Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes without significant alcohol consumption. It is closely associated with sedentarism, hypercaloric diets, obesity, dyslipidemia, insulin resistance, type 2 diabetes mellitus, and genetic predisposition. NAFLD comprises a spectrum of liver disorders, from simple steatosis to non-alcoholic (NASH) and liver cirrhosis. The complex etiological mechanisms include oxidative stress, inflammation, apoptosis, and fibrosis; therefore, its management is challenging. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), a class of antidiabetic drugs, have emerged as promising therapeutic agents due to their ability to improve key metabolic parameters, including obesity, dyslipidemia, insulin resistance, and hyperglycemia. This review explores the cellular mechanisms by which SGLT2i, either as monotherapy or combined with other treatments, modulate signaling pathways involved in lipid and carbohydrate metabolism. Additionally, we examine their effects on oxidative stress, inflammation, fibrosis, and apoptosis, which are critical drivers of NAFLD progression. This review is intended to summarize the multiple benefits of SGLT2 inhibitors and to educate healthcare providers on the therapeutic potential of these drugs in order to foster their incorporation into effective NAFLD management plans.

Recent decades have described parallel neuropathological mechanisms increasing the risk for developing late-onset Alzheimer's dementia (LOAD) in type 2 diabetes mellitus (T2DM); however, still little is known of the role of diabetic encephalopathy and brain atrophy in LOAD. The aim of this systematic review is to provide a comprehensive view on diabetic encephalopathy/cerebral atrophy, taking into account neuroimaging data, neuropathology, metabolic and endocrine mechanisms, amyloid formation, brain perfusion impairments, neuroimmunology, and inflammasome activation. Key switches were identified, to further meta-analyze genomic candidate loci and epigenetic modifications. For the qualitative meta-analysis of genomic bases extracted, human linkage studies were examined; for epigenetic mechanisms, data from both human and animal studies are described. For the systematic review of pathophysiological mechanisms, 1,259 publications were evaluated and 93 gene loci extracted for candidate risk linkages. Sixty-six publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight the insulin signaling system, vascular markers, inflammation and inflammasome pathways, amylin interactions, and glycosylation mechanisms. The protocol was registered with PROSPERO (ID: CRD42023440535).

Obesity cardiomyopathy (OCM) represents a rapidly growing health concern globally, characterized by metabolic, structural, and functional abnormalities of the heart. Current research has demonstrated that inflammation plays a pivotal role in obesity-induced cardiomyopathy, and that regular exercise can ameliorate lipid disturbances and inflammatory abnormalities effectively. However, the underlying mechanisms are not fully elucidated. We investigated the effects of an 8-week aerobic exercise intervention on myocardial structure, function, and inflammation in HFD-induced obese mice. The results revealed that aerobic exercise alleviated myocardium pyroptosis and inflammation by down-regulating the PI3K/AKT signaling pathway. Furthermore, the inhibition of the PI3K pathway by LY294002, coupled with exercise, attenuated and suppressed HFD-induced myocardial impairments, inflammation, and pyroptosis, with a synergistic effect. Based on these findings, we concluded that eight weeks of aerobic exercise synergizes with the inhibition of PI3K through inflammatory and pyroptosis mechanisms to improve obesity-associated myocardial remodeling and dysfunction. Therefore, long-term regular aerobic exercise represents a potential strategy in the treatment of OCM.

We aimed to determine whether inhibiting xanthine oxidase (XO) activity and NLRP-3 activation in the liver with febuxostat could influence the progression of metabolic dysfunction-associated steatotic liver disease (MASLD).

Sixty-four MASLD patients were divided into two groups: 32 patients received 80 mg of febuxostat daily, while the other 32 patients received 400 mg of vitamin E twice daily for 24 weeks. A gastroenterologist assessed the degree of steatosis using Fibroscan and controlled attenuation parameter (CAP) measurements at baseline and after six months. Additionally, hepatic steatosis index (HSI), HAIR-score, and levels of NLRP-3, TIM-3, HOMA-IR, MDA, uric acid, lipid profile, and liver function tests were measured before and after treatment.

Improvement in steatosis was observed in 50 % of febuxostat group and 46.9 % of vitamin E group. Both groups showed a significant reduction in CAP scores, with more pronounced decrease in vitamin E group (p < 0.001) compared to febuxostat group (p = 0.001). Febuxostat group exhibited significantly lower levels of NLRP-3, MDA, TIM-3, and uric acid compared to vitamin E group. HSI, HAIR score, and liver functions improved similarly in both groups.

Febuxostat appears to be effective in reducing steatosis in MASLD patients, suggesting its potential as a treatment option for non-cirrhotic MASLD.

gov identifier is NCT05574036, Registered October 6, 2022 - Retrospectively.

Diabetic encephalopathy (DE) is a neurological complication characterized by neuroinflammation, cognitive impairment, and memory decline, with its pathogenesis closely linked to the activation of the NLRP3 inflammasome. As a central regulator of the innate immune system, the NLRP3 inflammasome plays a pivotal role in DE progression by mediating neuroinflammation, pyroptosis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and microglial polarization. This review systematically explores the molecular mechanisms by which the NLRP3 inflammasome contributes to DE, focusing on its role in neuroinflammatory cascades and neuronal damage, as well as the diabetes-associated physiological changes that exacerbate DE pathogenesis. Furthermore, we summarize emerging therapeutic strategies targeting the NLRP3 inflammasome, including small-molecule inhibitors and bioactive compounds derived from traditional herbal medicine, highlighting their potential for DE treatment. These findings not only advance our understanding of DE but also provide a foundation for developing NLRP3-targeted pharmacological interventions.

Chronic inflammation is a hallmark for Metabolic Syndrome (MetS). It is also one of the most important risk factors for insulin resistance and metabolic disorders. Inflammasomes, which are intracellular multiprotein complexes within the innate immune system, regulate the production and maturation of pro-inflammatory cytokines including interleukin-1β (IL-1β) and IL-18 upon sensing pathogens or danger signals in the cytosol. A growing body of evidence indicates that inflammasomes play a pivotal role in the pathophysiology and progression of metabolic diseases, as deficiency in the key component of inflammasomes protects mice from high fat diet induced obesity and insulin resistance. Thus, in this review, we will summarize the role of inflammasomes in MetS and how to treat MetS by targeting inflammasomes. This may provide novel insights and therapeutic targets for treating metabolic disorders.

As people age, degenerative bone and joint diseases (DBJDs) become more prevalent. When middle-aged and elderly people are diagnosed with one or more disorders such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD), it often signals the onset of prolonged pain and reduced functionality. Chronic inflammation has been identified as the underlying cause of various degenerative diseases, including DBJDs. Recently, excessive activation of pyroptosis, a form of programed cell death (PCD) mediated by inflammasomes, has emerged as a primary driver of harmful chronic inflammation. Consequently, pyroptosis has become a potential target for preventing and treating DBJDs.

This review explored the physiological and pathological roles of the pyroptosis pathway in bone and joint development and its relation to DBJDs. Meanwhile, it elaborated the molecular mechanisms of pyroptosis within individual cell types in the bone marrow and joints, as well as the interplay among different cell types in the context of DBJDs. Furthermore, this review presented the latest compelling evidence supporting the idea of regulating the pyroptosis pathway for DBJDs treatment, and discussed the potential, limitations, and challenges of various therapeutic strategies involving pyroptosis regulation.

In summary, an interesting identity for the unregulated pyroptosis pathway in the context of DBJDs was proposed in this review, which was undertaken as a spoiler of peaceful coexistence between cells in a degenerative environment. Over the extended course of DBJDs, pyroptosis pathway perpetuated its activity through crosstalk among pyroptosis cascades in different cell types, thus exacerbating the inflammatory environment throughout the entire bone marrow and joint degeneration environment. Correspondingly, pyroptosis regulation therapy emerged as a promising option for clinical treatment of DBJDs.

Recent evidence has shown that increased levels of circulating long-chain ceramides predict atherosclerotic cardiovascular disease independently of cholesterol1,2. Although targeting ceramide signalling may provide therapeutic benefits beyond the treatment of hypercholesterolaemia, the underlying mechanism by which circulating ceramides aggravate atherosclerotic cardiovascular disease remains elusive. Here we examine whether circulating long-chain ceramides activate membrane G-protein-coupled receptors to exacerbate atherosclerosis. We perform a systematic screen that combines G-protein-signalling quantification, bioinformatic analysis of G-protein-coupled receptor expression and functional examination of NLRP3 inflammasome activation. The results suggest that CYSLTR2 and P2RY6 are potential endogenous receptors of C16:0 ceramide-induced inflammasome activation in both endothelial cells and macrophages. Inhibition of CYSLTR2 and P2RY6 genetically or pharmacologically alleviates ceramide-induced atherosclerosis aggravation. Moreover, increased ceramide levels correlate with the severity of coronary artery disease in patients with varying degrees of renal impairment. Notably, CYSLTR2 and P2RY6 deficiency mitigates chronic-kidney-disease-aggravated atherosclerosis in mice without affecting cholesterol or ceramide levels. Structural analyses of ceramide-CYSLTR2-Gq complexes reveal that both C16:0 and C20:0 ceramides bind in an inclined channel-like ligand-binding pocket on CYSLTR2. We further reveal an unconventional mechanism underlying ceramide-induced CYSLTR2 activation and the CYSLTR2-Gq interface. Overall, our study provides structural and molecular mechanisms of how long-chain ceramides initiate transmembrane Gq and inflammasome signalling through direct binding to CYSLTR2 and P2RY6 receptors. Therefore, blocking these signals may provide a new therapeutic potential to treat atherosclerosis-related diseases.

The presence of cholesterol crystals (CCs) in tissues was first described more than 100 years ago. CCs have a pathogenic role in various cardiovascular diseases, including myocardial infarction, aortic aneurysm and, most prominently, atherosclerosis. Although the underlying mechanisms and signalling pathways involved in CC formation are incompletely understood, numerous studies have highlighted the existence of CCs at various stages of atheroma progression. In this Review, we summarize the mechanisms underlying CC formation and the role of CCs in cardiovascular disease. In particular, we explore the established links between lipid metabolism across various cell types and the formation of CCs, with a focus on CC occurrence in the vasculature. We also discuss CC-induced inflammation as one of the pathogenic features of CCs in the atheroma. Finally, we summarize the therapeutic strategies aimed at reducing CC-mediated atherosclerotic burden, including approaches to inhibit CC formation in the vasculature or to mitigate the inflammatory response triggered by CCs. Addressing CC formation might emerge as a crucial component in our broader efforts to combat cardiovascular disease.

In order to investigate whether a central nervous system penetrant anti-inflammatory could augment or sustain obesity treatment with semaglutide (Wegovy), a glucagon-like peptide-1 receptor (GLP-1R) agonist, we tested two hypotheses in models of diet-induced obesity (DIO): 1) a centrally penetrant NLPR3 inhibitor, NT-0796, drives enhanced weight loss when combined with low-dose semaglutide, compared to monotherapy; and 2) NT-0796 monotherapy sustains weight loss induced by semaglutide.

Mice fed a standard high-fat or a polyunsaturated fatty acid diet served as models of DIO and were dosed with low-dose semaglutide, NT-0796, or combinations. Body weight, food intake, peripheral inflammatory markers, and hypothalamic glial fibrillary acidic protein expression were assessed.

Combined dosing of NT-0796 with semaglutide drove greater weight loss than either monotherapy alone, and this effect was enhanced in mice consuming the polyunsaturated fatty acid diet. In addition, NT-0796 sharply limited weight regain following cessation of semaglutide therapy and normalized markers of both peripheral inflammation and hypothalamic astrogliosis to a far greater extent than either semaglutide or calorie restriction.

Alleviation of obesity-associated inflammation via NLRP3 inhibition 1) constitutes an effective weight-loss strategy as monotherapy in mice with DIO, 2) augments the weight-loss efficacy of a subtherapeutic dose of semaglutide, and 3) blocks recovery of lost weight following cessation of semaglutide.

Over the past decade, significant advances have been made in our understanding of how NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes are activated. These findings provide detailed insights into the transcriptional and posttranslational regulatory processes, the structural-functional relationship of the activation processes, and the spatiotemporal dynamics of NLRP3 activation. Notably, the multifaceted mechanisms underlying the licensing of NLRP3 inflammasome activation constitute a focal point of intense research. Extensive research has revealed the interactions of NLRP3 and its inflammasome components with partner molecules in terms of positive and negative regulation. In this Review, we provide the current understanding of the complex molecular networks that play pivotal roles in regulating NLRP3 inflammasome priming, licensing and assembly. In addition, we highlight the intricate and interconnected mechanisms involved in the activation of the NLRP3 inflammasome and the associated regulatory pathways. Furthermore, we discuss recent advances in the development of therapeutic strategies targeting the NLRP3 inflammasome to identify potential therapeutics for NLRP3-associated inflammatory diseases. As research continues to uncover the intricacies of the molecular networks governing NLRP3 activation, novel approaches for therapeutic interventions against NLRP3-related pathologies are emerging.

Lipopolysaccharide (LPS, endotoxin) -mediated signaling of caspase-4 (human) and -11 (rodent) can induce the maturation of inflammatory cytokine IL-1β and cell pyroptosis, which is associated with the pathophysiology of many diseases such as obesity. However, the process by which LPS induces inflammation through caspase 4/11 is not fully understood. We found here that lncRNA29RIK plays a key role in LPS-mediated maturation of inflammatory cytokine IL-1β and pyroptosis of macrophages. Mechanistic ally, the binding of caspase 4/11 to LPS requires lncRNARIK to cause activation of the caspase 4/11 complex, which ultimately caused inflammation to promote sensitivity to high fat diet (HFD) -mediated obesity. Notably, lncRNA29RIK expression can be up-regulated by LPS. This lncRNA29 is highly conserved between humans and mice. Taken together, these results suggest that lncRNA29RIK determines the occurrence and progression of LPS-related diseases such as obesity.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck. More and more evidence emphasizes the importance of inflammation in the progression of OSCC. The main signaling pathway of acute and chronic inflammation consists of the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome.

This review focuses on the role of NLRP3 immune kinase body and giving a contribution to the development of new treatment strategies against OSCC.

The NLRP3 inflammasome plays a vital role in the pathogenesis and development of OSCC and may serve as a promising therapeutic target for autoimmune diseases.

The NOD-like receptor family, particularly the protein 3 that contains the pyrin domain (NLRP3), is an intracellular sensing protein complex responsible for detecting patterns associated with pathogens and injuries. NLRP3 plays a crucial role in the innate immune response. Currently, a wide range of research has indicated the crucial importance of NLRP3 in various inflammatory conditions. Similarly, the NLRP3 inflammasome plays a significant role in preserving intestinal balance and impacting the advancement of diseases. In addition, several randomized trials have demonstrated the safety and efficacy of targeting NLRP3 in the treatment of colitis, colorectal cancer, and related diseases. This review explores the mechanisms of NLRP3 assembly and activation in the gut. We describe its pathological significance in intestinal diseases. Finally, we summarize current and future therapeutic approaches targeting NLRP3 for intestinal diseases.

To identify biomarkers for diagnosis and classification of interstitial cystitis/bladder pain syndrome (IC/BPS) by urinary lipidomics coupled with machine learning.

Urine samples from 138 patients with IC/BPS, including 116 with Hunner lesion (HL) and 22 with no HL, and 71 controls were assessed by lipid chromatography-tandem mass spectrometry. Single and paired lipid analyses of differentially expressed lipids in each group were conducted to assess their diagnostic ability. Machine learning models were constructed based on the identified urinary lipids and patient demographic data, and a five-fold cross-validation method was applied for internal validation. Levels of urinary lipids were adjusted to account for urinary creatinine levels.

A total of 218 urinary lipids were identified. Single lipid analysis revealed that urinary levels of C24 ceramide and LPC (14:0) distinguished HL and no HL, with an area under the receiver operating characteristics curve of 0.792 and 0.656, respectively. Paired lipid analysis revealed that summed urinary levels of C24 ceramide and LPI (18:3), and subtraction of PG (36:5) from PC (38:2) distinguished HL and no HL even more accurately, with an area under the curve of 0.805 and 0.752, respectively. A machine learning model distinguished HL and no HL, with the highest area under the curve being 0.873 and 0.750, respectively. Limitations include the opaque black box nature of machine learning techniques.

Urinary levels of C24 ceramide, along with those of C24 ceramide plus LPI (18:3), could be potential biomarkers for HL. Machine learning-coupled urinary lipidomics may play an important role in the next-generation AI- driven diagnostic systems for IC/BPS.

Atherosclerosis (AS) is a chronic inflammatory condition associated with lipid deposition. The interaction between abnormal lipid metabolism and the inflammatory response has been identified as the underlying cause of AS. Lipid metabolism disorders are considered the basis of atherosclerotic lesion formation and macrophages are involved in the entire process of AS formation. Macrophages have a high degree of plasticity, and the change of their polarization direction can determine the progress or regression of AS. The disturbances in bioactive lipid metabolism affect the polarization of different phenotypes of macrophages, thus, affecting lipid metabolism and the expression of key signal factors. Therefore, understanding the interaction between lipid metabolism and macrophages as well as their key targets is important for preventing and treating AS and developing new drugs. Recent studies have shown that traditional Chinese medicines play a positive role in the prevention and treatment of AS, providing a basis for clinical individualized treatment.

Psoriasis and type 1 diabetes mellitus (T1DM) are chronic autoimmune diseases sharing common immunological pathways, particularly the involvement of interleukin 17 (IL-17), driving Th17-mediated inflammation. This review explores the overlap between psoriasis, obesity, T1DM, and necrobiosis lipoidica (NL), a skin condition associated with diabetes. Obesity exacerbates inflammation through immune cell activation in adipose tissue and the release of proinflammatory adipokines, such as leptin, resistin, and IL-18, which enhance autoimmune responses and insulin resistance. Leptin promotes the differentiation of Th1 and Th17 cells, which are central to autoimmune responses in both psoriasis and T1DM. The coexistence of psoriasis, T1DM, and insulin resistance further complicates metabolic control, increasing the risk of complications like diabetic nephropathy and cardiovascular disease. Biologic treatments targeting IL-17A and IL-17F offer promising therapeutic options for managing both skin and metabolic symptoms. The early identification and management of metabolic risk factors, along with personalized interventions, are essential to improve clinical outcomes in patients with psoriasis and T1DM, particularly in obese individuals. This case report and review highlight the complex interplay of these conditions and emphasize the need for integrated treatment strategies.

Adipose tissue maintains energy homeostasis by storing lipids during nutrient surplus and releasing them through lipolysis in times of energy demand. While lipolysis is essential for short term metabolic adaptation, prolonged metabolic stress requires adaptive changes that preserve energy reserves. Here, we report that β-adrenergic activation of adipocytes induces a transient and depot-specific infiltration of neutrophils into white adipose tissue (WAT), particularly in lipid-rich visceral WAT. Neutrophil recruitment requires the stimulation of both lipolysis and p38 MAPK activation in adipocytes. Recruited neutrophils locally secrete IL-1β, which suppresses lipolysis and limits excessive energy expenditure. Neutrophil depletion or blockade of IL-1β production increased lipolysis, leading to reduced WAT mass upon repeated β3-adrenergic stimulation. Together, these findings reveal an unexpected role of neutrophil-derived IL-1β in preserving lipid stores during metabolic stress, highlighting a physiological function of innate immune cells in maintaining energy homeostasis.

The innate immune system plays a crucial role in defending against Salmonella infection. Inflammasomes are macromolecular complexes that assemble in response to the recognition of pathogen- or danger-associated molecular patterns. These complexes serve as signaling platforms for the activation of inflammatory Caspases, which subsequently triggers the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. This process also initiates pyroptosis, a highly inflammatory form of programmed cell death characterized by lytic cell lysis. Salmonella are intracellular pathogens that proliferate within epithelial cells and macrophages, posing a significant public health risk in both developed and developing countries. During Salmonella infection, the canonical NLRP3 and NLRC4 inflammasome, as well as non-canonical inflammasome, are activated. Unlike NLRC4 and non-canonical inflammasomes, which play crucial roles during intestinal infection phases, the role of NLRP3 inflammasome in resisting Salmonella infection demonstrates a higher degree of complexity and uncertainty. Nonetheless, the activation of NLRP3 inflammasome, along with the downstream innate and adaptive responses, form a robust host immune barrier against potential pathogens. Therefore, successful pathogens must evolve multiple mechanisms to circumvent or counteract these immune barriers. Here we review and discuss the mechanisms of NLRP3 inflammasome activation triggered by intracellular Salmonella, as well as the multiple strategies employed by Salmonella to avoid or delay NLRP3 inflammasome activation. A deeper understanding of how NLRP3 inflammasomes recognize Salmonella and how pathogens evade NLRP3 activation has the potential to facilitate the development of novel prevention and control measures for Salmonella infection.

Chronic inflammation in type 2 diabetes (T2D), characterized by constitutively activated immune cells and elevated pro-inflammatory mediators along with hyperglycaemia and increased free fatty acids and branched chain amino acid levels, significantly alters the immuno-metabolic axis. Over the years, dietary intervention has been explored as an effective strategy for managing T2D. Evidence from experimental and clinical studies indicates that various diets, including Mediterranean, Nordic, Palaeolithic and ketogenic diets, increase insulin sensitivity, decrease gluconeogenesis, and adiposity, and exert anti-inflammatory effects, thus preserving immuno-metabolic homeostasis in individuals with T2D. Indian dietary sources are categorized as Sattvic, Rajasic, and Tamasic, depending on their impact on health and behaviour. The Yogic diet, commonly recommended during yoga practice, is predominantly Sattvic, emphasizing plant-based whole foods while limiting processed and high-glycaemic-index items. Yogic diet is also recommended for Mitahara, emphasizing mindful eating, which is attributed to calorie restriction. Adopting a Yogic diet, featuring low-fat vegetarian principles, strongly reduces inflammatory mediator levels. This diet not only ameliorates insulin resistance and maintains a healthy body weight but also regulates immunomodulation, enhances gut microbiome diversity and provides essential phytonutrients, collectively preventing inflammation. Although, preliminary studies show aforementioned beneficial role of Yogic diet in improving diabetes associated metabolic and inflammatory changes, precise cellular and molecular mechanisms are not yet understood. Hence, further studies are warranted to decipher the mechanisms. This review summarizes the multiple roles of Yogic diet and related dietary components in mitigating inflammation and enhancing glycaemic control in T2D.

Chronic diseases affecting the cardiovascular system, diabetes mellitus, neurodegenerative diseases, and various other organ-specific conditions, involve different underlying pathological processes. However, they share common risk factors that contribute to the development and progression of these diseases, including air pollution, hypertension, obesity, high cholesterol levels, smoking and alcoholism. In this review, we aim to explore the connection between four types of diseases with different etiologies and various risk factors. We highlight that the presence of risk factors induces regulated necrotic cell death, leading to the release of damage-associated molecular patterns (DAMPs), ultimately resulting in sterile inflammation. Therefore, DAMP-mediated inflammation may be the link explaining how risk factors can lead to the development and maintenance of chronic diseases. To explore these processes, we summarize the main cell death pathways activated by the most common life-threatening risk factors, the types of released DAMPs and how these events are associated with the pathophysiology of diseases with the highest mortality. Various risk factors, such as smoking, air pollution, alcoholism, hypertension, obesity, and high cholesterol levels induce regulated necrosis. Subsequently, the release of DAMPs leads to chronic inflammation, which increases the risk of many diseases, including those with the highest mortality rates.

Multiple sclerosis (MS) is widely acknowledged as a chronic inflammatory autoimmune disorder characterized by central nervous system (CNS) demyelination and neurodegeneration. The hyperactivation of immune and inflammatory responses is recognized as a pivotal factor contributing to the pathogenesis and progression of MS. Among various immune and inflammatory reactions, researchers have increasingly focused on the inflammasome, a complex of proteins. The initiation and activation of the inflammasome are intricately involved in the onset of MS. Notably, the NLRP3 inflammasome, the most extensively studied member of the inflammasome complex, is closely linked with MS. This review will delve into the roles of the NLRP3 inflammasome in the pathogenesis and progression of MS. Additionally, therapeutic strategies targeting the NLRP3 inflammasome for the treatment of MS, including natural compounds, autophagy regulators, and other small molecular compounds, will be detailed in this review.

Pyroptosis, a distinctive form of programmed cell death orchestrated by gasdermin proteins, manifests as cellular rupture, accompanied by the release of inflammatory factors. While pyroptosis is integral to anti-infection immunity, its aberrant activation has been implicated in tumorigenesis. The liver, as the body's largest metabolic organ, is rich in various enzymes and governs metabolism. It is also the primary site for protein synthesis. Recent years have witnessed the emergence of pyroptosis as a significant player in the pathogenesis of specific liver diseases, exerting a pivotal role in both physiological and pathological processes. A comprehensive exploration of pyroptosis can unveil its contributions to the development and regression of conditions such as hepatitis, cirrhosis, and hepatocellular carcinoma, offering innovative perspectives for clinical prevention and treatment. This review consolidates current knowledge on key molecules involved in cellular pyroptosis and delineates their roles in liver diseases. Furthermore, we discuss the potential of leveraging pyroptosis as a novel or existing anti-cancer strategy.

Obesity is a worldwide health problem with a rapidly rising incidence. In organ transplantation, increasing numbers of patients with obesity accumulate on waiting lists and undergo surgery. Obesity is in general conceptualized as a chronic inflammatory disease, potentially impacting alloimmune response and graft function. Here, we summarize our current understanding of cellular and molecular mechanisms that control obesity-associated adipose tissue inflammation and provide insights into mechanisms affecting transplant outcomes, emphasizing on the beneficial effects of weight loss on alloimmune responses.

The pathogenesis of acute lung injury (ALI) is characterized by an uncontrolled inflammatory response, marked by excessive production of reactive oxygen species (ROS) and the infiltration of inflammatory cells, particularly macrophages, which play a pivotal role in disease progression. The synergistic effect of ROS scavenging and macrophage repolarization provides a promising strategy for effective ALI treatment. Herein, we developed a novel type of self-assembling nanomicelles, which were composed of poly-L-glutamic acid (PLG) and 4-Hydroxymethyl phenylboronic acid (PBA). The nanomicelles (PPDex micelles) had a high drug-loading capacity for dexamethasone (Dex) based on boronic ester bonds, which exhibited reversible cleavage under inflammatory conditions characterized by elevated levels of ROS or decreased pH values. These PPDex micelles revealed rapid drug-responsive release behavior in the inflammatory environment, and in vivo studies demonstrated their efficacy in modulating cytokines, inhibiting oxidative stress, and promoting macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, which ultimately suppressed the progression of ALI. Moreover, the PPDex micelles had the effective ability to effectively suppress the NF-кB and ROS/NLRP3 inflammatory pathways. Therefore, this study presented a novel and potent therapeutic strategy for ALI treatment, which could promote the clinical application of polymer nanomicelles in the treatment of ALI.

Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 42, 566-622.

Exposure to ambient Ozone (O3) air pollution directly causes by its oxidative properties, respiratory epithelial cell injury, and cell death, which promote inflammation and hyperreactivity, posing a significant public health concern. Recent clinical and experimental studies have made strides in elucidating the mechanisms underlying O3-induced epithelial cell injury, inflammation, and airway hyperreactivity, which are discussed herein. The current data suggest that O3-induced oxidative stress is a central event-inducing oxeiptotic cell death pathway. O3-induced epithelial barrier damage and cell death, triggering the release of alarmins and damage-associated molecular patterns (DAMPs), with subsequent endogenous activation of Toll-like receptors (TLRs), DNA sensing pathways, and inflammasomes, activating interleukin-1-Myd88 inflammatory pathway with the production of a range of chemokines and cytokines. This cascade orchestrates lung tissue-resident cell activation in response to O3 in leukocyte and non-leukocyte populations, driving sterile innate immune response. Chronic inflammatory response to O3, by repeated exposures, supports a mixed phenotype combining asthma and emphysema, in which their exacerbation by other particulate pollutants potentially culminates in respiratory failure. We use data from lung single-cell transcriptomics to map genes of O3-damage sensing and signaling pathways to lung cells and thereby highlight potential hotspots of O3 responses. Deeper insights into these pathological pathways might be helpful for the identification of novel therapeutic targets and strategies.

Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The underlying mechanisms contributing to these pathological changes remain poorly understood. We propose that chronic inflammation-mediated networks and metabolic defects that exacerbate muscle dysfunction are critical factors in sarcopenia and related diseases. Consequently, utilizing specialized pro-resolving mediators (SPMs) that function through specific G-protein coupled receptors (GPCRs) may offer effective therapeutic options for these disorders. However, challenges such as a limited understanding of SPM/receptor signaling pathways, rapid inactivation of SPMs, and the complexities of SPM synthesis impede their practical application. In this context, stable small-molecule SPM mimetics and receptor agonists present promising alternatives. Moreover, the aged adipose-skeletal axis may contribute to this process. Activating non-SPM GPCRs on adipocytes, immune cells, and muscle cells under conditions of systemic, chronic, low-grade inflammation (SCLGI) could help alleviate inflammation and metabolic dysfunction. Recent preclinical studies indicate that both SPM GPCRs and non-SPM GPCRs can mitigate symptoms of aging-related diseases such as obesity and diabetes, which are driven by chronic inflammation and metabolic disturbances. These findings suggest that targeting these receptors could provide a novel strategy for addressing various chronic inflammatory conditions, including sarcopenia.

Panton-Valentine leukocidin (PVL) is a pore-forming toxin secreted by Staphylococcus aureus strains that cause severe infections. Bicomponent PVL kills phagocytes depending on cell surface receptors, such as complement 5a receptor 1 (C5aR1). How the PVL-receptor interaction enables assembly of the leukocidin complex, targeting of membranes, and insertion of a pore channel remains incompletely understood. Here, we demonstrate that PVL binds the anionic phospholipids, phosphatidic acid, and cardiolipin, under acidic conditions and targets lipid bilayers that mimic lysosomal and mitochondrial membranes, but not the plasma membrane. The PVL-lipid interaction was sufficient to enable leukocidin complex formation as determined by neutron reflectometry and the rupture of model membranes, independent of protein receptors. In phagocytes, PVL and its C5aR1 receptor were internalized depending on sphingomyelin and cholesterol, which were dispensable for the interaction of the toxin with the plasma membrane. Internalized PVL compromised the integrity of lysosomes and mitochondria before plasma membrane rupture. Preventing the acidification of organelles or the genetic loss of PVL impaired the escape of intracellular S. aureus from macrophages. Together, the findings advance our understanding of how an S. aureus toxin kills host cells and provide key insights into how leukocidins target membranes.

Cardiac lipotoxicity, characterized by excessive lipid accumulation in the cardiac tissue, is a critical contributor to the pathogenesis of diabetic heart. Recent research has highlighted the key mechanisms underlying lipotoxicity, including mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and cell apoptosis, which ultimately impair the cardiac function. Various therapeutic interventions have been developed to target these pathways, mitigate lipotoxicity, and improve cardiovascular outcomes in diabetic patients. Given the global escalation in the prevalence of diabetes and the urgent demand for effective therapeutic approaches, this review focuses on how targeting cardiac lipotoxicity may be a promising avenue for treating diabetes.

We aimed to identify the association between obesity and nonalcoholic fatty liver disease (NAFLD) and to quantify the mediating effects of insulin resistance (IR) and chronic inflammation through observational studies and Mendelian randomization (MR).

In the current study, three IR-related indicators and three indicators of inflammation were included. The individual and combined mediated effects of IR and inflammation in the association between obesity and NAFLD were investigated in two cross-sectional studies, the Fuqing Cohort from China and the National Health and Nutrition Examination Survey (NHANES). Total, direct, and indirect effects were estimated through direct counterfactual imputation estimation, and the proportion of mediating effects was calculated. We applied a two-step MR to determine the causal mediating role of IR and chronic inflammation in the pathway between obesity and NAFLD by using single nucleotide polymorphisms as instrumental variables to predict obesity, IR, and inflammation genetically.

In the Fuqing Cohort, all obese phenotypes were associated with an elevated NAFLD risk. Moreover, indicators of IR such as homeostatic model assessment of insulin resistance (HOMA-IR) and indicators of inflammation such as C-reactive protein (CRP) were significantly and positively associated with NAFLD risk. Individuals with obesity had significantly higher levels of IR and inflammation indicators compared to non-obese individuals. The indirect proportions of insulin and HOMA-IR accounted for 50.97-66.72% in the associations between obese phenotypes and NAFLD risk, while the proportions of inflammation indicators were < 14%. Similar results were observed in the NHANES analysis. In the MR analysis, the indirect effects of HOMA-IR and CRP were statistically significant with a greater mediated proportion explained by HOMA-IR than CRP.

Through two population-based studies and MR, we found the causal mediation roles of IR and inflammation in the association between obesity and NAFLD, in which HOMA-IR and CRP showed stable, significant mediation effects. Furthermore, HOMA-IR showed a higher mediation effect than CRP. We emphasize the vital role of HOMA-IR in NAFLD monitoring.

The discovery of DFV890 ((R)-1), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The (R)-enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((R)-1), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((R)-1) was also effective in an air pouch model of gout.

Obesity and obesity-related metabolic diseases are causally linked to inflammatory activation. Proinflammatory macrophage infiltration and NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation contribute to chronic inflammation and insulin resistance. Alleviating inflammatory responses is a reliable method to restore insulin sensitivity and reduce the severity of metabolic syndrome. Solanesol, rich in anti-inflammatory foods (potato, tomato, eggplant, chili peppers), has demonstrated anti-inflammatory properties, but whether it plays a beneficial role in obesity-induced chronic inflammation remains poorly understood. In this study, we investigated the effects of solanesol on the NLRP3 inflammasome and inflammatory responses both in vitro and in high-fat diet (HFD)-fed mice. We found that oral administration of solanesol reduced weight gain, insulin resistance, and inflammation in epididymal white adipose tissue (eWAT) in both HFD-fed obese mice and mice concurrently treated with a HFD. This effect was involved with reducing macrophage inflammation and inactivating the NLRP3 inflammasome by reducing the K+ efflux and reactive oxygen species (ROS) production in macrophages. Solanesol also reprogrammed the phenotype of inflammatory macrophages. Taken together, our study suggests that solanesol may be a promising candidate for treating obesity and obesity-related metabolic diseases.

Activation of inflammasomes is the activation of inflammation‑related caspase mediated by the assembly signal of multi‑protein complex and the maturity of inflammatory factors, such as IL‑1β and IL‑18. Among them, the Nod‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied type of inflammatory corpuscle at present, which is involved in the occurrence and development of numerous human diseases. Therefore, targeting the NLRP3 inflammasome has become the focus of drug development for related diseases. In this paper, the research progress of the NLRP3 inflammasome in recent years is summarized, including the activation and regulation of NLRP3 and its association with diseases. A deep understanding of the regulatory mechanism of NLRP3 will be helpful to the discovery of new drug targets and the development of therapeutic drugs.

Sirtuins (SIRTs) are NAD+-dependent deacetylases that mediate post-translational modifications of proteins. Seven members of the SIRT family have been identified in mammals. Importantly, SIRTs interact with numerous metabolic and inflammatory pathways. Thus, researchers have investigated their role in metabolic and inflammatory disorders.

In this review, we comprehensively discuss the involvement of SIRTs in the processes of pancreatic β-cell dysfunction, glucose tolerance, insulin secretion, lipid metabolism, and adipocyte functions. In addition, we describe the current evidence regarding modulation of the expression and activity of SIRTs in diabetes, diabetic complications, and obesity.

The development of specific SIRT activators and inhibitors that exhibit high selectivity toward specific SIRT isoforms remains a major challenge. This involves the need to elucidate the physiological pathways involving SIRTs, as well as their important role in the development of metabolic disorders. Molecular modeling techniques will be helpful to develop new compounds that modulate the activity of SIRTs, which may contribute to the preparation of new drugs that selectively target specific SIRTs. SIRTs hold promise as potential targets in metabolic disease, but there is much to learn about specific modulators and the final answers will await clinical trials.

Epigallocatechin-3-gallate (EGCG), the primary polyphenol in green tea, is renowned for its potent antioxidant properties. EGCG interacts with various cellular targets, inhibiting cancer cell proliferation through apoptosis and cell cycle arrest induction, while also modulating metabolic pathways. Studies have demonstrated its potential in addressing cancer development, obesity, and diabetes. Given the rising prevalence of metabolic diseases and cancers, EGCG is increasingly recognized as a promising therapeutic agent. This review provides a comprehensive overview of the latest findings on the effects of both free and nano-encapsulated EGCG on mechanisms involved in the management and prevention of hyperlipidemia, diabetes, and gastrointestinal (GI) cancers. The review highlights EGCG role in modulating key signaling pathways, enhancing bioavailability through nano-formulations, and its potential applications in clinical settings.