Search Results (8,524)

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by progressive dilation and weakening of the abdominal aortic wall. Despite advances in surgical repair, rupture remains associated with mortality rates exceeding 65%, and no effective pharmacological therapy exists to prevent disease progression. Increasing evidence highlights chronic inflammation, extracellular matrix degradation, and immune dysregulation as central drivers of AAA pathogenesis. Among these mechanisms, the thrombospondin-1 (TSP1)–CD47 signaling axis has emerged as a critical upstream regulator of vascular inflammation. By engaging CD47, TSP1 promotes macrophage activation, impairs efferocytosis, and sustains a self-perpetuating inflammatory loop that accelerates tissue destruction. This positions the TSP1–CD47 pathway as more than a bystander in aneurysm biology, linking immune activation with structural failure of the aortic wall. The therapeutic relevance of this axis is underscored by the development of CD47-targeted agents in oncology, which restore phagocytosis and immune balance. Repurposing such strategies for vascular medicine, in combination with advanced drug delivery systems, offers a promising avenue for disease-modifying therapy in AAA. Notably, two targeted drug delivery approaches have been described: both employ bispecific targeting of CD47 in combination with a macrophage-specific marker, using immunotoxins encapsulated in liposomal carriers to enhance selectivity and therapeutic efficacy. By shifting focus from structural repair to immune modulation, targeting the TSP1–CD47 axis with these strategies has the potential to redefine the clinical management of this condition. Full article

Oral infections caused by Candida spp. represent a major health concern due to the increasing resistance of these fungi to conventional antifungal agents. Photodynamic therapy (PDT) is a treatment based on the use of light at a specific wavelength that activates a photosensitizer (PS) in the presence of oxygen. The activated PS selectively binds to infected cells and induces apoptosis through the generation of reactive oxygen species (ROS). Previous biomolecular studies on Candida albicans have demonstrated that its infection triggers characteristic molecular signals, such as miRNA-146a and miRNA-155, which serve as inflammatory markers. This in vitro study aimed to evaluate the impact of PDT on the expression of their primary transcripts (pri-miRNAs) in a cell culture model of C. albicans infection. Human embryonic kidney (HEK-293) cells were infected with a multidrug-resistant strain of C. albicans (CA97) and subsequently exposed to curcumin-based PDT activated by blue light (470 nm). The expression of pri-miRNAs 146a and 155 was assessed before and after PDT treatment for each experimental group. The expression levels of pri-miRNAs increased approximately 2- to 3.5-fold following C. albicans infection but returned to baseline values after PDT treatment. The evaluation of pri-miRNAs 146a/155 may serve as a valuable research tool for monitoring early inflammatory responses induced by Candida infection, as well as a sensitive biomarker for assessing the effectiveness of photodynamic therapy in an in vitro cell culture model. Full article

This study investigated the effects of eight weeks of aerobic exercise training on body composition, lipid profiles, organokines (leptin, irisin), inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6]), and intestinal barrier permeability markers (zonulin, lipopolysaccharide-binding protein [LBP]) in overweight and obese women of different age groups. We hypothesized that aerobic exercise would improve cardiorespiratory fitness, body composition, lipid metabolism, and reduce pro-inflammatory responses and intestinal permeability, and that these effects would differ between age groups. A total of 32 participants with a body mass index (BMI) ≥ 23 kg/m² were randomly assigned to one of four groups (n = 8 per group): young exercise (YE), young control (YC), middle-aged exercise (ME), and middle-aged control (MC). The intervention consisted of treadmill running for 50 min per session, four times per week, at an intensity corresponding to 65% of the target heart rate (THR), calculated using the Karvonen formula, for a duration of eight weeks. Body composition variables included body weight, BMI, body fat mass (BFM), percentage body fat (PBF), lean body mass (LBM), and maximal oxygen uptake (VO₂max). Blood samples were analyzed for lipid profiles (total cholesterol [TC], triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C]), organokines, inflammatory markers, and intestinal barrier integrity biomarkers. After the intervention, the YE and ME groups exhibited significant reductions (p < 0.05) in body weight, BMI, BFM, PBF, TC, TG, LDL-C, leptin, hs-CRP, IL-6, zonulin, and LBP. In contrast, LBM and VO₂max significantly increased (p < 0.05) in both exercise groups. No significant changes were observed in irisin concentrations or HDL-C levels (p > 0.05). These results suggest that aerobic exercise training, irrespective of age, is effective in improving cardiorespiratory fitness, body composition, and lipid metabolism, while simultaneously reducing systemic inflammation and is associated with favorable changes in circulating biomarkers of intestinal barrier function in overweight and obese women. Full article

Background/Objectives: Overweight and obesity are associated with insulin resistance, atherogenic dyslipidemia, and low-grade inflammation. We evaluated analytical safety and within-person metabolic changes under the Adaptive Ketogenic–Mediterranean Protocol (AKMP) in real-world practice. Methods: Single arm, prospective pre–post cohort. We enrolled 112 adults; 105 completed 14 weeks of AKMP (12 in nutritional ketosis ≤ 20 g carbohydrate/day + 2 of gradual reintroduction). Fasting venous samples were analyzed in accredited laboratories (glycolipid profile, hepatic–renal function, inflammatory markers; insulin, thyroid hormones, cortisol). HOMA-IR, TyG, and remnant cholesterol (RC) were calculated; body composition was measured by segmental bioimpedance. Paired analyses were used, with hierarchical gatekeeping for the conditional co-primary outcome and prespecified Δ~Δ correlations. Results: HOMA-IR −52.8% (Δ −1.80; p < 0.001) and RC −35.1% (Δ −10.64 mg/dL; p < 0.001); fasting glucose −13.7 mg/dL, insulin −5.9 μU/L; TyG −0.23 and TG/HDL-c −1.21 (all p < 0.001). Lipids: TG −35.1% and LDL-c −11.2%; HDL-c remained stable. Anthropometry: weight −14.85 kg (−14.7%) and trunk fat −4.88 kg (−22.2%) (p < 0.001). Safety: no serious adverse events; GGT −47.0%, eGFR +11.0%, and CRP −24.6% (p < 0.001). Prespecified correlations supported the internal consistency of the glycolipid axis (e.g., ΔHOMA-IR~ΔTyG; ΔRC~ΔHOMA-IR). Conclusions: In adults with overweight or obesity, the AKMP was associated with improvements in the glucose–insulin axis, atherogenic profile (RC, TG/HDL-c, TG), and body composition, while maintaining a favorable safety profile. The protocol appears feasible in clinical practice and monitorable with routine laboratory tests, although randomized controlled trials are needed to confirm causality and long-term sustainability. Full article

Osteoarthritis (OA), a degenerative joint disease primarily affecting the hips and knees, is characterized by multifactorial dysregulation of chondrocyte homeostasis and currently lacks curative treatment options. Intra-articular hyaluronic acid (HA) injections have clinically provided symptomatic relief for three decades; however, HA’s rapid in vivo degradation by free radicals and hyaluronidases limits its efficacy. We hypothesized that adding niacinamide (vitamin B3) to linear HA hydrogels would provide ancillary anti-inflammatory and anti-catabolic properties, thereby improving HA-based viscosupplementation therapy. This preliminary preclinical mechanistic study investigated the functional effects of incorporating niacinamide into linear HA-based hydrogels using in vitro cellular models. Initially, Raw 264.7 macrophages and C28/I2 or SW1353 human chondrocytes were pre-treated with varying concentrations of HA/B3, with or without lipopolysaccharide (LPS) or interleukin-1β (IL-1β), respectively. Subsequently, pro-inflammatory and pro-catabolic markers were quantified biochemically. Results demonstrated that HA/B3 hydrogels exhibited enhanced functional stability compared to HA alone and possessed significant anti-inflammatory and anti-catabolic properties, without inducing cytotoxicity in either cell line. In Raw 264.7 macrophages, HA/B3 inhibited LPS-induced tumor necrosis factor-α (TNF-α) release and suppressed cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression. In vitro, HA/B3 hydrogels reduced IL-1β-induced IL-6 production in primary chondrocytes by 16% and suppressed PGE₂ concentration in both macrophages and chondrocytes by 60%, effects superior to HA alone. Finally, a rat primary articular chondrocyte model suggested slight anti-hypertrophic effects of HA/B3 in vitro. Collectively, these findings suggest that HA/B3 hydrogels possess anti-arthritic potential, highlighting a novel strategy for next-generation viscosupplement systems. Full article

Background/Objectives: Cardiovascular diseases (CVDs) remain a major cause of mortality globally, driven in part by oxidative stress and inflammation. The present study investigated the polyphenolic composition and cardioprotective potential of polyphenol-rich Citrullus lanatus (PRCL) rind extract against doxorubicin-induced cardiotoxicity in rats; Methods: High-performance liquid chromatography (HPLC) was employed to identify and quantify the major bioactive compounds present in the extract. Total 30 healthy male Wistar Kyoto rats were recruited and divided into 6 groups and various cardiovascular markers and antioxidant were measured in vivo and in vitro methods; Results: Ethanolic extraction of Citrullus lanatus rind yielded 19.58 g extract per 100 g of dry plant material. HPLC analysis identified five phenolic acids, i.e., gallic acid, p-hydroxybenzoic acid (PHBA), chlorogenic acid, caffeic acid, and vanillic acid, and two flavonoids, i.e., catechin and hesperetin, with PHBA (163.66 mg/g of extract) being the most abundant. Total phenolic and flavonoid content was determined to be 35.6 mg GAE/g and 12.8 mg CE/g, respectively. In vitro antioxidant assays showed moderate free radical scavenging, reducing power, and 86.9% inhibition of linoleic acid peroxidation. In vivo, Wistar rats were treated with doxorubicin (10 mg/kg) to induce cardiotoxicity, followed by PRCL extract administration (21 days at 250 and 500 mg/kg/day). The extract significantly improved body weight, serum lipid profile, and reduced cardiovascular risk indices. Antioxidant biomarkers (SOD, CAT, GPx, GSH) were restored, while lipid peroxidation (MDA) and inflammatory cytokines (TNF-α, IL-6) were significantly reduced in treated groups. The 500 mg/kg dose demonstrated superior efficacy, comparable to the standard quercetin group. Histopathological examination revealed notable protection of cardiac tissue architecture in the high-dose PRCL-500 group; Conclusions: These findings suggest that PRCL rind extract contains potent compounds having antioxidant and cardioprotective properties and may be used as a natural therapeutic agent against cardiotoxicity. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and is often prefaced by mild cognitive impairment (MCI). Detection of AD-related changes via blood-based biomarkers would enable critical therapeutic interventions early in disease progression. Neuronal enriched extracellular vesicle (NEEV) miRNAs regulate peripheral genes as a response to early AD brain changes and hence may have biomarker potential. Plasma NEEVs were captured from plasma samples of Mexican Americans (MAs) and Non-Hispanic Whites (NHWs) using an antibody against the neuronal surface marker CD171. miRNAs isolated from NEEVs were sequenced and analyzed using miRDeep2/DEseq2 and QIAGEN RNA-seq portal for differential expression between cognitively impaired (CI) and cognitively unimpaired controls. hsa-miR-122-5p was significantly underrepresented in the CI group in both MAs and NHWs compared to the healthy control. Other population-specific miRNAs (MAs: hsa-miR-26a-5p, hsa-let-7f-5p, and hsa-miR-139-5p, NHWs: hsa-miR-133a-3p, hsa-miR-125b-5p, and hsa-miR-100-5p) identified may have biomarker potential in AD precision medicine. Some of these differentially expressed miRNAs were associated with key AD-related comorbidities such as APOE genotype, age, and metabolic burden and were predicted to target genes within NF-κB -regulated inflammatory pathways. Together, these findings suggest that dysregulated miRNA networks may serve as a mechanistic link between comorbidity burden and AD-related neuroinflammation and neurodegeneration. Full article

Background/Objectives: Galectins contribute to the pathogenesis of osteoarthritis (OA) by amplifying inflammatory and catabolic signaling, yet targeted therapeutic approaches remain limited. Three Dimensional (3D) models offer a promising platform to study human OA pathophysiology and evaluate novel interventions. Methods: We established 3D pellet cultures derived from human OA chondrocytes to investigate galectin-induced extracellular matrix (ECM) remodeling and the chondroprotective potential of phytochemicals. OA pellets were stimulated with individual galectins (Gal-1, -3, -4, -8) or a Gal-1/-3/-8 mixture, followed by co-treatment with Brazilin, Diacerein, Quercetin, Resveratrol, or Avocado-Soybean Unsaponifiables (ASU). Morphological, histological, biochemical, and gene expression analyses were performed to assess tissue integrity and molecular responses. Results: Galectin treatment induced pronounced pellet shrinkage, matrix depletion, and upregulation of matrix-degrading enzymes (MMP-1, MMP-3, MMP-13, ADAMTS-4), while suppressing matrix synthesis markers (COL2A1, COL1A1), highlighting their cooperative catabolic effects. Co-treatment with phytochemicals conferred differential protection: Brazilin and Diacerein most consistently preserved pellet size, reduced matrix-degrading gene expression, and attenuated pro-MMP-13 secretion. Resveratrol restored histological matrix density but failed to suppress pro-MMP-13 secretion. Notably, no phytochemical fully restored COL2A1 expression under galectin-induced stress. Conclusions: Our study identifies Brazilin, Diacerein, and Resveratrol as promising modulators of galectin-driven cartilage degeneration and demonstrates the translational potential of patient-derived chondrogenic pellets as a human-relevant platform for preclinical drug evaluation in OA. The 3D culture effectively recapitulates key aspects of OA pathophysiology and offers a robust system to advance therapeutic discovery targeting ECM remodeling. Full article

Hepatorenal syndrome (HRS) is a high-mortality, potentially reversible form of kidney failure that arises from a tight hemodynamic–inflammatory coupling in cirrhosis. Contemporary redefinitions prioritize creatinine kinetics over static thresholds and recognize non-acute kidney injury (AKI) functional phenotypes, enabling earlier recognition but heightening the need for precise etiologic triage. This narrative synthesis integrates current concepts across pathophysiology, diagnosis and management. Portal hypertension, bacterial translocation and inflammatory mediators amplify splanchnic vasodilation and effective arterial underfilling. Compensatory neurohumoral activation precipitates renal vasoconstriction, intrarenal microcirculatory dysfunction and sodium–water retention. The pivotal diagnostic fork remains HRS–AKI versus acute tubular necrosis. A pragmatic, tiered strategy, structured volume assessment, filtration markers and a parsimonious tubular-injury panel offer actionable discrimination, whereas fractional excretion indices serve as adjuncts only. Initial therapy should be bundled and time-sensitive: remove nephrotoxins, treat infection and initiate albumin plus a vasoconstrictor. The transplant strategy should default to isolated liver transplantation unless end-stage renal disease is established. Future priorities include validated biomarker cut-offs, ultrasound-guided volume algorithms and pathway-based trials to reduce diagnostic delay and improve survival. Full article

Background/Objectives: Cyclophosphamide (CYC) is a commonly used alkylating agent for treating various cancers and autoimmune disorders. However, its use is often hampered by serious side effects, affecting multiple organs. This study aimed to explore whether tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, could offer protective benefits against CYC-induced organ toxicity in rats. Methods: Two different TFV doses (25 and 50 mg/kg) were tested. The researchers evaluated the effects of TFV on kidney and heart function biomarkers, oxidative stress, autophagy, apoptosis, and inflammatory markers. Results: The results showed that pre-treatment with TFV significantly reduced the harmful effects of CYC, as evidenced by decreasing the activity of serum lactate dehydrogenase (LDH) and creatine kinase-myocardial band (CK-MB), and the levels of serum creatinine (Cr.), blood urea nitrogen (BUN), and malondialdehyde (MDA). TFV also boosted antioxidant defenses by increasing the expression of key proteins such as Nrf2/HO-1, AMPK, and SIRT1. Also, TFV regulated inflammatory and apoptotic pathways (revealed by reducing IL-1β level and increasing Bcl-2 level) and improved autophagy (showed by reducing LC3 expression). Conclusions: Overall, these findings suggested that TFV has strong protective effects against CYC-induced organ toxicity, likely through its anti-inflammatory, antioxidant, and anti-apoptotic mechanisms. This points to TFV as a potential therapeutic agent to help mitigate the organ damage caused by CYC. Full article

Background/Objectives: This research aims to offer significant insights into the prospective application of bioactive hydrogels composed of alginate, gelatin, and grape skin extract from Serbia (GSE) for treating diabetic wounds, supporting the circular economy and environmental protection. Methods: An acute dermal irritation study was conducted according to OECD guidelines, revealing no visible signs of erythema or edema, confirming the hydrogel’s dermal safety. Afterwards, male Wistar rats were divided into four groups: untreated control (NC), silver sulfadiazine-treated (PC), hydrogel without extract (HG), and hydrogel with GSE (HG + GSE). Wound healing was assessed through a comprehensive approach that included macroscopic wound contraction; biochemical assessment of hydroxyproline content and oxidative stress markers (TBARS, SOD, CAT, GSH); quantification of inflammatory cytokines (TNF-α, IL-6); and histological examination of skin samples using hematoxylin–eosin (H&E) and Masson’s trichrome staining. Results: Daily HG+GSE application over 15 days accelerated wound closure, reaching 99.3% by day 15, surpassing PC (91.2%) and HG (87.7 ± 2.1%). Hydroxyproline levels followed a treatment-dependent pattern, with HG+GSE achieving the highest values throughout, reaching 6.78 ± 0.1 µg/mg dry tissue by day 15—more than double NC. The HG+GSE reduced lipid peroxidation while enhancing enzymatic and non-enzymatic antioxidant defenses and markedly lowered pro-inflammatory cytokine levels, indicating systemic anti-inflammatory activity. Histological analysis revealed faster re-epithelialization, increased collagen deposition, and more organized tissue architecture in the HG+GSE group. These outcomes are attributed to the sustained release of bioactive polyphenols such as naringin, caffeic acid, and epicatechin. Conclusions: Overall, this GSE-based hydrogel presents a multifunctional, biocompatible, sustainable, and effective strategy for diabetic wound care. Full article

Plasmacytoid dendritic cells (pDCs) are a unique subset of dendritic cells specialized in rapid and robust type I interferon (IFN) production, playing critical roles in the pathogenesis and pathomechanisms of many human diseases. Accurate identification of pDCs in peripheral blood mononuclear cells (PBMCs) is challenging due to dynamic and non-exclusive specific expression of surface markers such as blood dendritic cell antigen (BDCA)-2 and BDCA-4. Although BDCA-4 is generally more stably expressed than BDCA-2, prolonged stimulation or inflammatory conditions can induce its expression on multiple non-pDC cell types, reducing the accuracy of pDC identification. Here, we thoroughly investigated BDCA-4 expression dynamics on pDCs and other PBMC subsets following prolonged activation with Toll-like receptor (TLR) 7 and TLR9 agonists. Our flow cytometry analysis revealed a significant increase in BDCA-4-positive non-pDC populations after extended stimulation, primarily corresponding to CD14⁺ monocytes. To overcome this limitation, we performed a gating strategy combining BDCA-4 positivity with a cocktail of non-pDC markers, enabling the exclusion of non-pDCs and accurate identification of pDCs. This approach enables the reliable identification of pDCs within heterogeneous cell populations using only two fluorescent channels in healthy conditions and even during strong activation or pathological states characterized by chronic inflammation. Full article

Physical exercise triggers the release of short-lived exerkines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10), which may help reduce systemic inflammation and mitigate the risk of chronic disease. Despite their potential, the effects of these exercise-induced cytokines (termed exerkines) across diverse populations remain underexplored. This study evaluated how exercise-induced exerkines modulate inflammatory markers, based on changes observed before and after intervention. We systematically searched PubMed, Scopus, and Web of Science from January 2015 up to 7 February 2025, identifying 11 randomized controlled trials (RCTs) involving 1135 participants. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using a random-effects model to assess changes in IL-6, TNF-α, IL-10, C-reactive protein (CRP), and interferon-gamma (IFN-γ). Study quality was evaluated using the Cochrane Risk of Bias 2 tool. Exercise significantly reduced CRP (SMD = −0.77, 95% CI: −1.20 to −0.33, p = 0.001) and TNF-α (SMD = −1.09, 95% CI: −2.14 to −0.03, p = 0.043) while increasing IL-6 (SMD = 0.81, 95% CI: 0.10 to 1.53, p = 0.026). IL-10 showed a non-significant increase (SMD = 0.66, 95% CI: −0.09 to 1.41, p = 0.084), with no effect on IFN-γ. Heterogeneity was moderate for CRP (I² = 52.5%) but high for other markers (I² > 87%). These findings suggest that exerkines contribute to an anti-inflammatory shift in the short term, which is consistent with mechanisms that may underlie the preventive effects of exercise against cardiometabolic diseases; however, standardized protocols and longitudinal studies with clinical endpoints are needed to confirm any long-term benefits. Full article

Individuals with rheumatoid arthritis (RA) face increased cardiovascular mortality due to heart failure (HF) complications. Post-translational modifications, such as citrullination (CIT) and malondialdehyde–acetaldehyde (MAA) adduction, are implicated in RA pathogenesis. However, their role in RA-associated HF is not well understood. This study examines the deposition of MAA and CIT in cardiac tissues of RA-HF patients and investigates how MAA and CIT adducts on fibrinogen (FIB-MAA-CIT) drive crosstalk between macrophages and endothelial cells in vitro. We demonstrated elevated MAA and CIT adducts, strong perivascular MAA-CIT co-localization, and increased perivascular collagen deposition in the myocardium of RA-HF patients compared to non-RA HF controls. Treating human coronary artery endothelial cells (HCAECs) with FIB-MAA-CIT induced upregulation of inflammatory markers including MCP-1, IL-6, ICAM-1, and VCAM-1 compared to unmodified FIB. This response was amplified when HCAECs were treated with cell culture media obtained from FIB-MAA-CIT-stimulated macrophages. FIB-MAA-CIT activation of macrophages engaged NF-κB and p38 signaling pathways and inhibition of these pathways reduced FIB-MAA-CIT-mediated macrophage cytokine secretion and subsequent HCAEC responses. In summary, our findings support a novel mechanism by which endogenously modified proteins drive macrophage–endothelial cell crosstalk, promoting myocardial inflammation. Targeting these post-translational modifications may present novel therapeutic strategies to mitigate HF in RA. Full article

Background/Objectives: The C-reactive protein-to-lymphocyte ratio (CLR) has emerged as an inflammatory biomarker reflecting innate and adaptive immune responses. Its prognostic value in acute ischemic stroke patients undergoing mechanical thrombectomy remains unclear. This study investigated whether CLR predicts functional outcome, mortality, and symptomatic intracranial hemorrhage (sICH). Methods: In this multicenter retrospective study, 714 patients with anterior circulation large-vessel occlusion treated with mechanical thrombectomy between January 2024 and January 2025 were analyzed. Clinical, angiographic, and laboratory data, including CLR, were collected. CLR was calculated as CRP divided by lymphocyte count/1000. Outcomes were 90-day modified Rankin Scale (mRS; poor outcome = 3–6; mortality = 6) and sICH per ECASS II. Receiver operating characteristic (ROC) analyses identified optimal CLR cut-offs. Logistic regression analyses determined independent predictors of outcomes. Results: sICH occurred in 39 patients (5.5%). CLR correlated with higher baseline NIHSS and lower ASPECTS. ROC analyses showed that CLR predicted poor functional outcome and mortality with an identical cut-off (≥7.51; AUCs 0.634 and 0.664), and demonstrated strong discrimination for sICH (cut-off ≥ 10.64; AUC 0.855). In multivariable analyses, CLR remained an independent predictor across all outcomes (ORs 1.02, 1.02, and 1.03, all p < 0.001), in addition to established clinical factors. Conclusions: Admission CLR was independently associated with poor outcomes, mortality, and sICH after mechanical thrombectomy. As an easily obtainable marker from routine laboratory tests, CLR may provide additional prognostic information and complement established predictors, but prospective validation is required. Full article