Biochemistry, Genetics and Molecular Biology › Molecular Biology

Inflammasome and immune disorders

Works Count: 38780

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This cluster of papers focuses on the molecular mechanisms of inflammasome activation, regulation, and its role in inflammatory responses, cell death (pyroptosis), and immune-related diseases. It covers topics such as NLRP3 inflammasome, interleukin-1, caspase-1, and the involvement of mitochondria in inflammasome activation.

Keywords

Inflammasome; NLRP3; Pyroptosis; Interleukin-1; Caspase-1; Inflammation; Cell Death; Immune Response; Mitochondria; Autoinflammatory Diseases

Inflammation. Basic principles and clinical correlates

1989-01-01

John I. Gallin , Ira M. Goldstein , Ralph Snyderman

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Biologic basis for interleukin-1 in disease

1996-03-15

CA Dinarello

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The Inflammasome

2002-08-01

Fabio Martinon , Kimberly Burns , Jürg Tschopp

Inflammasomes: mechanism of action, role in disease, and therapeutics

2015-06-29

Haitao Guo , Justin Callaway , Jenny P.-Y. Ting

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Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death

2015-09-16

Jianjin Shi , Yue Zhao , Kun Wang +7 more

Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling

2015-09-16

Nobuhiko Kayagaki , Irma B. Stowe , Bettina L. Lee +7 more

Activation and regulation of the inflammasomes

2013-05-24

Eicke Latz , Tsan Sam Xiao , Andrea Stutz

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NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

2010-04-01

Peter Duewell , Hajime Kono , Katey J. Rayner +7 more

Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation

2009-06-01

Young-Sik Cho , Sreerupa Challa , David Moquin +4 more

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A role for mitochondria in NLRP3 inflammasome activation

2010-12-01

Rongbin Zhou , Amir S. Yazdi , Philippe Menu +1 more

Pyroptosis: host cell death and inflammation

2009-01-16

Tessa Bergsbaken , Susan L. Fink , Brad T. Cookson

NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice

2012-12-18

Michael T. Heneka , Markus P. Kummer , Andrea Stutz +7 more

Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica

2008-04-11

Catherine Dostert , Virginie Pétrilli , Robin van Bruggen +3 more

The inhalation of airborne pollutants, such as asbestos or silica, is linked to inflammation of the lung, fibrosis, and lung cancer. How the presence of pathogenic dust is recognized and … The inhalation of airborne pollutants, such as asbestos or silica, is linked to inflammation of the lung, fibrosis, and lung cancer. How the presence of pathogenic dust is recognized and how chronic inflammatory diseases are triggered are poorly understood. Here, we show that asbestos and silica are sensed by the Nalp3 inflammasome, whose subsequent activation leads to interleukin-1β secretion. Inflammasome activation is triggered by reactive oxygen species, which are generated by a NADPH oxidase upon particle phagocytosis. (NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate.) In a model of asbestos inhalation, Nalp3 –/– mice showed diminished recruitment of inflammatory cells to the lungs, paralleled by lower cytokine production. Our findings implicate the Nalp3 inflammasome in particulate matter–related pulmonary diseases and support its role as a major proinflammatory “danger” receptor.

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Gout-associated uric acid crystals activate the NALP3 inflammasome

2006-01-11

Fabio Martinon , Virginie Pétrilli , Annick Mayor +2 more

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Thioredoxin-interacting protein links oxidative stress to inflammasome activation

2009-12-20

Rongbin Zhou , Aubry Tardivel , Bernard Thorens +2 more

Origin and physiological roles of inflammation

2008-07-01

Ruslan Medzhitov

AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC

2009-01-21

Veit Hornung , Andrea Ablasser , Marie Charrel-Dennis +5 more

Inflammasomes in health and disease

2012-01-01

Till Strowig , Jorge Henao‐Mejia , Eran Elinav +1 more

Points of control in inflammation

2002-12-01

Carl Nathan

Inflammatory caspases are innate immune receptors for intracellular LPS

2014-08-05

Jianjin Shi , Yue Zhao , Yupeng Wang +5 more

Non-canonical inflammasome activation targets caspase-11

2011-10-16

Nobuhiko Kayagaki , Søren Warming , Mohamed Lamkanfi +7 more

Mechanisms and Functions of Inflammasomes

2014-05-01

Mohamed Lamkanfi , Vishva M. Dixit

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Cryopyrin activates the inflammasome in response to toxins and ATP

2006-01-11

Sanjeev Mariathasan , David S. Weiss , Kim Newton +7 more

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Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability

2009-05-25

Francesco Colotta , Paola Allavena , Antonio Sica +2 more

Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumors that are not epidemiologically related to inflammation. Recent studies … Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumors that are not epidemiologically related to inflammation. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. In the tumor microenvironment, smoldering inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, reduced response to hormones and chemotherapeutic agents. Recent data suggest that an additional mechanism involved in cancer-related inflammation (CRI) is induction of genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells. In a seminal contribution, Hanahan and Weinberg [(2000) Cell, 100, 57–70] identified the six hallmarks of cancer. We surmise that CRI represents the seventh hallmark.

The Inflammasomes: Guardians of the Body

2009-03-20

Fabio Martinon , Annick Mayor , Jürg Tschopp

The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of … The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1beta and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.

Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression

2009-07-02

Franz Bauernfeind , Gábor Horváth , Andrea Stutz +7 more

Abstract The IL-1 family cytokines are regulated on transcriptional and posttranscriptional levels. Pattern recognition and cytokine receptors control pro-IL-1β transcription whereas inflammasomes regulate the proteolytic processing of pro-IL-1β. The NLRP3 … Abstract The IL-1 family cytokines are regulated on transcriptional and posttranscriptional levels. Pattern recognition and cytokine receptors control pro-IL-1β transcription whereas inflammasomes regulate the proteolytic processing of pro-IL-1β. The NLRP3 inflammasome, however, assembles in response to extracellular ATP, pore-forming toxins, or crystals only in the presence of proinflammatory stimuli. How the activation of gene transcription by signaling receptors enables NLRP3 activation remains elusive and controversial. In this study, we show that cell priming through multiple signaling receptors induces NLRP3 expression, which we identified to be a critical checkpoint for NLRP3 activation. Signals provided by NF-κB activators are necessary but not sufficient for NLRP3 activation, and a second stimulus such as ATP or crystal-induced damage is required for NLRP3 activation.

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The NALP3 inflammasome is involved in the innate immune response to amyloid-β

2008-07-06

Annett Halle , Veit Hornung , Gabor C. Petzold +7 more

Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization

2008-07-06

Veit Hornung , Franz Bauernfeind , Annett Halle +5 more

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A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

2015-02-16

Rebecca C. Coll , Avril A. B. Robertson , Jae Jin Chae +7 more

Interleukin-1 in the pathogenesis and treatment of inflammatory diseases

2011-02-09

Charles A. Dinarello

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The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance

2011-01-09

Bolormaa Vandanmagsar , Yun‐Hee Youm , Anthony Ravussin +6 more

NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis

2011-05-01

Eran Elinav , Till Strowig , Andrew L. Kau +7 more

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Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion

2015-11-27

Wanting He , Haoqiang Wan , Lichen Hu +6 more

Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or … Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1β secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd−/− cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd−/− cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.

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Pore-forming activity and structural autoinhibition of the gasdermin family

2016-06-07

Jingjin Ding , Kun Wang , Wang Liu +6 more

Inflammasomes: mechanism of assembly, regulation and signalling

2016-06-13

Petr Brož , Vishva M. Dixit

Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores

2016-07-05

Xing Liu , Zhibin Zhang , Jianbin Ruan +4 more

Mechanism and Regulation of NLRP3 Inflammasome Activation

2016-09-24

Yuan He , Hideki Hara , Gabriel Núñez

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Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death

2016-12-05

Jianjin Shi , Wenqing Gao , Feng Shao

Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin

2017-04-28

Yupeng Wang , Wenqing Gao , Xuyan Shi +5 more

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

2017-08-27

Paul M. Ridker , Giulia Renda , Tom Thurén +7 more

Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.We conducted a … Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31).Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).

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Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

2018-01-23

Lorenzo Galluzzi , Ilio Vitale , Stuart A. Aaronson +7 more

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the … Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

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The molecular machinery of regulated cell death

2019-04-04

Daolin Tang , Rui Kang , Tom Vanden Berghe +2 more

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector … Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

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The NLRP3 inflammasome: molecular activation and regulation to therapeutics

2019-04-29

Karen V. Swanson , Meng Deng , Jenny P.‐Y. Ting

The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation

2019-07-06

Nathan Kelley , Devon Jeltema , Yanhui Duan +1 more

The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular … The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. However, the aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, and multiple molecular and cellular events, including ionic flux, mitochondrial dysfunction, and the production of reactive oxygen species, and lysosomal damage have been shown to trigger its activation. How NLRP3 responds to those signaling events and initiates the assembly of the NLRP3 inflammasome is not fully understood. In this review, we summarize our current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3.

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Mitochondria as multifaceted regulators of cell death

2019-10-21

Florian J. Bock , Stephen W. G. Tait

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Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

2019-11-16

Jean‐Claude Tardif , Simon Kouz , David D. Waters +7 more

Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout … Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis.

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Coronavirus infections and immune responses

2020-01-25

Geng Li , Yaohua Fan , Yanni Lai +7 more

Coronaviruses (CoVs) are by far the largest group of known positive-sense RNA viruses having an extensive range of natural hosts. In the past few decades, newly evolved Coronaviruses have posed … Coronaviruses (CoVs) are by far the largest group of known positive-sense RNA viruses having an extensive range of natural hosts. In the past few decades, newly evolved Coronaviruses have posed a global threat to public health. The immune response is essential to control and eliminate CoV infections, however, maladjusted immune responses may result in immunopathology and impaired pulmonary gas exchange. Gaining a deeper understanding of the interaction between Coronaviruses and the innate immune systems of the hosts may shed light on the development and persistence of inflammation in the lungs and hopefully can reduce the risk of lung inflammation caused by CoVs. In this review, we provide an update on CoV infections and relevant diseases, particularly the host defense against CoV-induced inflammation of lung tissue, as well as the role of the innate immune system in the pathogenesis and clinical treatment.

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Proinflammatory Cytokines

2000-08-01

Charles A. Dinarello

The Inflammasomes

2010-03-01

Kate Schroder , Jürg Tschopp

Nonresolving Inflammation

2010-03-01

Carl Nathan , Aihao Ding

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Lysosomal zinc nanomodulation blocks macrophage pyroptosis for counteracting atherosclerosis progression

2025-06-25

Ruiming Hu , Junchang Qin , Wei Feng +5 more | Science Advances

Macrophage pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn2+ features the strongest anti-inflammatory performance by screening 10 … Macrophage pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn2+ features the strongest anti-inflammatory performance by screening 10 representative metal ions, and the MTC1 agonists can trigger lysosomal Zn2+ release and inhibit pyroptosis in macrophages. Based on these findings, we further engineered a mucolipin TRP channel 1 (MTC1)-related therapeutic nanoplatform for endogenously triggering lysosomal zinc release to curb inflammation and block macrophage pyroptosis. This nanoplatform consists of mesoporous silica nanoparticles to deliver MTC1 agonists and carbon nanodots, which could synergistically exert antiatherosclerotic effect by scavenging toxic reactive oxygen species, inhibiting macrophage pyroptosis, modulating macrophage transition, and rebuilding atherosclerotic immune microenvironment. These findings demonstrate that macrophage pyroptosis can be efficiently blocked via leveraging self-lysosomal zinc pool, which provides the paradigm of lysosomal zinc modulation-involved nanotherapeutics for managing other inflammatory diseases.

GSDME-mediated pyroptosis in microglia exacerbates demyelination and neuroinflammation in multiple sclerosis: insights from humans and cuprizone-induced demyelination model mice

2025-06-25

Danjie Wang , Tongtong Zhang , Qi Shao +7 more | Cell Death and Differentiation

Unravelling the mechanism by which vildagliptin and linagliptin inhibit pyroptosis in lung injury through the NLRP3 inflammatory pathway in type 1 diabetic rats

2025-06-25

Ahmed A. Sedik , Nesma Esmat , Wagdy K. B. Khalil +1 more | Scientific Reports

Abstract Diabetes mellitus (DM) represents a multifactorial condition linked to hyperglycemia, which, can lead to damage across multiple organs, including the lungs. Nod-like receptor protein-3 (NLRP3)- mediated pyroptosis could contribute … Abstract Diabetes mellitus (DM) represents a multifactorial condition linked to hyperglycemia, which, can lead to damage across multiple organs, including the lungs. Nod-like receptor protein-3 (NLRP3)- mediated pyroptosis could contribute to the onset of DM consequences. Several approaches have been established aimed to minimizing the complications associated with DM. Among these, linagliptin and vildagliptin, di-peptidyl peptidase-4 (DPP-4) inhibitors, are known to exert not only antihyperglycemic effects but also additional beneficial biological activities. The current study investigated the impact of linagliptin and vildagliptin on pulmonary function, oxidative stress, and NLRP3-induced pyroptosis in rats. Thirty-two male Sprague Dawley rats were given a 7-day acclimatization period. A single intraperitoneal injection of freshly produced STZ (60 mg/kg) was utilized to develop DM type-1 in rats. Following STZ treatment, all rats were given a 5% glucose solution overnight. Blood glucose levels were monitored in overnight fasted rats 72 h later, with a threshold of 250 mg/dL or higher confirming the onset of DM. The diabetic rats were randomly allocated to treated daily with either vildagliptin (5 mg/kg/p.o.) or linagliptin (5 mg/kg/p.o.) for 30 days. Additionally, the typical control group received merely the vehicle. The findings revealed that vildagliptin improves pulmonary dysfunctions associated with DM by restoring glucose homeostasis, insulin, redox marker levels, and inflammatory indices. Additionally, the NLRP3-pyroptosis-mediated IL-1β was suppressed. Vildagliptin has been shown to mitigate the detrimental effects of diabetes mellitus (DM) on the lungs, as evidenced by a reduction in pathological lung alterations and a decrease in Caspase 3 expression, which is indicative of immunohistochemical changes. In conclusion, pyroptosis triggered by the NLRP3 inflammasome possibly exacerbate diabetic pulmonary injury in rats. Vildagliptin is superior to linagliptin in ameliorating diabetes-induced lung injury primarily via targeting the NLRP3 inflammasome pathway.

Resveratrol Alleviates Inflammatory Response Through P2X7/NLRP3 Signaling Pathway: In Silico and In Vitro Evidence from Activated Microglia

2025-06-24

Bianca Fagan Bissacotti , Marcylene Vieira da Silveira , Charles Elias Assmann +7 more | Pharmaceuticals

Background/Objectives: Chronic inflammation and inappropriate NLRP3 inflammasome regulation are related to many brain diseases. Purinergic mediators may play an important role in inflammation regulation and could be targeted for effective … Background/Objectives: Chronic inflammation and inappropriate NLRP3 inflammasome regulation are related to many brain diseases. Purinergic mediators may play an important role in inflammation regulation and could be targeted for effective therapies for these illnesses. We evaluated resveratrol’s anti-neuroinflammatory potential in BV-2 microglia cells using an innovative in vitro method of NLRP3 inflammasome activation, correlating with the P2X7 purinergic receptor. Methods: In silico analyses were used to estimate resveratrol’s interaction with NLRP3, and its cytotoxicity was measured for 24, 48, and 72 h. Moreover, microglia were exposed to lipopolysaccharide and nigericin to activate the NLRP3 inflammasome and treated with resveratrol between these inflammatory agents. Results: It was found that resveratrol has binding compatible with modulating NLRP3. Specifically, 0.1–25 µM of resveratrol presented a favorable safety profile in BV-2 cells. Microglia exposed to the inflammatory agents had increased levels of oxidative species, the P2X7 receptor, and pro-inflammatory cytokines. However, resveratrol decreased the NLRP3, caspase-1, IL-1β, IL-6, and TNF-α mRNA levels and protein density; on the other hand, IL-10 was increased, acting as a protector, preventing exacerbated inflammation. Under resveratrol exposure, P2X7 was negatively expressed, regulating inflammation to establish homeostasis and microglial proliferation. Additionally, resveratrol activates the A1 adenosine receptor, possibly correlated with neuroprotective effects. Conclusions: We confirmed the anti-neuroinflammatory action of resveratrol via the P2X7 receptor and NLRP3’s combined modulation, regulating the cell cycle and reducing pro-inflammatory and oxidant agents. Considering this pathway, resveratrol could be a candidate for further investigations as a potential treatment against neuroinflammatory diseases.

Rosmarinic Acid Ameliorates Type 2 Diabetic Osteoporosis by Reducing NLRP3 Expression and Alleviating Osteoblast Pyroptosis via the FOXO1/TXNIP Signaling Pathway

2025-06-24

Si‐xiang Feng , Runxun Ma , Yuli Huang +7 more | Journal of Agricultural and Food Chemistry

Unlike postmenopausal osteoporosis, Type 2 diabetic osteoporosis (T2DOP) occurs in a chronic high-glucose, inflammatory microenvironment, increasing fracture risk. Emerging evidence links osteoblast pyroptosis to T2DOP pathogenesis. While rosmarinic acid (RA) … Unlike postmenopausal osteoporosis, Type 2 diabetic osteoporosis (T2DOP) occurs in a chronic high-glucose, inflammatory microenvironment, increasing fracture risk. Emerging evidence links osteoblast pyroptosis to T2DOP pathogenesis. While rosmarinic acid (RA) exhibits antidiabetic and anti-inflammatory properties, its role in T2DOP remains unclear. We established a T2DOP mouse model using a high-fat diet and low-dose STZ, confirmed by micro-CT. RA's effects on osteoblast function and mitochondrial homeostasis were evaluated, with network pharmacology and molecular docking identifying potential targets. In vivo validation was performed through RA administration. Results showed pyroptosis activation and NLRP3 upregulation in T2DOP bone tissue. RA enhanced osteoblast proliferation, reduced pyroptosis, promoted mineralization, and mitigated mitochondrial dysfunction. The FOXO1/TXNIP pathway was identified as a key target, with RA suppressing NLRP3 activation via FOXO1/TXNIP modulation. This effect was reversed by FOXO1 inhibitor AS1842856. In vivo, RA preserved bone mass and microarchitecture in T2DOP mice. RA protects osteoblasts by improving mitochondrial function and inhibiting NLRP3-mediated pyroptosis through FOXO1/TXNIP signaling, offering a potential T2DOP treatment strategy.

Caspases as master regulators of programmed cell death: apoptosis, pyroptosis and beyond

2025-06-24

So Hee Dho , Minjung Cho , Wonjin Woo +2 more | Experimental & Molecular Medicine

Colchicine in Atherosclerotic Cardiovascular Disease – Weighing up the evidence so far

2025-06-24

Mau T. Nguyen , Adam J. Nelson , Peter J. Psaltis | European Journal of Preventive Cardiology

Association Between Pathogenic Variants in NLRP12 and Autoinflammatory Disease: A Comprehensive Systematic Review

2025-06-24

Nasimeh Vatandoost , Sajjad Biglari , Tayebeh Ranjbarnejad +5 more | International Journal of Immunogenetics

ABSTRACT Systemic auto‐inflammatory diseases (SAID) are rare inherited conditions characterized by dysregulation of the immune system, which leads to recurrent episodes of fever and systemic inflammation. Recent studies have identified … ABSTRACT Systemic auto‐inflammatory diseases (SAID) are rare inherited conditions characterized by dysregulation of the immune system, which leads to recurrent episodes of fever and systemic inflammation. Recent studies have identified pathogenic variants in the nucleotide‐binding leucine‐rich repeat‐containing receptor 12 (NLRP12) gene as potential contributors to autoinflammatory syndromes. Therefore, evaluating NLRP12 gene variants is crucial for the differential diagnosis of patients presenting symptoms associated with autoinflammatory diseases, specifically those known as NLRP12‐associated autoinflammatory disease (NLRP12‐AID). This study aims to identify causal variants in the NLRP12 gene encoding for NLRP12 and to discuss its pathogenesis, clinical features, and emerging treatment approaches. We used specific keywords for a systematic literature review via EMBASE, Scopus, ScienceDirect, Web of Science, and PubMed. Out of 874 articles, 27 met the inclusion criteria. To our knowledge, 103 patients with NLRP12 variants have been reported in the literature. All 60 variants in the NLRP12 coding gene were identified, including 49 classified as variants of uncertain significance (VUS), pathogenic, and likely pathogenic. The results show that the mean age of onset was 13.18 years. Fever was reported as the main symptom in 90% of cases of NLRP12‐AID. Other symptoms, such as rash and urticaria, occurred in 59% of cases, myalgia and arthralgia in 39% of cases, arthritis in less than 20%, and abdominal pain/diarrhea in 50% of patients. In summary, the clinical features of NLRP12‐AID are diverse and impact several tissues, particularly the musculoskeletal and gastrointestinal systems. In addition to familial cold autoinflammatory syndrome (FCAS) symptoms. Owing to its variable expression and incomplete penetrance, NLRP12‐AID is often misdiagnosed. Therefore, we believe that patients with a syndrome of undifferentiated recurrent fever should also undergo genetic evaluation for NLRP12.

Melatonin attenuates ischemia-reperfusion-induced acute kidney injury by regulating abnormal autophagy and pyroptosis through SIRT1-mediated p53 deacetylation

2025-06-24

Chen Sun , Jia Liu , Hongjun Li +1 more | International Immunopharmacology

Coexistence of Usher Syndrome, Familial Mediterranean Fever and Psoriatic Arthritis: A Rare Association

2025-06-23

Ali Nail Demir , Alper Uysal , Uğur Güngör Demir +2 more | Indian Journal of Rheumatology

Polyphenol‐Driven Modular Self‐Assembled Nano‐Antibiotic for Inflammation Control via Bacterial Infection Clearance and Pyroptosis Inhibition

2025-06-23

Zheng Wang , Jing Du , Xue Leng +5 more | Advanced Functional Materials

Abstract Bacterial infections and the resultant pyroptosis‐exacerbated inflammatory crises lead to a range of local or systemic diseases. Current therapeutic strategies are still constrained by host cellular barriers and biofilm, … Abstract Bacterial infections and the resultant pyroptosis‐exacerbated inflammatory crises lead to a range of local or systemic diseases. Current therapeutic strategies are still constrained by host cellular barriers and biofilm, significantly impeding spatiotemporal precision, and functional robustness. Notably, residual pathogen‐ and damage‐associated molecular patterns can manipulate host cell biology even after antibacterial monotherapy. In this study, a modular self‐assembly strategy for the nano‐antibiotic system (EM NPs) is developed through stepwise construction design, leveraging non‐covalent interactions between polyphenol frameworks and antibiotic molecules. The assembled modules exhibit intrinsic protonation capability and strong intermolecular affinity, facilitating the dynamic modulation of molecular interactions and surface charge reversal of the EM NPs under acidic conditions. This enables intracellular delivery through adaptive drug release behavior, lysosomal escape, and efficient cytoplasmic distribution. In vitro, EM NPs leverage polyphenol‐mediated cellular barrier penetration and biofilm‐targeted accumulation, achieving superior intracellular bacterial eradication and biofilm clearance compared to free antibiotics. Furthermore, the data validates that EM NPs modulate the mitochondria‐inflammasome axis to effectively suppress pyroptosis and subsequent inflammatory responses. In mouse models of periodontitis and sepsis, EM NPs significantly alleviate inflammation and tissue damage. Overall, this work provides a promising therapeutic strategy for comprehensively managing bacterial infection‐induced inflammation.

Efficacy and safety of colchicine post myocardial infarction: a systematic review, meta-analysis and meta-regression analysis of randomized clinical trials

2025-06-23

Farhan Naeem , Shehroze Tabassum , Muhammad Burhan +7 more | European Journal of Clinical Pharmacology

Pyroptosis in acute respiratory distress syndrome and pulmonary fibrosis

2025-06-23

Jinfeng Liao , Yangbo Liang , Zheng Liu +6 more | Biomedicine & Pharmacotherapy

Ameliorative effects of Urolithin A against Cadmium-induced NLRP3-mediated pyroptosis and cognitive deficits via regulating Aryl hydrocarbon receptor signaling

2025-06-22

Ying Zhu , Quan Yuan , Junhong Geng +7 more | Research Square (Research Square)

<title>Abstract</title> Cadmium (Cd) is an important environmental and industrial pollutant that induces neurotoxicity and neurobehavioral disorders in animals. Urolithin A (UA), a gut microbial-derived metabolite from polyphenolic compounds, exhibits potent … <title>Abstract</title> Cadmium (Cd) is an important environmental and industrial pollutant that induces neurotoxicity and neurobehavioral disorders in animals. Urolithin A (UA), a gut microbial-derived metabolite from polyphenolic compounds, exhibits potent neuroprotective effects in neurological disorders. Herein, we evaluated the ameliorative impact of UA on Cd exposure-evoked hippocampal injury and cognitive deficits in mice and disclosed the underlying molecular mechanisms. The results demonstrated that UA administration markedly mitigated hippocampal neuronal/synaptic injury and cognitive impairments in Cd-exposed mice. Mechanically, UA administration suppressed Cd exposure-triggered activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and subsequent neuronal pyroptosis in mice hippocampi and SH-SY5Y cells. Moreover, UA administration inhibited Cd-induced AhR activation and reduced the expression of CYP1A1, leading to mtROS elimination <italic>in vivo</italic> and <italic>in vitro</italic>. In conclusion, our findings revealed that UA mitigated Cd stress-driven aberrant NLRP3 inflammasome activation and its-mediated neuronal pyroptosis by promoting mtROS clearance, partly via the inhibition of the AhR-CYP1A1 signaling pathway, which ultimately contributed to the attenuation of neuronal/synaptic damage and cognitive deficits.

AIM2 activation mediated by RIPK1/3-dependent mitochondrial DNA release drives Aβ1−40-Induced retinal pigment epithelium injury

2025-06-21

Xiaoxu Huang , Tongqi Li , Guanran Zhang +7 more | Cell Communication and Signaling

The retinal pigment epithelium (RPE) degeneration and subsequent retinal atrophy are hallmarks of age-related macular degeneration (AMD). Amyloid-beta (Aβ), the primary component of amyloid plaques in Alzheimer's disease (AD), is … The retinal pigment epithelium (RPE) degeneration and subsequent retinal atrophy are hallmarks of age-related macular degeneration (AMD). Amyloid-beta (Aβ), the primary component of amyloid plaques in Alzheimer's disease (AD), is also present within drusen and is considered a critical factor contributing to RPE degeneration in AMD. Recent findings indicate that Aβ-induced inflammation plays a role in RPE degeneration. The aim of this study was to explore the molecular players and the precise mechanisms involved in this process, particularly the potential role of the absent in melanoma 2 (AIM2)-like receptors (ALRs) inflammasome. An animal model of Aβ1-40-induced RPE injury was established. Fundus photography, electrophysiology and hematoxylin-eosin staining were used to evaluate the morphological and functional RPE damage. Transcriptome sequencing was used to detect the differentially expressed genes between Aβ1-40 group and control group. The transcriptional and protein expression levels of AIM2 pathway and RIPK family members were detected. Adeno-associated virus vector 2/2 (AAV2/2)-shAIM2 was constructed to knockdown AIM2 expression in mice RPE cells. Aβ1-40-treated ARPE-19 cells and hRPE cells were employed to analyze the regulatory effects of RIPK family on mitochondrial DNA (mtDNA) release and AIM2 pathway activation. Aβ induces RPE damage through stimulation of AIM2 inflammasome and augmentation of caspase-1 and interleukin-1β (IL-1β). Knocking down AIM2 inhibits the release of inflammatory cytokines and alleviates the degeneration of the retina and RPE. Simultaneously, Aβ triggers the activation of RIPK1/RIPK3 kinases, as manifested by heightened protein expression and phosphorylation. Inhibiting RIPK1/RIPK3 phosphorylation dampens AIM2 inflammasome activity and curtails IL-1β secretion. Mechanistically, RIPK1/RIPK3 inhibition attenuates Aβ-induced Drp1(S616) hyperphosphorylation, consequently reducing mitochondrial fission and the efflux of mitochondrial DNA (mtDNA) into the cytosol. The diminished mtDNA release is responsible for attenuated AIM2 activation and subsequent inactivation of the stimulator of interferon genes (STING)/nuclear factor-kappa-B (NF-κB) signaling cascade. Our study is the first to validate AIM2's contribution in Aβ-induced RPE pathology and underscore the significance of the RIPK1/RIPK3-induced mtDNA release in modulating inflammatory responses, shedding light on the underlying mechanisms and potential therapeutics of AMD.

Large-Scale Restructuring of the Caspase-1 Gene Cluster Region in Mammals

2025-06-21

David Stevens , Tasman Daish , Frank Grützner

The inflammatory response is an important component of the host immune defence mechanism against pathogens. Activation of the NLRP3 inflammasome has been shown to have a wide range of triggers … The inflammatory response is an important component of the host immune defence mechanism against pathogens. Activation of the NLRP3 inflammasome has been shown to have a wide range of triggers including fungal, bacterial and viral components, cellular stress and environmental irritants. The NLRP3 inflammasome has been well characterised in mouse and humans but limited information is available from other mammalian species. In order to gain a better understanding of the evolution of genes involved in the NLRP3 inflammasome pathway, we examined them in mammalian species representing the three major groups (eutheria, metatheria and prototheria) and in chicken as an outgroup. Our results show that the inflammasome pathway machinery is generally well conserved though chicken appears to lack several key components and monotremes have a duplication of Syk. Analysis of the proinflammatory caspase cluster and neighboring genes revealed massive reorganisation as well as the previously described multiple duplications that occurred during mammalian evolution. Our data suggest that Caspase-1 moved to a new chromosomal region in early mammalian evolution. This was followed by expansion of the cluster and accumulation of additional genes regulating inflammatory responses such as Card16, Card17, Card18 and the Birc genes. The expansion of key gene families flanking Caspase-1 may have led to an expansion of inflammasome pathways and a more regulated immune system in humans through the CARD genes.

Gasdermin E in glioblastoma –pyroptosis resistance and tumor-promoting functions

2025-06-21

Ege Solel , Egil Brudvik , Lars Ystaas +7 more | Cell Death Discovery

Abstract Treatment of glioblastoma (GB), the most common and most aggressive malignant brain tumor, has made little progress over the past two decades. Despite extensive research on apoptosis and autophagy, … Abstract Treatment of glioblastoma (GB), the most common and most aggressive malignant brain tumor, has made little progress over the past two decades. Despite extensive research on apoptosis and autophagy, necrotic cell death mechanisms like pyroptosis, which have the potential to stimulate anti-tumor immune responses, remain largely underexplored in GB. Here, we investigated whether Gasdermin E (GSDME)-mediated pyroptosis can be induced in GB by employing the drug raptinal, an inducer of cytochrome c release. Using human patient-derived and mouse GB cell lines, we showed that raptinal promotes GSMDE cleavage. However, although a strong pyroptotic response was observed in mouse cell lines, it was weak in human cell lines. This resistance was partially reversed by the calcium chelator BAPTA-AM, indicating that membrane repair mechanisms may counteract the pyroptotic response. Gsdme knockout (KO) in mouse GB cells unexpectedly prolonged the survival of immunocompetent mice, demonstrating a tumor-promoting role of GSDME independent of its pyroptotic function. Analysis of the immune microenvironment revealed that Gsdme KO promoted infiltration of T cells, which was confirmed by spatial transcriptomic analysis of GB patient samples. In addition, Gsdme/GSMDE KO reduced the invasive capacity of mouse/human GB cells. In conclusion, active membrane repair mechanisms may impair the pyroptotic efficacy in GB. GSDME has a tumor-promoting role in GB by suppressing T cell infiltration and increasing tumor cell invasion.

Role of inflammasomes in diabetes mellitus: mechanisms, complications, and therapeutic potential

2025-06-21

K L Milan , B Megha , Kunka Mohanram Ramkumar | Molecular Biology Reports

Lysosomal Cathepsin S Escape Facilitates Near Infrared Light‐Triggered Pyroptosis Via an Antibody‐Indocyanine Green Conjugate

2025-06-20

Fan Chen , Xue‐Fei Tian , Teng Yang +7 more | Advanced Science

Abstract Pyroptosis is a proinflammatory programmed cell death (PCD) that is causally linked to antitumor immune responses, but the therapeutic potential of pyroptosis has been limited by the lack of … Abstract Pyroptosis is a proinflammatory programmed cell death (PCD) that is causally linked to antitumor immune responses, but the therapeutic potential of pyroptosis has been limited by the lack of tumor‐specific and controllable inducers. Here, it is reported that tumor‐specific pyroptosis can be spatiotemporally triggered via near‐infrared light (NIR‐pyroptosis) by using an antibody‐bound indocyanine green (ICG), a clinically approved and nontoxic fluorescent dye. Mechanistically, the key molecular steps are identified by which antibody‐bound ICG generates excessive reactive oxygen species (ROS) within lysosomes after internalization, leading to lysosomal membrane damage and the cytosolic release of cathepsin S (CTSS), which cleaves gasdermin D (GSDMD), IL‐18, and IL‐1β independently of caspase‐1, and thereby induces pyroptosis, while other cathepsin family members fail to cleave GSDMD. Functionally, in both ICAM1+ and HER2+ solid tumors, antibody‐bound ICG‐mediated NIR‐pyroptosis triggers potent and durable antitumor immune responses through the release of proinflammatory cytokines. Furthermore, NIR‐pyroptosis synergize with anti‐PD‐1 therapy by activating adaptive immune cells via upregulated IFN‐γ secretion. The findings identify CTSS as a novel enzyme for GSDMD cleavage and establish NIR‐pyroptosis as a non‐apoptotic anticancer modality, providing a promising opportunity to overcome apoptosis resistance in current cancer therapies.

Efficacy of Colchicine in Reducing Cardiovascular Events in Patients with Acute Coronary Syndrome: A Systematic Review

2025-06-20

Mayuri Quishpe , Mirella Sanunga , Joseline Ochoa +5 more | Cureus

Mechanisms and therapeutic potential of pharmacological agents targeting inflammasomes

2025-06-20

Haitao Li , Tiantian Liu , Xiaolei Shi +7 more | Biomedicine & Pharmacotherapy

Nigericin Induces Paraptosis‐Like Cell Death Instead of Pyroptosis in Corneal Keratocytes

2025-06-20

Xiangquan Mi , Xin J. Zhou , Shaochun Zhu +3 more | The FASEB Journal

ABSTRACT The purpose of this study was to examine the nature of the underlying molecular mechanisms of cell death in human keratocytes treated with nigericin, a known pyroptosis inducer. Human … ABSTRACT The purpose of this study was to examine the nature of the underlying molecular mechanisms of cell death in human keratocytes treated with nigericin, a known pyroptosis inducer. Human keratocytes were exposed to nigericin, and cell death was assessed through morphological analysis and detection of related molecular markers. Proteomic profiling was performed to identify cell death‐related proteins, with key findings validated by western blot. Additionally, organelle disruptions were examined using immunostaining techniques. Pyroptosis‐like cell death was observed morphologically in cultured keratocytes. Moreover, an elevated release of IL‐1beta was detected, accompanied by a significant loss of mitochondrial membrane potential. However, nigericin treatment induced a form of non‐inflammatory cell death characterized by extensive vacuolation, resembling paraptosis. This was accompanied by the absence of caspase‐3 activation and endoplasmic reticulum (ER) stress markers, along with increased accumulation of the autophagic marker LC3‐II. Proteomic analysis revealed the absence of key components of the canonical pyroptosis pathway, including proteins involved in inflammasome assembly and the gasdermin (GSDM) family. These results were further confirmed by western blot. Significant alterations were also observed in the Golgi apparatus, mitochondria, and lysosomes following nigericin treatment. These findings suggest that nigericin triggers a paraptosis‐like cell death in human keratocytes, rather than pyroptosis, as keratocytes lack the canonical executors of pyroptosis. This highlights an alternative mechanism of cell death in the cornea, warranting further exploration to understand its role and potential therapeutic implications.

Increased 25-hydroxycholesterol as an indicator for patients with vestibular neuritis

2025-06-20

Xuhua Song , J Liang , Congzhe Tian | Frontiers in Neurology

Background Vestibular neuritis (VN) is one of the most common diseases in vestibular vertigo. 25-hydroxycholesterol (25-HC) was correlated to neuroinflammation, however, whether the level of serum 25-HC could be used … Background Vestibular neuritis (VN) is one of the most common diseases in vestibular vertigo. 25-hydroxycholesterol (25-HC) was correlated to neuroinflammation, however, whether the level of serum 25-HC could be used to diagnose the VN occurrence remains unclear. Methods The enrolled patients were divided into VN and healthy control groups. Afterwards, the potential risk factors were assessed in these two groups. Subsequently, the complete blood count was performed upon hospital admission. Results The serum 25-HC and C-reactive protein (CRP) were detected in two groups using liquid chromatography-mass spectrometry and a high-sensitive immunonephelometric assay. Moreover, the correlation of 25-HC to inflammatory factors was analyzed. Finally, the receiver operating characteristic curve analysis was performed to predict the diagnosis effect of 25-HC in VN occurrence. The age, gender, BMI, living habits, disease history, and cholesterol did not affect the VN occurrence. However, 25-HC was dramatically increased in VN patients, meanwhile, peripheral blood leukocyte and neutrophil/lymphocyte ratio were also elevated in VN patients. Importantly, 25-HC was positively correlated to CRP and leukocytes. Additionally, the level of serum 25-HC could be used to predict the VN occurrence. Conclusion Serum 25-HC may diagnose the occurrence of VN.

Melatonin alleviates neuroinflammation in ischemic stroke by regulating cGAS-mediated microglial pyroptosis signaling

2025-06-19

Qian Li , Feng Lin , Tian Yu +7 more | Neural Regeneration Research

Abstract Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke. Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis. However, the role and … Abstract Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke. Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis. However, the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA (dsDNA)-sensing cyclic GMP-AMP synthase (cGAS) signaling warrant further study. Using middle cerebral artery occlusion mice, we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation. Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release, as reflected by γH2AX staining, as well as heightened activation of the cytosolic dsDNA-sensing cGASSTING pathway, both of which were notably suppressed by melatonin treatment. Melatonin also mitigated NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation and nuclear factor (NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke, while exhibiting the capacity to attenuate the immune response to ischemia in mice. This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain. Specifically, melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-α by microglia. Regarding neurological outcomes, melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice. Notably, the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity. We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles (Mϕ-MLT@FNGs), which exhibited therapeutic properties in middle cerebral artery occlusion mice. Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway. By doing so, melatonin rescues damaged brain tissue and protects neurological function, highlighting its potential as a neuroprotective treatment for ischemic stroke.

Interleukin-18 cytokine gene polymorphism 137G/C (rs187238) and susceptibility to tuberculosis in north India

2025-06-19

Karan Gupta , Vibha Uppal , Pranav Ish +3 more | Monaldi Archives for Chest Disease

Tuberculosis (TB) regained its position globally as the leading cause of mortality from a single infectious agent after being surpassed by COVID-19 for 3 years consecutively. Host genetic factors, particularly … Tuberculosis (TB) regained its position globally as the leading cause of mortality from a single infectious agent after being surpassed by COVID-19 for 3 years consecutively. Host genetic factors, particularly cytokine gene polymorphisms, play a significant role in influencing susceptibility to TB. Interleukin-18 (IL-18) is a proinflammatory cytokine involved in immune regulation against Mycobacterium tuberculosis. This study aimed to evaluate the association of IL-18 gene polymorphism (rs187238) with susceptibility to TB and its effect on serum IL-18 levels in a north Indian population. A case-control study was conducted with 100 newly diagnosed TB patients (pulmonary and extrapulmonary) and 100 age- and gender-matched healthy controls. Serum IL-18 levels were measured using sandwich enzyme-linked immunosorbent assay, and the IL-18 gene polymorphism at rs187238 was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The association between IL-18 polymorphism, TB susceptibility, and serum IL-18 levels was statistically evaluated. Mean serum IL-18 levels were significantly elevated in TB patients (400.42±149.58 pg/mL) compared to controls (96.05±40.67 pg/mL; p<0.01). The distribution of IL-18 genotypes showed that individuals with GC/CC genotypes had a significantly lower risk of developing TB compared to the GG genotype [odds ratio (OR)=0.31; 95% confidence interval (CI)=0.20-0.88; p=0.0167]. Additionally, the C allele conferred a protective effect against TB (OR=0.33; 95% CI=0.22-0.51; p<0.0001). Serum IL-18 concentrations varied significantly with genotype, with the highest levels observed in CC genotype carriers in both cases and controls (p<0.01). Thus, our study suggests that IL-18 polymorphism at rs187238 significantly influences susceptibility to TB in the north Indian population. The C allele and GC/CC genotypes appear to confer a protective effect, possibly through modulation of IL-18 serum levels. IL-18 rs187238 polymorphism may serve as an independent predictive marker for TB risk, though larger studies are recommended for validation.

Zinc ions trigger PANoptosis-like cell death in magnetic hyperthermia therapy of magnesium based implant for hepatocellular carcinoma

2025-06-19

Anhong Liu , Xiao Han , Qianqian Yang +7 more | APOPTOSIS

NLRP3 inflammasome: A link between systemic infection and Alzheimer’s disease

2025-06-19

Tatiana Barichello , Felipe Dal‐Pizzol | Neural Regeneration Research

MCC950 suppresses NLRP3-dependent neuroinflammation and ameliorates cognitive decline in a rat model of cerebral small vessel disease

2025-06-19

Meiyan Zhang , Xiaoyan Lan , Yue Gao +6 more | Neural Regeneration Research

Abstract Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia. However, there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel … Abstract Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia. However, there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease. In this study, we investigated the potential therapeutic effects of MCC950, a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor, on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats. Our results showed that chronic administration of MCC950 (10 mg/kg) to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation, thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors, including interleukin-1β and -18. A decrease in astrocytic and microglial activation was also observed. We also found that MCC950 significantly inhibited autophagy. More importantly, behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function, which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain, such as blood.brain barrier breakdown, white matter damage, and endothelial dysfunction. Thus, our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.

Integrative PANoptosis gene profiling reveals prognostic and therapeutic insights in prostate cancer

2025-06-19

Yi Wang , Yiheng Du , Xizhi Wang +6 more | Biomolecules and Biomedicine

Prostate cancer (PCa) remains a significant global health challenge, representing the most common solid tumor in men and the fifth leading cause of cancer-related death. Despite therapeutic advances, achieving a … Prostate cancer (PCa) remains a significant global health challenge, representing the most common solid tumor in men and the fifth leading cause of cancer-related death. Despite therapeutic advances, achieving a definitive cure remains difficult. Early diagnosis and personalized treatment strategies are crucial for improving patient outcomes. Programmed cell death—particularly PANoptosis, an inflammatory pathway that integrates pyroptosis, apoptosis, and necroptosis—has emerged as a promising therapeutic target in oncology.In this study, individuals with PCa were categorized into PANoptosis-high and PANoptosis-low subgroups based on the expression levels of 45 PANoptosis-related genes. Differential gene expression analysis and subsequent enrichment analyses were conducted to explore the biological pathways associated with each subgroup. A four-gene risk signature (CASP7, ADAR, DNM1L, and NAIP) was identified, showing strong predictive value for overall survival (OS) in both training and validation cohorts. This signature was independently associated with OS and showed meaningful correlations with the tumor microenvironment, particularly immune cell infiltration and immunotherapy responsiveness. These findings suggest that the PANoptosis-related gene signature may serve as a valuable prognostic biomarker and inform immunotherapeutic strategies in PCa management.

Inflammasomes and Signaling Pathways: Key Mechanisms in the Pathophysiology of Sepsis

2025-06-19

Jhan Sebastián Saavedra-Torres , María Virginia Pinzón Fernández , Martín Ocampo Posada +7 more | Cells

Sepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes-cytosolic multiprotein complexes of the innate immune system-serve as … Sepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes-cytosolic multiprotein complexes of the innate immune system-serve as critical platforms for sensing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Key sensors such as NLRP3, AIM2, and IFI16 initiate caspase-1 activation, IL-1β and IL-18 maturation, and gasdermin D-mediated pyroptosis. In sepsis, excessive inflammasome activation drives oxidative stress, endothelial dysfunction, immunothrombosis, and immune exhaustion. This maladaptive cascade is further aggravated by the release of DAMPs and procoagulant factors, compromising vascular integrity and immune homeostasis. Prolonged activation contributes to immunoparalysis, lymphopenia, and increased susceptibility to secondary infections. Inflammasome signaling also intersects with necroptosis and ferroptosis, amplifying systemic inflammation and tissue injury. Additionally, various pathogens exploit immune evasion strategies to modulate inflammasome responses and enhance virulence. Therapeutic interventions under investigation include selective NLRP3 inhibitors, IL-1 blockers, gasdermin D antagonists, and extracorporeal cytokine hemoadsorption. Emerging approaches emphasize biomarker-guided immunomodulation to achieve personalized therapy. While preclinical studies have shown promising results, clinical translation remains limited. Targeting inflammasomes may offer a path toward precision immunotherapy in sepsis, with potential to reduce organ dysfunction and improve survival.

Tangzhiqing Exacerbates Oxidized Low‐Density Lipoprotein‐Induced Cell Pyroptosis Through Activation of NLRP3 Inflammasome in Human Umbilical Vein Endothelial Cells

2025-06-19

Rui Chen , Zhihuan Zhou , Zhihui Song +4 more | Cell Biology International

Atherosclerosis (AS) is a chronic and progressive inflammatory condition affecting arterial walls. It is widely accepted that the deposition of low-density lipoprotein (LDL) and its adverse impact on endothelial cells … Atherosclerosis (AS) is a chronic and progressive inflammatory condition affecting arterial walls. It is widely accepted that the deposition of low-density lipoprotein (LDL) and its adverse impact on endothelial cells (ECs) play a pivotal role in the development of AS. Specifically, oxidized LDL (ox-LDL) has been validated as a trigger for inducing pyroptosis in ECs, thereby contributing significantly to intima inflammation and AS progression. However, the underlying molecular mechanisms require further investigation. In this study, we demonstrated that ox-LDL significantly upregulates the expression of pyrin domain-containing 3 (NLRP3) protein levels in ECs. This upregulation is associated with increased caspase-1 cleavage, interleukin-1β (IL-1β) maturation, and lactate dehydrogenase (LDH) release. Moreover, ox-LDL also upregulates the expression of ASC, caspase-1, GSDMD, IL-1β, and IL-18 proteins. The inhibition of NLRP3-specific inhibitor MCC950 or caspase-1-specific inhibitor VX-765 effectively suppressed the expression of cellular pyroptosis-associated proteins. Our findings highlight the crucial role of Tangzhi Qing (TZQ) in regulating ox-LDL-induced pyroptosis and inflammation through the activation of the NLRP3 inflammasome. This suggests that NLRP3 inflammasome could serve as a promising therapeutic target for mitigating diseases associated with atherosclerosis.

Cola acuminata extract’s inhibition of NLRP3 inflammasome in THP-1 cells as a potential treatment option for Parkinson’s disease

2025-06-19

Brice Ayissi Owona , Viviane Ndam Ngoungoure , Jordas Tchana Tchamba +2 more | Metabolic Brain Disease

Neonatal NLRP3 Inflammasome Activation Leads to Perineuronal Net Deficits in Early Adulthood

2025-06-19

Emre Tarakcioglu , Bilgesu Genc , Kemal Uğur Tüfekçi +1 more | Developmental Neurobiology

ABSTRACT Perineuronal nets (PNNs) are specialized extracellular matrix structures that surround certain neurons and play a critical role in protecting neurons from oxidative stress and maintaining synaptic stability in the … ABSTRACT Perineuronal nets (PNNs) are specialized extracellular matrix structures that surround certain neurons and play a critical role in protecting neurons from oxidative stress and maintaining synaptic stability in the central nervous system. They have roles in memory formation, and their loss has been linked to various mental alterations, such as anxiety, depression, and schizophrenia. While immune activation is known to degrade PNNs, it remains unclear whether inflammasomes are involved in PNN formation dynamics during neuronal development, where cases of sepsis are particularly high. In this study, we investigated how activation of the NLRP3 inflammasome in neonatal mouse brains influences PNNs. To explore this, neonatal wild‐type and Nlrp3 knockout mice were injected with lipopolysaccharide (LPS) or phosphate‐buffered saline (PBS) on postnatal day (PND) 9, and PNNs were visualized at early adulthood (PND60). In addition, NLRP3 inflammasome activation was confirmed on PND10, and behavioral tests were performed on PND60. LPS treatment in wild‐type mice reduced PNN‐positive neurons in the hippocampus and cortex compared to the PBS group, whereas Nlrp3 knockout mice showed no differences between treatment groups. Moreover, behavioral tests revealed that neonatal LPS injection resulted in anxiety‐ and depressive‐like behavior and that NLRP3 deficiency restrained this effect. These results highlight the key role of NLRP3 inflammasome activation in inflammation‐driven PNN reduction during neuronal development. NLRP3 inhibitors could thus serve as potential therapeutic agents to protect the neuronal extracellular matrix from inflammatory damage in early life.

Orexin A Ameliorates Ovarian Dysfunction in Premature Ovarian Insufficiency Mice by Inhibiting Granulosa Cell Pyroptosis via the AMPK/NLRP3 Pathway

2025-06-18

Fengqin Yu , Tong Wu , Lina Li +2 more | Biotechnology and Applied Biochemistry

ABSTRACT Premature ovarian insufficiency (POI) is a condition characterized by the early depletion of ovarian follicles, leading to infertility and various systemic complications. Granulosa cell (GC) pyroptosis contributes significantly to … ABSTRACT Premature ovarian insufficiency (POI) is a condition characterized by the early depletion of ovarian follicles, leading to infertility and various systemic complications. Granulosa cell (GC) pyroptosis contributes significantly to the pathogenesis of POI. Orexin A, a neuropeptide involved in regulating wakefulness, has been shown to exert anti‐inflammatory effects. This study investigates the potential protective role of orexin A in POI by targeting pyroptosis in ovarian GCs. We found that orexin A significantly reduced oxidative stress and the activation of the NLRP3 inflammasome in POI mice, thereby improving serum hormone levels and follicle count. Additionally, orexin A inhibited pyroptosis in cyclophosphamide (CTX)‐treated KGN cells by downregulating NLRP3, caspase‐1, and gasdermin D (GSDMD) expression. These effects were mediated through the activation of adenosine 5'‐monophosphate‐activated protein kinase (AMPK) signaling, which is known to regulate cellular metabolism and suppress inflammasome activation. In conclusion, orexin A has the potential to alleviate POI by inhibiting NOD‐like receptor thermal protein domain‐associated protein 3 (NLRP3) inflammasome‐mediated pyroptosis and activating AMPK signaling, offering a promising therapeutic approach for POI treatment.

Vitamin D Modified DSS-Induced Colitis in Mice via STING Signaling Pathway

2025-06-18

Zhihao Wu , Baohua Ma , Min Xiao +3 more | Biology

Although the underlying mechanisms are not yet fully understood, vitamin D has been proven to be associated with the pathogenesis of inflammatory bowel disease, participating in immune response and regulating … Although the underlying mechanisms are not yet fully understood, vitamin D has been proven to be associated with the pathogenesis of inflammatory bowel disease, participating in immune response and regulating gut microbiota composition. In this study, we established a dextran sodium sulfate-induced colitis model and intervened with vitamin D. Subsequently, colonic histopathology, serum biochemistry, transcription of inflammatory cytokines, gut microbiota, and key signaling pathways were examined. Our research demonstrated that intervention with vitamin D reduced the disease activity index of DSS-induced colitis and improved histopathological changes, protecting tight junction protein ZO-1 and intestinal glands from damage induced by DSS. Analysis of gut microbiota revealed alterations in both α diversity and β diversity in DSS-induced colitis, whereas interventions with active vitamin D corrected the changes in certain bacterial abundance and improved the composition of gut microbiota. The transcription levels of inflammatory cytokines, including IL-23, IL-1β, IFN-γ, IL-6, IL-17, and STING, were elevated in the DSS-induced colitis model. However, intervention with active vitamin D effectively suppressed the transcription of these factors. Finally, immunohistochemistry and Western blotting revealed that the intervention with vitamin D suppressed the expression of proteins associated with the STING pathway, including GATA1, STING, IRF3, and IKBα, leading to inhibition of downstream IFN-β production. Vitamin D administration can ameliorate the severity of DSS-induced colitis by preserving intestinal barrier integrity, modulating gut microbiota composition through suppression of the STING pathway.

Types, Molecular Mechanisms and Potential Therapeutic Targets of Programmed Endothelial Cell Death in Atherosclerosis

2025-06-18

Lu Kuang , Qijun Chen , Zenghui Liu +2 more | Journal of Cardiovascular Pharmacology

Atherosclerosis (AS) is a chronic progressive disease that occurs in the inner walls of arteries. Endothelial dysfunction is a key component in the early stages of atherosclerosis. Unhealthy lifestyle factors … Atherosclerosis (AS) is a chronic progressive disease that occurs in the inner walls of arteries. Endothelial dysfunction is a key component in the early stages of atherosclerosis. Unhealthy lifestyle factors (e.g., smoking), hypertension, hyperglycemia, and hyperlipidemia are important risk factors that may induce endothelial cell injury or even lead to cellular death. Hypertension contributes to AS by exerting mechanical stress that damages endothelial cells. Current studies have shown that vascular endothelial cells are mainly involved in programmed cell death pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, cuproptosis, parthanatos, and NETosis. This review synthesizes current knowledge on programmed cell death pathways in vascular endothelia during atherogenesis, delineating their triggering factors, molecular underpinnings, and potential regulatory targets.

Programmed cell death and tissue regeneration: A link that should be resolved

2025-06-18

Gelina S. Kopeina , Anastasia Efimenko , Tkachuk Va +1 more | Physiological Reviews

Cellular homeostasis is maintained by three important physiological processes: proliferation, characterized by an increase in cell number; differentiation, characterized by either an increase or decrease in cell number coincident with … Cellular homeostasis is maintained by three important physiological processes: proliferation, characterized by an increase in cell number; differentiation, characterized by either an increase or decrease in cell number coincident with changes in cellular genotype and function; and cell death, which promotes the elimination of cells. Two of these alterations, proliferation and differentiation, are tightly linked to regeneration. Currently, over 10 modes of programmed cell death are recognized. Among them are apoptosis, necroptosis, pyroptosis, ferroptosis, etc. Almost all of them are linked to tissue regeneration. Dead cells have a vital effect on the living cells around them. They release a wide range of stimuli (low-molecular-weight molecules, proteins, vesicles, etc.), which signal neighbors to proliferate and differentiate. Additionally, dying cells free the space and thus change the physical characteristics of tissue, arrange the elimination of dysfunctional cells, and promote regeneration. However, programmed cell death can inhibit cell proliferation and vice versa. Thus, stem cells are resistant to the induction of death and maintain their potential to affect tissue homeostasis and recovery after injury. Disturbances in the balance between cell death and regeneration lead to various pathologies. Given the importance of the interaction between cell death and regeneration, advances in this area could lay the foundation for the successful development of a rapidly growing, groundbreaking field of medicine called regenerative biomedicine, the goal of which is to support cell renewal and restore damaged organs and tissues. Here, we review these multilevel relationships to explore how cell death and regeneration balance each other.

NLRP3-Mediated PANoptosis and Associated Interventions in Endothelial Injury

2025-06-18

Aiwei Yan , Ting Cao , Xiao Li +3 more | Cardiovascular Toxicology

Novel Findings on the Development and Immunological Functions of Palatine Tonsils

2025-06-18

Nadiya Abulikemu , Zheng Liu , Yang Liu | Clinical Reviews in Allergy & Immunology

Intracerebroventricular calycosin attenuates cerebral ischemia-reperfusion injury in rats via HMGB1-dependent pyroptosis inhibition

2025-06-18

Yuhui Zhang , Qiguang Wu , Yijie Pan +6 more | Frontiers in Pharmacology

Introduction HMGB1-NLRP3 mediated pyroptosis was recently discovered to be a pathogenic cause of ischemic stroke. Our previous research has demonstrated the anti-inflammatory and anti-apoptotic properties of calycosin in mitigating cerebral … Introduction HMGB1-NLRP3 mediated pyroptosis was recently discovered to be a pathogenic cause of ischemic stroke. Our previous research has demonstrated the anti-inflammatory and anti-apoptotic properties of calycosin in mitigating cerebral ischemia-reperfusion injury (CIRI). However, its specific effects on HMGB1-NLRP3-mediated pyroptosis in ischemic stroke remain unclear. This study investigated the efficacy of calycosin in reducing pyroptosis-linked CIRI. Methods In vivo , a rat model of middle cerebral artery occlusion (MCAO) received varying doses of intracerebroventricular calycosin. Therapeutic efficacy was assessed using neurological deficit scores, TTC staining, H-E staining, Nissl staining, and immunohistochemistry. In vitro , HAPI microglial cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) and then treated with calycosin, HMGB1 siRNA, or MCC950. Cell survival was evaluated using the CCK8 assay. Ultrastructural changes were examined through transmission and scanning electron microscopy. Inflammatory cytokine levels were quantified by ELISA. The expression of pyroptosis-related proteins and genes was analyzed using Western blot and qRT-PCR. Results and Discussion Calycosin significantly reduced neurological impairments and brain infarction in a dose-dependent manner, alleviated neuronal damage and decreased the expression of pyroptosis-related markers, including NLRP3, GSDMD, HMGB1, IL-1β, IL-18, and caspase-1. These results indicate that calycosin enhances microglial cell survival and mitigates pyroptotic damage by inhibiting NLRP3 inflammasome activation, suggesting its potential as a neuroprotective therapy for ischemic stroke through the modulation of the HMGB1-dependent pyroptosis pathway.

Regulation of pyroptosis in diabetic nephropathy by long non-coding and circular RNAs

2025-06-18

Kiavash Hushmandi , Daniel J. Klionsky , Najma Farahani +4 more | Clinical and Experimental Medicine

Diabetic nephropathy (DN) is a major complication of diabetes mellitus, predominantly affecting the kidneys of diabetic patients and resulting in increased morbidity and mortality. Current standard treatments for diabetes have … Diabetic nephropathy (DN) is a major complication of diabetes mellitus, predominantly affecting the kidneys of diabetic patients and resulting in increased morbidity and mortality. Current standard treatments for diabetes have proven insufficient in halting the progression of DN, highlighting the urgent need for innovative and more effective therapeutic strategies. Pyroptosis, a pro-inflammatory regulated cell death process, has been previously associated with DN development. Recent evidence indicates that the NLRP3 inflammasome, a key inflammatory pathway complex, promotes DN through pyroptosis. Consequently, inhibiting inflammasome activity has emerged as a promising therapeutic target against DN, in conjunction with pyroptosis. This review introduces non-coding RNAs (ncRNAs), particularly circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs), as potential regulators of pyroptosis in DN, as recent studies have documented their dysregulation in DN pathogenesis. In this study, we aim to discuss the characteristics of lncRNAs, circRNAs, and pyroptosis and explore their potential interconnection in DN development. By elucidating the link between these RNA molecules and pyroptosis, our goal is to deepen our understanding of the underlying mechanisms of the disease. This knowledge could lead to the identification of new therapeutic targets and the development of innovative treatments for DN by modulating pyroptosis.

TAK1 inhibition activates pore-forming proteins to block intracellular bacterial growth through modulating mitochondria

2025-06-18

Wilfred López‐Pérez , Roland E González-Calderón , Kazuhito Sai +7 more | Cell Death and Disease

Abstract Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is a central mediator of intracellular host defense signaling promoting inflammatory gene expression. Hence, TAK1 is a prime target … Abstract Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), known as TAK1, is a central mediator of intracellular host defense signaling promoting inflammatory gene expression. Hence, TAK1 is a prime target of intracellular bacterial effectors in blocking inflammatory responses. However, when TAK1 is inhibited, host cells alternatively activate multiple cell death pathways, namely caspase 8-dependent apoptosis and pyroptosis, and receptor interacting protein kinase 3 (RIPK3)-dependent necroptosis. While these pathways ultimately lead to cell death, we found that they also modulate mitochondria to produce mitochondrial reactive oxygen species (ROS). Although as cell death executors, mixed lineage kinase-like (MLKL) and gasdermins are known to form pores in the plasma membrane, we found that TAK1 inhibition translocates them to mitochondria resulting in elevated mitochondrial ROS. Ablation of both MLKL and gasdermins diminished TAK1 inhibition-induced elevation of ROS and exacerbated intracellular bacterial colonization. Our results reveal that these cell death pathways have an alternative host defense role to prevent intracellular pathogen colonization.

Exploring a Novel Anti-Inflammatory Therapy for Diabetic Retinopathy Based on Glyco-Zeolitic-Imidazolate Frameworks

2025-06-17

Elena Díaz-Paredes , Francisco Martín-Loro , Rocío Rodríguez-Marín +4 more | Pharmaceutics

Background/Objectives: Diabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision … Background/Objectives: Diabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision loss in diabetic patients. Currently, there is no treatment capable of reversing retinal damage, which represents a significant burden on the quality of life of patients. (1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin stands outs as a prototype of the sp2-iminoglycolipids family for its beneficial neuroprotective effect against this chronic eye disease. Critical issues related to the low solubility and bioavailability of this glycolipid in biological settings are overcome by its encapsulation in a Zeolitic-Imidazolate Framework (ZIF) structure, resulting in homogeneous and biocompatible GlycoZIF nanoparticles. Cell studies show an enhanced cellular uptake compared with the free glycolipid, and importantly, its bioactivity is preserved once released inside cells. Methods: Extensive in vitro and ex vivo assays with diabetic retinopathy models unveil the mechanistic pathways of the designed GlycoZIF. Results: A reduction in proinflammatory mediators, increased heme oxygenase-1 level, inhibition of NLRP3 inflammasome, and reduced reactive gliosis is shown. Conclusions: These findings demonstrate for the first time the potential of Glyco-modified ZIFs for the treatment of diabetes-related ocular problems by controlling the immune-mediated inflammatory response.

Pyroptosis in Alzheimer’s Disease: Mechanisms and Therapeutic Potential

2025-06-17

Tian Tang | Cellular and Molecular Neurobiology

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles (NFTs), and neuroinflammation. Recent research has revealed that pyroptosis, an inflammatory programmed cell death (PCD), plays a … Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles (NFTs), and neuroinflammation. Recent research has revealed that pyroptosis, an inflammatory programmed cell death (PCD), plays a crucial role in AD pathology. The pyroptosis signaling cascade triggered by β-amyloid (Aβ) and hyperphosphorylated tau protein leads to the release of proinflammatory cytokines, forming a "neuroinflammation-neurodegeneration" vicious cycle. Therapeutic strategies targeting the pyroptosis signaling pathway show promise, with evidence suggesting that inhibition of inflammasomes, caspase-1, or gasdermin D (GSDMD) can alleviate AD-related pathological features. However, the specificity of the existing inhibitors is insufficient, and research on non-classical pyroptosis pathway remains in its early stages. More mechanisms and therapeutic strategies targeting pyroptosis-related pathway need to be explored to enhance the therapeutic efficacy. Targeting the pyroptosis pathway provides a novel direction for AD treatment. Exploring and summarizing its mechanisms along with the clinical translational applications of targeted inhibitors will offer fresh perspectives for moving beyond traditional "symptom control" therapies and achieving "pathology-modifying" interventions, holding significant scientific and clinical importance.

Pyroptosis Mediated by ROS/Caspase-3/GSDME Pathway in <i>Aspergillus fumigatus</i>–Induced Fungal Keratitis

2025-06-17

Jingze Kan , Shiqi Song , Mengzhu Liu +6 more | Investigative Ophthalmology & Visual Science

Gasdermin E (GSDME), cleaved by (casp-3) activation, is known as a key executor in pyroptosis. However, its role in fungal keratitis (FK) remains unclear. Thus we analyzed the role of … Gasdermin E (GSDME), cleaved by (casp-3) activation, is known as a key executor in pyroptosis. However, its role in fungal keratitis (FK) remains unclear. Thus we analyzed the role of GSDME, as well as its signaling pathway in Aspergillus fumigatus (AF)-induced FK. We conducted experiments using a mouse model and human corneal epithelial cells. Initially, we infected mice with AF at various time intervals and examined the progression of FK lesions, selecting the time point with the most severe lesions. Next, we pre-treated the subjects with various cytokine inhibitors that may influence pyroptosis. We then assessed the development of FK lesions and the production of inflammatory cytokines using qRT-PCR, flow cytometry, transmission electron microscopy, as well as Western blotting. The optimal stimulation time for corneal epithelial cells in mice and humans was determined to be three days and 12 hours, respectively. In both the mouse and corneal epithelial cell models, GSDME significantly mediated AF-induced pyroptosis downstream of the reactive oxygen species (ROS)/casp-3/GSDME pathway and greatly influenced the inflammatory process and keratitis in AF-induced FK. Overall, GSDME played a crucial role in pyroptosis during corneal inflammation. By modulating IL-1β release during pyroptosis, GSDME had a significant impact on the host immune response in FK. This process could be inhibited by blocking the ROS/casp-3/GSDME pathway, potentially offering a novel treatment option for reducing corneal opacity in FK.

The emerging role of cuproptosis in spinal cord injury

2025-06-16

Dongmin Xu , Liyu Hu , Jinming Zhou +3 more | Frontiers in Immunology

Copper is a vital trace element integral to numerous biological processes, including iron metabolism, neurotransmitter synthesis, mitochondrial respiration, oxidative stress regulation, and energy production. However, disturbances in copper metabolism can … Copper is a vital trace element integral to numerous biological processes, including iron metabolism, neurotransmitter synthesis, mitochondrial respiration, oxidative stress regulation, and energy production. However, disturbances in copper metabolism can result in pathological conditions, including cuproptosis—a newly recognized form of programmed cell death (PCD) marked by copper accumulation and the disruption of copper-dependent metabolic pathways. Cuproptosis has been associated with various diseases, such as cancer, metabolic disorders and neurodegenerative disorders. In the context of spinal cord injury (SCI), multiple pathological mechanisms, including oxidative stress, inflammation, and PCD could impact the patient’s prognosis with SCI. This review seeks to elucidate the pathophysiological underpinnings of SCI, the mechanisms and biological significance of copper homeostasis and the role of cuproptosis in SCI.

The role and mechanism of the NLRP3-IL-1β/IL-18 signaling axis in the progression of sepsis under an aging phenotype

2025-06-16

Chuchu Xu , Zhu Ren-jun , Qingfeng Dai +2 more | Life Sciences

An immune activator encapsulating PD-L1 siRNA for augmented immune checkpoint blockade immunotherapy through Zn2+ overload triggered pyroptosis

2025-06-16

Liming Gong , Yanhong Liu , Jing Feng +7 more | Journal of Nanobiotechnology

Breast cancer as a "cold" tumor presents an immunosuppressive microenvironment and inferior T-lymphocyte infiltration, leading to poor efficacy of immune checkpoint blockade (ICB) therapies. It is urgent to develop new … Breast cancer as a "cold" tumor presents an immunosuppressive microenvironment and inferior T-lymphocyte infiltration, leading to poor efficacy of immune checkpoint blockade (ICB) therapies. It is urgent to develop new effective combination treatment strategies. Pyroptosis is an inflammatory form of programmed cell death mediated by Caspase-1/GSDMD pathway, which can cause immunogenic cell death (ICD) and boost the immunogenicity of tumor. In this study, an immune activator (siRNAPD-L1@HA-ZIF-8) was proposed based on metal-organic framework (ZIF-8) nanosystem carrying Zn2+ and PD-L1 siRNA to improve anti-tumor immunotherapy through evoking pyroptosis combined with immune checkpoint blockade. We found that siRNAPD-L1@HA-ZIF-8 could disintegrate under low pH and release massive amounts of Zn2+, leading to elevated intracellular osmolarity and ROS, eventually resulting in pyroptosis. Zn2+ overload-triggered pyroptosis caused ICD effect and promoted the maturation of dendritic cells and infiltration of T-lymphocytes, which reprogramed the immunoecology of tumor from "cold" to "hot" state. Meanwhile, the co-delivered PD-L1 siRNA decreased the expression of PD-L1 protein on the tumor surface, relieving immune evasion and recovering the recognition and killing ability of cytotoxic T-lymphocytes, further boosting the immune response. This research not only confirmed the potential of ZIF-8 intrinsically as an immune activator that induces pyroptosis in combination with encapsulated PD-L1 siRNA-mediated ICB therapy for the first time, but also adequately revealed the immune responses mechanism by multiple techniques. This study will provide new strategies for pyroptosis-mediated treatments for augmented anti-tumor immunotherapy and greatly inspire the further development of immune activators based on Zn2+ overload-triggered pyroptotic pathway.