Search Results (8,622)

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

Dietary factors, including the consumption of isoflavones-rich foods of plant origin, may contribute to the reduced incidence of prostate cancer. Isoflavones, natural phytoestrogens often found in legumes, can modulate estrogen and androgen receptor signaling. This study aimed to evaluate the biological potential of isoflavone-rich extracts obtained from twelve species from the Fabaceae family, targeting prostate cancer cell viability, proliferation, inflammatory markers, prostate-specific antigen secretion, and 5α-reductase activity. The tested extracts showed moderate cytotoxic activity against prostate cancer cell lines, apart from highly susceptible PC3 cells, and only weak toxicity to normal prostate epithelial cells. Significant antiproliferative activity was observed, especially for Cytisus scoparius, Ononis arvensis, and Genista tinctoria, while most extracts reduced prostate-specific antigen (PSA) secretion in normal prostate cells. Furthermore, the extracts showed anti-inflammatory properties by reducing the pro-inflammatory cytokine interleukin 6 (IL-6) and improving cytokine balance indices. Multivariate analyses revealed correlations between total isoflavone content and antiproliferative activity. Full article

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal barrier disruption and dysregulated immune responses. While Intravenous Immunoglobulin (IVIG) is widely used for its immunomodulatory effects in various autoimmune conditions, its specific therapeutic mechanisms and molecular targets in colitis remain to be fully elucidated. Objective: To elucidate the therapeutic mechanisms of IVIG in dextran sodium sulfate (DSS)-induced colitis, with a focus on pyroptosis regulation via the NOD-like receptor (NLR) signaling pathway. Methods: Colitis was induced in mice via DSS administration. IVIG was administered intravenously during disease progression. Colon tissues underwent proteomic profiling, and key targets (GBP5, NLRP3, Pro-Caspase-1, GSDMD) were validated by Western blotting (WB), while interleukin (IL)-1β and IL-18 levels were quantified via ELISA. Results: IVIG significantly attenuated weight loss, Disease Activity Index (DAI) scores, colon shortening, and histopathological damage. Proteomics analysis identified 172 differentially expressed proteins between DSS and DSS + IVIG groups, with pronounced downregulation of GBP5 and NLR pathway components. IVIG suppressed GBP5/NLRP3/CASP1 activation, reduced GSDMD cleavage, and significantly decreased IL-1β production (while showing a decreasing trend for IL-18). Conclusions: IVIG ameliorates colitis by inhibiting the GBP5/NLRP3/CASP1-mediated pyroptosis pathway, highlighting its potential as a targeted therapy for ulcerative colitis. Full article

Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson–Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or viral genomes act as damage-associated molecular patterns. These stimuli activate innate and adaptive immune cascades, notably the Toll-like receptors, the NF-κB pathway, and the NLRP3 inflammasome. This immune activation establishes a pro-inflammatory microenvironment that promotes fibroblast reprogramming, myocardial edema, and progressive fibrotic or fibro-fatty remodeling. Inflammation is an active, core pathophysiological mechanism rather than a passive secondary bystander in cardiomyopathies. Recognizing these shared immune pathways provides a framework for improved risk stratification and highlights the potential for targeted immunomodulatory therapies to alter disease trajectories. Full article

Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, restores hyperglycemic conditions in patients with type 2 diabetes and has recently shown promising anti-inflammatory properties. In this study, we explored its potential to suppress osteoclast formation and bone loss triggered by lipopolysaccharide (LPS), an inflammatory agent. In animal models, the co-administration of liraglutide with LPS on the calvaria regions in mice markedly reduced osteoclast numbers and bone resorption areas relative to treatment with LPS alone. Furthermore, the expression levels of receptor activators of the NF-κB ligand (RANKL) and tumor necrosis factor (TNF)-α mRNA were notably lower in the group receiving liraglutide and LPS compared to treatment with LPS alone. Moreover, in vitro tests revealed that liraglutide has no direct inhibitory effect on RANKL-induced osteoclastogenesis and TNF-α-induced osteoclastogenesis. In addition, liraglutide had no direct inhibitory effect on LPS-stimulated RANKL expression in osteoblasts. Moreover, liraglutide effectively suppressed TNF-α mRNA expression in macrophages stimulated by LPS. These findings suggest that liraglutide prevents inflammatory bone destruction not by targeting osteoclast formation directly but by inhibiting the production of TNF-α within macrophages. Full article

Bitter phytochemicals, including alkaloids, terpenoids, and bitter glycosides, are abundant in medicinal food plants and exhibit well-documented anti-inflammatory, hypoglycemic, and other bioactivities relevant to human health. However, the inherent bitterness of these compounds presents a significant sensory barrier to patient compliance and limits their application as functional food ingredients. This review provides a comprehensive and interdisciplinary synthesis of current knowledge on bitter compounds in medicinal food plants, integrating perspectives from phytochemistry, molecular pharmacology, and sensory science. We summarize the major chemical classes of bitter phytochemicals, critically evaluate methods for their isolation and identification—from classical sensory-guided fractionation to modern computational approaches such as molecular docking and metabolomics—and analyze three principal strategies for bitterness regulation: physical removal, biological transformation, and sensory modulation (including molecular inclusion and TAS2R receptor blocking). We also briefly touch upon the extraoral expression of TAS2Rs and there suggested links to local immune responses and metabolic regulation, noting that this may be relevant to the concept of “taste–bioactivity homology.” The review further highlights ongoing challenges, such as the identification of unknown bitter compounds and the lack of standardized sensory evaluation systems, and outlines possible directions for improving bitterness analysis and regulation in medicinal food plants. Full article

Background: Adipose tissue is increasingly recognized as a highly dynamic endocrine and immunometabolic organ with marked functional heterogeneity. It serves as a reservoir for the active form of vitamin D₃, 1α,25-dihydroxyvitamin D₃ or calcitriol (1α,25-D₃), since it expresses enzymes responsible for its activation and inactivation and contains the vitamin D receptor (VDR). Through both classical and non-classical mechanisms, calcitriol modulates adipocyte proliferation and differentiation, protein expression and energy metabolism. This review aims to explore the signal transduction mechanisms of calcitriol in adipocytes, detailing the classical pathways mediated by the nuclear VDR (VDRn), as well as non-classical pathways involving membrane-associated VDR (VDRm), microRNAs, AMP-activated protein kinase (AMPK), and sirtuin 1 (SIRT1). Methods: A literature search was conducted using PubMed, ScienceDirect, and MDPI-indexed journals, prioritizing studies published within the last 10 years to ensure the inclusion of up-to-date evidence. Results: This review summarizes current knowledge on both classical and non-classical signaling pathways that are activated by calcitriol and highlights key molecular targets with potential relevance for drug development and therapeutic intervention. Through VDRn, calcitriol regulates the expression of proteins involved in inflammation and energy metabolism. Additionally, it modulates cellular processes such as energy production and secretion via the AMPK/SIRT1 axis and microRNA-mediated pathways, contributing to mitochondrial function and metabolic homeostasis. Conclusions: Calcitriol plays a central role in adipocyte biology by integrating multiple signaling pathways that regulate metabolic and inflammatory responses. These mechanisms highlight its potential as a therapeutic target and biomarker in metabolic diseases. Moreover, microRNAs emerge as critical posttranscriptional regulators in these processes, reinforcing their relevance as both biomarkers and targets for future interventions. Full article

Background/Objectives: Bitter taste receptors (T2Rs), specifically T2R38, are present in the respiratory epithelium and react with bacterial quorum-sensing molecules to induce an innate immunity response. Although TAS2R38 polymorphisms have been correlated with susceptibility to chronic rhinosinusitis (CRS), they have not yet been explored in odontogenic rhinosinusitis (ORS), a distinct form of CRS with particular microbial and inflammatory features. We aim to establish a proof-of-concept methodology for investigating TAS2R38 genetic variants in ORS using direct maxillary sinus tissue analysis and demonstrate the feasibility of this translational approach. Methods: We conducted a prospective pilot case–control study of 36 ORS patients and 37 controls undergoing septoplasty without sinonasal disease. Maxillary sinus mucosal biopsies were obtained intraoperatively with informed consent. Genomic DNA was extracted using the PureLink Genomic DNA Mini Kit and quantified via NanoDrop spectrophotometry. TAS2R38 haplotypes were determined and classified as taster (PAV/PAV), non-taster (AVI/AVI), or intermediate (PAV/AVI) phenotype. Results: Among fully classifiable canonical TAS2R38 phenotypes (32 ORS patients, 28 controls), distributions were: tasters 12.5% vs. 25.0%, non-tasters 31.3% vs. 25.0%, and intermediate 56.3% vs. 50.0%. AVI/AVI non-taster status was not significantly associated with ORS susceptibility (OR = 1.36, 95% CI: 0.44–4.25; Fisher’s exact p = 0.775). Conclusions: This proof-of-concept study demonstrates that genotyping-grade genomic DNA can be recovered from acutely inflamed maxillary sinus mucosa, validating this substrate for future tissue-based expression, functional, and microbiome analyses not obtainable from peripheral samples; germline genotyping itself does not require sinus tissue. The observed difference in non-taster prevalence (31.3% vs. 25.0%) did not reach statistical significance and is reported descriptively. This directional trend is hypothesis-generating only and, given the limited statistical power, does not constitute evidence for an association. The demonstrated feasibility, together with the established biological rationale, supports an adequately powered confirmatory study and lays the foundation for future investigation of taste receptor genetics in ORS pathogenesis, and potentially personalized therapeutic strategies. Full article

Prostate cancer remains a major therapeutic challenge, particularly after progression to castration-resistant disease, where persistent androgen receptor signaling, metabolic adaptation, immune escape, and treatment resistance jointly limit clinical benefit. Regulated cell death (RCD) is increasingly recognized not only as an endpoint of tumor cell elimination but also as a dynamic regulator of prostate cancer progression, therapeutic vulnerability, and tumor–immune interactions. In this review, we propose an immunometabolic framework in which androgen receptor signaling, lipid and redox metabolic reprogramming, oxidative stress, and therapeutic pressure converge to shape the susceptibility of prostate cancer cells to distinct RCD modalities. We focus on autophagy and ferroptosis as two extensively studied and translationally relevant pathways, while also discussing emerging roles of necroptosis, pyroptosis, and cuproptosis. Particular attention is given to how RCD-associated signals, including damage-associated molecular patterns, inflammatory mediators, and lipid peroxidation products, may remodel the tumor immune microenvironment and influence the transition between immune-cold and immune-inflamed phenotypes. We further summarize RCD-targeted therapeutic strategies, including ferroptosis induction, autophagy inhibition, nanodrug delivery systems, rational combination therapy, and biomarker-guided patient stratification. Finally, we discuss key translational barriers, including context-dependent biological effects, limited clinical validation, tumor heterogeneity, adaptive resistance, and insufficient predictive biomarkers. By integrating cell death biology with metabolic reprogramming, immune remodeling, and therapeutic resistance, this review highlights RCD as a promising but context-dependent therapeutic vulnerability in advanced prostate cancer. Full article

Earthworms possess a highly developed innate immune system based on the coordinated activity of coelomocytes and humoral factors present in the coelomic fluid. These immune components play a central role in host defence against pathogens, maintenance of physiological homeostasis, and adaptation to environmental stressors. Coelomocytes exhibit remarkable functional and morphological diversity, including participation in phagocytosis, encapsulation, extracellular trap formation, cytotoxic responses, wound healing, and regulation of oxidative and osmotic stress. In addition, coelomic fluid contains numerous biologically active molecules, such as lysenin, coelomic cytolytic factor 1, perforin, serine proteases, lysozyme, antimicrobial peptides, and pattern recognition receptors, which contribute to cellular and humoral immune responses. Recent studies have demonstrated that earthworm coelomocytes are highly sensitive to environmental pollutants, including heavy metals, pesticides, nanomaterials, and microplastics, highlighting their importance in ecotoxicological research and soil biomonitoring. Furthermore, antifungal, antimicrobial, anti-inflammatory, antipyretic, and cytotoxic activities associated with coelomocytes and coelomic fluid suggest promising applications in agriculture, biotechnology, and pharmaceutical research. This review summarises current knowledge regarding the classification, characteristics, immune functions, toxicological responses, and applied significance of earthworm coelomocytes and coelomic fluid, with particular emphasis on their role in environmental monitoring and potential biomedical applications. Full article

Background/Objectives: Enzalutamide and abiraterone acetate are commonly used androgen receptor pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC), including after docetaxel. However, real-world outcomes remain heterogeneous, and simple prognostic markers may help describe this variability. This study aimed to describe survival outcomes with enzalutamide and abiraterone acetate after docetaxel and to explore the prognostic value of a routine clinical-inflammatory risk classification. Methods: This retrospective single-center study included 136 patients with mCRPC treated with enzalutamide or abiraterone acetate after docetaxel. A composite risk classification was defined using four routinely available variables: pan-immune-inflammation value (PIV) > 457.99, time to castration resistance < 12 months, baseline hemoglobin ≤ 12 g/dL, and Gleason score ≥ 8. One point was assigned for each adverse factor, and patients were classified as low, moderate, or high risk. Overall survival (OS) was assessed using Kaplan–Meier estimates and Cox regression. The prognostic score and Cox regression-based nomogram were evaluated as exploratory tools. Results: Of the 136 patients, 8 (5.9%) were classified as low risk, 67 (49.3%) as moderate risk, and 61 (44.9%) as high risk. Median OS was not reached in the low-risk group, compared with 33.84 months in the moderate-risk group and 9.66 months in the high-risk group. In multivariable analysis, high-risk status was independently associated with worse OS (HR = 9.87; 95% CI: 2.38–40.92; p = 0.002). No statistically significant OS difference was observed between enzalutamide and abiraterone acetate in this non-randomized cohort (HR = 1.36; 95% CI: 0.90–2.06; p = 0.142). Conclusions: In this real-world post-docetaxel mCRPC cohort, no statistically significant OS difference was observed between enzalutamide and abiraterone acetate; however, the study was not designed to establish comparative effectiveness or therapeutic equivalence. The exploratory risk classification based on routine clinical and inflammatory variables was associated with distinct survival outcomes. External validation is required before clinical application. 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

Growth hormone-releasing hormone (GHRH) antagonists have displayed anti-neoplastic activity against a multitude of cancers in vitro, as well as in vivo, via xenografted tumors in nude mice. Following a successful demonstration of GHRH antagonists treating non-Hodgkin’s lymphoma and the discovery of GHRH mRNA and peptide products in immune cells, GHRH antagonism was explored in acute myeloid leukemia (AML), a disease characterized by a malignant expansion of immature myeloid progenitors, and poor 5-year survival. Targeted therapies have yielded breakthroughs in treatment response and overall survival, such as all-trans retinoic acid/arsenic trioxide (ATRA/ATO) for acute promyelocytic leukemia (APL), or FLT3 inhibitors, IDH inhibitors, and menin inhibitors for AML harboring actionable genetic lesions. However, therapeutic resistance remains a major barrier to durable remission. GHRH receptor (GHRH-R) has been reported in several experimental models of AML, including drug-resistant sublines. Significant time- and dose-dependent reduction in leukemic growth was observed in vitro and in vivo following MIA-602 treatment. FLT3 inhibitor resistance has been associated with activation of PI3K/AKT, ERK/MAPK, inflammatory, stromal, and apoptotic escape pathways. The documented effects of GHRH-R antagonism raise the possibility that it could influence signaling networks relevant to therapeutic resistance in AML. This hypothesis remains speculative; to date no studies have stratified AML by FLT3 status in the context of GHRH-R expression or GHRH antagonism, and there is currently no evidence that MIA-602 directly alters FLT3 receptor signaling or inhibitor sensitivity. Full article

Cross-presentation of exogenous antigens by dendritic cells (DCs) relies on the cytosolic pathway, enabling proteasomal processing and subsequent loading of antigenic peptides onto major histocompatibility complex class I (MHC-I) molecules. Although this pathway is central to CD8⁺ T-cell activation, the molecular mechanisms that regulate intracellular antigen processing and redistribution during cross-presentation remain incompletely defined. In this study, we investigated the contribution of the large-pore channel Pannexin-1 (Panx1) to antigen handling during cross-presentation. Using confocal microscopy and quantitative image analysis in granulocyte–macrophage colony-stimulating factor/interleukin-4 (GM-CSF/IL-4)-derived inflammatory bone marrow-derived dendritic cell (BMDC)-like cellsexposed to ovalbumin (OVA)–Alexa Fluor 488, we observed time-dependent changes in intracellular antigen distribution that were altered upon pharmacological inhibition of Panx1 with the blocking peptide 10Panx1. In parallel, functional assays revealed that Panx1 inhibition significantly reduced SIINFEKL peptide-dependentactivation of B3Z CD8⁺ T-cell hybridomas following pulsing with full-length OVA. Similar effects were observed in the cross-presentation-competent MUTU1940 dendritic cell line. Importantly, Panx1 inhibition did not significantly affect dendritic-cell viability or LPS-induced activation under the experimental conditions tested. In contrast, pharmacological inhibition or genetic deficiency of P2X7 receptor (P2X7) did not produce comparable reductions in cross-presentation, and combined inhibition did not result in additive effects under the experimental conditions tested. Together, these findings provide functional evidence supporting a role for Panx1 in regulating intracellular antigen redistribution associated with cross-presentation. While not establishing direct genetic causality, our data identify Panx1 as a modulatory component influencing antigen-processing events that culminate in CD8⁺ T-cell activation, thereby expanding the current framework of intracellular antigen-processing mechanisms involved in dendritic-cell-mediated cross-presentation. Full article