Search Results (4,085)

Asthma is defined as a chronic airway inflammatory disorder with over-activation of the immune system accompanied by the inability to resolve inflammation. SPMs are novel potent lipid mediators that play an important role in maintaining inflammation homeostasis and macrophages’ functional plasticity. This review will look into the potential function of SPM-programmed macrophage reprogramming as a novel therapeutic strategy for asthma. Unlike current anti-inflammatory treatments, which only focus on suppressing inflammation, SPMs can actively drive the inflammation resolution phase by promoting efferocytosis and wound healing while maintaining the defense against infection. In experimental asthma animal models, lipoxins, resolvins, protectins, and maresins have been demonstrated to alleviate inflammation and airway hyperresponsiveness, shift macrophages towards pro-resolving phenotypes and thus facilitate the resolution process. Levels of some SPM subclasses were found to be reduced in severe or uncontrolled asthmatics, indicating defective resolution pathways may contribute to asthma persistence. The mechanisms include down-regulation of pro-inflammatory cytokines, alteration of macrophage phenotype, improvement of immune homeostasis in the airway milieu, etc. These molecules have become highly promising therapeutic agents after the development of metabolically stable analogs, receptor-targeted agonists, and an improved delivery system. Multi-omics studies coupled with patient stratification based on biomarkers will potentially help in the future to develop personalized resolution-based therapy, in particular for those steroid-resistant and non-type 2 asthmatics. Nevertheless, the evidence provided so far is mainly preclinical; more challenges in terms of pharmacokinetics, formulation and formulation development, regulatory agency approval, and clinical validation remain and will be overcome through further studies, thus warranting investigation into SPM-mediated strategies for asthma and other chronic inflammatory diseases. Full article

The most persistent biomedical challenges of the 21st century are neurodegenerative disorders (NDs), where molecular alterations lead to devastating clinical consequences and progressive neuronal loss. The prevalence of neurodegeneration is continuously rising and becoming the main contributor to chronic disability and mortality. Despite their clinical differences, many conditions share pathogenic processes, including oxidative stress, protein misfolding and aggregation, mitochondrial dysfunction, and neuroinflammation. Instead of functioning independently, these processes cooperate to form a self-reinforcing network that gradually weakens synapses and ultimately leads to neuronal death. This study redefines neurodegeneration as a disorder of system-level failure by emphasizing poor cellular stress integration. In addition to demonstrating how gut microbiome gene networks impact inflammation and amyloid production, new research highlights the relationships between mitochondrial–lysosomal interactions, endoplasmic reticulum stress responses, and transcriptionally driven synaptic vulnerability. A key molecular topic is the interaction and pathogenic convergence of the JAK/STAT, HIF-1α, and Notch signaling pathways. Under ongoing metabolic stress, prolonged stimulation of this triad increases inflammation, hinders the regenerative processes, and maintains pseudo-hypoxic conditions, explaining why single-target treatments have mostly been unsuccessful. This review also explores progress in fluid, digital, and imaging biomarkers that facilitate early diagnosis and patient stratification, and assesses new disease-modifying approaches such as antisense oligonucleotides, immunomodulators, gene therapies, and small-molecular agents. Artificial intelligence is emphasized as an essential tool for integrating multimodal data, drug discovery and predictive modeling. Full article

Chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation, immune dysregulation, and increased susceptibility to infections. Obesity may influence these processes and has been proposed as a potential contributor to the so-called “obesity paradox”, although its effects on immune competence, viral burden, and survival are not yet fully understood. Seventy patients with severe to very severe COPD (GOLD stage 3–4) were stratified according to BMI (<30 vs. ≥30 kg/m²). Clinical and functional parameters were assessed together with biomarkers of oxidative stress, DNA damage, systemic inflammation, and T-cell subsets. A comprehensive viral panel, including Torque Teno virus (TTV), was also analyzed. Five-year survival was evaluated using Kaplan–Meier curves and Cox regression models. Patients with BMI ≥ 30 showed higher lymphocyte counts and increased CD4⁺ and CD8⁺ T-cell levels, accompanied by lower systemic inflammatory indices. No significant differences were observed in oxidative stress or DNA damage markers. In addition, TTV viremia (≥4 log₁₀ copies/mL) was more frequently observed among patients with lower BMI. Despite these differences, five-year survival did not significantly differ between the two groups. These findings suggest that BMI alone may have limited value as a predictor of outcomes in patients with advanced COPD. Conversely, immune-inflammatory indices and viral burden, particularly TTV viremia, could provide complementary information for risk assessment and may deserve further investigation as potential tools for personalized patient stratification. Full article

Background and Objectives: Routine laboratory markers may support diagnostic risk stratification for osteoporosis, but their incremental value beyond the Osteoporosis Self-Assessment Tool for Asians (OSTA) remains uncertain in referral-based practice. We evaluated whether serum uric acid, albumin, alkaline phosphatase (ALP), and systemic inflammatory indices improve prediction of DXA-defined osteoporosis beyond OSTA in postmenopausal women. Materials and Methods: This retrospective cross-sectional study included 3504 postmenopausal women referred for DXA between January 2021 and May 2025. Osteoporosis was defined as the lowest T-score ≤ −2.5 at the lumbar spine, total hip, or femoral neck. Sequential exclusions removed patients with chronic hepatobiliary disease, chronic systemic inflammatory disease, bone-active medication exposure, systemic glucocorticoid use, abnormal liver biochemistry, or missing required variables. Multivariable logistic regression assessed associations, and OSTA-based prediction models were internally validated using stratified 10-fold cross-validation. Results: Osteoporosis was present in 1660 women (47.4%). Higher BMI, uric acid, and albumin were independently associated with lower odds of osteoporosis, whereas ALP and calcium were associated with higher odds. OSTA alone achieved an AUC of 0.679. Adding uric acid, albumin, and ALP increased AUC to 0.695 and slightly improved the Brier score, with good calibration. Adding the systemic immune-inflammation index did not materially improve performance. Conclusions: Routine laboratory variables provided only modest incremental value beyond OSTA. The model should be interpreted as an exploratory referral-pathway prioritization approach, not as a standalone population-screening tool. It should not be used as a diagnostic surrogate for DXA or as a fracture-risk model. Full article

The respiratory system is directly exposed to various environmental factors, and specifically allergens and environmental pollutants, which are ligands/agonists of the aryl hydrocarbon receptor (AhR) and promote chronic lung diseases in humans. AhR, a ligand-activated transcription factor, is involved in the metabolism of xenobiotics, assigning their carcinogenic and toxic effects, and is also involved in normal homeostasis, organogenesis, and immune system function. Exogenous and endogenous AhR ligands are both high-molecular-weight compounds with a planar structure and low-molecular-weight compounds of diverse chemical structures. After entering the cell, the ligands bind to AhR and induce the activation of signaling cascades. The lung immune system responds to pathogens and environmental toxins first with a pro-inflammatory innate immune response, and then with an anti-inflammatory adaptive immune response. An imbalance between these immune systems may have an effect on the course of the disease. Activation of AhR by exogenous or endogenous ligands can affect this balance and lead to dysregulation of the immune response, leading to inflammatory complications in the lungs. Individual features of AhR expression or components of the AhR-dependent signaling pathway may also play a role in the superposition of the functions of these two links of immunity. This review summarizes advances in the comprehension of AhR’s role in immunomodulation and inflammatory responses in the lungs following data in experimental rodent models, in vitro studies utilizing lung structural cells and isolated immune cell lines, and humans. The molecular mechanisms of AhR’s regulation of immunity and inflammation and the potential of AhR as a therapeutic target for inflammatory lung disease are also considered. Full article

Adipose tissue remodeling is a dynamic process essential for metabolic homeostasis, enabling tissue expansion, extracellular matrix (ECM) turnover, angiogenesis, and coordinated immune adaptation. In obesity, however, maladaptive remodeling characterized by fibrosis, chronic low-grade inflammation, and hypoxia disrupts adipose plasticity and promotes systemic insulin resistance. Central to these processes is the tightly regulated homeostasis between proteases and their inhibitors, in which the serine protease inhibitor (serpin) superfamily represents an important yet underappreciated regulatory axis. Beyond their classical roles in coagulation and fibrinolysis, serpins regulate ECM remodeling, macrophage recruitment and polarization, cytokine signaling, angiogenic responses, adipokine activity, and insulin sensitivity, thereby orchestrating immune–metabolic crosstalk within adipose depots. Emerging evidence indicates that individual serpins exert distinct and context-dependent effects, with some promoting fibrosis, inflammation, and metabolic dysfunction, whereas others preserve adipose tissue homeostasis and metabolic function. This review synthesizes current knowledge on the structural and functional diversity of the serpin superfamily and examines their mechanistic roles in adipose tissue remodeling during obesity, with particular emphasis on how adipose-associated serpins regulate adipose tissue homeostasis, depot-specific remodeling, and immune–metabolic crosstalk. The review further discusses the experimental and translational applications of emerging single-cell and spatial transcriptomics, multi-omics, and computational approaches that may advance the understanding of serpin biology, improve the investigation of human adipose tissue, and accelerate the identification of clinically relevant serpin-related biomarkers and therapeutic targets for obesity and related metabolic disorders. By positioning serpins as key regulators of adipose tissue remodeling and immune–metabolic integration, this review highlights protease–antiprotease balance as a central determinant of metabolic health and identifies serpins as promising biomarkers and therapeutic targets for obesity and related metabolic disorders. Full article

Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent and now recognized as a systemic syndrome with diverse clinical phenotypes and multiorgan involvement. The predominant clinical phenotype has evolved from patients with isolated hypertensive heart disease to individuals with cardiometabolic (CM) abnormalities [obesity, insulin resistance, increased waist circumference (a surrogate for visceral adiposity), dyslipidemia, type 2 diabetes, and hypertension] that result in metabolic alterations leading to CM-HFpEF. Indeed, CM-HFpEF and metabolic dysfunction-associated fatty liver disease are recognized as two sides of the same coin. Chronic systemic inflammation is a defining pathophysiologic feature of CM-HFpEF, with visceral adipose tissue serving as a central driver. In this regard, lifestyle changes, including diet and exercise, are crucial for managing HFpEF. Several recent studies have shown that exercise training (aerobic and resistance combined) with or without calorie restriction is an effective therapeutic management strategy for improving exercise capacity, physical function, and quality of life in patients with clinically stable HFpEF. Also, the pharmacologic interventions that have proven beneficial in HFpEF so far (sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists) are effective due to their metabolic protective effects. In this review, we outline the current available evidence on lifestyle interventions in HFpEF management and therapeutics, discussing their modalities and potential mechanisms. Full article

Obesity is a major global health challenge strongly associated with increased cardiometabolic morbidity and mortality. In men, obesity is characterized by a predominance of visceral adiposity, which is metabolically active and closely linked to systemic inflammation, hormonal dysregulation, and adverse cardiovascular outcomes. Despite its clinical relevance, male obesity remains underrecognized as a distinct pathophysiological condition. This study aimed to analyze the inflammatory mechanisms underlying male obesity and their relationship with cardiometabolic risk. A structured narrative review was conducted based on a PICo-guided research question, with literature searches performed in PubMed/MEDLINE, Scopus, Web of Science, Embase, and ScienceDirect, covering publications from 2015 to 2026. Studies focusing on male obesity, inflammatory pathways, and cardiometabolic outcomes were included. Evidence indicates that visceral adipose tissue acts as an active endocrine organ, releasing pro-inflammatory cytokines such as TNF-α and IL-6, contributing to chronic low-grade inflammation. This inflammatory state is associated with insulin resistance (IR), endothelial dysfunction, and oxidative stress, mediated by intracellular pathways including NF-κB and JNK. Additionally, adipokine imbalance, characterized by reduced adiponectin and increased leptin levels, further exacerbates metabolic and vascular impairment. Hormonal alterations, particularly reduced testosterone levels, play a key role in amplifying visceral fat accumulation and inflammation, creating a bidirectional relationship between hypogonadism and metabolic dysfunction. Clinically, these mechanisms highlight the importance of integrating inflammatory biomarkers, body composition assessment, and hormonal evaluation into the management of male obesity. Emerging therapies, including GLP-1 receptor agonists and immunometabolic interventions, offer promising strategies for reducing cardiometabolic risk. In conclusion, male obesity represents a complex, inflammation-driven condition requiring a comprehensive and mechanism-based approach to improve clinical outcomes and guide future therapeutic developments. Full article

Mineralocorticoid receptor (MR) overactivation is a key driver of inflammation, fibrosis, and organ cross-talk across cardiorenal disease. Finerenone, a selective non-steroidal MR antagonist, has demonstrated robust renoprotective and cardioprotective benefits in patients with chronic kidney disease (CKD) and type 2 diabetes in large randomized clinical trials. Beyond its established role in diabetic kidney disease, emerging preclinical and clinical data suggest potential systemic effects through the attenuation of MR-driven inflammatory and fibrotic pathways. These include signals related to heart failure outcomes, atrial remodeling, pulmonary vascular biology, retinal microvascular integrity, and metabolic dysfunction. However, much of the evidence beyond established cardiorenal indications remains exploratory, based on preclinical studies, subgroup analyses, and post hoc evaluations. This review provides a critical synthesis of the established clinical evidence supporting finerenone in CKD and cardiovascular disease. It examines emerging, hypothesis-generating data regarding its potential systemic effects beyond diabetic kidney disease. Full article

Chronic coronary syndromes (CCSs) are increasingly recognized as complex immunometabolic vascular disorders in which coronary microvascular dysfunction (CMD), persistent low-grade inflammation, oxidative stress, and maladaptive cellular remodeling contribute to ischemic symptoms and adverse outcomes beyond epicardial stenosis. CMD represents a heterogeneous condition comprising both functional and structural endotypes and constitutes a major determinant of myocardial ischemia, heart failure progression, and adverse cardiovascular outcomes, even in the absence of obstructive coronary artery disease. Emerging evidence indicates that immunometabolic reprogramming of endothelial cells, vascular smooth muscle cells, and immune cells sustains microvascular dysfunction in CCSs. Metabolic shifts toward glycolysis, mitochondrial dysfunction, redox imbalance, and dysregulated lipid metabolism promote chronic inflammatory activation within the coronary microenvironment. Convergent mitochondrial stress (including NAD⁺ decline) and redox injury promote endothelial senescence and increase susceptibility to regulated cell death, progressively limiting vasodilatory reserve and predisposing to microvascular rarefaction. Pyroptosis and ferroptosis-like lipid peroxidation further exacerbate endothelial barrier disruption and inflammatory amplification. In parallel, inflammasome activation, iron-dependent lipid peroxidation, impaired autophagy, and endoplasmic reticulum stress form interconnected molecular networks that amplify vascular injury through self-reinforcing mechanisms. This narrative review integrates mechanistic and translational evidence linking immunometabolic dysregulation, mitochondrial stress, thromboinflammatory signaling, endothelial senescence, and regulated cell death to distinct CMD endotypes. We propose a systems-level framework in which coronary microvascular dysfunction is conceptualized as an immunometabolic vascular network disorder, with reduced coronary flow reserve (CFR)—often termed myocardial flow reserve (MFR) in PET studies—emerging as the integrative functional endpoint of these interacting molecular perturbations and a robust predictor of major cardiovascular events. Full article

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia and represents a major global public health concern due to its rapidly increasing prevalence. Although current pharmacological therapies effectively achieve glycemic control, their long-term use is limited by adverse effects, high costs, patient compliance issues, and increasing interest in safer, multi-targeted therapeutic strategies. In this context, plant-derived bioactive compounds have gained attention as complementary or alternative approaches to metabolic disease management. Gymnema sylvestre (Retz.) R.Br. ex Sm (GS), traditionally known as “gurmar” (“sugar destroyer”), is one of the most extensively studied medicinal plants with significant antidiabetic potential. This review evaluates the antidiabetic effects of G. sylvestre, focusing on its phytochemical composition, molecular mechanisms, and impact on diabetes-related complications. Major bioactive constituents, including triterpenoid saponins (gymnemic acids), gurmarin-like peptides, flavonoids, and sterols, regulate glucose homeostasis, inhibit intestinal glucose absorption, preserve pancreatic β-cell function, stimulate insulin secretion, modulate lipid metabolism, and suppress inflammatory signaling pathways. Experimental and clinical evidence indicates that G. sylvestre modulates oxidative stress and inflammation associated with complications such as nephropathy, neuropathy, retinopathy, vascular dysfunction, and dyslipidemia. This review adopts a mechanism-oriented framework integrating phytochemical structure–molecular target–metabolic outcome relationships and discusses emerging strategies, including nanotechnology-based delivery systems, molecular docking, and multi-component phytotherapy. Overall, G. sylvestre represents a promising multi-target phytotherapeutic agent, highlighting directions for future mechanistic and clinical research. Full article

Age-related decline in immune system function is characterized by reduced numbers of naïve lymphocytes, the accumulation of senescent cells, impaired function of all immune cell types, and chronic low-grade inflammation (inflammaging). These alterations contribute to increased susceptibility to infections and malignancies, as well as to autoimmunity and other age-associated diseases. This article reviews current evidence on lifestyle interventions that may mitigate immune aging. Lifestyle-related strategies, including regular physical activity, nutritional interventions (e.g., different diets, caloric restriction, and other fasting-related approaches), stress reduction, and vaccination, are discussed as key modulators of immune function and systemic inflammation. Notably, vitamin D supplementation has been shown to reduce the incidence of autoimmune diseases by 22%. In comparison, caloric restriction has led to a decrease in CRP and TNF-α by 40% and 50%, respectively. Emerging complementary approaches, such as mind–body practices and controlled cold exposure, show promise, though current evidence remains limited and inconsistent. Therefore, integrated lifestyle strategies may slow aging-related immune decline and support healthy aging. However, longitudinal trials are required to define the optimal intervention parameters, population-specific thresholds, and the long-term durability of immune rejuvenation. Full article

Chronic sleep deprivation (SD) disrupts gut–brain axis (GBA) homeostasis and is closely associated with gut microbiota dysbiosis, neuroinflammation, and depression-like behaviors. This study investigated whether fermentation enhances the antidepressant-like effects of Dendrobium officinale by comparing fermented Dendrobium officinale (FDO) with unfermented Dendrobium officinale (DO) in a chronic SD mouse model. FDO significantly ameliorated anxiety and depressive-like behaviors in SD mice. It reshaped gut microbial structures, enriched beneficial bacteria taxa such as Dubosiella, [Eubacterium]_coprostanoligenes_group, and Allobaculum, and increased SCFA levels. FDO also enhanced colonic ZO-1 and Occludin expression and reduced serum levels of LPS and the pro-inflammatory cytokines. At the central nervous system level, FDO inhibited the activation of hippocampal microglia and astrocytes; alleviated neuroinflammation; restored hippocampal TPH2, 5-hydroxytryptamine (5-HT), and 5-HIAA levels; and modulated the 5-HT_1A/5-HT_2A receptor balance. In addition, FDO upregulated BDNF, PSD-95, and SYN expression and reduced corticosterone (CORT) levels. Compared with DO, FDO showed more pronounced regulatory effects. Correlation analysis suggested that 5-HT may link gut microbial metabolites, inflammation, and synaptic plasticity. In summary, these findings support FDO as a potential GBA-targeted functional food for SD-related depressive-like behaviors. Full article

Acute kidney injury, a broad term associated with diverse etiologies, is a common pathological condition that develops into chronic disease via mechanisms that have yet to be fully understood. Key processes that promote chronic disease transition include mitochondrial dysfunction and aberrant complement system activation, specifically inducing inflammation and accumulation of pro-fibrotic changes. Although emerging evidence strongly indicates that these two processes are closely intertwined, identification of appropriate therapeutic targets remains limited. Among complement proteins, terminal portions of the cascade, including complement 5 (C5), exert particularly robust effects on mitochondrial function across tissues, including the kidney. Moreover, C5 is the most terminal portion of the cascade to produce a highly pro-inflammatory anaphylatoxin, positioning C5 as an ideal clinical target during kidney injury/disease. In this review, we will hence summarize current knowledge regarding mitochondrial contributions to kidney pathophysiology through the lens of the close relationship between mitochondria and the complement system, particularly C5. Full article

Chronic rhinosinusitis (CRS) constitutes a multicausal inflammatory disease of the nose and paranasal sinuses, often associated with olfactory dysfunction (OD), a symptom that significantly impacts patients’ quality of life. OD in CRS was traditionally thought to be related to mechanical obstruction of the olfactory cleft, but is now considered to be multifactorial, involving conductive, inflammatory, and sensorineural mechanisms as well. Type-2 inflammatory response (high interleukins IL-4, IL-5, IL-13), eosinophilia, and increased IgE are involved in epithelial damage, impaired neurogenesis, and persistent olfactory loss, especially in chronic rhinosinusitis with nasal polyps (CRSwNP). In addition, peripheral chronic inflammation may also play a role in central neural remodeling, which may potentially affect olfactory function. Objective psychophysical testing is necessary to accurately assess olfactory function because self-reports may lack reliability. Management strategies aim at reducing inflammation and restoring sinonasal ventilation. First-line therapy with intranasal corticosteroids and short courses of systemic corticosteroids may be useful for symptomatic relief. Biologic agents directed against type-2 inflammation have demonstrated significant benefits in selected cases. Functional Endoscopic Sinus Surgery (FESS) plays an important role in the treatment of refractory CRS to restore the airflow and to improve the delivery of topical drugs. Olfactory outcomes following surgery, however, are variable and often incomplete, reflecting underlying inflammation and neuroepithelial damage. Disease recurrence, especially in type-2–driven CRS, affects long-term outcomes, underscoring the necessity to incorporate surgery in an individualized, endotype-informed treatment strategy. Full article