Diabetic cardiomyopathy (DCM) is a leading cause of heart failure (HF) among individuals with diabetes, presenting a significant medical challenge due to its complex pathophysiology and the lack of targeted therapies. Pyroptosis, a pro-inflammatory form of programmed cell death (PCD), is the predominant mode of cell death in the primary resident cells involved in DCM. It has been reported to be critical in DCM's onset, progression, and pathogenesis. Non-coding RNAs (ncRNAs), diverse transcripts lacking protein-coding potential, are essential for cellular physiology and the progression of various diseases. Increasing evidence indicates that ncRNAs are pivotal in the pathogenesis of DCM by regulating pyroptosis. This observation suggests that targeting the regulation of pyroptosis by ncRNAs may offer a novel therapeutic approach for DCM. However, a comprehensive review of this topic is currently lacking. Our objective is to elucidate the regulatory role of ncRNAs in pyroptosis associated with DCM and to elucidate the relationships among these factors. Additionally, we explored how ncRNAs influence pyroptosis and contribute to the pathophysiology of DCM. By doing so, we aim to identify new research targets for the clinical diagnosis and treatment of DCM.

Inflammasomes are multiprotein complexes of the innate immune system that mediate inflammatory responses to infection and to local and systemic stress and tissue injury. The principal function is to facilitate caspase-1 auto-activation and subsequently maturation and release of the effectors interleukin (IL)-1β and IL-18. The atrial-specific NLRP3 inflammasome is a unifying causal feature of atrial fibrillation (AF) development, progression and recurrence after ablation. Many AF-associated risk factors and co-morbidities converge mechanistically on the activation of this central inflammatory signaling platform. This review presents the historical conceptual development of a distinct atrial inflammasome and its potential causal involvement in AF. We follow the early observations linking systemic and local inflammation with AF, to the emergence of an atrial-intrinsic NLRP3 inflammasome operating within not just immune cells but also in resident atrial fibroblasts and cardiomyocytes. We outline the key developments in understanding how the atrial NLRP3 inflammasome and its effector IL-1β contribute causally to cellular and tissue-level arrhythmogenesis in different pathological settings, and outline candidate therapeutic concepts verified in preclinical models of atrial cardiomyopathy and AF.

Acute gouty arthritis is a metabolic disease characterized by hyperuricemia, with acute attacks involving neutrophil-released NETs activating immune responses through their major component, DNA, as danger-associated molecular patterns (DAMPs).

To investigate whether DNA from NETs activates the AIM2 inflammasome in synovial fibroblasts during acute gouty arthritis attacks, inducing pyroptosis and exacerbating inflammation.

The AIM2 gene knockdown mouse model of acute gouty arthritis was constructed, the joint pathological changes were observed by H&E staining, the synovium fibroblasts and neutrophils were sorted by flow cytometry, and the expressions of AIM2, Caspase-1 and GSDMD related proteins were detected by Western blot. The levels of TNF-α, IL-6, IL-1β and IL-18 in serum and cell supernatant were detected by ELISA. Neutrophils were induced to release NETs by urate, and NETs markers (dsDNA, MPO-DNA, NE-DNA) were detected by immunofluorescence (Cit-H3, PAD4) and ELISA. NETs media were co-cultured with synovial fibroblasts, cell activity and migration were evaluated by CCK8 and scrape assay, markers of synovitis (Thy1, VCAM-1, PDPN) were detected by immunofluorescence, and pyroptosis was evaluated by TUNEL and LDH release. By silencing or overexpression of AIM2 gene, Western blot and ELISA, the role of AIM2 in NETs induced pyrodeath and inflammatory response was investigated.

AIM2 gene knockdown significantly alleviated the symptoms of MSU-induced acute gouty arthritis in mice, reducing joint swelling and pathological damage. Expression levels of inflammatory factors (TNF-α, IL-6, IL-1β, IL-18) and cleaved Caspase-1/Caspase-1, GSDMD-NT/GSDMD) were decreased. It was found that neutrophils released NETs in response to sodium urate stimulation, manifested by significant upregulation of Cit-H3 and PAD4, as well as increased dsDNA, MPO-DNA, and NE-DNA complexes. NETs can induce inflammatory response in synovial fibroblasts, which is manifested as decreased cell activity and migration ability, increased release of inflammatory factors, and significantly increased markers of synovitis (Thy1, VCAM-1, PDPN). In addition, NETs induce scorch death of synovium fibroblasts by activating AIM2 inflammatories, which aggravates the inflammatory response, and AIM2 gene knockdown can effectively inhibit the scorch death and inflammatory response induced by NETs, indicating that NETs play a key role in the occurrence and development of gout arthritis through AIM2-mediated scorch death of synovium fibroblasts.

NETs-activated AIM2-mediated synovial fibroblast pyroptosis plays a crucial role in acute gouty arthritis, providing a new therapeutic target.

Cardiomyocyte signalling pathways are central to maintaining the structural and functional integrity of the heart. Dysregulation of these pathways contributes to the onset and progression of heart diseases, including heart failure, arrhythmias and cardiomyopathies. This review focuses on very recent work on dysfunctional cardiomyocyte signalling and its role in the pathophysiology of heart disease. We discuss key pathways, including immune signalling within cardiomyocytes, signalling associated with microtubule dysfunction, Hippo-yes-associated protein signalling and adenosine monophosphate-activated protein kinase signalling, highlighting how aberrations in their regulation lead to impaired cardiomyocyte functions and pinpointing the potential therapeutic opportunities in these pathways. This review underscores the complexity of cardiomyocyte signalling networks and emphasises the need for further dissecting signalling pathways to prevent cardiomyocyte dysfunction.

Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.

Absent in melanoma 2(AIM2) exacerbates atherosclerosis by inflammasome assembly. However, AIM2-mediated inflammation in diabetic cardiomyopathy remains incompletely understood. Here we investigate the role of AIM2 in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. By RNA-seq, we found that AIM2 were significantly upregulated in HG-induced macrophages, upregulation of AIM2 in cardiac infiltrating macrophages was confirmed in a high-fat diet (HFD)/streptozotocin (STZ)-induceddiabetic mouse model . Therefore, AIM2 knockout mice were constructed. Compared to WT mice, HFD/STZ-induced cardiac hypertrophy and dysfunction were significantly improved in AIM2-/- mice, despite no changes in blood glucose and body weight. Further, AIM2 deficiency inhibited cardiac recruitment of M1-macrophages and cytokine production. Mechanistically, AIM2-deficient macrophgaes reduced IL-1β and TNF-α secretion, which impaired the NLRC4/IRF1 signaling in cardiomyocytes, and reduced further recruitment of macrophages, attenuated cardiac inflammation and hypertrophy, these effects were confirmed by silencing IRF1 in WT mice, and significantly reversed by overexpression of IRF1 in AIM2-/- mice. Taken together, our findings suggest that AIM2 serves as a novel target for the treatment of diabetic cardiomyopathy.

Cardiovascular diseases (CVDs) continue to be a substantial global healthcare burden despite considerable progress in therapies. The inflammatory response during the progression of CVD has attracted considerable attention. Mitochondria serve as the principal energy source for the heart. In cardiovascular illnesses, mitochondrial homeostasis is disrupted, accompanied by structural and functional impairments. During mitochondrial stress or injury, mitochondrial damage-associated molecular patterns (mtDAMPs), such as mitochondrial DNA, cardiolipin, N-formyl peptide, and adenosine triphosphate, are released to activate pattern recognition receptors and trigger immunological responses. Inflammatory responses mediated by mtDAMPs substantially contribute to the pathophysiology of cardiovascular illnesses. In this review, we discuss the molecular mechanisms by which different mtDAMPs control the inflammatory response, address the pathological consequences of mtDAMPs in inducing or exacerbating the inflammatory response in CVDs, and summarize potential therapeutic targets in relevant experimental studies. Preventing or reducing mtDAMP release may play a role in CVD progression by alleviating the inflammatory response.

DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights the involvement of DNA sensors in metabolic and cardiovascular diseases. Elevated levels of modified, damaged, or ectopically localized self-DNA and non-self-DNA have been observed in patients and animal models with obesity, diabetes, fatty liver disease, and cardiovascular disease. The accumulation of cytosolic DNA aberrantly activates DNA signaling pathways, driving the pathological progression of these disorders. This review highlights the roles of specific DNA sensors, such as cyclic AMP-GMP synthase and stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9), interferon gamma-inducible protein 16 (IFI16), DNA-dependent protein kinase (DNA-PK), and DEAD-box helicase 41 (DDX41) in various metabolic disorders. We explore how DNA signaling pathways in both immune and non-immune cells contribute to the development of these diseases. Furthermore, we discuss the intricate interplay between metabolic stress and immune responses, offering insights into potential therapeutic targets for managing metabolic and cardiovascular disorders. Understanding the mechanisms of DNA sensor signaling in these contexts provides a foundation for developing novel interventions aimed at mitigating the impact of these pervasive health issues.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes. Transient receptor potential melastatin 2 (TRPM2) activity increases in diabetic oxidative stress state, and it is involved in myocardial damage and repair. We explore the protective effect of TRPM2 knockdown on the progression of DCM. A type 2 diabetes animal model was established in C57BL/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100-mg/kg streptozotocin (STZ). Genetic knockdown of TRPM2 in heart was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 9 carrying TRPM2 shRNA. Neonatal rat ventricular myocytes was exposed to 45 mM of high-glucose (HG) stimulation for 72 h in vitro to mimic the in vivo conditions. Western blot, real-time quantitative PCR (RT-qPCR), immunohistochemistry and fluorescence, electron, CCK-8, and flow cytometry were used to evaluate the phenotype of cardiac inflammation, fibrosis, apoptosis, and autophagy. Mice with HFD/STZ-induced diabetes exhibited systolic and diastolic dysfunction, as demonstrated by increased myocardial apoptosis and autophagy inhibition in the heart. Compared to control group, the protein expression of TRPM2, bax, cleaved caspase-3, and P62 was significantly elevated, and the protein expression of bcl-2 and LC3-II was significantly decreased in the myocardial tissues of the HFD/STZ-induced diabetes group. Knockdown of TRPM2 significantly reversed the HFD/STZ-induced myocardial apoptosis and autophagy inhibition. TRPM2 silencing attenuated HG-induced apoptosis and autophagy inhibition in primary cardiomyocytes via regulating the MEK/ERK mTORC1 signaling pathway. TRPM2 knockdown attenuates hyperglycemia-induced myocardial apoptosis and promotes autophagy in HFD/STZ-induced diabetic mice or HG-stimulated cardiomyocytes via regulating the MEK/ERK and mTORC1 signaling pathway.

Absent in melanoma 2 (AIM2) is a protein encoded by the AIM2 gene located on human chromosomes, AIM2 can recognize and bind to double stranded DNA (dsDNA), leading to the assembly of the AIM2 inflammasome. The AIM2 inflammasome plays important proinflammation role in many diseases, and can induce pyroptotic cell death. It has also been closely linked to the development and progression of metabolic diseases and can be activated in obesity, diabetes, nonalcoholic fatty liver disease, and atherosclerosis. In this article, we mainly review the role of AIM2 in glucose metabolism, especially in obesity-related disorders of glucose and lipid metabolism, and provide insights to better understand the role of AIM2 in the pathogenesis, and clinical treatment of metabolic disease.

Diabetes is a major risk factor for cardiovascular diseases, and myocardial damage caused by hyperglycemia is the main cause of heart failure. However, there is still a lack of systematic understanding of myocardial damage caused by diabetes. At present, we believe that the cellular inflammatory damage caused by hyperglycemia is one of the causes of diabetic cardiomyopathy. Pyroptosis, as a proinflammatory form of cell death, is closely related to the occurrence and development of diabetic cardiomyopathy. Therefore, this paper focuses on the important role of inflammation in the occurrence and development of diabetic cardiomyopathy. From the perspective of pyroptosis, we summarize the pyroptosis of different types of cells in diabetic cardiomyopathy and its related signaling pathways. It also summarizes the treatment of diabetic cardiomyopathy, hoping to provide methods for the prevention and treatment of diabetic cardiomyopathy by inhibiting pyroptosis.

Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Its blindness rate is high; therefore, finding a reasonable and safe treatment plan to prevent and control DR is crucial. Currently, there are abundant and diverse research results on the treatment of DR by Chinese medicine Traditional Chinese medicine compounds are potentially advantageous for DR prevention and treatment because of its safe and effective therapeutic effects.

To investigate the effects of Buqing granule (BQKL) on DR and its mechanism from a systemic perspective and at the molecular level by combining network pharmacology and in vivo experiments.

This study collected information on the drug targets of BQKL and the therapeutic targets of DR for intersecting target gene analysis and protein-protein interactions (PPI), identified various biological pathways related to DR treatment by BQKL through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and preliminarily validated the screened core targets by molecular docking. Furthermore, we constructed a diabetic rat model with a high-fat and high-sugar diet and intraperitoneal streptozotocin injection, and administered the appropriate drugs for 12 weeks after the model was successfully induced. Body mass and fasting blood glucose and lipid levels were measured, and pathological changes in retinal tissue were detected by hematoxylin and eosin staining. ELISA was used to detect the oxidative stress index expression in serum and retinal tissue, and immunohistochemistry, real-time quantitative reverse transcription PCR, and western blotting were used to verify the changes in the expression of core targets.

Six potential therapeutic targets of BQKL for DR treatment, including Caspase-3, c-Jun, TP53, AKT1, MAPK1, and MAPK3, were screened using PPI. Enrichment analysis indicated that the MAPK signaling pathway might be the core target pathway of BQKL in DR treatment. Molecular docking prediction indicated that BQKL stably bound to these core targets. In vivo experiments have shown that compared with those in the Control group, rats in the Model group had statistically significant (P < 0.05) severe retinal histopathological damage; elevated blood glucose, lipid, and malondialdehyde (MDA) levels; increased Caspase-3, c-Jun, and TP53 protein expression; and reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, ganglion cell number, AKT1, MAPK1, and MAPK3 protein expression. Compared with the Model group, BQKL group had reduced histopathological retinal damage and the expression of blood glucose and lipids, MDA level, Caspase-3, c-Jun and TP53 proteins were reduced, while the expression of SOD, GSH-Px level, the number of ganglion cells, AKT1, MAPK1, and MAPK3 proteins were elevated. These differences were statistically significant (P < 0.05).

BQKL can delay DR onset and progression by attenuating oxidative stress and inflammatory responses and regulating Caspase-3, c-Jun, TP53, AKT1, MAPK1, and MAPK3 proteins in the MAPK signaling pathway mediates these alterations.

Inflammatory diseases compromise a clinically common and diverse group of conditions, causing detrimental effects on body functions. Gasdermins (GSDM) are pore-forming proteins, playing pivotal roles in modulating inflammation. Belonging to the GSDM family, gasdermin D (GSDMD) actively mediates the pathogenesis of inflammatory diseases by mechanistically regulating different forms of cell death, particularly pyroptosis, and cytokine release, in an inflammasome-dependent manner. Aberrant activation of GSDMD in different types of cells, such as immune cells, cardiovascular cells, pancreatic cells and hepatocytes, critically contributes to the persistent inflammation in different tissues and organs. The contributory role of GSDMD has been implicated in diabetes mellitus, liver diseases, cardiovascular diseases, neurodegenerative diseases, and inflammatory bowel disease (IBD). Clinically, alterations in GSDMD levels are potentially indicative to the occurrence and severity of diseases. GSDMD inhibition might represent an attractive therapeutic direction to counteract the progression of inflammatory diseases, whereas a number of GSDMD inhibitors have been shown to restrain GSDMD-mediated pyroptosis through different mechanisms. This review discusses the current understanding and future perspectives on the role of GSDMD in the development of inflammatory diseases, as well as the clinical insights of GSDMD alterations, and therapeutic potential of GSDMD inhibitors against inflammatory diseases. Further investigation on the comprehensive role of GSDM shall deepen our understanding towards inflammation, opening up more diagnostic and therapeutic opportunities against inflammatory diseases.

PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. As a distinct pathway, the execution of PANoptosis cannot be hindered by targeting other cell death pathways, such as pyroptosis, apoptosis, or necroptosis. Instead, targeting key PANoptosome components can serve as a strategy to prevent this form of cell death. Given the physiological relevance in several diseases, PANoptosis is a pivotal therapeutic target. Notably, previous research has primarily focused on the role of PANoptosis in cancer and infectious and inflammatory diseases. By contrast, its role in cardiovascular diseases has not been comprehensively discussed. Here, we review the available evidence on PANoptosis in cardiovascular diseases, including cardiomyopathy, atherosclerosis, myocardial infarction, myocarditis, and aortic aneurysm and dissection, and explore a variety of agents that target PANoptosis, with the overarching goal of providing a novel complementary approach to combatting cardiovascular diseases.

Candida albicans is among the most prevalent invasive fungal pathogens for immunocompromised individuals and novel therapeutic approaches that involve immune response modulation are imperative. Absent in melanoma 2 (AIM2), a pattern recognition receptor for DNA sensing, is well recognized for its involvement in inflammasome formation and its crucial role in safeguarding the host against various pathogenic infections. However, the role of AIM2 in host defense against C. albicans infection remains uncertain. This study reveals that the gene expression of AIM2 is induced in human and mouse innate immune cells or tissues after C. albicans infection. Furthermore, compared to their wild-type (WT) counterparts, Aim2-/- mice surprisingly exhibit resistance to C. albicans infection, along with reduced inflammation in the kidneys post-infection. The resistance of Aim2-/- mice to C. albicans infection is not reliant on inflammasome or type I interferon production. Instead, Aim2-/- mice display lower levels of apoptosis in kidney tissues following infection than WT mice. The deficiency of AIM2 in macrophages, but not in dendritic cells, results in a phenocopy of the resistance observed in Aim2-/- mice against C. albican infection. The treatment of Clodronate Liposome, a reagent that depletes macrophages, also shows the critical role of macrophages in host defense against C. albican infection in Aim2-/- mice. Furthermore, the reduction in apoptosis is observed in Aim2-/- mouse macrophages following infection or treatment of DNA from C. albicans in comparison with controls. Additionally, higher levels of AKT activation are observed in Aim2-/- mice, and treatment with an AKT inhibitor reverses the host resistance to C. albicans infection. The findings collectively demonstrate that AIM2 exerts a negative regulatory effect on AKT activation and enhances macrophage apoptosis, ultimately compromising host defense against C. albicans infection. This suggests that AIM2 and AKT may represent promising therapeutic targets for the management of fungal infections.

Cardio-cerebrovascular diseases encompass pathological changes in the heart, brain and vascular system, which pose a great threat to health and well-being worldwide. Moreover, metabolic diseases contribute to and exacerbate the impact of vascular diseases. Inflammation is a complex process that protects against noxious stimuli but is also dysregulated in numerous so-called inflammatory diseases, one of which is atherosclerosis. Inflammation involves multiple organ systems and a complex cascade of molecular and cellular events. Numerous studies have shown that inflammation plays a vital role in cardio-cerebrovascular diseases and metabolic diseases. The absent in melanoma 2 (AIM2) inflammasome detects and is subsequently activated by double-stranded DNA in damaged cells and pathogens. With the assistance of the mature effector molecule caspase-1, the AIM2 inflammasome performs crucial biological functions that underpin its involvement in cardio-cerebrovascular diseases and related metabolic diseases: The production of interleukin-1 beta (IL-1β), interleukin-18 (IL-18) and N-terminal pore-forming Gasdermin D fragment (GSDMD-N) mediates a series of inflammatory responses and programmed cell death (pyroptosis and PANoptosis). Currently, several agents have been reported to inhibit the activity of the AIM2 inflammasome and have the potential to be evaluated for use in clinical settings. In this review, we systemically elucidate the assembly, biological functions, regulation and mechanisms of the AIM2 inflammasome in cardio-cerebrovascular diseases and related metabolic diseases and outline the inhibitory agents of the AIM2 inflammasome as potential therapeutic drugs.

Heart failure (HF) poses a significant world health challenge due to the increase in the aging population and advancements in cardiac care. In the pathophysiology of HF, the inflammasome has been correlated with the development, progression, and complications of HF disease. Discovering biomarkers linked to inflammasomes enhances understanding of HF diagnosis and prognosis. Directing inflammasome signaling emerges as an innovative therapeutic strategy for managing HF. The present review aims to delve into this inflammatory cascade, understanding its role in the development of HF, its potential role as biomarker, as well as the prospects of modulating inflammasomes as a therapeutic approach for HF.

Morphologically, cell death can be divided into apoptosis and necrosis. Apoptosis, which is a type of regulated cell death, is well tolerated by the immune system and is responsible for hemostasis and cellular turnover under physiological conditions. In contrast, necrosis is defined as a form of passive cell death that leads to a dramatic inflammatory response (also referred to as necroinflammation) and causes organ dysfunction under pathological conditions. Recently, a novel form of cell death named regulated necrosis (such as necroptosis, pyroptosis, and ferroptosis) was discovered. Distinct from apoptosis, regulated necrosis is modulated by multiple internal or external factors, but meanwhile, it results in inflammation and immune response. Accumulating evidence has indicated that regulated necrosis is associated with multiple diseases, including diabetes. Diabetes is characterized by hyperglycemia caused by insulin deficiency and/or insulin resistance, and long-term high glucose leads to various diabetes-related complications. Here, we summarize the mechanisms of necroptosis, pyroptosis, and ferroptosis, and introduce recent advances in characterizing the associations between these three types of regulated necrosis and diabetes and its complications.

Ischemic stroke (IS) is a significant global public health issue with a high incidence, disability, and mortality rate. A robust inflammatory cascade with complex and wide-ranging mechanisms occurs following ischemic brain injury. Inflammasomes are multiprotein complexes in the cytoplasm that modulate the inflammatory response by releasing pro-inflammatory cytokines and inducing cellular pyroptosis. Among these inflammasomes, the Absent in Melanoma 2 (AIM2) inflammasome shows the ability to detect a wide range of pathogen DNAs, thereby triggering an inflammatory response. Recent studies have indicated that the aberrant expression of AIM2 inflammasome in various cells is closely associated with the pathological processes of ischemic brain injury. This paper summarizes the expression and regulatory role of AIM2 in CNS and peripheral immune cells and discusses current therapeutic approaches targeting AIM2 inflammasome. These findings aim to serve as a reference for future research in this field.

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to the release of pro-inflammatory cytokines and is essential for innate defence against infection and danger signals. These secreted cytokines improve the inflammatory response caused by tissue damage and associated inflammation. Consequently, the development of NLRP3 inflammasome inhibitors are viable option for the treatment of diverse inflammatory disorders. The significant anti-inflammatory effects of the NLRP3 inhibitors have severe side effects. Hence, the application of NLRP3 inhibitors against inflammatory disease has not yet been understood and most of the developed inhibitors are unsuccessful in clinical trials. The processes behind the NLRP3 complex, priming, and activation are the main emphasis of this review, which also covers therapeutical inhibitors of the NLRP3 inflammasome and potential therapeutic strategies for directing the NLRP3 inflammasome towards clinical development.

Diabetic cardiomyopathy (DCM) is a pathophysiological condition triggered by diabetes mellitus (DM), which can lead to heart failure (HF). One of the most important cellular processes associated with DCM is the death of cardiomyocytes. Gasdermin D (GSDMD) plays a key role in mediating pyroptosis, a type of programmed cell death closely associated with inflammasome activation. Recent studies have revealed that pyroptosis is induced during hyperglycemia, which is crucial to the development of DCM. Although the effects of pyroptosis on DCM have been discussed, the relationship between DCM and GSDMD is not fully clarified. Recent studies gave us the impetus for clarifying the meaning of GSDMD in DCM. The purpose of this review is to summarize new and emerging insights, mainly discussing the structures of GSDMD and the mechanism of pore formation, activation pathways, molecular mechanisms of GSDMD-mediated pyroptosis, and the therapeutic potential of GSDMD in DCM. The implications of this review will pave the way for a new therapeutic target in DCM.

Pyroptosis is a form of programmed cell death mediated by gasdermins, particularly gasdermin D (GSDMD), which is widely expressed in tissues throughout the body. GSDMD belongs to the gasdermin family, which is expressed in a variety of cell types including epithelial cells and immune cells. It is involved in the regulation of anti-inflammatory responses, leading to its differential expression in a wide range of diseases. In this review, we provide an overview of the current understanding of the major activation mechanisms and effector pathways of GSDMD. Subsequently, we examine the importance and role of GSDMD in different diseases, highlighting its potential as a pan-biomarker. We specifically focus on the biological characteristics of GSDMD in several diseases and its promising role in diagnosis, early detection, and differential diagnosis. Furthermore, we discuss the application of GSDMD in predicting prognosis and monitoring treatment efficacy in cancer. This review proposes a new strategy to guide therapeutic decision-making and suggests potential directions for further research into GSDMD.

Hypertrophic cardiomyopathy (HCM) is a complicated, heterogeneous genetic condition that causes left ventricular hypertrophy, fibrosis, hypercontractility, and decreased compliance. Despite the advances made over the past 3 decades in understanding the molecular and cellular mechanisms aggravating HCM, the relationship between pathophysiological stress stimuli and distinctive myocyte growth profiles is still imprecise. Currently, mavacamten, a selective and reversible inhibitor of cardiac myosin ATPase, is the only drug approved by the US FDA for the treatment of HCM. Thus, there is an unmet need for developing novel disease-specific therapeutic approaches. This article provides an overview of emerging therapeutic targets for the treatment of HCM based on various molecular pathways and novel developments that are hopefully soon to enter the clinical study. These newly discovered targets include the dual specificity tyrosine-phosphorylation-regulated kinase 1B, the absence of the melanoma 1 inflammasome, the leucine-rich repeat kinase 2 enzyme, and the cluster of differentiation 147.

Chronic kidney disease (CKD) represents an independent risk factor for cardiovascular diseases (CVD). Accordingly, CKD patients show a substantial increased risk of cardiovascular mortality. Inflammation represents an important link between CKD and CVD. The interaction between endothelial cells and effector cells of the innate immune system plays a central role in the development and progression of inflammation. Vascular injury causes endothelial dysfunction, leading to augmented oxidative stress, increased expression of leukocyte adhesion molecules and chronic inflammation. CKD induces numerous metabolic changes, creating a uremic milieu resulting in the accumulation of various uremic toxins. These toxins lead to vascular injury, endothelial dysfunction and activation of the innate immune system. Recent studies describe CKD-dependent changes in monocytes that promote endothelial dysfunction and thus CKD progression and CKD-associated CVD. The NLR family pyrin domain containing 3-interleukin-1β-interleukin-6 (NLRP3-IL-1β-IL-6) signaling pathway plays a pivotal role in the development and progression of CVD and CKD alike. Several clinical trials are investigating targeted inhibition of this pathway indicating that anti-inflammatory therapeutic strategies may emerge as novel approaches in patients at high cardiovascular risk and nonresolving inflammation. CKD patients in particular would benefit from targeted anti-inflammatory therapy, since conventional therapeutic regimens have limited efficacy in this population.

Diabetes mellitus (DM) and its complications are important, worldwide public health issues, exerting detrimental effects on human health and diminishing both quality of life and lifespan. Pyroptosis, as a new form of programmed cell death, plays a critical role in DM and its complications. Exercise has been shown to be an effective treatment for improving insulin sensitivity or preventing DM. However, the molecular mechanisms underlying the effects of exercise on pyroptosis-related diseases remain elusive. In this review, we provided a comprehensive elucidation of the molecular mechanisms underlying pyroptosis and the potential mechanism of exercise in the treatment of DM and its complications through the modulation of anti-pyroptosis-associated inflammasome pathways. Based on the existing evidence, further investigation into the mechanisms by which exercise inhibits pyroptosis through the regulation of inflammasome pathways holds promising potential for expanding preventive and therapeutic strategies for DM and facilitating the development of novel therapeutic interventions.

Hyperglycemia and insulin resistance or deficiency are characteristic features of diabetes. Diabetes is accompanied by cardiomyocyte hypertrophy, fibrosis and ventricular remodeling, and eventually heart failure. In this study, we established a diabetic cardiomyopathy (DCM) mouse model to explore the role and mechanism of miR-200a-3p in DCM.

We used db/db mice to simulate the animal model of DCM and the expression of miR-200a-3p was then examined by RT-qPCR. Tail vein injection of mice was done with rAAV-miR-200a-3p for 8 weeks, and cardiac function was assessed by cardiac ultrasound. The levels of myocardial tissue injury, fibrosis, inflammation, apoptosis and autophagy in mice were detected by histological staining, TUNEL and other molecular biological experiments.

miR-200a-3p expression levels were significantly decreased in the myocardium of DCM mice. Diabetic mice developed cardiac dysfunction and presented pathological changes such as myocardial injury, myocardial interstitial fibrosis, cardiomyocyte apoptosis, autophagy, and inflammation. Overexpression of miR-200a-3p expression significantly ameliorated diabetes induced-cardiac dysfunction and myocardial injury, myocardial interstitial fibrosis, cardiomyocyte apoptosis, and inflammation, and enhanced autophagy. Mechanistically, miR-200a-3p interacted with FOXO3 to promote Mst1 expression and reduce Sirt3 and p-AMPK expression.

In type 2 diabetes, increased miR-200a-3p expression enhanced autophagy and participated in the pathogenic process of cardiomyopathy throug7 Mst1/Sirt3/AMPK axis regulation by its target gene FOXO3. This conclusion provides clues for the search of new gene targeted therapeutic approaches for diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is widely recognized as a major contributing factor to the development of heart failure in patients with diabetes. Previous studies have demonstrated the potential benefits of traditional herbal medicine for alleviating the symptoms of cardiomyopathy. We have chemically designed and synthesized a novel compound called aloe-emodin derivative (AED), which belongs to the aloe-emodin (AE) family of compounds. AED was formed by covalent binding of monomethyl succinate to the anthraquinone mother nucleus of AE using chemical synthesis techniques. The purpose of this study was to investigate the effects and mechanisms of AED in treating DCM. We induced type 2 diabetes in Sprague-Dawley (SD) rats by administering a high-fat diet and streptozotocin (STZ) injections. The rats were randomly divided into six groups: control, DCM, AED low concentration (50 mg/kg/day), AED high concentration (100 mg/kg/day), AE (100 mg/kg/day), and positive control (glyburide, 2 mg/kg/day) groups. There were eight rats in each group. The rats that attained fasting blood glucose of ˃16.7 mmol/L were considered successful models. We observed significant improvements in cardiac function in the DCM rats with both AED and AE following four weeks of intragastric treatment. However, AED had a more pronounced therapeutic effect on DCM compared to AE. AED exhibited an inhibitory effect on the inflammatory response in the hearts of DCM rats and high-glucose-treated H9C2 cells by suppressing the pyroptosis pathway mediated by the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain 3 (NLRP3) inflammasome. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes showed a significant enrichment in the NOD-like receptor signaling pathway compared to the high-glucose group. Furthermore, overexpression of NLRP3 effectively reversed the anti-pyroptosis effects of AED in high-glucose-treated H9C2 cells. This study is the first to demonstrate that AED possesses the ability to inhibit myocardial pyroptosis in DCM. Targeting the pyroptosis pathway mediated by the NLRP3 inflammasome could provide a promising therapeutic strategy to enhance our understanding and treatment of DCM.

Both absent in melanoma 2 (AIM2) and interferon-inducible protein 16 (IFI16) are intracellular innate immune receptors that recognize double-stranded DNA released during pathogenic infection, leading to the assembly of the inflammasome. The assembly of the inflammasome results in the secretion of bioactive interleukin (IL)-1β and IL-18 and induces cell death through an inflammatory process called pyroptosis. Although the AIM2 inflammasome is generally harmful in the context of some aseptic inflammatory illnesses, it plays a protective role in infectious diseases. During inflammatory processes, there is competition between IFI16 and AIM2. In this review, we explore the impacts of IFI16 and AIM2 in infectious disease and aseptic inflammation, respectively, and how they compete.

Diabetic cardiomyopathy (DCM) is highly prevalent and increases the risk of heart failure and sudden death. Therefore, proper and effective treatments for DCM are in urgent demand. Danlou tablet (Dan) is reported to confer protective effects on several heart diseases. However, to our knowledge, whether Dan provides protection against DCM is unclear. In this study, we explored the effect of Dan on DCM with the in vitro DCM model using AC16 cardiomyocytes. We found that Dan treatment significantly reduced cardiomyocyte apoptosis and oxidative stress in high-glucose (HG)-treated cardiomyocytes, as evidenced by decreased Annexin V-FITC+ cardiomyocytes, intracellular reactive oxygen species (ROS) levels, Bax/Bcl2 ratio, and cleaved-Caspase3/Caspase3 ratio. Interestingly, Dan treatment caused a decreased level of microRNA-34a (miR-34a), which could enhance cardiomyocyte apoptosis. Furthermore, miR-34a mimic blocked Dan's effect in apoptosis prevention. Finally, we observed that the miR-34a mimic effectively decreased the level of sirtuin 1 (SIRT1), while the miR-34a inhibitor increased the level of SIRT1. And downregulation of SIRT1 effectively reversed the effect of miR-34a inhibitor on cardiomyocyte apoptosis. Taken together, our study showed that Dan prevented HG-induced cardiomyocyte apoptosis through downregulating miR-34a and upregulating SIRT1. Our study has provided experimental support for the potential use of Dan in treating DCM. Further detailed study of Dan and the underlying mechanisms may shed light on the prevention and treatment of DCM.

PANoptosis is a newly identified type of regulated cell death that consists of pyroptosis, apoptosis, and necroptosis, which simultaneously occur during the pathophysiological process of infectious and inflammatory diseases. Although our previous literature mining study suggested that PANoptosis might occur in neuronal ischemia/reperfusion injury, little experimental research has been reported on the existence of PANoptosis. In this study, we used in vivo and in vitro retinal neuronal models of ischemia/reperfusion injury to investigate whether PANoptosis-like cell death (simultaneous occurrence of pyroptosis, apoptosis, and necroptosis) exists in retinal neuronal ischemia/reperfusion injury. Our results showed that ischemia/reperfusion injury induced changes in morphological features and protein levels that indicate PANoptosis-like cell death in retinal neurons both in vitro and in vivo. Ischemia/reperfusion injury also significantly upregulated caspase-1, caspase-8, and NLRP3 expression, which are important components of the PANoptosome. These results indicate the existence of PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons and provide preliminary experimental evidence for future study of this new type of regulated cell death.

Diabetic cardiomyopathy (DCM) is one of the common cardiovascular complications of diabetes and a leading cause of death in diabetic patients. Mitochondrial metabolism and immune-inflammation are key for DCM pathogenesis, but their crosstalk in DCM remains an open issue. This study explored the separate roles of mitochondrial metabolism and immune microenvironment and their crosstalk in DCM with bioinformatics.

DCM chip data (GSE4745, GSE5606, and GSE6880) were obtained from NCBI GEO, while mitochondrial gene data were downloaded from MitoCarta3.0 database. Differentially expressed genes (DEGs) were screened by GEO2R and processed for GSEA, GO and KEGG pathway analyses. Mitochondria-related DEGs (MitoDEGs) were obtained. A PPI network was constructed, and the hub MitoDEGs closely linked to DCM or heart failure were identified with CytoHubba, MCODE and CTD scores. Transcription factors and target miRNAs of the hub MitoDEGs were predicted with Cytoscape and miRWalk database, respectively, and a regulatory network was established. The immune infiltration pattern in DCM was analyzed with ImmuCellAI, while the relationship between MitoDEGs and immune infiltration abundance was investigated using Spearman method. A rat model of DCM was established to validate the expression of hub MitoDEGs and their relationship with cardiac function.

MitoDEGs in DCM were significantly enriched in pathways involved in mitochondrial metabolism, immunoregulation, and collagen synthesis. Nine hub MitoDEGs closely linked to DCM or heart failure were obtained. Immune analysis revealed significantly increased infiltration of B cells while decreased infiltration of DCs in immune microenvironment of DCM. Spearman analysis demonstrated that the hub MitoDEGs were positively associated with the infiltration of pro-inflammatory immune cells, but negatively associated with the infiltration of anti-inflammatory or regulatory immune cells. In the animal experiment, 4 hub MitoDEGs (Pdk4, Hmgcs2, Decr1, and Ivd) showed an expression trend consistent with bioinformatics analysis result. Additionally, the up-regulation of Pdk4, Hmgcs2, Decr1 and the down-regulation of Ivd were distinctly linked to reduced cardiac function.

This study unraveled the interaction between mitochondrial metabolism and immune microenvironment in DCM, providing new insights into the research on potential pathogenesis of DCM and the exploration of novel targets for medical interventions.

Chronic hyperglycemia induces reactive oxygen species that have an essential function in tissue injuries in cases of diabetic cardiomyopathy. The mechanism of the absent in melanoma 2 (AIM2)-associated inflammasome response in diabetic cardiomyopathy is unknown. Therefore, this study was performed to investigate the role of AIM2 and its molecular mechanisms. Diabetic rats received 1 × 10⁸ viral injections of 5'-GGTCACCAGTTCCTCAGTT-3' (n = 15) or 5'-TTCTCCGAACGTGTCACGT-3' (negative control group, n = 15). Normal rats (n = 15) and diabetic rats (n = 15) were also included in the experiment. Ex vivo study was performed on primary cardiomyocytes for different concentrations of glucose. AIM2 inhibition did not affect any of the metabolic parameters (p > 0.05 for all). AIM2 protein levels were significantly increased in rats with diabetes mellitus compared with those in the control group (p < 0.0001, q = 32.044). Also, viral injection (sequence: 5'-GGTCACCAGTTCCTCAGTT-3') decreased the diabetes mellitus-induced increase in expression of AIM2 protein levels (p < 0.0001, q = 27.129). Cardiac dysfunctions were reported in rats with diabetes mellitus characterized by several parameters (p < 0.01 for all). The diabetic myocardium of rats was reported to have higher deposits of extracellular matrix compared to the control rats (p < 0.001). These effects were downregulated by viral injection (sequence: 5'-GGTCACCAGTTCCTCAGTT-3'). Ex vivo research revealed that high glucose concentrations significantly increased AIM2 protein expression, reactive oxygen species, and cell death. AIM2 protein in diabetic cardiomyopathy is associated with reactive oxygen species production and cardiomyocyte death.

The pivotal role of inflammation in the pathophysiology of heart-failure (HF) development and progression has long been recognized. High blood levels of pro-inflammatory and inflammatory markers are present and associated with adverse outcomes in patients with HF. In addition, there seems to be an interrelation between inflammation and neurohormonal activation, the cornerstone of HF pathophysiology and management. However, clinical trials involving anti-inflammatory agents have shown inconclusive or even contradictory results in improving HF outcomes. In the present review, we try to shed some light on the reciprocal relationship between inflammation and HF in an attempt to identify the central regulating factors, such as inflammatory cells and soluble mediators and the related inflammatory pathways as potential therapeutic targets.

Absent in melanoma 2 (AIM2) is a cytoplasmic sensor that recognises the double-strand DNA. AIM2 inflammasome is a protein platform in the cell that initiates innate immune responses by cleaving pro-caspase-1 and converting IL-1β and IL-18 to their mature forms. Additionally, AIM2 inflammasome promotes pyroptosis by converting Gasdermin-D (GSDMD) to GSDMD-N fragments. An increasing number of studies have indicated the important and decisive roles of the AIM2 inflammasome, IL-1β, and pyroptosis in cardiovascular diseases, such as coronary atherosclerosis, myocardial infarction, ischaemia/reperfusion injury, heart failure, aortic aneurysm and ischaemic stroke. Here, we review the molecular mechanism of the activation and effect of the AIM2 inflammasome in cardiovascular disease, revealing new insights into pathogenic factors that may be targeted to treat cardiovascular disease and related dysfunctions.

Acute myocardial infarction (AMI) is one of the main reasons of cardiovascular disease-related death. The introduction of percutaneous coronary intervention to clinical practice dramatically decreased the mortality rate in AMI. Adverse cardiac remodeling is a serious problem in cardiology. An increase in the effectiveness of AMI treatment and prevention of adverse cardiac remodeling is difficult to achieve without understanding the mechanisms of reperfusion cardiac injury and cardiac remodeling. Inhibition of pyroptosis prevents the development of postinfarction and pressure overload-induced cardiac remodeling, and mitigates cardiomyopathy induced by diabetes and metabolic syndrome. Therefore, it is reasonable to hypothesize that the pyroptosis inhibitors may find a role in clinical practice for treatment of AMI and prevention of cardiac remodeling, diabetes and metabolic syndrome-triggered cardiomyopathy. It was demonstrated that pyroptosis interacts closely with apoptosis and autophagy. Pyroptosis could be inhibited by nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 inhibitors, caspase-1 inhibitors, microRNA, angiotensin-converting enzyme inhibitors, angiotensin Ⅱ receptor blockers, and traditional Chinese herbal medicines.

Knee osteoarthritis (KOA), whose prevalence keeps rising, is still unsolved pathobiological/therapeutical problem. Historically, knee osteoarthritis was thought to be a "wear and tear" disease, while recent etiology hypotheses stressed it as a chronic, low-grade inflammatory disease. Inflammasomes mediated by the innate immunity systems have an important role in inflammatory diseases including KOA. A deluge of recent studies focused on the NLRP3 inflammasome with suggestions that its pharmacologic block would hinder degeneration. However, known inflammasomes are numerous and can also trigger IL-1β/IL-18 production and cells' pyroptotic death. Among them, AIM2 inflammasome is involved in key aspects of various acute and chronic inflammatory diseases. Therefore, while presently leaving out little-studied inflammasomes in KOA, this review focuses on the AIM2 inflammasomes that participate in KOA's complex mechanisms in conjunction with the activation of AIM2 inflammasomes in other diseases combined with the current studies on KOA mechanisms. Although human-specific data about it are relatively scant, we stress that only a holistic view including several inflammasomes including AIM2 inflammasome and other potential pathogenetic drivers will lead to successful therapy for knee osteoarthritis.

Heart failure remains a considerable clinical and public health problem, it is the dominant cause of death from cardiovascular diseases, besides, cardiovascular diseases are one of the leading causes of death worldwide. The survival of patients with heart failure continues to be low with 45-60% reported deaths within five years. Apoptosis, necrosis, autophagy, and pyroptosis mediate cardiac cell death. Acute cell death is the hallmark pathogenesis of heart failure and other cardiac pathologies. Inhibition of pyroptosis, autophagy, apoptosis, or necrosis reduces cardiac damage and improves cardiac function in cardiovascular diseases. Pyroptosis is a form of inflammatory deliberate cell death that is characterized by the activation of inflammasomes such as NOD-like receptors (NLR), absent in melanoma 2 (AIM2), interferon-inducible protein 16 (IFI-16), and their downstream effector cytokines: Interleukin IL-1β and IL-18 leading to cell death. Recent studies have shown that pyroptosis is also the dominant cell death process in cardiomyocytes, cardiac fibroblasts, endothelial cells, and immune cells. It plays a crucial role in the pathogenesis of cardiac diseases that contribute to heart failure. This review intends to summarize the therapeutic implications targeting pyroptosis in the main cardiac pathologies preceding heart failure.

Pyroptosis is a form of pro-inflammatory, necrotic cell death mediated by proteins of the gasdermin family. Various heart diseases, including myocardial ischemia/reperfusion injury, myocardial infarction, and heart failure, involve cardiomyocyte and non-myocyte pyroptosis. Cardiomyocyte pyroptosis also causes the release of pro-inflammatory cytokines. Recent studies have confirmed that pyroptosis is predominantly triggered by both the canonical and non-canonical inflammasome pathways, which independently facilitate caspase-1 or caspase-11/4/5 activation and gasdermin D (GSDMD) cleavage. Cardiac fibroblast and myeloid cell pyroptosis also contributes to the pathogenesis and development of heart diseases. This review summarizes the recent studies on pyroptosis in heart diseases and discusses the associated therapeutic targets.

Heart disease is the leading cause of death worldwide. Cardiomyopathy is a disease characterized by the heart muscle damage, resulting heart in a structurally and functionally change, as well as heart failure and sudden cardiac death. The key pathogenic factor of cardiomyopathy is the loss of cardiomyocytes, but the related molecular mechanisms remain unclear. Ferroptosis is a newly discovered regulated form of cell death, characterized by iron accumulation and lipid peroxidation during cell death. Recent studies have shown that ferroptosis plays an important regulatory roles in the occurrence and development of many heart diseases such as myocardial ischemia/reperfusion injury, cardiomyopathy and heart failure. However, the systemic association of ferroptosis and cardiomyopathy remains largely unknown and needs to be elucidated. In this review, we provide an overview of the molecular mechanisms of ferroptosis and its role in individual cardiomyopathies, highlight that targeting ferroptosis maybe a potential therapeutic strategy for cardiomyopathy therapy in the future.

Cardiovascular diseases are known as the leading cause of morbidity and mortality worldwide. As an innate immune signaling complex, inflammasomes can be activated by various cardiovascular risk factors and regulate the activation of caspase-1 and the production and secretion of proinflammatory cytokines such as IL-1β and IL-18. Accumulating evidence supports that inflammasomes play a pivotal role in the progression of atherosclerosis, myocardial infarction, and heart failure. The best-known inflammasomes are NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes, among which NLRP3 inflammasome is the most widely studied in the immune response and disease development. This review focuses on the activation and regulation mechanism of inflammasomes, the role of inflammasomes in cardiovascular diseases, and the research progress of targeting NLRP3 inflammasome and IL-1β for related disease intervention.

The pathogenesis of cardiovascular disease (CVD) is complex and multifactorial, and inflammation plays a central role. Inflammasomes are multimeric protein complexes that are activated in a 2-step manner in response to infection or tissue damage. Upon activation the proinflammatory cytokines, interleukins-1β and -18 are released. In the last decade, the evidence that inflammasome activation plays an important role in CVD development became stronger. We discuss the role of different inflammasomes in the pathogenesis of CVD, focusing on atherosclerosis and heart failure. This review also provides an overview of existing experimental studies and clinical trials on inflammasome inhibition as a therapeutic target in these disorders.