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Biomedicine & Pharmacotherapy =... Dec 2023Sepsis is a life-threatening systemic inflammatory response syndrome caused by the host imbalanced response to infection. Lung injury is the most common complication of... (Review)
Review
Sepsis is a life-threatening systemic inflammatory response syndrome caused by the host imbalanced response to infection. Lung injury is the most common complication of sepsis and one of the leading causes of patient death. Pyroptosis is a specific programmed cell death characterized by the release of inflammatory cytokines. Appropriate pyroptosis can reduce tissue damage and exert a protective effect against infection during sepsis. However, overactivated pyroptosis results in massive cell death, leading to septic shock, multiple organ dysfunction syndrome, and even an increased risk of secondary infection. Recent studies suggest that pyroptosis can interact with and cross-regulate other types of cell death programs to establish a complex network of cell death, which participates in the occurrence and development of septic lung injury. This review will focus on the interactions between pyroptosis and other types of cell death, including apoptosis, necroptosis, PANoptosis, NETosis, autophagy, and ferroptosis, to summarize the role of pyroptosis in sepsis-induced lung injury, and will discuss the potential therapeutic strategies of targeting pyroptosis during sepsis treatment.
Topics: Humans; Pyroptosis; Lung Injury; Cell Death; Apoptosis; Sepsis
PubMed: 38000360
DOI: 10.1016/j.biopha.2023.115914 -
Cell Death & Disease Jul 2023Pyroptosis is a novel inflammatory form of regulated cell death (RCD), characterized by cell swelling, membrane rupture, and pro-inflammatory effects. It is recognized... (Review)
Review
Pyroptosis is a novel inflammatory form of regulated cell death (RCD), characterized by cell swelling, membrane rupture, and pro-inflammatory effects. It is recognized as a potent inflammatory response required for maintaining organismal homeostasis. However, excessive and persistent pyroptosis contributes to severe inflammatory responses and accelerates the progression of numerous inflammation-related disorders. In pyroptosis, activated inflammasomes cleave gasdermins (GSDMs) and generate membrane holes, releasing interleukin (IL)-1β/18, ultimately causing pyroptotic cell death. Mechanistically, pyroptosis is categorized into caspase-1-mediated classical pyroptotic pathway and caspase-4/5/11-mediated non-classical pyroptotic pathway. Renal fibrosis is a kidney disease characterized by the loss of structural and functional units, the proliferation of fibroblasts and myofibroblasts, and extracellular matrix (ECM) accumulation, which leads to interstitial fibrosis of the kidney tubules. Histologically, renal fibrosis is the terminal stage of chronic inflammatory kidney disease. Although there is a multitude of newly discovered information regarding pyroptosis, the regulatory roles of pyroptosis involved in renal fibrosis still need to be fully comprehended, and how to improve clinical outcomes remains obscure. Hence, this review systematically summarizes the novel findings regarding the role of pyroptosis in the pathogenesis of renal fibrosis and discusses potential biomarkers and drugs for anti-fibrotic therapeutic strategies.
Topics: Humans; Pyroptosis; Clinical Relevance; Inflammasomes; Inflammation; Nephritis; Caspase 1; Fibrosis
PubMed: 37500614
DOI: 10.1038/s41419-023-06005-6 -
Clinical and Experimental Hypertension... Dec 2023Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains...
BACKGROUND
Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains unclear. We investigated the role of GSDMD-mediated pyroptosis in the pathogenesis of cardiac remodeling in pressure overload.
METHODS
Wild-type (WT) and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. Four weeks after surgery, left ventricular structure and function were evaluated by echocardiographic, invasive hemodynamic and histological analysis. Pertinent signaling pathways related to pyroptosis, hypertrophy and fibrosis were investigated by histochemistry, RT-PCR and western blotting. The serum levels of GSDMD and IL-18 collected from healthy volunteers or hypertensive patients were measured by ELISA.
RESULTS
We found TAC induced cardiomyocyte pyroptosis and release of pro-inflammatory cytokines IL-18. The serum GSDMD level was significantly higher in hypertensive patients than in healthy volunteers, and induced more dramatic release of mature IL-18. GSDMD deletion remarkably mitigated TAC-induced cardiomyocyte pyroptosis. Furthermore, GSDMD deficiency in cardiomyocytes significantly reduced myocardial hypertrophy and fibrosis. The deterioration of cardiac remodeling by GSDMD-mediated pyroptosis was associated with activating JNK and p38 signaling pathways, but not ERK or Akt signaling pathway.
CONCLUSION
In conclusion, our results demonstrate that GSDMD serves as a key executioner of pyroptosis in cardiac remodeling induced by pressure overload. GSDMD-mediated pyroptosis activates JNK and p38 signaling pathways, and this may provide a new therapeutic target for cardiac remodeling induced by pressure overload.
Topics: Animals; Mice; Cardiomegaly; Fibrosis; Hypertension; Interleukin-18; Mice, Inbred C57BL; Myocytes, Cardiac; Pyroptosis; Ventricular Remodeling; Gasdermins; Humans
PubMed: 36906959
DOI: 10.1080/10641963.2023.2189138 -
Frontiers in Immunology 2023Pyroptosis, a novel form of programmed cell death (PCD) discovered after apoptosis and necrosis, is characterized by cell swelling, cytomembrane perforation and lysis,... (Review)
Review
Pyroptosis, a novel form of programmed cell death (PCD) discovered after apoptosis and necrosis, is characterized by cell swelling, cytomembrane perforation and lysis, chromatin DNA fragmentation, and the release of intracellular proinflammatory contents, such as Interleukin (IL) 8, IL-1β, ATP, IL-1α, and high mobility group box 1 (HMGB1). Our understanding of pyroptosis has increased over time with an increase in research on the subject: gasdermin-mediated lytic PCD usually, but not always, requires cleavage by caspases. Moreover, new evidence suggests that pyroptosis induction in tumor cells results in a strong inflammatory response and significant cancer regression, which has stimulated great interest among scientists for its potential application in clinical cancer therapy. It's worth noting that the side effects of chemotherapy and radiotherapy can be triggered by pyroptosis. Thus, the intelligent use of pyroptosis, the double-edged sword for tumors, will enable us to understand the genesis and development of cancers and provide potential methods to develop novel anticancer drugs based on pyroptosis. Hence, in this review, we systematically summarize the molecular mechanisms of pyroptosis and provide the latest available evidence supporting the antitumor properties of pyroptosis, and provide a summary of the various antitumor medicines targeting pyroptosis signaling pathways.
Topics: Humans; Pyroptosis; Apoptosis; Caspases; Apoptosis Regulatory Proteins; Neoplasms
PubMed: 38016064
DOI: 10.3389/fimmu.2023.1290885 -
International Journal of Nanomedicine 2024Pyroptosis, a pro-inflammatory and lytic programmed cell death pathway, possesses great potential for antitumor immunotherapy. By releasing cellular contents and a large... (Review)
Review
Pyroptosis, a pro-inflammatory and lytic programmed cell death pathway, possesses great potential for antitumor immunotherapy. By releasing cellular contents and a large number of pro-inflammatory factors, tumor cell pyroptosis can promote dendritic cell maturation, increase the intratumoral infiltration of cytotoxic T cells and natural killer cells, and reduce the number of immunosuppressive cells within the tumor. However, the efficient induction of pyroptosis and prevention of damage to normal tissues or cells is an urgent concern to be addressed. Recently, a wide variety of nanoplatforms have been designed to precisely trigger pyroptosis and activate the antitumor immune responses. This review provides an update on the progress in nanotechnology for enhancing pyroptosis-based tumor immunotherapy. Nanomaterials have shown great advantages in triggering pyroptosis by delivering pyroptosis initiators to tumors, increasing oxidative stress in tumor cells, and inducing intracellular osmotic pressure changes or ion imbalances. In addition, the challenges and future perspectives in this field are proposed to advance the clinical translation of pyroptosis-inducing nanomedicines.
Topics: Pyroptosis; Humans; Immunotherapy; Neoplasms; Nanostructures; Animals; Nanomedicine; Oxidative Stress
PubMed: 38882539
DOI: 10.2147/IJN.S457309 -
Biomedicine & Pharmacotherapy =... Dec 2023Programmed cell death (PCD) is a key mechanism for the study of anticancer drugs and has a significant impact on the development and management of cancer. A growing... (Review)
Review
Programmed cell death (PCD) is a key mechanism for the study of anticancer drugs and has a significant impact on the development and management of cancer. A growing amount of data indicates that different kinds of PCD, particularly pyroptosis, apoptosis, and necroptosis, interact closely. Recent research has revealed the existence of the distinct inflammatory PCD modality known as PANoptosis, which is controlled by complex PANoptosome complexes built by combining elements from different PCD pathways. No single PCD route is sufficient to explain all of the physiologic effects seen in PANoptosis. Numerous studies have demonstrated that PANoptosis can successfully stop cancer cells from growing, proliferating, and developing drug resistance. As a result, it has changed the focus of targeted anticancer therapy. In this review, we outlined the molecular processes of PANoptosis activation and modulation as well as the mechanisms of innate immune cell death. In order to provide a theoretical foundation for the development of drugs targeting PANoptosis as an anti-cancer target, we also highlight the PANoptosomes discovered to date and give an overview of the implications of PANoptosis in cancer treatment.
Topics: Apoptosis; Cell Death; Necroptosis; Pyroptosis; Neoplasms
PubMed: 37837884
DOI: 10.1016/j.biopha.2023.115696 -
Seminars in Immunology Sep 2023Unconventional protein secretion (UPS) allows the release of specific leaderless proteins independently of the classical endoplasmic reticulum (ER)-Golgi secretory... (Review)
Review
Unconventional protein secretion (UPS) allows the release of specific leaderless proteins independently of the classical endoplasmic reticulum (ER)-Golgi secretory pathway. While it remains one of the least understood mechanisms in cell biology, UPS plays an essential role in immunity as it controls the release of the IL-1 family of cytokines, which coordinate host defense and inflammatory responses. The unconventional secretion of IL-1β and IL-18, the two most prominent members of the IL-1 family, is initiated by inflammasome complexes - cytosolic signaling platforms that are assembled in response to infectious or noxious stimuli. Inflammasomes activate inflammatory caspases that proteolytically mature IL-1β/- 18, but also induce pyroptosis, a lytic form of cell death. Pyroptosis is caused by gasdermin-D (GSDMD), a member of the gasdermin protein family, which is activated by caspase cleavage and forms large β-barrel plasma membrane pores. This pore-forming activity is shared with other family members that are activated during infection or upon treatment with chemotherapy drugs. While the induction of cell death was assumed to be the main function of gasdermin pores, accumulating evidence suggests that they have also non-lytic functions, such as in the release of cytokines and alarmins, or in regulating ion fluxes. This has raised the possibility that gasdermin pores are one of the main mediators of UPS. Here, I summarize and discuss new insights into gasdermin activation and pore formation, how gasdermin pores achieve selective cargo release, and how gasdermin pore formation and ninjurin-1-driven plasma membrane rupture are executed and regulated.
Topics: Humans; Gasdermins; Pyroptosis; Inflammasomes; Caspases; Cytokines; Interleukin-1
PubMed: 37473560
DOI: 10.1016/j.smim.2023.101811 -
Cell Communication and Signaling : CCS Nov 2023The outcome of patients with colon cancer is still unsatisfied nowadays. Simvastatin is a type of statins with anti-cancer activity, but its effect on colon cancer cells...
BACKGROUND
The outcome of patients with colon cancer is still unsatisfied nowadays. Simvastatin is a type of statins with anti-cancer activity, but its effect on colon cancer cells remains unclear. The present study is intended to determine the underlying mechanism of simvastatin in treatment of colon cancer.
METHODS
The viability and pyroptosis rate of cells treated and untreated with simvastatin were analysed by CCK-8 and flow cytometry assays, respectively. We used DCFH-DA and flow cytometry to detect reactive oxygen species (ROS) production. Levels of pyroptosis markers were detected by western blotting analysis or immunofluorescence staining. Besides, the anticancer properties of simvastatin on colon cancer were further demonstrated using a cell line based xenograft tumor model.
RESULTS
Simvastatin treatment in HCT116 and SW620 induced pyroptosis and suppressed cell proliferation, with changes in the expression level of NLPR3, ASC, cleaved-caspase-1, mature IL-1β, IL-18 and GSDMD-N. Moreover, inhibition of caspase-1 and ROS attenuated the effects of simvastatin on cancer cell viability. In addition, it was identified that simvastatin has an anti-tumor effect by down-regulating ROS production and inducing downstream caspase-1 dependent pyroptosis in the subcutaneous transplantation tumors of HCT116 cells in BALB/c nude mice.
CONCLUSIONS
Our in vitro and in vivo results indicated that simvastatin induced pyroptosis through ROS/caspase-1/GSDMD pathway, thereby serving as a potential agent for colon cancer treatment. Video Abstract.
Topics: Mice; Animals; Humans; Pyroptosis; Caspase 1; Reactive Oxygen Species; Simvastatin; Mice, Nude; HCT116 Cells; Disease Models, Animal; Colonic Neoplasms; Phosphate-Binding Proteins; Pore Forming Cytotoxic Proteins
PubMed: 37974278
DOI: 10.1186/s12964-023-01359-y -
International Journal of Biological... 2023Pyroptosis is a form of cell death that is characterized by the destruction of the cell, and it has implications in both the immune system and cancer immunotherapy. The... (Review)
Review
Pyroptosis is a form of cell death that is characterized by the destruction of the cell, and it has implications in both the immune system and cancer immunotherapy. The gasdermin family is responsible for the activation of pyroptosis, which involves the formation of pores in the cellular membrane that permit the discharge of inflammatory factors. The inflammasome response is a powerful mechanism that helps to eliminate bacteria and cancer cells when cellular damage occurs. As tumor cells become more resilient to apoptosis, other treatments for cancer are becoming more popular. It is essential to gain a thorough understanding of pyroptosis in order to use it in cancer treatment, considering the intricate association between pyroptosis and the immune system's defensive reaction against tumors. This review offers an overview of the mechanisms of pyroptosis, the relationship between the gasdermin family and pyroptosis, and the interplay between pyroptosis and anti-tumor immunity. In addition, the potential implications of pyroptosis in cancer immunotherapy are discussed. Additionally, we explore future research possibilities and introduce a novel approach to tumor treatment.
Topics: Pyroptosis; Gasdermins; Apoptosis; Cell Death; Immunotherapy
PubMed: 37705746
DOI: 10.7150/ijbs.86855 -
Cell Death and Differentiation Sep 2023Critical COVID-19 patients admitted to the intensive care unit (ICU) frequently suffer from severe multiple organ dysfunction with underlying widespread cell death....
Critical COVID-19 patients admitted to the intensive care unit (ICU) frequently suffer from severe multiple organ dysfunction with underlying widespread cell death. Ferroptosis and pyroptosis are two detrimental forms of regulated cell death that could constitute new therapeutic targets. We enrolled 120 critical COVID-19 patients in a two-center prospective cohort study to monitor systemic markers of ferroptosis, iron dyshomeostasis, pyroptosis, pneumocyte cell death and cell damage on the first three consecutive days after ICU admission. Plasma of 20 post-operative ICU patients (PO) and 39 healthy controls (HC) without organ failure served as controls. Subsets of COVID-19 patients displayed increases in individual biomarkers compared to controls. Unsupervised clustering was used to discern latent clusters of COVID-19 patients based on biomarker profiles. Pyroptosis-related interleukin-18 accompanied by high pneumocyte cell death was independently associated with higher odds at mechanical ventilation, while the subgroup with high interleuking-1 beta (but limited pneumocyte cell death) displayed reduced odds at mechanical ventilation and lower mortality hazard. Meanwhile, iron dyshomeostasis with a tendency towards higher ferroptosis marker malondialdehyde had no association with outcome, except for the small subset of patients with very high catalytic iron independently associated with reduced survival. Forty percent of patients did not have a clear signature of the cell death mechanisms studied in this cohort. Moreover, repeated moderate levels of soluble receptor of advanced glycation end products and growth differentiation factor 15 during the first three days after ICU admission are independently associated with adverse clinical outcome compared to sustained lower levels. Altogether, the data point towards distinct subgroups in this cohort of critical COVID-19 patients with different systemic signatures of pyroptosis, iron dyshomeostasis, ferroptosis or pneumocyte cell death markers that have different outcomes in ICU. The distinct groups may allow 'personalized' treatment allocation in critical COVID-19 based on systemic biomarker profiles.
Topics: Humans; COVID-19; SARS-CoV-2; Pyroptosis; Ferroptosis; Prospective Studies; Biomarkers
PubMed: 37582864
DOI: 10.1038/s41418-023-01204-2