Acute lung injury (ALI) is a life-threatening condition with high rates of morbidity and mortality. Recently, there has been growing evidence suggesting a link between lncRNA HOTAIR and ALI. Nonetheless, the precise role and mechanism of lncRNA HOTAIR in ALI remain to be fully elucidated. siHOTAIR transfection, qPCR detection (HOTAIR), ELISA (TNF-α, IL-6, and IL-1β), Lactate detection, Glucose uptake experiment, Cell Apoptosis Analysis, Fluorescence in situ hybridization (FISH) assay. Through siHOTAIR transfection, we discovered that HOTAIR plays a role in the secretion of inflammatory factors in ALI and further regulates glucose uptake and metabolism in lung epithelial cells. Moreover, a comparison between HOTAIR knockdown cells and HOTAIR overexpression cells revealed that HOTAIR promotes cellular aerobic sugar metabolism, leading to increased secretion of inflammatory factors and cell apoptosis. Our in-depth research also identified an interaction between HOTAIR and the LIN28 protein. Knocking down HOTAIR resulted in the downregulation of LIN28 protein expression, which subsequently inhibited the expression of the glucose transporter GLUT1. This indicates that HOTAIR facilitates glucose uptake and boosts cellular aerobic glycolysis by modulating the LIN28 protein, thereby promoting inflammation and apoptosis in acute lung injury. The research findings presented in this article offer significant insights into the function of HOTAIR in ALI and suggest a potential therapeutic target for the treatment of this condition.

Recent advancements in immunometabolism have highlighted the critical role of metabolite sensors in regulating immune responses. Metabolites such as lactate, succinate, itaconate, and β-hydroxybutyrate influence immune cell function by interacting with specific sensors. These metabolites act as signaling molecules, linking cellular metabolic changes to immune responses. Lactate, a metabolite commonly produced under hypoxic conditions, has emerged as a major regulator of innate immunity. Key enzymes, including AARS1 and AARS2, function as intracellular lactate sensors, catalyzing lactylation on proteins like cGAS, which plays a central role in DNA sensing and immune activation. The lactylation of cGAS inhibits its activity, modulating immune responses by balancing inflammation and immune tolerance. Metabolite sensors, like MCT1, also contribute to immune modulation, particularly in cancer and chronic inflammatory diseases. Therapeutically, targeting these sensors offers potential for restoring immune function, especially in cancer immunotherapy. However, challenges in specificity, off-target effects, and long-term safety require further investigation. This article explores the emerging role of metabolite sensors in immune regulation, with a focus on lactate sensors, and outlines potential therapeutic strategies to enhance immune responses in metabolic diseases.

This study aims to evaluate the effect of dapagliflozin (DAPA) on malignant ventricular arrhythmias (MVA) after acute myocardial infarction (AMI).

A single-center, prospective and observational cohort study was conducted. We enrolled AMI patients from the ChangZhou Acute Myocardial Infarction Registry between January 2018 and November 2023. They were divided into two groups according to the use of dapagliflozin. The median follow-up time was 211 days. The primary endpoint of the study was the incidence of MVA during hospitalization, and the secondary endpoint was all-cause mortality rate during the follow-up period. Kaplan-Meier survival analysis and multifactorial logistic regression analysis were performed to assess the association between DAPA and the risk of MVA. Enrolled patients were matched on a 1:1 propensity score.

Of the 2607 AMI patients enrolled, MVA were reported postoperatively in 123 (4.7%)patients. Cardiovascular death occurred in 93 (3.6%) patients. The average age of the enrolled patients was 65.03 ± 0.27 years. Of participants assigned to dapagliflozin, 8 out of 363 patients (2.2%) experienced MVA compared with 115 out of 2244 patients (5.1%) in the control group (odds ratio, OR = 0.392; 95% confidence interval, 95% CI: 0.171-0.900; P = 0.027). After 1:1 propensity score matching, DAPA remained able to reduce the risk of MVA in patients with AMI. (OR = 0.340; 95% CI: 0.121-0.960; P = 0.042). At a median follow-up of 211 days, all-cause mortality remained lower in the DAPA group than in the control group after matching (P = 0.033).

Dapagliflozin may attenuate the risk of MVA and all-cause mortality in elderly AMI patients, highlighting its potential as a therapeutic adjunct. However, these findings require validation in large-scale randomized trials.

The intricate relationship between gut microbiota and the brain has emerged as a pivotal area of research, particularly in understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This complex condition is characterized by debilitating fatigue, cognitive dysfunction, and a wide array of systemic manifestations, posing significant challenges for diagnosis and treatment. Recent studies highlight the microbiota-gut-brain axis as a crucial pathway in ME/CFS pathophysiology, suggesting that alterations in gut microbial composition may impact immune responses, neurochemical signaling, and neuronal health. This narrative review systematically explores English-language scholarly articles from January 1995 to January 2025, utilizing databases such as PubMed, Scopus, and Web of Science. The findings underscore the potential for targeted therapeutic interventions aimed at correcting gut dysbiosis. As research progresses, a deeper understanding of the microbiota-gut-brain connection could lead to innovative approaches for managing ME/CFS, ultimately enhancing the quality of life for affected individuals.

Acute myocardial infarction (MI) remains one of the major causes of death worldwide, and innovative treatment strategies for MI represent a major challenge in cardiovascular medicine. Caloric restriction (CR) is the most potent nonpharmacological intervention known to prevent age-related disorders and extend lifespan. CR reduces glycolysis and elevates ketone body metabolism. However, whether and how CR or ketone body prevents the progression of MI remains poorly defined.

Mice treated with CR and β-hydroxybutyrate (β-OHB) underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiographic measurements. Histological analysis, fluorescence-activated cell sorting, and immunofluorescence were used to assess myocardial neovascularization and macrophage filtration. The interaction and modification of β-OHB on PHD2 were analyzed by molecular docking, cellular thermal shift assay, liquid chromatography with tandem mass spectrometry, and coimmunoprecipitation. Macrophage-specific PHD2 K239R and K385R knock-in mice were used to determine the functional significance of β-OHB/PHD2 axis in vivo.

Twelve weeks of CR markedly rescued postinfarction cardiac function by enhancing neovascularization. CR significantly increased circulating and cardiac ketone bodies, including β-OHB and acetoacetate. We identified β-OHB but not acetoacetate selectively targeted macrophages to stimulate VEGF (vascular endothelial growth factor) production in the peri-infarct area to promote neovascularization and cardiac repair. Mechanistically, β-OHB binds to and induces lysine β-hydroxybutyrylation of PHD2 at lysines 239 and 385, thus blocking its function in the hydroxylation of HIF-1α (hypoxia-inducible factor 1α) and resulting in enhanced HIF1α-dependent VEGF transcription and secretion. More importantly, specific PHD2 lys239 and lys385 mutations in macrophages abolished the preventive effects of exogenous β-OHB on MI in mice.

These data reveal a novel regulation of lysine β-hydroxybutyrylation on PHD2 and demonstrate a promising and therapeutic role for β-OHB/PHD2 in effectively accelerating neovascularization and preserving heart function after cardiac ischemia.

The dynamic modification of proteins by many metabolites suggests an intimate link between energy metabolism and post-translational modifications (PTMs). For instance, starvation and low-carbohydrate diets lead to the accumulation of β-hydroxybutyrate (BHB), whose blood concentrations can reach millimolar levels, concomitant with the accumulation of lysine β-hydroxybutyrylation (Kbhb) of proteins. Here we report that class I histone deacetylases (HDACs) unexpectedly catalyze the formation of Kbhb. Through mutational analysis, we show a shared reliance on key active site amino acids for classical deacetylation and noncanonical HDAC-catalyzed β-hydroxybutyrylation. On the basis of these data, we propose that HDACs catalyze a condensation reaction between the free amine group on lysine and the BHB carboxylic acid, thereby generating an amide bond. This reversible HDAC activity is not limited to BHB and extends to multiple short-chain fatty acids, representing a novel mechanism of PTM deposition relevant to metabolically sensitive proteome modifications.

Autism is highly heritable, however actionable genetic findings are only found in a minority of patients. Many people with autism suffer loss of neurodevelopmental skills, known as autistic regression. The cause of regression is poorly understood, and the diagnostic and therapeutic pathways are lacking.

We used untargeted metabolomics using a UPLC-Q-Exactive-HFx Mass Spectrometry to examine cerebrospinal fluid (CSF) from twenty-two patients with autistic regression compared to sixteen controls with neurodevelopmental disorders (but not autistic regression) and thirty-four controls with other neurological disease (headache, encephalitis, epilepsy). The twenty-two patients with autistic regression consisted of two groups: early (infantile) autistic regression <2 years of age (n = 8), and later regression of skills >4 years of age, often in the context of pre-existing developmental concerns (n = 14). Metabolites of interest were then quantified and validated using targeted assays.

Untargeted case-control studies revealed good separation of patients from controls using multivariate analysis. β-hydroxybutyrate was significantly decreased in the CSF of patients with autistic regression, and the findings were validated using a targeted β-hydroxybutyrate assay. The sphingolipid, sphingosine-1-phosphate was significantly elevated in the discovery case-control studies, and sphingolipid metabolism pathways were also significantly dysregulated. We therefore developed a targeted metabolite assay of forty sphingolipids. After FDR correction, 21 of the 40 sphingolipids were significantly dysregulated (pFDR < 0.05) (Benjamini-Hochberg correction) in autistic regression compared to the neurodevelopmental controls, and 26 of the 40 sphingolipids were significantly dysregulated in autistic regression compared to other neurological controls, with elevated ceramides, hexosylceramides, sphingosines (including sphingosine-1-phosphate), and sulfatides. By contrast, sphingomyelin levels were generally decreased in autistic regression.

Our data shows the potential utility of CSF metabolomics in the context of autistic regression, a clinical syndrome which has historically lacked pathophysiological biomarkers and disease modifying therapies.

Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance, and Ainsworth and SCHF Neuroscience grant scheme.

Acute respiratory distress syndrome (ARDS) is present in >10% of all people admitted to critical care and is associated with severe morbidity and mortality. Despite more than half a century since its first description, no efficacious pharmacological therapies have been developed, and little progress has been made in improving clinical outcomes. Neutrophils are the principal drivers of ARDS, with their priming and subsequent aberrant downstream functions, including interleukin (IL) 1β and IL-18 secretion, central to the disease pathogenesis. The dominant pathways through which IL-1β and IL-18 are believed to be elaborated are multimeric protein structures called inflammasomes that consist of sensor proteins, adaptor proteins and an effector enzyme. The inflammasome's initial activation depends on one of a variety of damage-associated (DAMP) or pathogen-associated (PAMP) molecular patterns. However, once activated, a common downstream inflammatory pathway is initiated regardless of the specific DAMP or PAMP involved. Several inflammasomes exist in humans. The nucleotide-binding domain leucine-rich repeat (NLR) family, pyrin domain-containing 3 (NLRP3), inflammasome is the best described in the context of ARDS and is known to be activated in both infective and sterile cases. The NLR family, caspase activation and recruitment domain-containing 4 (NLRC4) and absent in melanoma 2 (AIM2) inflammasomes have also been implicated in various ARDS settings, as have inflammasome-independent pathways. Further work is required to understand human biology as much of our knowledge is extrapolated from rodent experimental models. Experimental lung injury models have demonstrated beneficial responses to inflammasome, IL-1β and IL-18 blockade. However, findings have yet to be successfully translated into humans with ARDS, likely due to an underappreciation of the central role of the neutrophil inflammasome. A thorough understanding of inflammasome pathways is vital for critical care clinicians and researchers and for the development of beneficial therapies. In this review, we describe the central role of the inflammasome in the development of ARDS and its potential for immunomodulation, highlighting key areas for future research.

Skeletal muscle wasting is a critical clinical problem associated with several diseases that significantly impair patient outcomes due to the progressive loss of muscle mass and function. This study explores the potential of 3-hydroxybutyrate (3-HB) as a therapeutic agent to counteract muscle atrophy by promoting the proliferation and differentiation of C2C12 myoblasts. Using nuclear magnetic resonance (NMR)-based metabolomics analysis, we uncover the underlying mechanisms by which 3-HB exerts its effects. Our findings demonstrate that 3-HB exerts its effects through two distinct mechanisms: as a metabolic substrate and as a signaling molecule. As a metabolic substrate, 3-HB enhances myoblast energy efficiency by stimulating the expression of G protein-coupled receptor 109a (GPR109a), which subsequently upregulates the 3-HB transporters MCT1 and CD147, the utilization enzyme OXCT1, and phosphorylated AMPK, thereby increasing ATP production. As a signaling molecule, 3-HB activates GPR109a, promoting calcium influx, improving calcium homeostasis, and increasing the expression of Ca2+-related proteins such as CAMKK2. This signaling cascade activates calcineurin (CaN), facilitating NFAT translocation to the nucleus and gene expression that drives myoblast proliferation and differentiation. By elucidating the dual regulatory roles of 3-HB in energy metabolism and cellular signaling, this study not only advances our understanding of muscle physiology but also highlights the potential of 3-HB as a novel therapeutic approach for the prevention or treatment of skeletal muscle atrophy.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.

Intermittent fasting (IF) and ketogenic diets (KDs) have recently attracted much attention in the scientific literature and in popular culture and follow a longer history of exercise and caloric restriction (CR) research. Whereas IF involves cyclic metabolic switching (CMS) between ketogenic and non-ketogenic states, KDs and CR may not. In this Perspective, I postulate that the beneficial effects of IF result from alternating between activation of adaptive cellular stress response pathways during the fasting period, followed by cell growth and plasticity pathways during the feeding period. Thereby, I establish the cyclic metabolic switching (CMS) theory of IF. The health benefits of IF may go beyond those seen with continuous CR or KDs without CMS owing to the unique interplay between the signalling functions of the ketone β-hydroxybutyrate, mitochondrial adaptations, reciprocal activation of autophagy and mTOR pathways, endocrine and paracrine signalling, gut microbiota, and circadian biology. The CMS theory may have important implications for future basic research, clinical trials, development of pharmacological interventions, and healthy lifestyle practices.

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.

Iatrogenic peripheral hyperinsulinemia, resulting from peripheral insulin administration in type 1 diabetes, may increase insulin resistance and impair endothelial function. We hypothesized that lowering iatrogenic peripheral hyperinsulinemia via a one-week, reduced-carbohydrate diet (RCD) would improve insulin sensitivity and endothelial function compared with an isocaloric standard carbohydrate diet (SCD).

In this randomized, single-blinded, crossover trial, we studied 12 adults with type 1 diabetes. Participants completed both a one-week RCD and a one-week SCD, separated by a three-week washout. After each intervention, we measured insulin sensitivity using a hyperinsulinemic-euglycemic clamp and assessed endothelial function via brachial-artery flow-mediated vasodilation (FMD).

The RCD reduced total daily insulin doses by 16% compared with the SCD. Despite this reduction, insulin sensitivity did not improve (median glucose infusion rates: RCD 8.1 mg/kg FFM/min [IQR 6.7-10.1] vs. SCD 8.6 mg/kg FFM/min [7.0-11.0], p = 0.47). Similarly, endothelial function did not differ significantly (FMD after RCD 7.50% [3.25-15.5] vs. SCD 9.81% [4.96-14.3], p = 0.91). Although higher insulin doses correlated with lower insulin sensitivity under both conditions, lowering insulin dose through the RCD alone did not yield measurable improvements.

Although a one-week RCD significantly lowered insulin requirements, it failed to enhance insulin sensitivity or endothelial function in adults with type 1 diabetes. These findings underscore the complex and dynamic relationship between insulin exposure and cardiometabolic health. Similar basal overnight insulin delivery may have masked potential benefits by the time of testing, highlighting the need for further studies to refine strategies aimed at mitigating hyperinsulinemia's adverse effects.

ClinicalTrials.gov NCT04118374.

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Amyloid-β (Aβ) accumulation and neurofibrillary tangles are two key histological features resulting in progressive and irreversible neuronal loss and cognitive decline. The macrophages of the central nervous system (CNS) belong to the innate immune system and comprise parenchymal microglia and CNS-associated macrophages (CAMs) at the CNS interfaces (leptomeninges, perivascular space and choroid plexus). Microglia and CAMs have received attention as they may play a key role in disease onset and progression e. g., by clearing amyloid beta (Aβ) through phagocytosis. Genome-wide association studies (GWAS) have revealed that human microglia and CAMs express numerous risk genes for AD, further highlighting their potentially critical role in AD pathogenesis. Microglia and CAMs are tightly controlled by environmental factors, such as the host microbiota. Notably, it was further reported that the composition of the gut microbiota differed between AD patients and healthy individuals. Hence, emerging studies have analyzed the impact of gut bacteria in different preclinical mouse models for AD as well as in clinical studies, potentially enabling promising new therapeutic options.

Immunometabolic processes maintain physiological homeostasis and are implicated in various chronic diseases. Fasting and exercise independently alter metabolic and immunological processes; their combination could provide insights into immunometabolic interactions. Using a randomized crossover design, 15 healthy adults (six females, nine males, 26.5 ± 4.3 years) fasted for 60 h with and without the addition of a 3 h cycling bout (65%-80% VO2 peak). Fasting alone (FAST) and with exercise (FEX) reduced plasma glucose, insulin, respiratory exchange ratio, and increased β-hydroxybutyrate (BHB; all p < 0.01). FEX elicited more rapid changes in glucose and BHB and higher BHB concentrations at 60 h (all p < 0.01). Both conditions decreased circulating TNF-⍺ concentrations and increased IL-10 (p < 0.01), although the increase in IL-10 appeared to be driven by the FEX condition (p = 0.03). IL-6 concentrations tended to increase in both conditions (p = 0.1). Total white blood cell count remained unchanged after 60 h in both conditions, with only modest changes in some leukocyte subpopulations. Collectively, the observed changes in circulating cytokine concentrations support an overall anti-inflammatory effect of prolonged fasting, while the maintenance of leukocyte concentrations suggests immune function is not compromised. Despite greater metabolic strain, the addition of prolonged exercise did not appear to augment changes in systemic cytokines and leukocytes.

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.

We investigated whether plasma β-hydroxybutyrate levels, a genetic risk score for Alzheimer's disease, and their interaction are associated with incident Alzheimer's disease.

Using data from the UK Biobank-a population-based cohort study of adults aged 40-69 years, we assessed associations between baseline plasma β-hydroxybutyrate level, genetic risk score for Alzheimer's disease, and incident Alzheimer's disease. Incident Alzheimer's disease data were collected through linked data from hospital admissions and death registries.

In total, 261,933 adults were included, 1978 of whom developed incident Alzheimer's disease. Plasma β-hydroxybutyrate concentrations were not independently associated with Alzheimer's disease incidence after adjusting for covariates, whereas a higher genetic predisposition was linked to increased Alzheimer's disease incidence. Interactions were observed between plasma β-hydroxybutyrate concentrations and genetic risk for Alzheimer's disease on Alzheimer's disease incidence (P < 0.001).

Further studies are warranted to elucidate the impact of plasma β-hydroxybutyrate status on Alzheimer's disease incidence.

Time-restricted feeding (TRF) is a lifestyle intervention that aims to maintain a consistent daily cycle of feeding and fasting to support robust circadian rhythms. Recently, it has gained scientific, medical, and public attention due to its potential to enhance body composition, extend lifespan, and improve overall health, as well as induce autophagy and alleviate symptoms of diseases like cardiovascular diseases, type 2 diabetes, neurodegenerative diseases, cancer, and ischemic injury. However, there is still considerable debate on the primary factors that contribute to the health benefits of TRF. Despite not imposing strict limitations on calorie intake, TRF consistently led to reductions in calorie intake. Therefore, while some studies suggest that the health benefits of TRF are primarily due to caloric restriction (CR), others argue that the key advantages of TRF arise not only from CR but also from factors like the duration of fasting, the timing of the feeding period, and alignment with circadian rhythms. To elucidate the roles and mechanisms of TRF beyond CR, this review incorporates TRF studies that did not use CR, as well as TRF studies with equivalent energy intake to CR, which addresses the previous lack of comprehensive research on TRF without CR and provides a framework for future research directions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant public health concern, with its progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis leading to severe outcomes including cirrhosis, hepatocellular carcinoma, and liver failure. Whereas obesity and excess energy intake are well-established contributors to the development and progression of MASLD, the distinct role of specific macronutrients is less clear. This review examines the mechanistic pathways through which dietary fatty acids and sugars contribute to the development of hepatic inflammation and fibrosis, offering a nuanced understanding of their respective roles in MASLD progression. In terms of addressing potential therapeutic options, human intervention studies that investigate whether modifying the intake of dietary fats and carbohydrates affects MASLD progression are reviewed. By integrating this evidence, this review seeks to bridge the gap in the understanding between the mechanisms of macronutrient-driven MASLD progression and the effect of altering the intake of these nutrients in the clinical setting and presents a foundation for future research into targeted dietary strategies for the treatment of the disease.

Mounting an immune response is a nutritionally demanding process that requires the systemic redistribution of energy stores towards the immune system. This is facilitated by cytokine-induced insulin resistance, which simultaneously promotes the mobilization of lipids and carbohydrates while limiting their consumption in immune-unrelated processes, such as development, growth, and reproduction. However, this adaptation also restricts the availability of nutrients to vital organs, which must then be sustained by alternative fuels. Here, we employed an experimental model of severe bacterial infection in Drosophila melanogaster to investigate whether ketogenesis may represent a metabolic adaptation for overcoming periods of nutritional scarcity during the immune response. We found that the immune response to severe bacterial infection is accompained by increased ketogenesis in the fat body and macrophages, leading to elevated levels of β-hydroxybutyrate in circulation. Although this metabolic adaptation is essential for survival during infection, it is not required for the elimination of the pathogen itself. Instead, ketone bodies predominately serve as an energy source for the brain neurons during this period of nutrient scarcity.

In a rapidly expanding body of literature, the major role of energy metabolism in determining the response and polarization status of macrophages has been examined, and it is currently a very active area of research. The metabolic flux through different metabolic pathways in the macrophage is interconnected and complex and could influence the polarization of macrophages. Earlier studies suggested glucose flux through cytosolic glycolysis is a prerequisite to trigger the pro-inflammatory phenotypes of macrophages while proposing that fatty acid oxidation is essential to support anti-inflammatory responses by macrophages. However, recent studies have shown that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully defined yet. In this review, we systematically reviewed and summarized the literature regarding the role of energy metabolism in controlling macrophage activity and how that might be altered in cardiometabolic diseases, namely heart failure, obesity, and diabetes. We critically appraised the experimental studies and methodologies in the published studies. We also highlighted the challenging concepts in macrophage metabolism and identified several research questions yet to be addressed in future investigations.

There is growing interest in the ketogenic diet as a treatment for bipolar disorder (BD), and there are promising anecdotal and small case study reports of efficacy. However, the neurobiological mechanisms by which diet-induced ketosis might ameliorate BD symptoms remain to be determined, particularly in manic and hypomanic states-defining features of BD. Identifying these mechanisms will provide new markers to guide personalized interventions and provide targets for novel treatment developments for individuals with BD. In this critical review, we describe recent findings highlighting 2 types of neurobiological abnormalities in BD: 1) mitochondrial dysfunction and 2) neurotransmitter and neural network functional abnormalities. We link these abnormalities to mania/hypomania and depression in BD and then describe the biological underpinnings by which the ketogenic diet may have a beneficial effect in individuals with BD. We end the review by describing approaches that can be employed in future studies to elucidate the neurobiology that underlies the therapeutic effect of the ketogenic diet in BD. Doing this may provide marker predictors to identify individuals who will respond well to the ketogenic diet, as well as offer neural targets for novel treatment developments for BD.

The venom peptides from terrestrial as well as aquatic species have demonstrated potential in regulating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a sophisticated assemblage present in immune cells responsible for detecting and responding to external mediators. The NLRP3 inflammasome plays a role in several pathological conditions such as type 2 diabetes, hyperglycemia, Alzheimer's disease, obesity, autoimmune disorders, and cardiovascular disorders. Venom peptides derived from animal venoms have been discovered to selectively induce certain signalling pathways, such as the NLRP3 inflammasome, mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Experimental evidence has demonstrated that venom peptides can regulate the expression and activation of the NLRP3 inflammasome, resulting in the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Furthermore, these peptides have been discovered to impede the activation of the NLRP3 inflammasome, therefore diminishing inflammation and tissue injury. The functional properties of venom proteins and peptides obtained from snakes, bees, wasps, and scorpions have been thoroughly investigated, specifically targeting the NLRP3 inflammasome pathway, venom proteins and peptides have shown promise as therapeutic agents for the treatment of certain inflammatory disorders. This review discusses the pathophysiology of NLRP3 inflammasome in the onset of various diseases, role of venom as therapeutics. Further, various venom components and their role in the modulation of NLRP3 inflammasome are discoursed. A substantial number of venomous animals and their toxins are yet unexplored, and to comprehensively grasp the mechanisms of action of them and their potential as therapeutic agents, additional research is required which can lead to the development of novel therapeutics.

Diabetes mellitus is a common metabolic disease in humans and cats. Cats share several features of human type-2 diabetes and can be considered an animal model for this disease. In the last decade, sodium-glucose transporter 2 inhibitors (SGLT2i) have been used successfully as a class of hypoglycemic drug that inhibits the reabsorption of glucose from the renal proximal tubules, consequently managing hyperglycemia through glycosuria. Furthermore, SGLT2i have been shown to have cardiac, renal, and other protective effects in diabetic humans acting as a pleiotropic drug. Currently, at least six SGLT2i are approved by the Food and Drug Administration (FDA) for use in humans with type-2 diabetes, and recently, two drugs were approved for use in diabetic cats. This narrative review focuses on the use of SGLT2i to treat diabetes mellitus in humans and cats. We summarize the human data that support the use of SGLT2i in controlling type-2 diabetes and protecting against cardiovascular and renal damage. We also review the available literature regarding other benefits of these drugs in humans as well as the effects of SGLT2i in cats. Adverse effects related to the use of these hypoglycemic drugs are also discussed.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by neurodegeneration, axonal damage, demyelination, and inflammation. Recently, gut dysbiosis has been linked to MS and other autoimmune conditions. Namely, gut microbiota has a vital role in regulating immune function by influencing immune cell development, cytokine production, and intestinal barrier integrity. While balanced microbiota fosters immune tolerance, dysbiosis disrupts immune regulation, damages intestinal permeability, and heightens the risk of autoimmune diseases. The critical factor in shaping the gut microbiota and modulating immune response is diet. Research shows that high-fat diets rich in saturated fats are associated with disease progression. Conversely, diets rich in fruits, yogurt, and legumes may lower the risk of MS onset and progression. Specific dietary interventions, such as the Mediterranean diet (MD) and ketogenic diet, have shown potential to reduce inflammation, support neuroprotection, and promote CNS repair. Probiotics, by restoring microbial balance, may also help mitigate immune dysfunction noted in MS. Personalized dietary strategies targeting the gut microbiota hold promise for managing MS by modulating immune responses and slowing disease progression. Optimizing nutrient intake and adopting anti-inflammatory diets could improve disease control and quality of life. Understanding gut-immune interactions is essential for developing tailored nutritional therapies for MS patients.

Asthma is a chronic respiratory condition characterized by airway inflammation, remodeling, and hyperresponsiveness to triggers causing airway constriction. Bronchial smooth muscle plays a critical role by narrowing airways, leading to obstruction and breathing difficulties, often exacerbated by mast cell infiltration and histamine release. Whereas current treatments, including bronchodilators, corticosteroids, and biologics provide effective management for most patients, alternative therapies are needed for difficult-to-treat asthma. Recent research highlights the potential of therapeutic ketosis, achieved through dietary interventions or supplementation with exogenous ketones, to reduce airway hyperresponsiveness and inflammation. Ketone bodies, known for providing energy during carbohydrate scarcity, also influence asthma by activating cell-surface receptors and transporters. In vivo, interventions like weight loss and caloric restriction increase ketone body levels, correlating with improved asthma symptoms, reduced oxidative stress, and inflammation. These effects suggest ketone bodies, particularly β-hydroxybutyrate, may play a therapeutic role in mitigating bronchoconstriction and smooth muscle contraction in asthma. We utilize human bronchial smooth muscle cells (in vitro) and mouse precision-cut lung slices (PCLS) (ex vivo) to assess the effects of BHB on histamine-induced bronchoconstriction. Brightfield microscopy showed that BHB reduces contraction in human bronchial smooth muscle cells, an effect involving free fatty acid receptor 3 (FFAR3) activation. Light microscopy of PCLS revealed that BHB inhibits airway narrowing and cellular extrusion, demonstrating its ability to mitigate bronchoconstriction by suppressing smooth muscle contraction. These results implicate bronchial smooth muscle as a cellular target of therapeutic ketosis, an important contributor to the beneficial effects of BHB in preclinical models of asthma.

Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.

Cognitive impairments are common clinical manifestation of Alzheimer's disease, vascular dementia, type 2 diabetes mellitus, and autoimmune diseases. Emerging evidence has suggested a strong correlation between peripheral chronic inflammation and cognitive impairments. For example, nearly 40% of individuals with inflammatory bowel disease also suffer from cognitive impairments. In this condition, NLRP3 inflammasome (NLRP3-I) generating pro-inflammatory cytokines like IL-1β serves as a significant effector, and its persistence exerts adverse effects to both periphery and the brain. Moreover, investigations on serum biomarkers of mild cognitive impairments have shown NLRP3-I components' upregulation, suggesting the involvement of peripheral inflammasome pathway in this disorder. Here, we systematically reviewed the current knowledge of NLRP3-I in inflammatory disease to uncover its potential role in bridging peripheral chronic inflammation and cognitive impairments. This review summarizes the molecular features and ignition process of NLRP3-I in inflammatory response. Meanwhile, various effects of NLRP3-I involved in peripheral inflammation-associated disease are also reviewed, especially its chronic disturbances to brain homeostasis and cognitive function through routes including gut-brain, liver-brain, and kidney-brain axes. In addition, current promising compounds and their targets relative to NLRP3-I are discussed in the context of cognitive impairments. Through the detailed investigation, this review highlights the critical role of peripheral NLRP3-I in the pathogenesis of cognitive disorders, and offers novel perspectives for developing effective therapeutic interventions for diseases associated with cognitive impairments. The present review outlines the current knowledge on the ignition of NLRP3-I in inflammatory disease and more importantly, emphasizes the role of peripheral NLRP3-I as a causal pathway in the development of cognitive disorders. Although major efforts to restrain cognitive decline are mainly focused on the central nervous system, it has become clear that disturbances from peripheral immune are closely associated with the dysfunctional brain. Therefore, attenuation of these inflammatory changes through inhibiting the NLRP3-I pathway in early inflammatory disease may reduce future risk of cognitive impairments, and in the meantime, considerations on such pathogenesis for combined drug therapy will be required in the clinical evaluation of cognitive disorders.

Bis-octanoyl-(R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentration rapidly after ingestion. KE is hypothesized to improve function in older adults. Whilst many studies have investigated KE in young adults, they have not been studied in healthy older adults (HOA), for whom age-related differences in metabolism may alter the effects. This randomized, observational, open-label study in HOA (n = 30, 50% male, age = 76.5y) aimed to elucidate tolerance, blood BHB and glucose concentrations for 4h following consumption of either 12.5 or 25 g of BO-BD formulated in ready-to-drink beverage (n = 30), and re-constituted powder (n = 21) with a meal. All study interventions were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥0.5 mM) until the end of the study. Peak BHB concentration (Cmax) and incremental area under the curve (iAUC) were significantly greater with 25 vs 12.5 g of BO-BD in both formulations. There were no significant differences in Cmax or iAUC between formulations. Blood glucose increased in all conditions following the meal, with no consistent significant differences between conditions. These results demonstrate that both powder and beverage formulations of the KE, BO-BD, induce ketosis in HOA adults, facilitating future research on functional effects of KE in aging.

Asthma is a common airway condition causing breathing difficulties due to reversible airflow obstruction. It often affects obese individuals, with symptoms triggered by environmental factors that induce immune responses, leading to inflammation and bronchoconstriction. Bronchial smooth muscle (BSM) plays a central role in airway narrowing, driven by type 2 immune responses involving cytokines like IL-4, IL-5, and IL-13, along with leukocytes including eosinophils and type 2 T-helper cells. These responses cause structural changes such as fibrosis and airway thickening, while BSM cells worsen asthma by releasing pro-inflammatory cytokines in response to allergens, microbial signals, or inflammatory cytokines from other cells. While current treatments manage asthma in most patients, alternative therapies are needed for difficult-to-treat cases, particularly prevalent in obese, allergic individuals. Emerging research suggests that therapeutic ketosis, induced by dietary changes or ketone supplementation, may reduce airway hyperresponsiveness and inflammation. The primary ketone body, β-hydroxybutyrate (BHB), produced during carbohydrate scarcity, acts via cell-surface receptors and transporters, potentially mitigating asthma symptoms. Weight loss and caloric restriction increase ketone levels, correlating with reduced inflammation and improved asthma outcomes. We hypothesized that β-hydroxybutyrate (BHB) reduces bronchoconstriction and inflammation in asthma by targeting bronchial smooth muscle. Using human bronchial smooth muscle cells (HBSMC) in vitro, we demonstrate herein that BHB suppresses IL-1β-induced pro-inflammatory cytokine production through Free Fatty Acid Receptor 3 (FFAR3) activation. These findings suggest that bronchial smooth muscle is a key target of therapeutic ketosis, supporting BHB's potential benefits in preclinical asthma models.

The inclusion of immunomodulatory strategies as supportive therapies in ischemic heart disease (IHD) has garnered significant support over recent years. Several such approaches appear to be unified through their ultimate target, the NLRP3 inflammasome. This review presents a brief update on immunomodulatory strategies in the continuum of conditions constituting ischemic heart disease and emphasising on the seemingly unifying mechanism of NLRP3 activation as well as modulation across these conditions.

The NLRP3 inflammasome is a multiprotein complex assembled upon inflammatory stimulation, causing the release of pro-inflammatory cytokines and initiating pyroptosis. The NLRP3 pathway is relevant in inflammatory signalling of cardiac immune cells as well as non-immune cells in the myocardium, including cardiomyocytes, fibroblasts and endothelial cells. In addition to a focus on clinical outcome and efficacy trials of targeting NLRP3-related pathways, the potential connection between immunomodulation in cardiology and the NLRP3 pathway is currently being explored in preclinical trials. Colchicine, cytokine-based approaches and SGLT2 inhibitors have emerged as promising agents. However, the conditions comprising IHD including atherosclerosis, coronary artery disease (CAD), myocardial infarction (MI) and ischemic cardiomyopathy/heart failure (iCMP/HF) are not equally amenable to immunomodulation with the respective drugs. Atherosclerosis, coronary artery disease and ischemic cardiomyopathy are affected by chronic inflammation, but the immunomodulatory approach to acute inflammation in the post-MI setting remains a pharmacological challenge, as detrimental and regenerative effects of myocardial inflammation are initiated in unison. The NLRP3 inflammasome lies at the center of cell mediated inflammation in IHD. Recent trial evidence has highlighted anti-inflammatory effects of colchicine, interleukin-based therapy as well as SGLT2i in IHD and that the respective drugs modulate the NLRP3 inflammasome.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

The endothelium is pivotal in multiple physiological processes, such as maintaining vascular homeostasis, metabolism, platelet function, and oxidative stress. Emerging evidence in the past decade highlighted the immunomodulatory function of endothelium, serving as a link between innate, adaptive immunity and inflammation. This review examines the regulation of the immune-inflammatory axis by the endothelium, discusses physiological immune functions, and explores pathophysiological processes leading to endothelial dysfunction in various metabolic disturbances, including hyperglycemia, obesity, hypertension, and dyslipidaemia. The final section focuses on the novel, repurposed, and emerging therapeutic targets that address the immune-inflammatory axis in endothelial dysfunction.

The impact of fecal microbiota transplantation (FMT) on the TLR4/MYD88/NF-kB signaling pathway in the colon in the ulcerative colitis model, as well as the incidence of anxiety behaviors caused by the colitis model was investigated.

Twenthy four ats were induced with ulcerative colitis using a 4 % acetic acid solution administered intrarectally and were subsequently treated with prednisolone and FMT. The study examined several indicators, such as TLR4, MYD88, and NF-κB mRNA expression, along with oxidative stress factors. Additionally, it examined the relationship between anxiety-related behaviors and colitis and assessed the pro-inflammatory cytokines in the hippocampus.

FMT led to lower disease score index and improved colon tissue pathology findings. This was associated with reduced mRNA expression of TLR4, MYD88, and NF-κB, as well as lower levels of TOS, and higher levels of TAC, GSH, and GSSG in colon tissues. FMT was found to reduce anxiety in both the open field and elevated plus maze tests. Additionally, levels of IL-6 and TNF-a were decreased in the hippocampus.

FMT suppressed acetic acid-induced colitis by inhibiting the TLR4/MYD88/NF-kB signaling pathway. FMT reduced anxiety in open field and plus maze tests, and resulted in decreased levels of IL-6 and TNF-a in the hippocampus.

The kidneys produce daily about 180 liters of urine but only about 2 liters are excreted. The proximal tubule plays an important role in reabsorbing the majority of filtered urine and many metabolites such as sugars, amino acids, salts or phosphate that are contained in this large volume. Reabsorption of these important metabolites is mediated by a diverse group of highly specialized transport proteins. Another group of transport proteins in the proximal tubule is responsible for the active secretion of metabolic waste products or toxins and drugs into urine. All these transporters have in common that they are directly linked to kidney metabolism and indirectly to whole-body metabolism and functions. In recent years, it has become evident that modulation of these transporters may influence the onset, progression and consequences of kidney disease. This review summarizes recent developments in this field and discusses some examples of drugs already in clinical use or in development. The examples include inhibitors of sugar transporters (SGLT2 inhibitors) that are successfully used in patients with kidney disease, diabetes or heart failure. Likewise, indirect inhibitors (acetazolamide) of an transporter absorbing sodium in exchange for protons (NHE3) are used mostly in patients with heart failure or for prevention of high altitude disease, while direct inhibitors show promise in preclinical studies to reduce damage in episodes of acute kidney disease or high blood pressure. Modulators of transporters mediating the excretion of urate have been used in patients with gout and are also discussed to prevent kidney disease. Novel drugs in development target transporters for phosphate, amino acids, or toxin and drug excretion and may be helpful for specific conditions associated with kidney disease. The advantages and challenges associated with these (novel) drugs targeting proximal tubule transport are discussed.

The proximal tubule is responsible for reabsorbing about 60% of filtered solutes and water and is critical for the secretion of metabolic waste products, drugs and toxins. A large number of highly specialized ion channels and transport proteins belonging to the SLC and ABC transporter families are involved. Their activity is directly or indirectly linked to ATP consumption and requires large quantities of energy and oxygen supply. Moreover, the activity of these transporters is often coupled to the movement of Na+ ions thus influencing also salt and water balance, as well as transport and regulatory processes in downstream segments. Because of their relevance for systemic ion balance, for renal metabolism or for affecting regulatory processes, proximal tubule transporters are attractive targets for existing drug and for novel strategies to reduce kidney disease progression or to alleviate the consequences of decreased kidney function. In this review, the relevance of some major proximal tubule transport systems as drug targets in individuals with chronic kidney disease (CKD) is discussed. Inhibitors of the sodium-glucose cotransporter 2, SGLT2, are now part of standard therapy in patients with CKD and/or heart failure. Also, indirect inhibition of Na+/H+-exchangers by carbonic anhydrase inhibitors and uricosuric drugs have been used for decades. Inhibition of phosphate and amino acid transporters have recently been proposed as novel principles to remove excess phosphate or to protect the proximal tubule metabolically, respectively. In addition, organic cation and anion transporters involved in drug and toxin excretion may serve as targets of new drugs. The advantages and challenges associated with (novel) drugs targeting proximal tubule transport are discussed.

Epilepsy is a chronic neurological disorder caused by abnormal discharges of neurons in the brain, which seriously affects the quality of life of patients. Although there are various drug treatments available, many epilepsy patients still experience seizures with the effect of drugs and develop refractory epilepsy. The ketogenic diet can treat drug-refractory epilepsy by regulating the body's metabolism and can enhance the quality of life by improving their cognition, behavior, and sleep quality. However, there is no unified conclusion on the mechanism through which the ketogenic diet plays a therapeutic role in epilepsy. This article provides a review of the possible mechanisms of how the ketogenic diet exerts a protective effect on epilepsy.

Recent research highlights the critical role of inflammation in accelerating amyloid beta and phosphorylated tubulin-associated protein tau cascade and Alzheimer's disease (AD) progression. Emerging evidence suggests that exercise influences AD by modulating inflammatory responses. We conducted a comprehensive search across multiple online databases. Our approach focused on previous and recent studies exploring the links among inflammation, AD, and the effects of exercise, specifically targeting research articles and books published in English. We pointed out that inflammation extends from the periphery to the central nervous system, facilitated by macrophage/microglial NLRP3 (nucleotide-binding domain, leucine rich-containing family, pyrin domain-containing protein 3) inflammasome signaling, which exacerbates classical AD mechanisms. Moreover, we provided further insights into the modulation of inflammasome signaling through exercise and exerkines, which may contribute to mitigating AD development. These insights deepen our understanding of AD mechanisms and offer the potential for identifying key therapeutic targets and biomarkers crucial for effective disease management and treatment. HIGHLIGHTS: Inflammation is potentially linked to the acceleration of classical Alzheimer's disease (AD) pathogenesis, including the pathways involving amyloid beta and phosphorylated tau, mediated by pro-inflammatory cytokines. Inflammation, initiated by the nucleotide-binding domain, leucine rich-containing family, pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway within M1-type macrophages/microglia, may contribute to neuroinflammation and AD progression. Exercise has the potential to reduce inflammation and the development of AD by influencing NLRP3 inflammasome signaling via exerkines.

Nod-like receptor protein 3 (NLRP3) is a member of the leucine-rich repeat-containing protein (NLR) canonical inflammasome family. It regulates the pathophysiology of cancer by facilitating immune responses and apoptotic proteins. Furthermore, it has been observed that chemotherapy activates NLRP3 in human malignancies. The secretion of IL-1β and IL-22 to promote cancer spread may be triggered by NLRP3 activation. Furthermore, earlier studies have exhibited that NLRP3 may cause medication resistance when used in cancer treatments given that cell viability may be regulated by NLRP3 depletion. Additionally, clinical studies have demonstrated correlation between NLRP3 expression, lymphogenesis, and cancer metastasis. Various NLRP3 agonists may cause the EMT process, stimulate IL-1β and Wnt/β-catenin signaling, and alter miRNA function in drug-resistant cells. This review seeks to clarify the possibility involvement of NLRP3-related pathways in the control of cancer cells' resistance to widely used treatment approaches, such as chemotherapy. In the end, an improved perception of the corresponding mechanisms behind NLRP3's tumor-supporting activities will help NLRP3-based treatments advance in the future.

The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.

Recently, a growing focus has been on identifying critical mechanisms in neurological diseases that trigger a cascade of events, making it easier to target them effectively. One such mechanism is the inflammasome, an essential component of the immune response system that plays a crucial role in disease progression. The NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome is a subcellular multiprotein complex that is widely expressed in the central nervous system (CNS) and can be activated by a variety of external and internal stimuli. When activated, the NLRP3 inflammasome triggers the production of proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) and facilitates rapid cell death by assembling the inflammasome. These cytokines initiate inflammatory responses through various downstream signaling pathways, leading to damage to neurons. Therefore, the NLRP3 inflammasome is considered a significant contributor to the development of neuroinflammation. To counter the damage caused by NLRP3 inflammasome activation, researchers have investigated various interventions such as small molecules, antibodies, and cellular and gene therapy to regulate inflammasome activity. For instance, recent studies indicate that substances like micro-RNAs (e.g., miR-29c and mR-190) and drugs such as melatonin can reduce neuronal damage and suppress neuroinflammation through NLRP3. Furthermore, the transplantation of bone marrow mesenchymal stem cells resulted in a significant reduction in the levels of pyroptosis-related proteins NLRP3, caspase-1, IL-1β, and IL-18. However, it would benefit future research to have an in-depth review of the pharmacological and biological interventions targeting inflammasome activity. Therefore, our review of current evidence demonstrates that targeting NLRP3 inflammasomes could be a pivotal approach for intervention in neurological disorders.

The heart - brain axis (HBA) is the physiological interactions between the cardiovascular and nervous systems through autonomic nerves, hormones, and cytokines. Patients diagnosed with diabetes mellitus have an increased risk of the cardiovascular and neurological diseases. However, recent evidence demonstrated that different antidiabetic drugs may delay cognitive impairment and improve cardiovascular outcomes. This review examines the impact of antidiabetic drugs on the HBA in patients with diabetes.

Metformin improves the cardiovascular and cognitive outcomes through adenosine 5'-monophosphate-activated protein kinase activation. Sodium-glucose cotransporter-2 inhibitors reduce inflammation, oxidative stress by inhibiting the NLRP3 inflammasome thereby reducing the incidence of heart failure and formation of beta-amyloid and neurofibrillary tangles in the brain. Dipeptidyl peptidase-4 inhibitors exhibit neuroprotective effects in Alzheimer's disease by reducing amyloid-beta and tau pathology and inflammation but may exacerbate heart failure risk due to increased sympathetic activity and prolonged β-adrenergic stimulation. Glucagon-like peptide-1 receptor agonists exhibit neuroprotective effects in Alzheimer's and Parkinson's diseases by reducing neuroinflammation, but may increase sympathetic activity, potentially elevating heart rate and blood pressure, despite their cardioprotective benefits.

Antidiabetes medications have the potential to improve cardiovascular and cognitive outcomes; however, additional studies are required to substantiate these effects.