Search Results (11,612)

Atherosclerotic cardiovascular disease (ASCVD) is increasingly recognized not merely as a lipid-storage disorder but as a chronic, lipid-driven inflammatory condition of the arterial wall. Despite the widespread use of statins and other lipid-lowering therapies, a substantial “residual inflammatory risk” persists, propelling the search for targeted immunopharmacological interventions. At the forefront of this inflammatory cascade is the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which serves as a central orchestrator of vascular inflammation by linking metabolic dysregulation to the innate immune response. Atherogenic danger signals—such as oxidized low-density lipoprotein (ox-LDL) and cholesterol crystals—trigger NLRP3 activation through reactive oxygen species (ROS) generation, lysosomal rupture, and potassium efflux. This, in turn, drives the maturation of pro-inflammatory cytokines (IL-1β and IL-18) and initiates macrophage pyroptosis. In this review, we systematically evaluate the immunomodulatory potential of natural products—both complex extracts and single bioactive compounds—in inhibiting the NLRP3 inflammasome axis. We detail the pharmacological mechanisms by which these natural agents intercept inflammatory signaling at multiple stages: suppressing TLR4/NF-κB-mediated priming, scavenging mitochondrial ROS, and restoring autophagic flux via AMPK/mTOR pathways to prevent inflammasome assembly. By critically analyzing these pathways, we highlight natural product-derived inhibitors as a promising class of immunomodulators capable of attenuating atherosclerotic progression and addressing the persistent challenge of residual inflammatory risk. Full article

Background: Post-cardiac arrest syndrome (PCAS) following out-of-hospital cardiac arrest (OHCA) is driven by global ischemia–reperfusion injury, endothelial dysfunction, and a dysregulated inflammatory response. This cascade frequently culminates in profound vasoplegia and multiorgan failure, even when guideline-directed post-resuscitation management is applied. Hemoadsorption using the CytoSorb device may attenuate hyperinflammation and vasoplegia by removing circulating inflammatory and injury-related mediators. Methods: This single-centre, retrospective cohort study compared adults with PCAS following OHCA who received hemoadsorption with propensity score-matched controls (1:1 matching; n = 50 per group). For patients treated with hemoadsorption, data were analyzed within predefined intervals covering the 24 h preceding therapy initiation (T1) and the 24 h following the completion of the hemoadsorption treatment period (T2). Controls were evaluated at time points aligned to those of their matched hemoadsorption counterparts. Hemodynamic, metabolic, respiratory, and organ injury markers were assessed. Results: Formal between-group comparisons of temporal change between T1 and T2 showed no statistically significant differences between hemoadsorption-treated patients and matched controls across key parameters, including VIS (Δ −18.7 vs. −7.7; p = 0.183) and lactate (Δ −1.8 vs. −1.25 mmol/L; p = 0.780), as well as markers of organ injury, pH, and oxygenation. In exploratory ANCOVA models, only base excess was associated with treatment group (p = 0.035). Survival to hospital discharge was comparable (48% vs. 40%; p = 0.423), with similar neurological outcomes. Within the hemoadsorption group, pre–post comparisons around hemoadsorption initiation (T1–T2) demonstrated marked improvements, including reduced vasoactive support (VIS 70.0 to 12.1; p = 0.039), substantial lactate clearance (4.1 to 1.1 mmol/L; p < 0.001), and declines in organ injury markers (AST, ALT, LDH, myoglobin), alongside more pronounced platelet reduction compared with controls (129 to 57 × 10³/µL vs. 189 to 123 × 10³/µL). However, adjusted analyses indicated that these changes were primarily driven by baseline shock severity rather than a treatment-specific effect. Conclusions: In this propensity score-matched cohort of PCAS patients after OHCA, hemoadsorption was associated with within-group physiological changes but showed no detectable advantage over matched controls, with similar survival. These findings are hypothesis-generating and warrant prospective studies with standardized timing and phenotype-guided patient selection. Full article

Saskatoon berry (SB), a traditional food of Indigenous people, has been associated with cardiometabolic benefits in animal models; however, its effects on humans remain unclear. This study investigated the effects of dried SB consumption on cardiometabolic outcomes, gut microbiota, and short-chain fatty acids (SCFAs) profiles in healthy adults. In a 10-week, single-arm, and open-label trial, 20 healthy adults consumed 40 g/day of freeze-dried whole SB. Biochemical measures, physical exams, dietary records, participant feedback, and fecal samples were collected before and after the intervention. Gut microbiota composition and fecal SCFAs were profiled using 16S-rRNA sequencing and gas chromatography–mass spectrometry, respectively. SB intake significantly reduced fasting plasma glucose, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), non-high-density lipoprotein-cholesterol (non-HDL-c), systolic blood pressure, and high-sensitivity C-reactive protein, while increasing dietary fiber intake. Fiber intake was negatively correlated with TC, LDL-c and non-HDL-c (p < 0.05). The relative abundance of fecal Prevotellaceae increased after SB consumption and was positively correlated with multiple fecal SCFAs (p < 0.05–0.0001), while being negatively associated with lipid profiles and blood pressure. No adverse cardiovascular, hepatic, or renal dysfunction were observed; however, the significant increase in sugar intake may pose a risk for elevated blood glucose. Therefore, limiting other high-sugar foods during SB supplementation may be advisable for individuals with glucose intolerance. Overall, SB intake improved glucose and lipid metabolism and lowered blood pressure and inflammatory markers in healthy adults. These cardiometabolic benefits may be mediated by fiber and anthocyanins in SB and through modulation of gut microbiota and SCFA production; however, further confirmation is needed in subsequent randomized controlled trials. Full article

Skin wound management in veterinary medicine requires therapies able to control inflammation, limit microbial burden, and support tissue repair. This study evaluated the anti-inflammatory, wound-healing, and immunomodulatory effects of four novel topical formulations combining synthetic anti-inflammatory drugs, antibiotics, and plant extracts in rat experimental models. Burn injury was induced in male Wistar rats for wound-healing assessment, while kaolin- and dextran-induced paw edema models were used to assess anti-inflammatory activity. The tested formulations were meloxicam, dexamethasone, and levofloxacin; thyme extract with meloxicam and dexamethasone; burdock extract with dexamethasone and levofloxacin; and thyme extract combined with burdock extract. Wound evolution was monitored macroscopically, edema was quantified by plethysmometry, and selected inflammatory mediators were measured by immunoassay. In the burn model, the thyme-containing formulation with meloxicam and dexamethasone, and the thyme–burdock formulation, achieved complete wound closure by the end of follow-up, whereas the reference product did not. In the acute inflammation models, all innovative formulations significantly reduced edema at the main early time points compared with the negative control and outperformed the reference product. The thyme–burdock formulation also showed the most favorable immunomodulatory profile, including normalization of interleukin-10 and marked reduction in interleukin-1 beta in both models. These results support the potential of multi-component topical formulations, particularly plant extract-based combinations, as promising candidates for veterinary wound care. Full article

This narrative review examines topical anti-inflammatory therapies in veterinary medicine through the lens of the One Health framework, integrating pharmacology, dermatology, ecotoxicology, food safety, and regulatory science. It discusses the interconnected roles of veterinarians, pharmacists, environmental scientists, public health authorities, and regulatory bodies in addressing antimicrobial resistance, environmental contamination, zoonotic transmission, and drug residues in food-producing animals. By emphasising cross-sector collaboration, the review highlights how coordinated strategies can enhance animal welfare, safeguard human health, and reduce ecological burden. The article analyses inflammatory conditions in companion and farm animals and compares systemic versus topical anti-inflammatory approaches. Particular attention is given to corticosteroids, NSAIDs, immunomodulators, pro-resolving lipid mediators, and plant-derived bioactives, alongside advances in vehicles such as lipid nanocarriers and biodegradable film-forming systems designed to minimise systemic absorption and environmental dispersion. Regulatory considerations, residue control, pharmacovigilance gaps, and sustainability-oriented formulation strategies are critically addressed. Topical anti-inflammatory therapies, when rationally designed and monitored under One Health principles, represent a strategic opportunity to improve therapeutic precision while limiting systemic toxicity and ecological impact. Future directions should prioritise translational research, eco-compatible formulation design, and harmonised regulatory frameworks. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by immune dysregulation that leads to widespread inflammation and damage across multiple organs. B lymphocytes play a vital role in SLE, with abnormal development and activation leading to autoreactive antibody production and immune complex formation, which damages tissues. Methods: The PPARα agonist WY14643 has anti-inflammatory effects in various inflammatory conditions, including CNS diseases. We investigated whether WY14643 decreases inflammatory mediator production in CD45R⁺ cells in the MRL/lpr mouse model of SLE. Flow cytometry was used to evaluate WY14643’s impact on the expression of IFN-γ, IL-6, iNOS, MCP-1, IL-1α, IL-2, Notch-1, Notch-3, GITR, and NF-κB p65 in splenic CD45R⁺ B cells. Additionally, we assessed the effect of WY14643 on the mRNA levels of these markers in the kidney using RT-PCR. Results: WY14643 decreased inflammatory markers such as CD45R⁺IFN-γ⁺, CD45R⁺IL-6⁺, CD45R⁺iNOS⁺, CD45R⁺MCP-1⁺, CD45R⁺IL-1α⁺, CD45R⁺IL-2⁺, CD45R⁺Notch1⁺, CD45R⁺Notch3⁺, CD45R⁺GITR⁺, and CD45R⁺NF-κB p65⁺ in splenic cells from MRL/lpr mice. Furthermore, WY14643 also lowered mRNA expression of IFN-γ, IL-6, iNOS, MCP-1, IL-2, IL-1α, Notch-1, Notch-3, GITR, and NF-κB p65 in the kidney. Conclusions: This study shows that WY14643 inhibits the production of inflammatory mediators and significantly reduces autoimmune features, including kidney inflammation, in MRL/lpr mice. Our results indicate that WY14643, a PPAR-α agonist, could be a potential therapy for lupus nephritis. Full article

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a systemic metabolic disorder characterized by impaired metabolic flexibility involving the liver, skeletal muscle, and adipose tissue. Although weight loss has traditionally been emphasized in its management, emerging evidence suggests that exercise exerts therapeutic effects beyond body weight reduction. This narrative review aims to examine exercise as a metabolic therapy for MASLD by integrating mechanistic insights and clinical evidence. Exercise improves hepatic steatosis, insulin resistance, mitochondrial function, and inflammatory signaling through interconnected pathways, including activation of AMPK-related signaling, enhanced fatty acid oxidation, and muscle–liver crosstalk mediated by myokines. Importantly, these benefits can occur independently of weight loss, supporting a shift from weight-centered to metabolism-focused treatment strategies. Both aerobic and resistance exercise demonstrate efficacy, with combined approaches providing complementary benefits. In conclusion, exercise should be considered a central therapeutic strategy for MASLD by restoring metabolic flexibility rather than solely promoting weight reduction. Future research should focus on optimizing individualized and sustainable exercise prescriptions to enhance long-term clinical outcomes. Full article

Neuropsychiatric conditions constitute a major and growing global health burden, with prevalence rates that continue to rise worldwide. Although these disorders have traditionally been studied primarily from a neuronal perspective, accumulating evidence indicates that immune dysregulation and inflammatory processes play a central role in their pathophysiology. In this review, we advance the hypothesis that nitric oxide (NO)-mediated alterations in blood–brain barrier (BBB) integrity represent a critical mechanistic link between inflammation and central nervous system dysfunction in neuropsychiatric disorders. NO is a gaseous multifunctional signaling molecule involved in vascular homeostasis and immune responses, and its dysregulated production, together with aberrant protein S-nitrosylation, has been implicated in several neuropsychiatric conditions. However, the specific mechanisms by which NO signaling contributes to BBB dysfunction remain incompletely defined. Here, we synthesize current evidence supporting a role for NO-dependent vascular and inflammatory pathways in BBB disruption and discuss how these processes may contribute to the onset and progression of neuropsychiatric conditions. Clarifying these mechanisms may provide novel insights into disease pathogenesis and identify therapeutic targets aimed at preserving BBB integrity and limiting neuroinflammation. Full article

Background/Objectives: Atopic dermatitis (AD)-related skin inflammation involves the release of cytokines and chemokines from keratinocytes; therefore, keratinocyte-based models are widely used to evaluate the anti-inflammatory potential of botanical extracts. This study examined the relationship between phytochemical profiles and anti-inflammatory potential of baobab fruit 30% and 70% ethanol extracts (BE-30 and BE-70, respectively) in a TNF-α/IFN-γ (TI)-stimulated HaCaT keratinocyte model. Methods: The anti-inflammatory effects of both extracts were evaluated by measuring cytokine and chemokine secretion in TI-stimulated HaCaT cells. Phytochemical characterization was performed using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and targeted high-performance liquid chromatography (HPLC). Results: Both extracts were non-cytotoxic. TI-stimulation markedly increased interleukin (IL)-6, IL-8 and monocyte chemotactic protein (MCP)-1 secretion, while BE-30 and BE-70 significantly reduced all three mediators in a dose-dependent manner. At comparable doses, BE-70 exhibited greater inhibition than BE-30. BE-30 showed a non-monotonic IL-8 response at low concentrations, whereas BE-70 consistently reduced IL-8 in a dose-dependent manner. LC–MS/MS profiling revealed a polyphenol-rich composition, including flavonol glycosides and related phenolic compounds. HPLC confirmed the presence of four marker analytes (procyanidin B2, epicatechin, rutin and tiliroside), which were enriched in BE-70. The content of these four polyphenols was 1.94-fold higher in BE-70. Conclusions: Baobab fruit extracts exhibit anti-inflammatory activity associated with polyphenols. These findings suggest that they could be used as analytical standards and in dermatological applications. Full article

Activating PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3Kα-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3Kα-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3Kα inhibitor-induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 μM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (ΔΨm) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2) were quantified by ELISA. Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3-mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. This study provides evidence that alpelisib-based therapy under hyperglycemic conditions is associated with oxidative, mitochondrial, and inflammatory stress responses in human cardiomyocytes, recapitulating key features of cardiometabolic stress relevant to PI3Kα-targeted therapy. Importantly, dapagliflozin markedly attenuated these alterations, supporting a potential cardioprotective role that may extend beyond glycemic control. These findings provide a mechanistic rationale for further investigation of SGLT2 inhibition as a cardiometabolic protective strategy in patients receiving PI3Kα inhibitor-based cancer therapy. Full article

Despite the identification of several mediators of arteriogenesis, the growth of natural bypass, the role of lymphocytes, particularly T cells, in this process remains poorly defined. Among these, γδ T cells, which express alternative T cell receptors, have emerged as a key immune component. This study examined the roles of αβ and γδ T cells in arteriogenesis using a murine hindlimb model. While the absence of αβ T cells did not affect arteriogenesis, γδ T cell depletion markedly reduced vascular cell proliferation and perfusion recovery. Early phase analyses revealed impaired mast cell activation, whereas platelet–neutrophil aggregates and neutrophil extravasation were unaffected. In the later proliferative phase, γδ T cell depletion hindered perivascular M2-like (MRC1⁺) macrophage accumulation. Flow cytometric analysis of whole blood in wildtype mice revealed a temporal shift in γδ T cell populations from a CD27⁺/CD39⁻ phenotype, commonly associated with pro-inflammatory functions and IFNγ production, to CD39⁺ phenotypes, which have been linked to anti-inflammatory properties and IL-10 production. In rescue experiments, administration of IFNγ to γδ T cell-depleted mice restored mast cell activation, whereas IL-10 treatment reestablished M2-like (MRC1⁺) macrophage accumulation. These findings collectively identify γδ T cells as critical regulators of both early and late phases of arteriogenesis through coordinated inflammatory and regenerative mechanisms. Full article

Uterine fibroids (leiomyomas) are common benign smooth muscle tumors that impose substantial symptom burden and healthcare costs worldwide. Although uterine fibroid (leiomyoma) pathogenesis is multifactorial, hypoxia has emerged as a key feature of the uterine fibroid (leiomyoma) microenvironment, particularly within poorly perfused tumor cores. Hypoxia-inducible factor-1α (HIF-1α) is a central transcriptional regulator of cellular adaptation to low oxygen and coordinates downstream programs that support angiogenesis, metabolic reprogramming, cell survival, and extracellular matrix (ECM) remodeling. In uterine fibroids (leiomyomas), these HIF-1α–dependent processes intersect with steroid hormone signaling, growth factor pathways, inflammatory mediators, and redox imbalance, together promoting tumor persistence and progressive fibrosis. This review synthesizes the molecular regulation of HIF-1α, highlights major HIF-linked effector pathways relevant to uterine fibroid (leiomyoma) biology, and emphasizes mechanistic crosstalk with estrogen- and progesterone-responsive signaling, TGF-β/SMAD-driven fibrosis, NF-κB-mediated inflammation, and metabolic checkpoint pathways including mTOR and AMPK. Finally, we evaluate emerging therapeutic strategies that target HIF-1α directly or indirectly through upstream regulators. Full article

Oxidative stress and inflammation are interconnected pathological processes involved in the progression of neurodegenerative, cardiovascular, and metabolic diseases, highlighting the need for multifunctional therapeutic agents targeting multiple pathways. In this study, two novel hybrid compounds were designed and synthesized in three steps by conjugating butylated phenolic moieties derived from butylated hydroxytoluene and p-coumaric acid with proline and γ-aminobutyric acid (GABA). The aim was the combination of antioxidant, anti-inflammatory, and cytoprotective properties within a single molecular framework. The compounds were evaluated using a comprehensive panel of in vitro and in vivo assays to assess antioxidant, metal-reducing, iron-chelating, antiglycation, anti-inflammatory, and acetylcholinesterase inhibitory activities. Both compounds exhibited significant antioxidant activity, with compound 2 demonstrating superior radical scavenging ability against DPPH, ABTS·⁺ and hydrogen peroxide (IC₅₀ 86 μM, 25 μM and 104 μM, respectively), enhanced ferric-reducing capacity (up to 91% of trolox activity), and strong iron-chelating activity (61.3%). Compound 2 also showed potent inhibition of lipid peroxidation (IC₅₀ 17.5 μM) and moderate antiglycation effects (44%), indicating substantial cytoprotective potential. Furthermore, both compounds selectively inhibited COX-2 over COX-1 and demonstrated moderate lipoxygenase inhibition, while compound 2 exhibited significant in vivo anti-inflammatory activity (53%), exceeding that of ibuprofen. Moderate acetylcholinesterase inhibition was also observed. In summary, the results confirm the design rationale, indicating that compound 2 could be further optimized as a multi-targeting molecule directed against oxidative stress- and inflammation-mediated conditions. Full article

Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined. Full article

Background: Ulcerative colitis, a chronic inflammatory disorder of the intestine, represents a major health concern worldwide. This study aimed to explore the in vivo efficacy of rice bran protein hydrolysates in mitigating UC. Methods: Rice bran protein hydrolysates with enhanced antioxidant activity were prepared via co-treatment with Alcalase and Lactiplantibacillus plantarum 13110. Results: Compared with hydrolysates obtained using Alcalase in isolation (RHP), the co-treated rice bran (CRB) protein hydrolysates exhibited significantly higher antioxidant capacity. Structural characterization revealed marked alterations in molecular weight distribution, amino acid composition, and RHP spectral features, based on Fourier transform infrared spectroscopy, during fermentation with L. plantarum 13110. The 500 mg/kg·bw CRB intervention effectively attenuated oxidative stress and inflammatory responses in dextran sulfate sodium (DSS)-induced colitic mice, as evidenced by significantly reduced colonic levels (p < 0.05) of pro-inflammatory mediators (TNF-α, IL-1β, IL-6, and LPS), decreased serum concentrations of fatty acid-binding protein 2 (FABP2), diamine oxidase (DAO), and D-lactic acid (D-LA), and increased colonic IL-10 content (p < 0.05). These changes were associated with ulcerative colitis amelioration and improved intestinal barrier function. Conclusions: Thus, CRB exhibits promising prophylactic effects against ulcerative colitis, suggesting its potential for therapeutic application. Full article