المؤلفون: Tiancheng Dong, Dingkao Huang, Zhengzheng Jin

المصدر: Journal of Cardiothoracic Surgery, Vol 19, Iss 1, Pp 1-10 (2024)

مصطلحات موضوعية: Gut microbiota metabolite sodium butyrate, Cardiac fibroblasts, Myofibroblasts, NLRP3 inflammasomes, Caspase-1, Cell pyroptosis, Surgery, RD1-811, Anesthesiology, RD78.3-87.3

الوصف: Abstract Background Cardiac fibroblasts (CFs) are activated after initial injury, and then differentiate into myofibroblasts (MFs), which play a pivotal role as the primary mediator cells in pathological remodeling. Sodium butyrate (NaB), being a metabolite of gut microbiota, exhibits anti-inflammatory property in local therapies on sites other than the intestine. Thus, this study aimed to probe the mechanism by which NaB regulates CFs transdifferentiation through the NLRP3/Caspase-1 pyroptosis pathway. Methods CFs were cultured in vitro and induced into MFs by TGFβ1. CFs were identified by immunofluorescence labelling technique of vimentin and α-SMA, followed by treatment with NaB or NLRP3 inflammasome inhibitor (CY-09) and its activator [nigericin sodium salt (NSS)]. The expression levels of α-SMA, GSDMD-N/NLRP3/cleaved Caspase-1 proteins, and inflammatory factors IL-1β/IL-18/IL-6/IL-10 were determined using immunofluorescence, Western blot and ELISA. Cell proliferation and migration were evaluated using the CCK-8 assay and the cell scratch test, respectively. Results Following the induction of TGFβ1, CFs exhibited increased expression levels of α-SMA proteins and IL-6/IL-10, as well as cell proliferative and migratory abilities. TGFβ1 induced CFs to differentiate into MFs, while NaB inhibited this differentiation. NaB inactivated the NLRP3/Caspase-1 pyroptosis pathway. CY-09 demonstrated inhibitory effects on the NLRP3/Caspase-1 pyroptosis pathway, leading to a reduction in TGFβ1-induced CFs transdifferentiation. NSS activated the NLRP3/Caspase-1 pyroptosis pathway, and thus partially counteracting the inhibitory effect of intestinal microbiota metabolite NaB on CFs transdifferentiation. Conclusion NaB, a metabolite of the gut microbiota, inhibited the activation of the NLRP3/Caspase-1 pyroptosis pathway in TGFβ1-induced CFs, repressed the transdifferentiation of CFs into MFs.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1749-8090Test

الوصول الحر: https://doaj.org/article/094c8a546b354fb6a6e2e361ff4eb423Test

المؤلفون: Lincheng Zhang, Haotian Bai, Jing Zhou, Lilin Ye, Leiqiong Gao

المصدر: Cell Insight, Vol 3, Iss 3, Pp 100153- (2024)

مصطلحات موضوعية: Tumor cell pyroptosis, Tumor microenvironment, Immunotherapy, Anti-PD-1/PD-L1 ICB, Biology (General), QH301-705.5, Medicine (General), R5-920

الوصف: Peripheral tumor-specific CD8+ T cells often fail to infiltrate into tumor parenchyma due to the immunosuppression of tumor microenvironment (TME). Meanwhile, a significant portion of tumor-specific CD8+ T cells infiltrated into TME are functionally exhausted. Despite the enormous success of anti-PD-1/PD-L1 immune-checkpoint blockade (ICB) treatment in a wide variety of cancer types, the majority of patients do not respond to this treatment largely due to the failure to efficiently drive tumor-specific CD8+ T cell infiltration and reverse their exhaustion states. Nowadays, tumor cell pyroptosis, a unique cell death executed by pore-forming gasdermin (GSDM) family proteins dependent or independent on inflammatory caspase activation, has been shown to robustly promote immune-killing of tumor cells by enhancing tumor immunogenicity and altering the inflammatory state in the TME, which would be beneficial in overcoming the shortages of anti-PD-1/PD-L1 ICB therapy. Therefore, in this review we summarize the current progresses of tumor cell pyroptosis in enhancing immune function and modulating TME, which synergizes anti-PD-1/PD-L1 ICB treatment to achieve better anti-tumor effect. We also enumerate several strategies to better amply the efficiency of anti-PD-1/PD-L1 ICB therapy by inducing tumor cell pyroptosis.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2772892724000087Test; https://doaj.org/toc/2772-8927Test

الوصول الحر: https://doaj.org/article/847676e75c594a9ea4244035fe0f8d95Test

المؤلفون: Shiying Xie, Shicong Song, Sirui Liu, Qiong Li, Wei Zou, Jianting Ke, Cheng Wang

المصدر: Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-19 (2024)

مصطلحات موضوعية: (Pro)renin receptor, Diabetic kidney disease, Renal tubular cell pyroptosis, Dipeptidyl peptidase 4, Medicine

الوصف: Abstract Background (Pro)renin receptor (PRR) is highly expressed in renal tubules, which is involved in physiological and pathological processes. However, the role of PRR, expressed in renal tubular epithelial cells, in diabetic kidney disease (DKD) remain largely unknown. Methods In this study, kidney biopsies, urine samples, and public RNA-seq data from DKD patients were used to assess PRR expression and cell pyroptosis in tubular epithelial cells. The regulation of tubular epithelial cell pyroptosis by PRR was investigated by in situ renal injection of adeno-associated virus9 (AAV9)-shRNA into db/db mice, and knockdown or overexpression of PRR in HK-2 cells. To reveal the underlined mechanism, the interaction of PRR with potential binding proteins was explored by using BioGrid database. Furthermore, the direct binding of PRR to dipeptidyl peptidase 4 (DPP4), a pleiotropic serine peptidase which increases blood glucose by degrading incretins under diabetic conditions, was confirmed by co-immunoprecipitation assay and immunostaining. Results Higher expression of PRR was found in renal tubules and positively correlated with kidney injuries of DKD patients, in parallel with tubular epithelial cells pyroptosis. Knockdown of PRR in kidneys significantly blunted db/db mice to kidney injury by alleviating renal tubular epithelial cells pyroptosis and the resultant interstitial inflammation. Moreover, silencing of PRR blocked high glucose-induced HK-2 pyroptosis, whereas overexpression of PRR enhanced pyroptotic cell death of HK-2 cells. Mechanistically, PRR selectively bound to cysteine-enrich region of C-terminal of DPP4 and augmented the protein abundance of DPP4, leading to the downstream activation of JNK signaling and suppression of SIRT3 signaling and FGFR1 signaling, and then subsequently mediated pyroptotic cell death. Conclusions This study identified the significant role of PRR in the pathogenesis of DKD; specifically, PRR promoted tubular epithelial cell pyroptosis via DPP4 mediated signaling, highlighting that PRR could be a promising therapeutic target in DKD.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1479-5876Test

الوصول الحر: https://doaj.org/article/30408afc84ac4b3f998e18d2466a3b74Test

المؤلفون: Yongkang Zhang, Yaming Wang, Hao Zhang, Fan Qi, Eryan Li, Changhua Li

المصدر: Small Science, Vol 4, Iss 2, Pp n/a-n/a (2024)

مصطلحات موضوعية: cell pyroptosis, immunogenic cell death, photosensitizers, stimuli-responsiveness, tumor immunotherapy, Materials of engineering and construction. Mechanics of materials, TA401-492

الوصف: Pyroptosis is a recently defined form of immunogenic cell death that shows great promise in cancer immunotherapy. However, almost all small‐molecule pyroptosis‐inducing agents (PyAs) reported to date indiscriminately induce pyroptosis in multiple cell types, leading to off‐target pyroptotic death of normal and immune cells. One promising approach to addressing this biosafety issue is the design of conditionally activatable PyAs that specifically respond to disease biomarkers. Herein, a general solution for facilely tailoring and synthesizing activatable PyAs based on a newly developed class of photoactive PyAs, termed PyPSs, is reported. The unique structurally encoded properties of PyPSs, including endo reticulum targeting, hypoxia tolerance, and sensing properties, excitingly meet a demanding set of performance requirements for constructing conditionally activatable PyAs for cancer immunotherapy. Based on PyPS‐1 scaffold, hypoxia‐activatable PyPS‐NF as a proof‐of‐concept example is prepared, demonstrating specific hypoxia‐activated pyroptotic cell death and favorable immunotherapeutic efficacy of solid tumors. Herein, a general design strategy for tailoring activatable PyAs to precisely control GSDME‐mediated cell pyroptosis is established, with great potential to advance cancer immunotherapy.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2688-4046Test

الوصول الحر: https://doaj.org/article/32e131b50da54c7ea0f7f0815465cefdTest

المؤلفون: Shunli Liang, Linsheng Xu, Xilin Xin, Rongbo Zhang, You Wu

المصدر: PeerJ, Vol 12, p e16818 (2024)

مصطلحات موضوعية: Cerebral infarction, Bioinformatics, Cell pyroptosis gene, Middle cerebral artery occlusion model, Pyroptosis genetic verification, Medicine, Biology (General), QH301-705.5

الوصف: Objective Cerebral infarction is the main cause of death in patients with cerebrovascular diseases. Our research aimed to screen and validate pyroptosis-related genes in cerebral infarction for the targeted therapy of cerebral infarction. Methods and results A total of 1,517 differentially expressed genes (DEGs) were obtained by DESeq2 software analysis. Gene set enrichment analysis results indicated that genes of middle cerebral artery occlusion (MCAO) mice aged 3 months and 18 months were enriched in pyroptosis, respectively. Differentially expressed pyroptosis-related genes (including Aim2, Casp8, Gsdmd, Naip2, Naip5, Naip6 and Trem2) were obtained through intersection of DEGs and genes from pyroptosis Gene Ontology Term (GO:0070269), and they were up-regulated in the brain tissues of MCAO mice in GSE137482. In addition, Casp8, Gsdmd, and Trem2 were verified to be significantly up-regulated in MCAO mice in GSE93376. The evaluation of neurologic function and triphenyltetrazolium chloride staining showed that the MCAO mouse models were successfully constructed. Meanwhile, the expressions of TNF-α, pyroptosis-related proteins, Casp8, Gsdmd and Trem2 in MCAO mice were significantly up-regulated. We selected Trem2 for subsequent functional analysis. OGD treatment of BV2 cell in vitro significantly upregulated the expressions of Trem2. Subsequent downregulation of Trem2 expression in OGD-BV2 cells further increased the level of pyroptosis. Therefore, Trem2 is a protective factor regulating pyroptosis, thus influencing the progression of cerebral infarction. Conclusions Casp8, Gsdmd and Trem2 can regulate pyroptosis, thus affecting cerebral infarction.

وصف الملف: electronic resource

العلاقة: https://peerj.com/articles/16818.pdfTest; https://peerj.com/articles/16818Test/; https://doaj.org/toc/2167-8359Test

الوصول الحر: https://doaj.org/article/561083605b1c4efe9336a7744d025bcfTest

المؤلفون: Huimin Yuan, Xue Pian, Jian Cui, Shujing Zhang, Yanru Yu, Aorou Li, Shuxin Yan, Fengjie Zheng

المصدر: Journal of Traditional Chinese Medical Sciences, Vol 10, Iss 4, Pp 461-469 (2023)

مصطلحات موضوعية: Atopic dermatitis, Mahuang Lianqiao Chixiaodou decoction, NLRP3, Cell pyroptosis, Keratinocytes, Miscellaneous systems and treatments, RZ409.7-999

الوصف: Objective: To investigate the efficacy and mechanism of Mahuang Lianqiao Chixiaodou decoction (MLCD) in intervening in the “internal and external crosstalk” between skin barrier dysfunction and immune inflammation in an atopic dermatitis-like (AD-like) mouse model via the NOD-like receptor protein 3 (NLRP3) pyroptosis pathway. Methods: AD-like model mice were induced with 2,4-dinitrofluorobenzene and treated with MLCD or mometasone furoate gel (MF, positive control) for 7 days. Pathological changes in skin tissue were examined using Masson or methamphetamine blue staining. A smart skin analyzer, flow cytometry, fluorescence quantitative polymerase chain reaction, and western blotting were used to observe and evaluate skin barrier dysfunction, immune inflammatory responses, and skin cell pyroptosis in AD-like mice. Results: MLCD and MF improved skin damage and reduced pathological tissue damage and mast cell infiltration in AD-like mice to varying degrees. MLCD significantly reduced skin pigmentation and inflammatory status (P = .005 and P = .038, respectively), increased the percentage of splenic CD4+CD3+ T cells (P = .022), decreased the CD8+CD3+ T cell percentage (P = .044), decreased the CD8+CD3+/CD3+ ratio (P = .031) and increased the CD4+CD3+/CD8+CD3+ ratio (P = .027). MLCD also significantly decreased the mRNA expression levels of cell scorch-related factors NLRP3, casp-1, interleukin (IL)-1β, and IL-18 (P = .027, P

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2095754823000595Test; https://doaj.org/toc/2095-7548Test

الوصول الحر: https://doaj.org/article/5ce6e7ffa4714029a61891f38f2a33b8Test

المؤلفون: Shiying Xie, Shicong Song, Sirui Liu, Qiong Li, Wei Zou, Jianting Ke, Cheng Wang

مصطلحات موضوعية: Biophysics, Biochemistry, Cell Biology, Genetics, Molecular Biology, Physiology, Immunology, Developmental Biology, Marine Biology, Cancer, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, (Pro)renin receptor, Diabetic kidney disease, Renal tubular cell pyroptosis, Dipeptidyl peptidase 4

الوصف: Additional file 1: Figure S1. Schematic diagram showing the injection sites of adeno-associated virus (AAV9-shPRR or negative control (AAV9-shNC). Figure S2. Pathological changes of glomerulus in DKD patients. A, B Representative transmission electron microscopy images of glomerular basement membrane in renal sections from DKD patients and health controls (A) and quantitative analysis of glomerular basement membrane (GBM) (B). n=5. Bar=1 μm C–F Representative immunohistochemistry staining images of WT-1 and CD31 in renal sections from DKD patients and health controls (C, E) and quantitative analysis (D, F). n=5. Bar=10μm. Data are presented as mean ± SEM of biologically independent samples. ∗∗P < 0.01. P values were determined by Student’s t-test for comparison between two groups. Figure S3. Knockdown of PRR or DPP4 alleviated high glucose induced pyroptotic morphological changes of HK-2 cells. Representative scanning electron microscope (SEM) images of HK-2 cells under different treatments. Scale bars: 20 μm. Figure S4. PRR exerted pyroptotic effects independent of Ang II in HK-2 cells. A and B Representative western blot analyses (A) and quantitative data (B) showed that blocking Ang II receptor with losartan had no significant effect on PRR overexpression induced protein expression of NLRP3, cleaved-Caspase1, GSDMD-N, IL-1β and IL-18 in HK-2 cells (n = 3). Data are presented as mean ± SEM of biologically independent samples. ∗P < 0.05, ∗∗P < 0.01, ns P>0.05. One-way ANOVA was used to analyze the data among multiple groups, followed by Tukey’s post hoc test. Figure S5. PRR promoted EMT and EndMT in the kidney of db/db mice. A and B Representative western blot analyses (A) and quantitative data (B) showed that AAV9-shPRR reduced the expression of α-SMA and Vimentin and restored the abundance of E-Cadherin and CD 31in the kidney of db/db mice (n = 6). Data are presented as mean ± SEM of biologically independent samples. ∗∗P < 0.01. One-way ANOVA was used to analyze the data among multiple groups, ...

العلاقة: https://figshare.com/articles/journal_contribution/Additional_file_1_of_Pro_renin_receptor_mediates_tubular_epithelial_cell_pyroptosis_in_diabetic_kidney_disease_via_DPP4-JNK_pathway/24953127Test

الإتاحة: https://doi.org/10.6084/m9.figshare.24953127.v1Test
https://figshare.com/articles/journal_contribution/Additional_file_1_of_Pro_renin_receptor_mediates_tubular_epithelial_cell_pyroptosis_in_diabetic_kidney_disease_via_DPP4-JNK_pathway/24953127Test

المؤلفون: Jie Li, Tian Yu, Juan Sun, Mingwei Ma, Zicheng Zheng, Weiming Kang, Xin Ye

المصدر: Computational and Structural Biotechnology Journal, Vol 23, Iss , Pp 990-1004 (2024)

مصطلحات موضوعية: Cell pyroptosis, Gastric cancer, Single-cell RNA sequencing, Immune infiltration, Prognostic signature, Biotechnology, TP248.13-248.65

الوصف: Cell pyroptosis, a Gasdermin-dependent programmed cell death characterized by inflammasome, plays a complex and dynamic role in Gastric cancer (GC), a serious threat to human health. Therefore, the value of pyroptosis-related genes (PRGs) as prognostic biomarkers and therapeutic indicators for patients needs to be exploited in GC. This study integrates single-cell RNA sequencing (scRNA-seq) dataset GSE183904 with GC transcriptome data from the TCGA database, focusing on the expression and distribution of PRGs in GC at the single-cell level. The prognostic signature of PRGs was established by using Cox and LASSO analyses. The differences in long-term prognosis, immune infiltration, mutation profile, CD274 and response to chemotherapeutic drugs between the two groups were analyzed and evaluated. A tissue array was used to verify the expression of six PRGs, CD274, CD163 and FoxP3. C12orf75, VCAN, RGS2, MKNK2, SOCS3 and TNFAIP2 were successfully screened out to establish a signature to potently predict the survival time of GC patients. A webserver (https://pumc.shinyapps.io/GastricCancerTest/) for prognostic prediction in GC patients was developed based on this signature. High-risk score patients typically had worse prognoses, resistance to classical chemotherapy, and a more immunosuppressive tumor microenvironment. VCAN, TNFAIP2 and SOCS3 were greatly elevated in the GC while RGS2 and MKNK2 were decreased in the tumor samples. Further, VCAN was positively related to the infiltrations of Tregs and M2 TAMs in GC TME and the CD274 in tumor cells. In summary, a potent pyroptosis-related signature was established to accurately forecast the survival time and treatment responsiveness of GC patients.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2001037024000266Test; https://doaj.org/toc/2001-0370Test

الوصول الحر: https://doaj.org/article/330bffe28b1046c9950af109af29267bTest

المؤلفون: Fangfang Liu, Yangyang Zhang, Yining Shi, Kai Xiong, Fugui Wang, Jin Yang

المصدر: BMC Molecular and Cell Biology, Vol 23, Iss 1, Pp 1-16 (2022)

مصطلحات موضوعية: Ceramide, Endothelial cell, Cell pyroptosis, TXNIP/NLRP3/GSDMD signalling pathway, Vascular endothelial cell, Cytology, QH573-671

الوصف: Abstract Background Pyroptosis of endothelial cells is a new cause of endothelial dysfunction in multiple diseases. Ceramide acts as a potential bioactive mediator of inflammation and increases vascular endothelial permeability in many diseases, whether it can aggravate vascular endothelial injury by inducing cell pyroptosis remains unknown. This study was established to explore the effects of C8-ceramide (C8-Cer) on human umbilical vein vascular endothelial cells (HUVECs) and its possible underlying mechanism. Methods HUVECs were exposed to various concentrations of C8-Cer for 12 h, 24 h, 48 h. The cell survival rate was measured using the cell counting kit-8 assay. Western blotting and Real-time polymerase chain reaction (RT-PCR) were used to detect the pyroptosis-releated protein and mRNA expressions, respectively. Caspase-1 activity assay was used to detect caspase-1 activity. Hoechst 33342/propidium iodide double staining and flow cytometry were adopted to measure positive staining of cells. Lactate dehydrogenase release assay and enzyme-linked immunosorbent assay were adopted to measure leakage of cellular contents. FITC method was used to detect the permeability of endothelial cells. ROS fluorescence intensity were detected by flow cytometry. Results The viability of HUVECs decreased gradually with the increase in ceramide concentration and time. Ceramide upregulated the expression of thioredoxin interacting protein (TXNIP), NLRP3, GSDMD, GSDMD-NT, caspase-1 and Casp1 p20 at the protein and mRNA level in a dose-dependent manner. It also enhanced the PI uptake in HUVECs and upregulated caspase-1 activity. Moreover, it promoted the release of lactate dehydrogenase, interleukin-1β, and interleukin-18. Meanwhile, we found that ceramide led to increased vascular permeability. The inhibitor of NLRP3 inflammasome assembly, MCC950, was able to disrupt the aforementioned positive loop, thus alleviating vascular endothelial cell damage. Interestingly, inhibition of TXNIP either chemically using verapamil or genetically using small interfering RNA (siRNA) can effectively inhibit ceramide-induced pyroptosis and improved cell permeability. In addition, ceramide stimulated reactive oxygen species (ROS) generation. The pretreatment of antioxidant N-acetylcysteine (NAC), ROS scavenger, blocked the expression of pyroptosis markers induced by C8-cer in HUVECs. Conclusion The current study demonstrated that C8-Cer could aggravate vascular endothelial cell damage and increased cell permeability by inducing cell pyroptosis. The results documented that the ROS-dependent TXNIP/NLRP3/GSDMD signalling pathway plays an essential role in the ceramide-induced pyroptosis in HUVECs.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2661-8850Test

الوصول الحر: https://doaj.org/article/fb4182c078914192856e11eb5d07f957Test

المؤلفون: Hai-Ying Wu, Kan liu, Jing-Li Zhang

المصدر: Molecular Medicine, Vol 28, Iss 1, Pp 1-21 (2022)

مصطلحات موضوعية: Preeclampsia, LINC00240, Oxidative stress, Cell pyroptosis, Macrophage polarization, Trophoblasts, Therapeutics. Pharmacology, RM1-950, Biochemistry, QD415-436

الوصف: Abstract Background This study aimed to investigate the effects of LINC00240/miR-155/Nrf2 axis on trophoblast function and macrophage polarization in the pathogenesis of preeclampsia. Methods Bindings between LINC00240, miR-155 and Nrf2 were validated by dual luciferase reporter assay or RNA-immunoprecipitation. Cell proliferation, migration, invasion, and pyroptosis were detected by CCK-8, clone formation, wound healing, Transwell system, and flow cytometry, respectively. Macrophage polarization was tested by flow cytometry. The expression levels of LINC00240, miR-155, Nrf2, and oxidative stress and pyroptosis-related markers in in vitro and in vivo preeclampsia models were analyzed by qPCR, western blot, or ELISA assays. Blood pressure, urine protein levels, liver and kidney damages, and trophoblast markers in placenta tissues were further studied in vivo. Results Placenta tissues from preeclampsia patients and animals showed decreased LINC00240 and Nrf2 and increased miR-155 expression levels, and the decreased M2 macrophage polarization. LINC00240 directly bound and inhibited expression of miR-155, which then inhibited oxidative stress-induced pyroptosis, promoting proliferation, migration and invasion abilities of trophoblasts, and M2 macrophage polarization. Inhibition of miR-155 led to increased Nrf2 expression and similar changes as LINC00240 overexpression in trophoblast function and macrophage polarization. Overexpression of LINC00240 in in vivo preeclampsia model decreased blood pressure, urine protein, liver and kidney damages, increased fetal weight and length, and induced trophoblast function and M2 macrophage polarization. Conclusion LINC00240 inhibited symptoms of preeclampsia through regulation on miR-155/Nrf2 axis, which suppressed oxidative stress-induced pyroptosis to improve trophoblast function and M2 macrophage polarization. LINC00240 could be a potential therapeutic target for preeclampsia.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1076-1551Test; https://doaj.org/toc/1528-3658Test

الوصول الحر: https://doaj.org/article/78d26e735614438a9572eb56960beadcTest