3, Caspase­1 and IL­1ß) were performed to assess the expression of NLRP3/GSDMD signaling pathway. TUNEL staining was performed to assess apoptosis of liver tissue. The serum expression levels of inflammatory factors (IL­6, IL­18, IL­1ß and TNF­α) were assessed using ELISA and inflammation of liver tissue was assessed using immunohistochemistry (Ly6G and CD68) and RT­qPCR (TNF­α, Il­6, Mcp­1, Cxcl­1, Cxcl­2). A Cell Counting Kit­8 was performed to assess cell viability and apoptosis. Protein and gene expression were analyzed by western blotting (PCNA, CCND1) and RT­qPCR (CyclinA2, CyclinD1 and CyclinE1). Through investigation of an APAP­induced acute liver injury model (AILI), the present study demonstrated that APAP overdose induced activation of NLRP3 and cleavage of gasdermin D (GSDMD) in hepatocytes, both in vivo and in vitro. Additionally, mice with hepatocyte­specific knockout of Nlrp3 exhibited reduced liver injury and lower mortality following APAP intervention, accompanied by decreased infiltration of inflammatory cells and attenuated inflammatory response. Furthermore, pharmacological blockade of NLRP3/GSDMD signaling using MCC950 or disulfiram significantly ameliorated liver injury and reduced hepatocyte death. Notably, hepatocyte Nlrp3 deficiency promoted liver recovery by enhancing hepatocyte proliferation. Collectively, the present study demonstrated that inhibition of the NLRP3 inflammasome protects against APAP­induced acute liver injury by reducing hepatocyte pyroptosis and suggests that targeting NLRP3 may hold therapeutic potential for treating AILI.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Acetaminofen/efeitos adversos , Piroptose , Caspase 3 , Fator de Necrose Tumoral alfa , Interleucina-6 , Hepatócitos/metabolismo
13.
Vet Res ; 55(1): 26, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38414065

RESUMO

Pyroptosis is a form of programmed cell death characterized by cell swelling, pore formation in the plasma membrane, lysis, and releases of cytoplasmic contents. To date, the molecular mechanism of human and murine Gasdermin D-mediated pyroptosis have been fully investigated. However, studies focusing on molecular mechanism of bovine Gasdermin D (bGSDMD)-mediated pyroptosis and its function against pathogenic infection were unclear. In the present study, we demonstrate that bovine caspase-1 (bCaspase-1) cleaves bGSDMD at amino acid residue D277 to produce an N-terminal fragment (bGSDMD-p30) which leads to pyroptosis. The amino acid residues T238 and F239 are critical for bGSDMD-p30-mediated pyroptosis. The loop aa 278-299, L293 and A380 are the key sites for autoinhibitory structure of the full length of bGSDMD. In addition, bCaspase-3 also cleaves bGSDMD at residue Asp86 without inducing cell death. Therefore, our study provides the first detailed elucidation of the mechanism of bovine GSDMD-mediated pyroptosis. The results will establish a significant foundation for future research on the role of pyroptosis in bovine infectious diseases.


Assuntos
Gasderminas , Piroptose , Animais , Bovinos , Humanos , Camundongos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Aminoácidos , Inflamassomos/metabolismo
14.
J Ovarian Res ; 17(1): 29, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302986

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a frequent and complicated endocrine disease that remains a major reason for infertility. Bushenhuoluo Decotion (BSHLD) has been validated to exhibit curative effects on PCOS. This study was aimed to explore the potential mechanism underlying the therapeutic action of BSHLD. METHODS: PCOS rat model was induced by dehydroepiandrosterone (DHEA). Serum hormone and cytokines levels and ovarian pathological alterations were measured to assess ovarian function. Exosomes (Exos) were identified by Transmission electron microscopy and Nanoparticle Tracking Analysis. RT-qPCR, Western blotting, immunohistochemical staining, and immunofluorescence staining were performed to detect molecule expressions. Proliferation and pyroptosis of granulosa cells (GCs) were evaluated by CCK-8 and flow cytometry, respectively. The binding relationship between miR-30a-5p and suppressor of cytokine signaling 3 (SOCS3) was verified by dual luciferase reporter and RIP assays. RESULTS: BSHLD treatment improved serum hormone abnormality, insulin sensitivity, and ovarian morphologic changes of PCOS rats. Moreover, BSHLD treatment restrained the excessive autophagy and pyroptosis in ovarian tissues of PCOS rats. Moreover, BSHLD reduced the expression of miR-30a-5p in serum, serum-derived Exos, and ovarian tissues, thus inhibiting autophagy and NLRP3-mediated pyroptosis in GCs. Mechanistically, SOCS3 was proved as a target of miR-30a-5p and could activate mTOR/P70S6K pathway to repress autophagy. The inhibitory effect of miR-30a-5p deficiency on autophagy and pyroptosis of GCs was attenuated by rapamycin. CONCLUSION: Collectively, BSHLD suppressed autophagy and pyroptosis to improve POCS by regulating exosomal miR-30a-5p/SOCS3/mTOR signaling.


Assuntos
Medicamentos de Ervas Chinesas , MicroRNAs , Extratos Vegetais , Síndrome do Ovário Policístico , Animais , Feminino , Humanos , Ratos , Autofagia , Hormônios , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Síndrome do Ovário Policístico/patologia , Piroptose , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Extratos Vegetais/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico
15.
Front Immunol ; 15: 1322468, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38304430

RESUMO

The gasdermin (GSDM) protein family plays a pivotal role in pyroptosis, a process critical to the body's immune response, particularly in combatting bacterial infections, impeding tumor invasion, and contributing to the pathogenesis of various inflammatory diseases. These proteins are adept at activating inflammasome signaling pathways, recruiting immune effector cells, creating an inflammatory immune microenvironment, and initiating pyroptosis. This article serves as an introduction to the GSDM protein-mediated pyroptosis signaling pathways, providing an overview of GSDMs' involvement in tumor immunity. Additionally, we explore the potential applications of GSDMs in both innovative and established antitumor strategies.


Assuntos
Gasderminas , Neoplasias , Humanos , Piroptose , Inflamassomos , Microambiente Tumoral
16.
Iran J Kidney Dis ; 1(1): 18-26, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38308547

RESUMO

INTRODUCTION: Chronic kidney disease (CKD) is one of the major chronic human diseases worldwide. Puerarin, extensively used in traditional Chinese medicine, has shown favorable clinical effects in treating CKD. Here, we aimed to elucidate the mechanism by which puerarin alleviates CKD. METHODS: We constructed an animal model of CKD and intragastrically administered 400 mg/kg puerarin to the rat models. The extent of kidney injury was evaluated by performing hematoxylin and eosin staining. Then, we quantified the renal function indicators, inflammatory cytokines, apoptosis-related factors, and pyroptosis-related factors. HK-2 cells were treated with lipopolysaccharide (400 ng/mL) in H2O2 (200 µM) to induce oxidative stress. Then, the cells were treated with puerarin and transfected with overexpressed lncRNA NEAT1 vectors. Finally, the regulatory functions of lncRNA NEAT1 in cell apoptosis and pyroptosis were investigated. RESULTS: Puerarin treatment alleviated kidney damage and suppressed inflammation and apoptosis in the CKD rat model. Puerarin ameliorated pyroptosis in the CKD model by inhibiting caspase-1 and GSDMD-N expression. LncRNA NEAT1 was down-regulated in the CKD model after puerarin treatment. Puerarin enhanced cell viability when lncRNA NEAT1 was overexpressed, and the inhibition of apoptosis was reversed in the LPS/H2O2-stimulated HK-2 cells. Furthermore, lncRNA NEAT1 overexpression blocked the anti-pyroptosis effect of Puerarin in the CKD model. CONCLUSION: Puerarin inhibits pyroptosis and inflammation by regulating lncRNA NEAT1, thereby ameliorating CKD.  DOI: 10.52547/ijkd.7565.


Assuntos
Isoflavonas , Falência Renal Crônica , MicroRNAs , RNA Longo não Codificante , Insuficiência Renal Crônica , Humanos , Ratos , Animais , Piroptose , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/farmacologia , Transdução de Sinais/genética , Peróxido de Hidrogênio/farmacologia , Células Epiteliais , Apoptose , Insuficiência Renal Crônica/tratamento farmacológico , Inflamação , MicroRNAs/genética
17.
World J Gastroenterol ; 30(3): 252-267, 2024 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-38314135

RESUMO

BACKGROUND: Ulcerative colitis (UC) is an inflammatory condition with frequent relapse and recurrence. Evidence suggests the involvement of SLC6A14 in UC pathogenesis, but the central regulator remains unknown. AIM: To explore the role of SLC6A14 in UC-associated pyroptosis. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, and immunohistochemical were used to assess SLC6A14 in human UC tissues. Lipopolysaccharide (LPS) was used to induce inflammation in FHC and NCM460 cells and model enteritis, and SLC6A14 levels were assessed. Pyroptosis markers were quantified using enzyme-linked immunosorbent assay, Western blotting, and qRT-PCR, and EdU incubation, CCK-8 assays and flow cytometry were used to examine proliferation and apoptosis. Mouse models of UC were used for verification. RESULTS: SLC6A14 was increased and correlated with NLRP3 in UC tissues. LPS-induced FHC and NCM460 cells showed increased SLC6A14 levels. Reducing SLC6A14 increased cell proliferation and suppressed apoptosis. Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1ß, IL-18, NLRP3). NLRP3 overexpression counteracted the effects of sh-SLC6A14 on LPS-induced FHC and NCM460 cell pyroptosis. SLC6A14 improved the mucosa in mice with dextran sulfate sodium-induced colitis. CONCLUSION: SLC6A14 promotes UC pyroptosis by regulating NLRP3, suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis.


Assuntos
Sistemas de Transporte de Aminoácidos , Colite Ulcerativa , Colite , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Camundongos , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Colite Ulcerativa/induzido quimicamente , Inflamassomos/metabolismo , Lipopolissacarídeos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose
18.
J Matern Fetal Neonatal Med ; 37(1): 2311809, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38326276

RESUMO

BACKGROUND AND AIM: Globally, the prevalence of gestational diabetes mellitus (GDM) is rising each year, yet its pathophysiology is still unclear. To shed new light on the pathogenesis of gestational diabetes mellitus and perhaps uncover new therapeutic targets, this study looked at the expression levels and correlations of SIRT1, SREBP1, and pyroptosis factors like NLRP3, Caspase-1, IL-1, and IL-18 in patients with GDM. METHODS: This study involved a comparative analysis between two groups. The GDM group consisted of 50 GDM patients and the control group included 50 pregnant women with normal pregnancies. Detailed case data were collected for all participants. We utilized real-time quantitative PCR and Western Blot techniques to assess the expression levels of SIRT1 and SREBP1 in placental tissues from both groups. Additionally, we employed an enzyme-linked immunosorbent assay to measure the serum levels of SIRT1, SREBP1, and pyroptosis factors, namely NLRP3, Caspase-1, IL-1ß, and IL-18, in the patients of both groups. Subsequently, we analyzed the correlations between these factors and clinical. RESULTS: The results showed that there were significantly lower expression levels of SIRT1 in both GDM group placental tissue and serum compared to the control group (p < 0.01). In contrast, the expression of SREBP1 was significantly higher in the GDM group than in the control group (p < 0.05). Additionally, the serum levels of NLRP3, Caspase-1, IL-1ß, and IL-18 were significantly elevated in the GDM group compared to the control group (p < 0.01). The expression of SIRT1 exhibited negative correlations with the expression of FPG, OGTT-1h, FINS, HOMA-IR, SREBP1, IL-1ß, and IL-18. However, there was no significant correlation between SIRT1 expression and OGTT-2h, NLRP3, or Caspase-1. On the other hand, the expression of SREBP1 was positively correlated with the expression of IL-1ß, Caspase-1, and IL-18, but has no apparent correlation with NLRP3. CONCLUSIONS: Low SIRT1 levels and high SREBP1 levels in placental tissue and serum, coupled with elevated levels of pyroptosis factors NLRP3, Caspase-1, IL-1ß, and IL-18 in serum, may be linked to the development of gestational diabetes mellitus. Furthermore, these three factors appear to correlate with each other in the pathogenesis of GDM, offering potential directions for future research and therapeutic strategies.


Assuntos
Diabetes Gestacional , Feminino , Humanos , Gravidez , Caspases , Interleucina-18 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Placenta/metabolismo , Piroptose , Sirtuína 1 , Esteróis
19.
Cell Death Dis ; 15(2): 118, 2024 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-38331883

RESUMO

Diabetic retinopathy is a common microvascular complication of diabetes and a leading cause of blindness. Pyroptosis has emerged as a mechanism of cell death involved in diabetic retinopathy pathology. This study explored the role of GSDME-mediated pyroptosis and its regulation by TNFSF15 in diabetic retinopathy. We found GSDME was upregulated in the progression of diabetic retinopathy. High glucose promoted GSDME-induced pyroptosis in retinal endothelial cells and retinal pigment epithelial cells, attributed to the activation of caspase-3 which cleaves GSDME to generate the pyroptosis-executing N-terminal fragment. TNFSF15 was identified as a binding partner and inhibitor of GSDME-mediated pyroptosis. TNFSF15 expression was increased by high glucose but suppressed by the caspase-3 activator Raptinal. Moreover, TNFSF15 protein inhibited high glucose- and Raptinal-induced pyroptosis by interacting with GSDME in retinal cells. Collectively, our results demonstrate TNFSF15 inhibits diabetic retinopathy progression by blocking GSDME-dependent pyroptosis of retinal cells, suggesting the TNFSF15-GSDME interaction as a promising therapeutic target for diabetic retinopathy.


Assuntos
Ciclopentanos , Diabetes Mellitus , Retinopatia Diabética , Fluorenos , Humanos , Piroptose/fisiologia , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Caspase 3/metabolismo , Células Endoteliais/metabolismo , Glucose/metabolismo , Diabetes Mellitus/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
20.
Cell Death Dis ; 15(2): 125, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336839

RESUMO

Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents a promising target for treating hematologic and solid tumors. However, it is unknown whether the JAK1/2-STAT3 pathway is activated in ATC, and the anti-cancer effects and the mechanism of action of its inhibitor, ruxolitinib (Ruxo, a clinical JAK1/2 inhibitor), remain elusive. Our data indicated that the JAK1/2-STAT3 signaling pathway is significantly upregulated in ATC tumor tissues than in normal thyroid and papillary thyroid cancer tissues. Apoptosis and GSDME-pyroptosis were observed in ATC cells following the in vitro and in vivo administration of Ruxo. Mechanistically, Ruxo suppresses the phosphorylation of STAT3, resulting in the repression of DRP1 transactivation and causing mitochondrial fission deficiency. This deficiency is essential for activating caspase 9/3-dependent apoptosis and GSDME-mediated pyroptosis within ATC cells. In conclusion, our findings indicate DRP1 is directly regulated and transactivated by STAT3; this exhibits a novel and crucial aspect of JAK1/2-STAT3 on the regulation of mitochondrial dynamics. In ATC, the transcriptional inhibition of DRP1 by Ruxo hampered mitochondrial division and triggered apoptosis and GSDME-pyroptosis through caspase 9/3-dependent mechanisms. These results provide compelling evidence for the potential therapeutic effectiveness of Ruxo in treating ATC.


Assuntos
Nitrilas , Pirazóis , Pirimidinas , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Dinâmica Mitocondrial , Piroptose , Caspase 9/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Apoptose
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