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.

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.

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.

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.

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.

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.

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.

The correlation between chronic obstructive pulmonary disease (COPD) and Type 2 diabetes mellitus (T2DM) has long been recognized, but their shared molecular underpinnings remain elusive. This study aims to uncover common genetic markers and pathways in COPD and T2DM, providing insights into their molecular crosstalk.

Utilizing the Gene Expression Omnibus (GEO) database, we analyzed gene expression datasets from six COPD and five T2DM studies. A multifaceted bioinformatics approach, encompassing the limma R package, unified matrix analysis, and weighted gene co-expression network analysis (WGCNA), was deployed to identify differentially expressed genes (DEGs) and hub genes. Functional enrichment and protein-protein interaction (PPI) analyses were conducted, followed by cross-species validation in Mus musculus models. Machine learning techniques, including random forest and LASSO regression, were applied for further validation, culminating in the development of a prognostic model using XGBoost.

Our analysis revealed shared DEGs such as KIF1C, CSTA, GMNN, and PHGDH in both COPD and T2DM. Cross-species comparison identified common genes including PON1 and CD14, exhibiting varying expression patterns. The random forest and LASSO regression identified six critical genes, with our XGBoost model demonstrating significant predictive accuracy (AUC = 0.996 for COPD).

This study identifies key genetic markers shared between COPD and T2DM, providing new insights into their molecular pathways. Our XGBoost model exhibited high predictive accuracy for COPD, highlighting the potential utility of these markers. These findings offer promising biomarkers for early detection and enhance our understanding of the diseases' interplay. Further validation in larger cohorts is recommended.

Cardiomyopathies are a heterogeneous group of disorders that can lead to fulminant heart failure and sudden cardiac death. In recent years, the prevalence of all types of cardiomyopathies has shown an upward trend globally. Up to 40% of patients with cardiomyopathy-related heart failure have diabetes mellitus (DM). With the fast global spread of DM, the prevalence of DCM is increasing accordingly and it remains the leading cause of morbidity and mortality in chronic diabetic patients. NLRP3 inflammasome significantly contributes to the development and pathological progression of DCM. Targeting the inflammasome or any of the mediators along its activation pathway provides new potential therapeutic targets for developing specialized drugs to treat DCM.In this comprehensive review, we sought to introduce and summarize the non-coding RNAs with potential therapeutic effects targeting NLRP3 inflammasome signaling in DCM. We hope this general overview can aid future research in developing new therapies for DCM.

Overweight patients with cardiovascular disease (CVD) tend to survive longer than normal-weight patients, a phenomenon known as the "obesity paradox". The phenotypic characteristics of adipose distribution in these patients (who survive longer) often reveal a larger proportion of subcutaneous white adipose tissue (scWAT), suggesting that the presence of scWAT is negatively associated with all-cause mortality and that scWAT appears to provide protective benefits in patients facing unhealthy states. Exercise-mediated browning is a crucial aspect of the benign remodeling process of adipose tissue (AT). Reduced accumulation, reduced inflammation, and associated adipokine secretion are directly related to the reduction in CVD mortality. This paper summarized the pathogenetic factors associated with AT accumulation in patients with CVD and analyzed the possible role and pathway of exercise-mediated adipose browning in reducing the risk of CVD and CVD-related mortality. It is suggested that exercise-mediated browning may provide a new perspective on the "obesity paradox"; that is, overweight CVD patients who have more scWAT may gain greater cardiovascular health benefits through exercise.

Using a data-driven approach, six clusters with different risk profiles and burden of complications were recently identified in middle-aged people before the diagnosis of type 2 diabetes (T2D). We aimed to investigate whether these clusters could be generalised to older people and if subclinical inflammation was related to their cardiometabolic risk profiles.

We assigned 843 participants of the KORA F4 study aged 61-82 years without T2D to the six previously defined phenotype-based clusters. Based on 73 biomarkers of subclinical inflammation, we derived an inflammation-related score ("inflammatory load") using principal component analysis to assess subclinical inflammation. Risk factors, inflammatory load as well as prevalence and incidence of (pre)diabetes-related complications were compared between the clusters using pairwise comparisons and regression analyses.

Clusters 1 and 2 had the lowest cardiometabolic risk, whereas clusters 5 and 6 the highest. T2D risk was highest in clusters 3, 4, 5, and 6 compared with the low-risk cluster 2 (age- and sex-adjusted ORs between 3.6 and 34.0). In cross-sectional analyses, there were significant between-cluster differences in chronic kidney disease (CKD), distal sensorimotor polyneuropathy (DSPN) and cardiovascular disease (all p < 0.045). In prospective analyses (mean follow-up time 6.5-8.3 years), clusters differed significantly in CKD and DSPN incidence, but not in incident CVD or all-cause mortality. The inflammatory load was highest in the high-risk cluster 5 and lowest in cluster 2. Adjustment for the inflammatory load had only a minor impact on the aforementioned differences in outcomes between clusters.

Our findings extend the knowledge about the previously identified six phenotype-based clusters in older people without T2D. Differences between clusters were more pronounced for T2D risk than for prevalent or incident (pre)diabetes-related complications and absent for mortality. The high cardiometabolic risk corresponded to the high inflammatory load in cluster 5 but not to the lower inflammatory load of high-risk clusters 3 and 6.

It is generally believed that refined grains lack nutritional value compared to whole grains. The objective of this study was to investigate whether refined highland barley (RHB) holds the potential to combat obesity-associated insulin resistance.

Thirty-two male 6-week-old C57BL/6J mice were randomly divided into four groups fed with a normal chow diet, a high-fat diet (HFD), a 30% RHB supplemented HFD diet, and a 30% whole-grain highland barley (WGHB) supplemented HFD diet. We examined the anti-obesity and anti-insulin resistance effects of RHB and compared them with WGHB in mice.

RHB intervention effectively improved obesity and insulin resistance, enhanced the intestinal mucosal barrier, and reduced inflammation. Moreover, it promoted the abundance of beneficial gut bacteria such as Akkermansia, Bifidobacterium, Lachnospiraceae_NK4A136_group, Lachnospiraceae_UCG-001, Alloprevotella, and increased the production of short-chain fatty acids (SCFAs) in faeces. Additionally, RHB intervention modulated liver gene transcription, downregulating inflammatory genes like IRF3/7, STAT1/2, NLRP3, and TLR2.

RHB could effectively alleviate obesity-related insulin resistance by targeting gut microbiota and liver transcriptomics, and its beneficial impacts are comparable to those of WGHB.

The nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a critical modulator in inflammatory disease. Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome, Muckle-Wells syndrome, and familial cold autoinflammatory syndrome 1. To date, a great effort has been made to decode the underlying mechanisms of NLRP3 activation. The priming and activation of NLRP3 drive the maturation and release of active interleukin (IL)-18 and IL-1β to cause inflammation and pyroptosis, which can significantly trigger many diseases including inflammatory diseases, immune disorders, metabolic diseases, and neurodegenerative diseases. The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials. Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields. In this minireview, we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways. We then reviewed the molecular and cellular pathways of NLRP3 in many diseases, including obesity, diabetes, and other metabolic diseases. In addition, we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy. Finally, clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.

Obesity has been identified as an independent risk factor for severe COVID-19 unfavorable outcomes. Several factors, such as increased ACE2 receptor expression and chronic inflammation, can contribute to this relationship, yet the activation of the NLRP3 inflammasome pathway is also a key element. Our primary goal was to determine whether chronic NLRP3 inflammasome activation in people with obesity is different in critical COVID-19 and in critical chronic conditions. A retrospective analysis was conducted using clinical data and post-mortem lung tissue samples from 14 COVID-19 patients with obesity (group A) and 9 patients with obesity who died from non-COVID-19 causes (group B). Immunohistochemical analysis assessed twelve markers related to the NLRP3 inflammasome pathway. Group A showed a significantly higher expression of ASC (p = 0.0387) and CASP-1 (p = 0.0142). No significant differences were found for IL-8, TNF-α, NF-kB, NLRP3, IL-1β, and gasdermin-D. Group B had higher levels of IL-6 (p < 0.0001), IL-18 (p = 0.002), CASP-9 (p < 0.0001), and HIF (p = 0.0327). We concluded that COVID-19 activates the NLRP3 inflammasome pathway, possibly leading to pyroptotic cell death mediated by caspase-1. In contrast, people with obesity without COVID-19, despite exhibiting some markers of the NLRP3 inflammasome, are more likely to experience necroptosis mediated by caspase-9.

Diabetes mellitus (DM) and its various complications, including diabetic nephropathy, retinopathy, neuropathy, cardiovascular disease, and ulcers, pose significant challenges to global health. This review investigates the potential of procyanidins (PCs), a natural polyphenolic compound, in preventing and managing diabetes and its complications. PCs, recognized for their strong antioxidant, anti-inflammatory, and anti-hyperglycemic properties, play a crucial role in reducing oxidative stress and enhancing endothelial function, which are essential for managing diabetic complications. This review elucidates the molecular mechanisms by which PCs improve insulin sensitivity and endothelial health, thereby providing protection against the various complications of diabetes. The comprehensive analysis underscores the promising therapeutic role of PCs in diabetes care, indicating the need for further clinical studies to confirm and leverage their potential in comprehensive diabetes management strategies.

Background: Recent studies have shown that Nlrp3 inflammasome activation is importantly involved in podocyte dysfunction induced by nicotine. The present study was designed to test whether acid sphingomyelinase (Asm) and ceramide signaling play a role in mediating nicotine-induced Nlrp3 inflammasome activation and subsequent podocyte damage. Methods and Results: Nicotine treatment significantly increased the Asm expression and ceramide production compared to control cells. However, prior treatment with amitriptyline, an Asm inhibitor significantly attenuated the nicotine-induced Asm expression and ceramide production. Confocal microscopic and biochemical analyses showed that nicotine treatment increased the colocalization of NLRP3 with Asc, Nlrp3 vs. caspase-1, IL-1β production, caspase-1 activity, and desmin expression in podocytes compared to control cells. Pretreatment with amitriptyline abolished the nicotine-induced colocalization of NLRP3 with Asc, Nlrp3 with caspase-1, IL-1β production, caspase-1 activity and desmin expression. Immunofluorescence analyses showed that nicotine treatment significantly decreased the podocin expression compared to control cells. However, prior treatment with amitriptyline attenuated the nicotine-induced podocin reduction. In addition, nicotine treatment significantly increased the cell permeability, O2 production, and apoptosis compared to control cells. However, prior treatment with amitriptyline significantly attenuated the nicotine-induced cell permeability, O2 production and apoptosis in podocytes. Conclusions: Asm is one of the important mediators of nicotine-induced inflammasome activation and podocyte injury. Asm may be a therapeutic target for the treatment or prevention of glomerulosclerosis associated with smoking.

The complement system plays a crucial role in various pathophysiological conditions, including snake envenomation. In this study, we investigated the effects of Bitis arietans venom on the complement system using an ex vivo human whole blood model. Our findings demonstrate that B. arietans venom was able to activate the complement system, leading to a significant increase in the production of anaphylatoxins (C3a/C3a-desArg, C5a/C5a-desArg) and the soluble Terminal Complement Complex (sTCC). Inhibition of the C3 component by Cp40, a C3-C3b inhibitor, resulted in the reduction of C3a/C3a-desArg, C5a/C5a-desArg, and sTCC levels to baseline in venom-stimulated samples. Furthermore, treatment with Cp40 promoted a substantial decrease in the production of pro-inflammatory mediators, such as Prostaglandin E2 (PGE2), IL-8/CXCL8, MCP-1/CCL2, and MIG/CXCL9. To further elucidate the molecular mechanisms, we utilized the THP-1 cell line differentiated into M0 macrophages. Incubation of these macrophages with human plasma, from the human whole blood treated with B. arietans venom, resulted in the expression of the NLRP3 inflammasome and the production of IL-8 and IL-1β. Importantly, Cp40 was able to diminish the production of these cytokines, as well as the levels of ASC and caspase-1 proteins. In conclusion, our results indicate that the inhibition of the complement by Cp40 at C3/C3b level can modulate the inflammatory response and inflammasome activation induced by B. arietans venom. These findings suggest that complement inhibition may be a promising therapeutic approach for managing the inflammatory complications associated with this snake envenomation.

In this review, we summarize the molecular effects of time-restricted eating (TRE) and its possible role in appetite regulation. We also discuss the potential clinical benefits of TRE in obesity.

TRE is an emerging dietary approach consisting in limiting food intake to a specific window of time each day. The rationale behind this strategy is to restore the circadian misalignment, commonly seen in obesity. Preclinical studies have shown that restricting food intake only during the active phase of the day can positively influence several cellular functions including senescence, mitochondrial activity, inflammation, autophagy and nutrients' sensing pathways. Furthermore, TRE may play a role by modulating appetite and satiety hormones, though further research is needed to clarify its exact mechanisms. Clinical trials involving patients with obesity or type 2 diabetes suggest that TRE can be effective for weight loss, but its broader effects on improving other clinical outcomes, such as cardiovascular risk factors, remain less certain. The epidemic proportions of obesity cause urgency to find dietary, pharmacological and surgical interventions that can be effective in the medium and long term. According to its molecular effects, TRE can be an interesting alternative to caloric restriction in the treatment of obesity, but the considerable variability across clinical trials regarding population, intervention, and follow-up duration makes it difficult to reach definitive conclusions.

In recent years, increasing evidence has supported that high-fat diet (HFD) can induce the chronic, low-grade neuroinflammation in the brain, which is closely associated with the impairment of cognitive function. As the key organelles responsible for energy metabolism in the cell, mitochondria are believed to involved in the pathogenesis of a variety of neurological disorders. This review summarizes the current progress in the field of the relationship between HFD exposure and neurodegenerative diseases, and outline the major routines of HFD induced neuroinflammation and its pathological significance in the pathogenesis of neurodegenerative diseases. Furthermore, the article highlights the pivotal role of mitochondrial dysfunction in driving the neuroinflammation in the setting of HFD. Danger-associated molecular patterns (DAMPs) from damaged mitochondria can activate innate immune signaling pathways, while mitochondrial dysfunction itself can lead to metabolic remodeling of inflammatory cells, thus inducing neuroinflammation. More importantly, mitochondrial damage, neuroinflammation, and insulin resistance caused by HFD form a mutually reinforcing vicious cycle, ultimately leading to the death of neurons and promoting the progression of neurodegenerative diseases. Thus, in-depth elucidation of the role and underlying mechanisms of mitochondrial dysfunction in HFD-induced metabolic disorders may not only expand our understanding of the mechanistic linkages between HFD and etiology of neurodegenerative diseases, but also help develop the specific strategies for the prevention and treatment of neurodegenerative diseases.

Response to dupilumab for chronic rhinosinusitis with nasal polyps, albeit almost always excellent, is still not predictable. Our study focuses on the role of body mass index (BMI) on the efficacy of dupilumab.

We present a retrospective multicentre study of 106 patients on dupilumab, stratified in 3 subgroups of BMI. The main therapeutic outcomes investigated were Nasal Polyp Score (NPS), Sino-Nasal-Outcome Test - 22 (SNOT-22), Sniffin' Sticks Identification test and visuo-analogical scale, and the different timing of response, according to De Corso et al. criteria.

Dupilumab treatment led to a progressive improvement for all outcomes at all time points. Comparing the different metabolic subgroups, a late response in terms of decrease in NPS was observed only in 3 obese patients. A significant decrease was also found in SNOT-22 score at 6 and 12 months, which was less marked in overweight/obese patients.

Our study confirmed the efficacy of dupilumab in each BMI subgroup. However, the efficacy seems to follow different timing with respect to patients' BMI. Our data suggest that patients with a compromised metabolic state present more severe disease at baseline and a possibly delayed response to dupilumab.

The senescence of smooth muscle is one of the independent risk factors in atherosclerosis progression in which the vascular inflammation plays an important role on vascular dysfunction. This study is designed to explore the novel vascular aging biomarkers and screen the potential molecular interventional targets through bioinformatic analysis.

Transcriptional analysis was conducted based on the GSE16487 open access database, which included 15 human vascular tissue samples from two groups: young group (≤ 60 years old, n = 8) and aged group (≥ 75 years old, n = 7). There were 275 differential expression genes (119 upregulated and 156 downregulated genes) with minimum 1.5-fold change between two groups. 9 genes were mainly participated in inflammation-related signaling pathways, in which narciclasine was validated as the most effective candidate for modulation the ceramide synthesis. In vitro and animal study demonstrated that narciclasine reversed vascular aging by inhibiting skeletal muscle-specific ceramide synthase 1 (CerS1), reducing the ceramide level derived from CerS1, and improving fat deposition and circulating glycolipid metabolism.

Narciclasine attenuates vascular aging and modulates the cross-talk between inflammation and metabolism via inhibiting skeletal muscle-specific ceramide synthase 1.

Myelodysplastic syndromes (MDS) are a genetically complex and phenotypically diverse set of clonal hematologic neoplasms that occur with increasing frequency with age. MDS has long been associated with systemic inflammatory conditions and disordered inflammatory signaling is implicated in MDS pathogenesis. A rise in sterile inflammation occurs with ageing and the term "inflammaging" has been coined by to describe this phenomenon. This distinct form of sterile inflammation has an unknown role in in the pathogenesis of myeloid malignancies despite shared correlations with age and ageing-related diseases. More recent is a discovery that many cases of MDS arise from clonal hematopoiesis of indeterminate potential (CHIP), an age associated, asymptomatic pre-disease state. The interrelationship between ageing, inflammation and clonal CHIP is complex and likely bidirectional with causality between inflammaging and CHIP potentially instrumental to understanding MDS pathogenesis. Here we review the concept of inflammaging and MDS pathogenesis and explore their causal relationship by introducing a novel framing mechanism of "pre-clonal inflammaging" and "clonal inflammaging". We aim to harmonize research on ageing, inflammation and MDS pathogenesis by contextualizing the current understanding of inflammaging and the ageing hematopoietic system with what is known about the etiology of MDS via its progression from CHIP.

Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for cirrhosis and hepatocellular carcinoma, for which there is currently no effective treatment. This study aimed to investigate the regulatory mechanism between endoplasmic reticulum stress (ER stress) and pyroptosis in the liver under the context of MASH.

Pyroptosis was examined in both in vivo and in vitro ER stress models. The expression levels of nucleotide-binding oligomerisation domain-like receptor protein 3 (NLRP3), gasdermin D (GSDMD), caspase-1, IL-1β, and IL-18 tended to increase, and "ASC specks" colocalised with the swollen ER in living cells. However, in the pyroptotic model, increased ER stress was not observed. Moreover, the overexpression of inositol-requiring enzyme 1α (IRE-1α), one of the main ER stress sensors, led to increases in the levels of NLRP3 and GSDMD. However, after IRE-1α was blocked by chemical inhibitors or siRNAs, pyroptosis was also abrogated. These data showed that ER stress regulated pyroptosis through IRE-1α. Furthermore, the immunoprecipitation results clearly indicated that GSDMD efficiently bound to IRE-1α when ER stress was stimulated. In the MASH model, IRE-1α was specifically inhibited by pharmacological or genetic methods, which improved the pathology of MASH by alleviating ER stress and pyroptosis. In patients with MASH, both ER stress markers and pyroptosis markers including IRE-1α, glucose-regulated protein 78, GSDMD/GSDMD-N, p20, and NLRP3, are highly expressed in the liver.

This study revealed that ER stress may regulate pyroptosis through IRE-1α-GSDMD pathway, which accelerates the progression of MASH. These findings may offer new insights for the treatment of MASH.

Innate training of macrophages can be beneficial for the clearance of pathogens. However, for certain chronic conditions, innate training can have detrimental effects due to an excessive production of pro-inflammatory cytokines. Obesity is a condition that is associated with a range of increased pro-inflammatory training stimuli including the free fatty acid palmitate. Mesenchymal stromal cells (MSCs) are powerful immunomodulators and known to suppress inflammatory macrophages via a range of soluble factors. We show that palmitate training of murine bone-marrow-derived macrophages and human monocyte-derived macrophages (MDMs) results in an increased production of TNFα and IL-6 upon stimulation with lipopolysaccharide and is associated with epigenetic remodeling. Palmitate training led to metabolic changes, however, MSCs did not alter the metabolic profile of human MDMs. Using a transwell system, we demonstrated that human bone marrow MSCs block palmitate training in both murine and human macrophages suggesting the involvement of secreted factors. MSC disruption of the training process occurs through more than one pathway. Suppression of palmitate-enhanced TNFα production is associated with cyclooxygenase-2 activity in MSCs, while secretion of interleukin-1 receptor antagonist by MSCs is required to suppress palmitate-enhanced IL-6 production in MDMs.

Chronic inflammatory diseases, e.g., obesity, cardiovascular disease and type-2 diabetes, progressively suppress the anti-inflammatory heat shock response (HSR) by impairing the synthesis of key components, perpetuating inflammation. Monitoring HSR progression offers predictive value for countering chronic inflammation. This study quantified HSR in high-fat diet (HFD) and normal chow (NC) mice by measuring 70 kDa heat shock protein (HSP70) expression after heat treatment of whole blood samples. To align with human translational relevance, animals were housed within their thermoneutral zone (TNZ). Whole blood was heat-challenged weekly at 42 °C for 1-2 hours over 22 weeks, and ΔHSP70 was calculated as the difference between HSP70 expressions at 42 °C and 37 °C. Results correlated with fasting glycaemia, oral glucose tolerance test, intraperitoneal insulin tolerance test and 2-hour post-glucose load glycaemia. ΔHSP70 levels >0.2250 indicated normal fasting glycaemia, while levels <0.2125 signalled insulin resistance and type-2 diabetes onset. A logistic model (five-parameter logistic) showed progressive HSR decline, with HFD mice exhibiting earlier ΔHSP70 reduction (t1/2 = 3.14 weeks) compared with NC mice (t1/2 = 8.24 weeks), highlighting compromised anti-inflammatory capacity in both groups of mice maintained at TNZ. Remarkably, even NC mice surpassed insulin resistance thresholds by week 22, relevant as control diets confronted interventions. Observed HSR decline mirrors tissue-level suppression in obese and type-2 diabetic individuals, underscoring HSR failure as a hallmark of obesity-driven inflammation. This study introduces a practical whole-blood assay to evaluate HSR suppression, allowing assessment of glycaemic status during obesity onset before any clinical manifestation.

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrinopathy in reproductive-aged women, contributing to 75% of infertility cases due to ovulatory dysfunction. The condition poses significant health and psychological challenges, making the study of its pathogenesis and treatment a research priority. This study investigates the effects of Mogroside V (MV) on PCOS, focusing on its anti-inflammatory and anti-insulin resistance properties.

Forty-five female Sprague-Dawley rats were divided into three groups: control, PCOS model, and MV treatment. The PCOS model was induced using a high-fat diet and letrozole. The MV treatment group was subsequently administered MV after the establishment of the PCOS model. The study monitored body mass, assessed estrous cycle changes, and measured serum hormone levels. Transcriptome sequencing and bioinformatics were used to identify differentially expressed genes related to inflammation and insulin resistance. Expression of pyroptosis and insulin resistance markers was analyzed using qRT-PCR, Western blot, and IHC. Additionally, an in vitro model assessed MV's impact on inflammation and insulin resistance.

The PCOS group exhibited elevated serum testosterone (T), luteinizing hormone (LH), insulin, and fasting glucose levels, along with increased insulin resistance (HOMA-IR) and decreased estradiol (E2), which were reversed by MV treatment. Transcriptome analysis identified significant gene expression changes between groups, particularly in pathways related to NLRP3 inflammation and insulin metabolism. MV treatment normalized the expression of ovarian pyroptosis factors (NLRP3, Caspase-1, GSDMD) and inflammatory cytokines (IL-1β, IL-18). In cellular models, MV increased E2 levels, reduced LDH release, and decreased the expression of insulin resistance and pyroptosis markers. Correlation analysis showed pyroptosis factors were positively correlated with HOMA-IR and IGF1, and negatively with IGF1R and E2 levels.

MV improves PCOS by reducing pyroptosis and insulin resistance, enhancing insulin sensitivity, and promoting estrogen synthesis, thereby restoring granulosa cell function and follicular development.

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. 00, 000-000.

Apical periodontitis (AP) is an inflammatory immune response in periapical tissues caused by microbial infections. Failure of root canal treatment or delayed healing is often due to intracanal or extra-radicular bacteria. However, beyond microbial factors, the patient's systemic health can significantly influence the progression and healing of AP. Metabolic syndrome is a risk factor and it is characterized by a cluster of interconnected metabolic risk factors, including abdominal obesity, hyperlipidemia, hypertension, and hyperglycemia.

A comprehensive literature review was conducted on apical periodontitis and metabolic syndrome, and their impact on the roles of different immune cell populations.

Both AP and metabolic syndrome are inflammatory diseases that involve complex and interwoven immune responses. The affected immune cells are categorized into the innate (neutrophils, macrophages, and dendritic cells) and adaptive immune systems (T cells and B cells).

Metabolic diseases and AP are closely correlated, possibly intertwined in a two-way relationship driven by a shared dysregulated immune response.

Understanding the pathophysiology and immune mechanisms underlying the two-way relationship between metabolic syndrome and AP can help improve treatment outcomes and enhance the overall well-being of patients with endodontic disease complicated by metabolic syndrome.

Obesity and associated metabolic disturbances worsen brain ischemia outcome. High fat diet (HFD)-fed mice are obese and have cerebrovascular remodeling and worsened brain ischemia outcome. We determined whether HFD-induced cerebrovascular remodeling impaired reperfusion to the ischemic penumbra. Six-week-old C57BL/6J or matrix metalloprotease-9 knockout (MMP-9-/-) mice were on HFD or regular diet (RD) for 12 to 14 months before a 60-min left middle cerebral arterial occlusion (MCAO). Photoacoustic microscopy was performed at left cerebral frontal cortex. HFD increased cerebrovascular density and tortuosity in C57BL/6J mice but not in MMP-9-/- mice. Blood flow to the ischemic penumbra slowly recovered but did not reach the baseline 2 h after MCAO in RD-fed mice. Oxygen extraction fraction was increased to maintain cerebral metabolic rate of oxygen (CMRO2) throughout brain ischemia and reperfusion period. This blood flow recovery was worsened in HFD-fed mice, leading to decreased CMRO2. MMP-9-/- attenuated these HFD effects. HFD increased MMP-9 activity and interleukin 1β. Pyrrolidine dithiocarbamate, an anti-inflammatory agent, abolished the HFD effects. Interleukin 1β increased MMP-9 activity. In summary, HFD induces cerebrovascular remodeling, leading to worsened recovery of blood supply to the ischemic penumbra to contribute to poor outcome after brain ischemia. Neuroinflammation may activate MMP-9 in HFD-fed mice.

Irritable bowel syndrome (IBS) is a chronic disorder of the gastrointestinal tract. Its pathogenesis involves multiple factors, including visceral hypersensitivity and immune activation. NLRP3 inflammasome is part of the nucleotide-binding oligomerization domain-like receptor (NLR) family, a crucial component of the innate immune system. Preclinical studies have demonstrated that inhibiting NLRP3 reduces visceral sensitivity and IBS symptoms, like abdominal pain, and diarrhea, suggesting that targeting the NLRP3 might represent a novel therapeutic approach for IBS. This review aims to assess the NLRP3 inhibitors (tranilast, β-hydroxybutyrate, Chang-Kang-fang, paeoniflorin, coptisine, BAY 11-7082, and Bifidobacterium longum), highlighting the signaling pathways, and their potential role in IBS symptoms management was assessed. Although premature, knowledge of the action of synthetic small molecules, phytochemicals, organic compounds, and probiotics might make NLRP3 a new therapeutic target in the quiver of physicians' therapeutic choices for IBS symptoms management.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney diseases resulting in enormous socio-economic burden. Accumulated evidence has indicated that C-reactive protein (CRP) exacerbates DKD by enhancing renal inflammation and fibrosis through TGF-β/Smad3 signaling. NLRP3 inflammasome is the key sensor contributing to renal inflammation. However, whether CRP enhances inflammation in DKD via NLRP3 inflammasome-related pathway remains unknown. In this study, we demonstrate that CRP promotes DKD via Smad3-mediated NLRP3 inflammasome activation as mice overexpressing human CRP gene exhibits accelerated renal inflammation in diabetic kidneys, which is associated with the activation of Smad3 and NLRP3 inflammasomes. In contrast, blockade of CPR signaling with a neutralizing anti-CD32 antibody attenuates CRP-induced activation of Smad3 and NLRP3 in vitro. Importantly, genetic deletion or pharmacological inhibition of Smad3 also mitigates CRP-induced activation of NLRP3 in diabetic kidneys or in high glucose-treated cells. Mechanistically, we reveal that Smad3 binds to the NLRP3 gene promoter, which is enhanced by CRP. Taken together, we conclude that CRP induces renal inflammation in DKD via a Smad3-NLRP3 inflammasome-dependent mechanism. Thus, targeting CRP or Smad3-NLRP3 pathways may be a new therapeutic potential for DKD.

Inflammatory diseases impair the reparative properties of endothelial progenitor cells (EPC); however, the involvement of diabetes in EPC dysfunction associated with myocardial infarction (MI) remains unknown.

A model was established combining high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice with myocardial infarction. The therapeutic effects of transplanted wild-type EPC, Nlrp3 knockout EPC, and Nlrp3 overexpression EPC were evaluated. Chip and Luciferase assay revealed CEBPB regulated the transcriptional expression of Nlrp3 as a transcription factor in EPC stimulated by high glucose (HG) or advanced glycation end products (AGEs). CO-IP results suggested that USP14 selectively suppressed NLRP3 degradation. KEGG enrichment revealed PI3K/ Akt/mTOR signaling showed striking significance in the entire pathway.

In our study, wild-type, Nlrp3 knockout and Nlrp3 overexpressed EPC, intracardiac injections effectively improved cardiac function, increased angiogenesis, and reduced infarct size in mice with myocardial infarction. However, in the HFD/STZ-induced diabetic mice model combined with myocardial infarction, Nlrp3 knockout EPC significantly restored angiogenic capacity. Mechanically, CEBPB regulated the transcriptional level of Nlrp3 as a transcription factor in EPC. Meanwhile, we found that USP14 selectively suppressed NLRP3 protein degradation through the USP motif on the NACHT domain in mediating inflammasome activation. Cardiac functional outcomes in recipient mice after intramyocardial injection of shNlrp3 EPC overexpressing CEBPB or USP14 validated the modulation of EPC function by regulating Nlrp3 transcription or post-translational modification. Furthermore, KEGG enrichment and validation at the protein levels revealed PI3K/ Akt/mTOR cascade might be a downstream signal for NLRP3 inflammasome.

Our study provides a new understanding of how diabetes affected progenitor cell-mediated cardiac repair and identifies NLRP3 as a new therapeutic target for improving myocardial infarction repair in inflammatory diseases.

The NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in human acute and chronic liver diseases. However, the role and cell-specific contribution of NLRP3 in liver regeneration remains unclear. Here, we found that NLRP3 was highly activated during the early stage of liver regeneration via 70% partial hepatectomy (PHx) mice model and clinical data. Global NLRP3 depletion or pharmacologically blocking NLRP3 significantly enhanced liver regeneration, while NLRP3 overexpression impaired it after PHx. Furthermore, mice with myeloid-specific knockout of Nlrp3 (Nlrp3Δmye), rather than hepatocyte-specific knockout (Nlrp3Δhep), showed improved liver regeneration compared to control (Nlrp3fl/fl). Mechanistically, deficiency of Nlrp3 promoted myeloid-epithelial-reproductive tyrosine kinase (MerTK)-mediated efferocytosis, thereby inducing macrophages toward a pro-reparative Ly6Clo phenotype. Notably, NLRP3 inhibition by MCC950 effectively reversed the impairment of liver regeneration after PHx in mice fed a high-fat diet. Our findings provide a potential therapeutic strategy for the prevention and treatment of post-hepatectomy liver failure.

Obesity leads to a number of health problems, including learning and memory deficits that can be passed on to the offspring via a developmental programming process. However, the mechanisms involved in the deleterious effects of obesity on cognition remain largely unknown. This study aimed to assess the impact of obesity on the production of sphingolipids (ceramides and sphingomyelins) in the brain and its relationship with the learning deficits displayed by obese individuals. We also sought to determine whether the effects of obesity on brain sphingolipid synthesis could be passed on to the offspring. Learning abilities and brain concentration of sphingolipids in male and female control and obese founder rats (F0) and their offspring (F1) were evaluated, respectively, by the novel object recognition test and by ultra-performance liquid chromatography tandem mass spectrometry. In addition, a global lipidome profiling of the cerebral cortex and hippocampus was performed. Both male and female F0 rats showed impaired learning and increased concentrations of ceramides and sphingomyelins in the hippocampus and frontal cortex compared to their control counterparts. However, the overall lipidome profile of these brain regions did not change with obesity. Remarkably, the alterations in brain sphingolipid synthesis, as well as the cognitive impairment induced by obesity, were also present in adult F1 male rats born to obese mothers or sired by obese fathers and were associated with enhanced expression of mRNAs coding for enzymes involved in the de novo synthesis of ceramides. These results show that the cognitive deficits and impaired sphingolipid metabolism induced by obesity can be transmitted to the offspring through both the maternal and paternal lineages and suggest that an increase in the brain concentration of sphingolipids could play a causal role in the cognitive deficits associated with obesity.