scholarly journals Pyroptosis: Mechanisms and Links with Fibrosis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3509
Author(s):  
Zihao Song ◽  
Quan Gong ◽  
Jiawei Guo
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Organ Failure ◽  
Significant Role ◽  
Proinflammatory Cytokines ◽  
Healthcare Burden ◽  
Caspase 1 ◽  
Terminal Fragment ◽  
Novel Targets ◽  
Approved Drugs

Fibrosis is responsible for approximately 45% of deaths in the industrialized world and has been a major global healthcare burden. Excessive fibrosis is the primary cause of organ failure. However, there are currently no approved drugs available for the prevention or treatment of fibrosis-related diseases. It has become evident that fibrosis is characterized by inflammation. In a large number of studies of various organs in mice and humans, pyroptosis has been found to play a significant role in fibrosis. Pyroptosis is a form of programmed cell death mediated by the N-terminal fragment of cysteinyl aspartate-specific proteinase (caspase)-1-cleaved gasdermin D (GSDMD, producing GSDMD-N) that gives rise to inflammation via the release of some proinflammatory cytokines, including IL-1β, IL-18 and HMGB1. These cytokines can initiate the activation of fibroblasts. Inflammasomes, an important factor upstream of GSDMD, can activate caspase-1 to trigger the maturation of IL-1β and IL-18. Moreover, the inhibition of inflammasomes, proinflammatory cytokines and GSDMD can prevent the progression of fibrosis. This review summarizes the growing evidence indicating that pyroptosis triggers fibrosis, and highlights potential novel targets for antifibrotic therapies.

scholarly journals Recent Advancements in Toxin and Antitoxin Systems Involved in Bacterial Programmed Cell Death

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Ming-xi Hu ◽  
Xiao Zhang ◽  
Er-li Li ◽  
Yong-Jun Feng
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Significant Role ◽  
Environmental Stresses ◽  
Biological Processes ◽  
Eukaryotic Organisms ◽  
Evolutionary Perspectives

Programmed cell death (PCD) systems have been extensively studied for their significant role in a variety of biological processes in eukaryotic organisms. Recently, more and more researches have revealed the existence of similar systems employed by bacteria in response to various environmental stresses. This paper summarized the recent researching advancements in toxin/antitoxin systems located on plasmids or chromosomes and their regulatory roles in bacterial PCD. The most studied yet disputedmazEFsystem was discussed in depth, and possible roles and status of such a special bacterial death and TA systems were also reviewed from the ecological and evolutionary perspectives.

scholarly journals Methanol Extract of Coleus amboinicus (Lour) Exhibited Antiproliferative Activity and Induced Programmed Cell Death in Colon Cancer Cell WiDr

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Farida Laila ◽  
Dedi Fardiaz ◽  
Nancy Dewi Yuliana ◽  
M. Rizal M. Damanik ◽  
Fitriya Nur Annisa Dewi
Keyword(s):  
Colon Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Brine Shrimp ◽  
Methanol Extract ◽  
Standard Drug ◽  
Caspase 1 ◽  
Coleus Amboinicus

Coleus amboinicus(Lour) (CA) has been reported to possess many pharmacological activities. In this study, evaluation of cytotoxicity using brine shrimp lethality bioassay and MTT assay using WiDr cell lines was carried out. The expression of several genes responsible for programmed cell death of the methanol extract of CA was also investigated. The morphology of the cells undergoing apoptosis was detected using Hoechst staining assay. The gene expression of BAX, BCL2, P53, Caspase 1, 7, 8, and 9 of treated samples with different concentrations (10, 15, 25 & 50 µg/ml) were measured with RT PCR. The phytochemical profiles were investigated using LC MS. The results showed that the lethality concentration (LC50) of methanol extract using brine shrimp was 34.545 µg/ml and the extract exhibited good antiproliferative activity against cancer cells WiDr with IC50 value (8.598 ± 2.68 µg/ml) as compared to standard drug 5-fluorouracil (IC50 value 1.839 ± 0.03 µg/ml). There was apoptotic evidences from the morphology of treated cells. The expressions of BAX,P53, and Caspase 9 were upregulated in lower concentration of the extract (10 and 15 µg/ml) but downregulated in higher concentration (25 and 50 µg/ml). BCL2 as anti-apoptotic gene was downregulated in all concentrations. Caspase 1 and Caspase 7 were upregulated in high concentration (25 and 50 µg/ml), but downregulated in lower concentrations. These data provide a mode of cell death for the methanol extract of CA in low concentrations corresponding to apoptosis with intrinsic pathway. Many valuable compounds identified including caffeic acid, rosmarinic acid, malic acid, eicosapentanoic acid, benserazide, alpha-linolenic acid, betaine, Salvanolic B, 4-hydroxibenzoic acid and firulic acid have been previously reported as being active agents against many cancer cells. This study suggested that CA might become an effective ingredient for health-beneficial foods to prevent colon cancer.

The Pros and Cons of Apoptosis Assays for Use in the Study of Cells, Tissues, and Organs

2002 ◽  
Vol 8 (5) ◽  
pp. 375-391 ◽  
Author(s):  
Michiko Watanabe ◽  
Midori Hitomi ◽  
Kathy van der Wee ◽  
Florence Rothenberg ◽  
Steven A. Fisher ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Significant Role ◽  
Normal Development ◽  
Abnormal Development ◽  
New Techniques ◽  
Advantages And Disadvantages ◽  
Adult Tissues ◽  
Pros And Cons

Programmed cell death or apoptosis occurs in many tissues during normal development and in the normal homeostasis of adult tissues. Apoptosis also plays a significant role in abnormal development and disease. Increased interest in apoptosis and cell death in general has resulted in the development of new techniques and the revival of old ones. Each assay has its advantages and disadvantages that can render it appropriate and useful for one application, but inappropriate or difficult to use in another. Understanding the strengths and limitations of the assays would allow investigators to select the best methods for their needs.

scholarly journals Exploring the Focal Role of Pyroptosis in Diabetes Mellitus

2021 ◽  
Vol 11 (5) ◽  
pp. 13557-13572
Keyword(s):  
Diabetes Mellitus ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Defense Mechanism ◽  
Death Process ◽  
Membrane Pores ◽  
Caspase 1 ◽  
Cell Death Process ◽  
Physiological Outcomes

Diabetes mellitus is a T cell-mediated disease associated with the depletion of beta cells responsible for insulin production. Although the disease is T cell-mediated, it undergoes various biochemical responses and programmed cell death. Programmed cell death, a distinct biochemical pathway in which cells die by eliciting various physiological outcomes. Pyroptosis, apoptosis, and necrosis are the three major forms of programmed cell death that function as a defense mechanism against various infections, diseases, and microorganisms. This review article focuses on the various pathological mechanisms of pyroptosis. Pyroptosis is distinguished by the caspase-1-dependent formation of plasma membrane pores, resulting in the release of pro-inflammatory cytokines, leading to cell lysis. Caspase-1, a protease which is an interleukin-1L-1β converting enzyme that initiates the cell death process by converting interleukin-1L-1β into mature inflammatory cytokine (mature form). Emerging evidence has made pyroptosis a vital trigger as well as an endogenic regulator of diabetes mellitus.

scholarly journals Embryonic stem cell-derived exosomes inhibit doxorubicin-induced TLR4-NLRP3-mediated cell death-pyroptosis

2019 ◽  
Vol 317 (2) ◽  
pp. H460-H471 ◽  
Author(s):  
Zahra Tavakoli Dargani ◽  
Dinender K. Singla
Keyword(s):  
Cell Death ◽  
Proinflammatory Cytokines ◽  
Embryonic Stem ◽  
Protective Effects ◽  
H9c2 Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Tnf Α

Doxorubicin (Dox)-induced cardiac side effects are regulated through increased oxidative stress and apoptosis. However, it remains unknown whether Dox induces the specific inflammatory-mediated form of cell death called pyroptosis. The current study is undertaken to determine whether Dox induces pyroptosis in an in vitro model and to test the potential of exosomes derived from embryonic stem cells (ES-Exos) in inhibiting pyroptosis. H9c2 cells were exposed to Dox to generate pyroptosis and then subsequently treated with exosomes to investigate the protective effects of ES-Exos. Mouse embryonic fibroblast-exosomes (MEF-Exos) were used as a cell line control. We confirmed pyroptosis by analyzing the presence of Toll-like receptor 4 (TLR4)-pyrin domain containing-3 (NLRP3) inflammasome that initiates pyroptosis, which was further confirmed with pyroptotic markers caspase-1, IL-1β, caspase-11, and gasdermin-D. The presence of inflammation was confirmed for proinflammatory cytokines, TNF-α, and IL-6. Our data show that Dox exposure significantly ( P < 0.05) increases expression of TLR4, NLRP3, pyroptotic markers (caspase-1, IL-1β, caspase-11, and gasdermin-D), and proinflammatory cytokines (TNF-α and IL-6) in H9c2 cells. The increased expression of inflammasome, pyroptosis, and inflammation was significantly ( P < 0.05) inhibited by ES-Exos. Interestingly, our cell line control, MEF-Exos, did not show any protective effects. Furthermore, our cytokine array data suggest increased anti-inflammatory (IL-4, IL-9, and IL-13) and decreased proinflammatory cytokines (Fas ligand, IL-12, and TNF-α) in ES-Exos, suggesting that anti-inflammatory cytokines might be mediating the protective effects of ES-Exos. In conclusion, our data show that Dox induces pyroptotic cell death in the H9c2 cell culture model and is attenuated via treatment with ES-Exos. NEW & NOTEWORTHY Doxorubicin (Dox)-induced cardiotoxicity is mediated through increased oxidative stress, apoptosis, and necrosis. We report for the first time as per the best of our knowledge that Dox initiates Toll-like receptor 4 and pyrin domain containing-3 inflammasome formation and induces caspase-1-mediated inflammatory pyroptotic cell death in H9c2 cells. Moreover, we establish that inflammation and pyroptosis is inhibited by embryonic stem cell-derived exosomes that could be used as a future therapeutic option to treat Dox-induced cardiotoxicity.

scholarly journals Proinflammatory Caspase-2-Mediated Macrophage Cell Death Induced by a Rough Attenuated Brucella suis Strain

2011 ◽  
Vol 79 (6) ◽  
pp. 2460-2469 ◽  
Author(s):  
Fang Chen ◽  
Xicheng Ding ◽  
Ying Ding ◽  
Zuoshuang Xiang ◽  
Xinna Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Macrophage Cell ◽  
Proinflammatory Response ◽  
Transcriptional Responses ◽  
Content Type ◽  
Caspase 1 ◽  
Pathway Gene ◽  
Tnf Α ◽  
Caspase 2

ABSTRACTBrucellaspp. are intracellular bacteria that cause an infectious disease called brucellosis in humans and many domestic and wildlife animals.B. suisprimarily infects pigs and is pathogenic to humans. The macrophage-Brucellainteraction is critical for the establishment of a chronicBrucellainfection. Our studies showed that smooth virulentB. suisstrain 1330 (S1330) prevented programmed cell death of infected macrophages and rough attenuatedB. suisstrain VTRS1 (a vaccine candidate) induced strong macrophage cell death. To further investigate the mechanism of VTRS1-induced macrophage cell death, microarrays were used to analyze temporal transcriptional responses of murine macrophage-like J774.A1 cells infected with S1330 or VTRS1. In total 17,685 probe sets were significantly regulated based on the effects of strain, time and their interactions. A miniTUBA dynamic Bayesian network analysis predicted that VTRS1-induced macrophage cell death was mediated by a proinflammatory gene (the tumor necrosis factor alpha [TNF-α] gene), an NF-κB pathway gene (the IκB-α gene), the caspase-2 gene, and several other genes. VTRS1 induced significantly higher levels of transcription of 40 proinflammatory genes than S1330. A Mann-Whitney U test confirmed the proinflammatory response in VTRS1-infected macrophages. Increased production of TNF-α and interleukin 1β (IL-1β) were also detected in the supernatants in VTRS1-infected macrophage cell culture. Hyperphosphorylation of IκB-α was observed in macrophages infected with VTRS1 but not S1330. The important roles of TNF-α and IκB-α in VTRS1-induced macrophage cell death were further confirmed by individual inhibition studies. VTRS1-induced macrophage cell death was significantly inhibited by a caspase-2 inhibitor but not a caspase-1 inhibitor. The role of caspase-2 in regulating the programmed cell death of VTRS1-infected macrophages was confirmed in another study using caspase-2-knockout mice. In summary, VTRS1 induces a proinflammatory, caspase-2- and NF-κB-mediated macrophage cell death. This unique cell death differs from apoptosis, which is not proinflammatory. It is also different from classical pyroptosis, which is caspase-1 mediated.

scholarly journals Mycobacterial infections due to PD-1 and PD-L1 checkpoint inhibitors

ESMO Open ◽  
2020 ◽  
Vol 5 (4) ◽  
pp. e000866 ◽  
Author(s):  
Kartik Anand ◽  
Geetanjali Sahu ◽  
Ethan Burns ◽  
Allyne Ensor ◽  
Joe Ensor ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
Drug Administration ◽  
Checkpoint Inhibitors ◽  
Food And Drug Administration ◽  
Mycobacterial Infection ◽  
Cancer Subtypes ◽  
Atypical Mycobacterial Infection ◽  
Approved Drugs

BackgroundImmune checkpoint inhibitors that block programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved outcomes for many cancer subtypes but do exhibit toxicity, in the form of immune-related adverse events.ObjectiveThe aim of this study was to investigate the emerging toxicities of PD-1 and PD-L1 inhibitors including acute or reactivation of tuberculosis (TB) and atypical mycobacterial infection (AMI).MethodsThis study was completed as a retrospective review using the US Food and Drug Administration Adverse Events Reporting System (FAERS) for incidence of TB and AMI due to PD-1 and PD-L1 inhibitors compared with other FDA (Food and Drug Administration) approved drugs. The statistical methods included disproportionality signal analysis using the reporting OR (ROR) to compare cases. The 95% Wald CI was reported to assess the precision of the ROR.ResultsOut of the 10 146 481 adverse events (AEs) reported to FAERS for all drugs between 1 January 2015 and 31 March 2020, 73 886 AEs were due to the five FDA approved PD-1/PD-L1 inhibitors. Seventy-two cases of TB were due to PD-1/PD-L1 inhibitors. Specifically, 45 cases (62.5%) due to nivolumab, 18 (25%) due to pembrolizumab, 5 (7%) due to atezolizumab and 4 (5.5%) due to durvalumab. There were 13 cases of AMI: 9 (69.3%) due to nivolumab, 2 (15.3%) due to pembrolizumab and 1 (7.7%) each due to durvalumab and atezolizumab. Avelumab was not attributed to any AE of TB or AMI. From analysis of the FAERS database, the calculated ROR for TB due to PD-1/PD-L1 inhibitors was 1.79 (95% CI, 1.42 to 2.26) (p<0.0001) and for AMI was 5.49 (95% CI, 3.15 to 9.55) (p<0.0001).ConclusionPD-1/PD-L1 inhibitors used in the treatment of cancer subtypes is associated with increased TB and AMI risk. Although this complication is rare, clinicians using PD-1/PD-L1 inhibitors should be aware of the risks.

scholarly journals White spot syndrome virus infection induces Caspase 1-mediated antiviral cell death in crustacean

2018 ◽  
Author(s):  
Geng Yang ◽  
Jiajia Wang ◽  
Tao Luo ◽  
Jun Wei ◽  
Yadong Yang ◽  
...  
Keyword(s):  
Cell Death ◽  
Virus Infection ◽  
Programmed Cell Death ◽  
White Spot Syndrome Virus ◽  
White Spot ◽  
Cytokine Network ◽  
Adaptive Immune ◽  
Caspase 1 ◽  
Cell Death Pathway ◽  
White Spot Syndrome

AbstractIn vertebrates, pyroptosis is an intensely inflammatory form of programmed cell death which is dependent on Caspase 1 activation and release of cytoplasmic cytokines including IL-1β. This death pathway is critical for controlling pathogenic infection by mobilizing immune cells and stimulating the development of adaptive immune response. In invertebrates, however, due to the lack of adaptive immune response, it is still elusive whether Caspase 1-dependent cell death pathway exists. In this study, our data showed that Caspase 1-mediated cell death was activated by white spot syndrome virus (WSSV) infection to control the virus in shrimp. Caspase 1 had a higher expression level in hemocytes and lymphoid-like organ in shrimp and WSSV infection was significantly promoted upon the inhibition of Caspase 1 enzymatic activity. IL-1β-like protein was identified as the substrate of Caspase 1 and its interaction with Caspase 1 was validated ectopically and endogenously. Moreover, IL-1β like protein was released into extracellular contents under WSSV infection and Prophenoloxidase system was activated, resulting in the reduction of WSSV copiesin vivo. Our data unraveled a previously unidentified mechanism through which Caspase 1-dependent cell death controlled virus infection in shrimp. Therefore, our study opened the possibility that an invertebrate cytokine network might be operative and regulate host defenses against virus infection as in vertebrates.Author SummaryThe elimination of infected cells by programmed cell death is considered as one of the most important anti-pathogen responses. Pyroptosis is one form of programmed cell death, which is mediated by Caspase 1 activation. Activated Caspase 1 can process the inactive precursors of interleukin 1β (IL-1β) into mature inflammatory cytokines to induce potent immune responses. Meanwhile, pyroptosis also induces morphologic changes, DNA fragmentation and chromatin condensation to destroy infected cells. However, due to the lack of efficient adaptive immune responses, it is still unclear whether Caspase 1-mediated cell death also exits and plays such an important role in defending hosts from pathogen invasion in invertebrates. In our data, Caspase 1 gene was characterized and Caspase 1-mediated cell death pathway was validated in shrimp. The Caspase 1-mediated cell death pathway was enhanced by white spot syndrome virus (WSSV) infection to control the virus in shrimp. IL-1β-like protein was cleaved by Caspase 1 and released into extracellular contents under WSSV infection to activate Prophenoloxidase system, leading to the reduction of WSSV copies in shrimp in vivo. On the other hand, silencing ofCaspase 1orIL-1β-likegene facilitated virus infection in shrimp. Our study indicated that Casapase-1-mediated cell death played an important antiviral role in shrimp against WSSV infection and opened the possibility that an invertebrate cytokine network might be operative.

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