Background/Objectives: Chronic synovitis is a hallmark of osteoarthritis (OA) progression, driving cartilage degradation via inflammatory mediators. While the MAPK signaling pathway is implicated in OA pathogenesis its activation patterns in hip synovium remain poorly characterized, and regional differences within the synovial membrane have not been systematically examined. This research aims to determine the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and the Epidermal Growth Factor Receptor (EGFR) in the MAPK signaling pathway in the synovial membrane of osteoarthritic hips. Methods: We compared synovial immunofluorescence expression of the aforementioned proteins in a control (CTRL) group of subjects with femoral neck fractures and a group with hip OA. Results: Higher ERK1/2 immunoexpression was detected in the intima compared with the subintima in the CTRL group (p < 0.05), and a similar distribution was observed in the OA group (p < 0.0001). The intima of the OA group exhibited a considerably greater area percentage of positive signal than the intima of the CTRL group (p < 0.01). In all groups examined, we observed that p38 MAPK expression was markedly more positive in the intima than in the subintima (p < 0.0001), but without statistically significant differences between groups. JNK and EGFR immunoexpression were higher in the intima than in the subintima across all analyzed groups, but the difference did not reach statistical significance (p > 0.05). No differences in the expression of these two markers were detected between the CTRL and OA groups (p > 0.05). Differential analysis of the GEO dataset revealed no significant differences in expression between the OA and CTRL groups in the expression of MAPK1, MAPK3, MAPK8, MAPK9, MAPK10, and MAPK11. EGFR was significantly elevated in OA compared to CTRLs in the differential analysis of the GEO dataset. Conclusions: This study provides the first comprehensive analysis of MAPK pathway activation in hip OA synovium, revealing ERK1/2 as a key player with region-specific upregulation in the synovial intima. Combined with elevated EGFR expression, these findings suggest potential therapeutic targets for hip OA synovitis. The discordance between protein and mRNA levels for ERK1/2 indicates post-transcriptional regulation, warranting further investigation into phosphorylation status and functional activation. Our results support the development of targeted interventions for hip OA, a condition with limited treatment options beyond joint replacement.

Background/Objectives: The meninges, the protective membranes covering the central nervous system, undergo complex developmental processes that are critical for CNS integrity and function. Connexin 37 (Cx37) and 40 (Cx40), members of the connexin family of gap junction proteins, have been implicated in various physiological and pathological processes. They play a critical role in cell–cell communication. The aim of our study was to investigate the expression of connexins Cx37, Cx40, and Panx1 in the meninges of both human and murine models (yotari and wild type) at the 6th week/E13.5 and 8th week/E15.5 of developmental stages. Methods: Human embryonic tissues (6th–8th week, n = 4 for the 6th week and n = 4 for the 8th week) and mouse embryos (yotari Dab1−/− and wild type, E13.5–E15.5) were collected and fixed in 4% paraformaldehyde. Paraffin sections were stained for Cx37, Cx40, and Panx1 using immunofluorescence. Images were analyzed in ImageJ, and statistical comparisons were performed using one-way ANOVA with Tukey’s post hoc test (p < 0.05). Results: Cx37 was consistently expressed across all developmental stages, with the highest threshold area percentage observed at E13.5 and E15.5 in murine leptomeninges, demonstrating statistically significant differences compared to controls (p < 0.05) and notably from corresponding human stages (p < 0.001). Strong Cx37 staining intensity at E13.5 was noted in both wild-type and yot mice, while human leptomeninges displayed mild staining at the 6th week of development. In contrast, both human and murine pachymeninges exhibited moderate Cx37 expression. Additionally, the expression of Cx37 in wild-type mice surpassed that of human samples at both E13.5 and E15.5 stages (p < 0.01 and p < 0.001, respectively). For the developing dura mater, Cx37 expression peaked at E15.5 in yot mice, significantly different from both wild-type and human dura mater (p < 0.01 and p < 0.05). Cx40 expression was highest in the leptomeninges at E15.5. Panx1 was similarly expressed across stages, with the highest threshold area percent observed in wild-type leptomeninges and pachymeninges at E15.5, showing significant differences compared to yot mice and human samples (p < 0.05). Both leptomeninges and pachymeninges exhibited mild Panx1 staining at E13.5, while stronger staining was observed at E15.5 in murine samples, contrasting with mild intensity in human counterparts. Conclusions: These findings highlight the implications of Dab1 deficiency for the expression of gap junction proteins during meninges development, implicating their importance in intercellular communication that is essential for normal meningeal and neurodevelopmental processes.

Simple Summary Eye cancers can damage vision and, in some cases, threaten life. Retinoblastoma mainly affects children, while uveal melanoma is the most common eye cancer in adults. Doctors need better ways to judge how aggressive these tumors are and to find new treatment targets. We examined five proteins that help cells handle nutrients and signals, Megalin, Cubilin, Caveolin-1, GIPC1, and DAB2IP, in normal eye tissue, retinoblastoma, and different forms of choroidal melanoma. Using fluorescent staining, we measured the amount of each protein present, then compared our results with publicly available gene data and patient survival information. Our goal was to learn whether changes in these proteins track with tumor type and outcome. These findings may support the development of future tools for diagnosis, risk prediction, and therapy design in eye cancer.

The heart’s relentless contractile activity depends critically on mitochondrial function to meet its extraordinary bioenergetic demands. Mitochondria, through oxidative phosphorylation, not only supply ATP but also regulate metabolism, calcium homeostasis, and apoptotic signaling, ensuring cardiomyocyte viability and cardiac function. Mitochondrial dysfunction is a hallmark of cardiomyopathies and heart failure, characterized by impaired oxidative phosphorylation, excessive production of reactive oxygen species (ROS), dysregulated calcium handling, and disturbances in mitochondrial dynamics and mitophagy. These defects culminate in energetic insufficiency, cellular injury, and cardiomyocyte death, driving heart disease progression. Diverse cardiomyopathy phenotypes exhibit distinct mitochondrial pathologies, from acute ischemia-induced mitochondrial collapse to chronic remodeling seen in dilated, hypertrophic, restrictive, and primary mitochondrial cardiomyopathies. Mitochondria also orchestrate cell death and inflammatory pathways that worsen cardiac dysfunction. Therapeutic strategies targeting mitochondrial dysfunction, including antioxidants, modulators of mitochondrial biogenesis, metabolic therapies, and innovative approaches such as mitochondrial transplantation, show promise but face challenges in clinical translation. Advances in biomarker discovery and personalized medicine approaches hold promise for optimizing mitochondrial-targeted therapies. Unlike previous reviews that examined these pathways or interventions individually, this work summarizes insights into mechanisms with emerging therapeutic strategies, such as SGLT2 inhibition in HFpEF, NAD+ repletion, mitochondrial transplantation, and biomarker-driven precision medicine, into a unified synthesis. This framework underscores the novel contribution of linking basic mitochondrial biology to translational and clinical opportunities in cardiomyopathy and heart failure. This review synthesizes the current understanding of mitochondrial biology in cardiac health and disease, delineates the molecular mechanisms underpinning mitochondrial dysfunction in cardiomyopathy and heart failure, and explores emerging therapeutic avenues aimed at restoring mitochondrial integrity and improving clinical outcomes in cardiac patients.

The kidney’s intricate physiology relies on finely tuned gene regulatory networks that coordinate cellular responses to metabolic, inflammatory, and fibrotic stress. Beyond protein-coding transcripts, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of renal biology. By modulating transcriptional, post-transcriptional, and epigenetic pathways, ncRNAs govern podocyte integrity, tubular adaptation, intercellular signaling, and immune activation. Dysregulation of these networks is now recognized as a hallmark of major kidney diseases, ranging from diabetic nephropathy and acute kidney injury to chronic kidney disease, glomerulopathies, and polycystic kidney disease. Mechanistic studies have revealed how pathogenic ncRNAs drive apoptosis, inflammation, fibrosis, and cystic remodeling, while protective ncRNAs mitigate these processes, highlighting their dual roles as both disease mediators and therapeutic targets. The exceptional stability of ncRNAs in urine, plasma, and exosomes further positions them as minimally invasive biomarkers with diagnostic and prognostic value. Translational advances include anti-miR and mimic-based therapies (e.g., lademirsen targeting miR-21, miR-29 mimics, anti-miR-17 oligonucleotides), alongside lncRNA silencing strategies, although challenges in delivery, safety, and redundancy remain significant. This review integrates molecular mechanisms with translational perspectives, providing a comprehensive synthesis of how ncRNAs shape renal pathophysiology. By bridging mechanistic insights with emerging diagnostic and therapeutic applications, we highlight the potential of ncRNAs to transform nephrology, paving the way for biomarker-driven precision medicine and novel interventions aimed at intercepting kidney injury at its regulatory roots. In clinical terms, ncRNA-based biomarkers and therapeutics promise earlier detection, more precise risk stratification, and individualized treatment selection within precision nephrology.

Background/Objectives: Hip osteoarthritis (HOA) is a progressive joint disease characterized by cartilage loss, subchondral bone changes, and synovial inflammation. While tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and transforming growth factor-beta 1 (TGF-β1) are recognized as key mediators of joint pathology, their compartment-specific expression in the human hip synovium remains insufficiently characterized. Therefore, we aimed to investigate their localization and expression in the intimal and subintimal compartments of synovial tissue in patients with HOA compared to controls (CTRL). Methods: Synovial membrane samples were obtained from 19 patients with primary HOA undergoing total hip arthroplasty and 10 CTRL subjects undergoing arthroplasty for acute femoral neck fracture without HOA. Specimens were processed for hematoxylin and eosin (H&E) and immunofluorescence staining. Expression of TNFR1, IL-6, and TGF-β1 was quantified in the intima and subintima using ImageJ analysis. Group differences were assessed using two-way Analysis of variance (ANOVA) with Tukey’s test when assumptions were met; for heteroscedastic outcomes we applied Brown–Forsythe ANOVA with Dunnett’s T3 multiple comparisons. Results: Histological analysis confirmed synovitis in HOA samples, with intimal hyperplasia and mononuclear infiltration. IL-6 was significantly upregulated in the intima of HOA synovium compared with CTRLs, while subintimal expression remained unchanged. In contrast, TGF-β1 expression was reduced in the HOA intima, eliminating the normal intima–subintima gradient. For TNFR1, the within-HOA contrast (int > sub) was significant, whereas the intimal HOA vs. CTRL comparison showed a non-significant trend. Transcriptomic analysis supported IL-6 upregulation, while TNFR1 and TGF-β1 did not reach statistical significance at the mRNA level in an orthogonal, non-hip (knee-predominant) dataset. Conclusions: These findings demonstrate compartment-specific cytokine dysregulation in HOA, with increased intimal TNFR1 and IL-6 alongside reduced intimal TGF-β1. The synovial lining emerges as a dominant site of inflammatory signaling, underscoring its importance in disease progression.

Simple Summary Advanced gastric cancer is generally associated with a poor prognosis. Stroma AReactive Invasive Front Area (SARIFA) is a recently recognized aggressive histological feature, defined as five tumor cells in direct contact with adipocytes within perigastric, submucosal, or perivascular adipose tissue. The aim of our retrospective study was to evaluate the correlation of SARIFA with pathohistological variables and its impact on overall survival. A cohort of 102 Croatian patients with locally advanced gastric cancer was analyzed, and a significant association between SARIFA and nodal metastases as well as perineural invasion was observed. Patients with both lymphovascular invasion and SARIFA had a significantly higher proportion of affected lymph nodes. They also exhibited a shorter, though not statistically significant, overall survival compared with patients with one or neither of these factors (median 9.2 vs. 16.1 months). A positive SARIFA status may serve as a biomarker of invasiveness and an additional prognostic risk factor. Abstract Background/Objectives: Advanced gastric cancer usually has an unfavorable prognosis. Stroma AReactive Invasion Front Area (SARIFA) is a newly recognized biomarker of aggressiveness, easily recognized as five tumor cells in direct contact with adipocytes in perigastric, submucosal, and perivascular adipose tissue. We investigated this phenomenon and correlated it with other pathohistological variables. Material and Methods: The sample includes 102 Croatian patients with locally advanced gastric cancer, who underwent total gastrectomy/lymphadenectomy between 2012–2018 and in 2023 at University Hospital Split, Croatia, and had pathological stage pT3 or pT4. Representative histological specimens were analyzed for SARIFA, and results were compared with other variables and overall survival. External validation and gene expression analysis of CD36 and FABP4 were performed using the TCGA-STAD cohort. Results: SARIFA was significantly associated with positive pN status (p = 0.009) and perineural invasion (p = 0.043). Patients with SARIFA had a more than fivefold increased risk of nodal involvement (OR = 6.35; 95% CI: 1.35–29.84; p = 0.019). Lymphovascular invasion (LVI) was associated with nodal disease (OR = 4.39; 95% CI: 1.194–16.143; p = 0.026), and SARIFA was marginally associated (OR = 4.886; 95% CI: 0.985–24.241; p = 0.052). Patients who had both LVI and SARIFA had a higher proportion of affected lymph nodes (p = 0.009). SARIFA status did not significantly affect overall survival. Gene expression analysis showed a significant increase in CD36 expression, while FABP4 expression was elevated but not statistically significant, in SARIFA-positive cases. Conclusions: SARIFA could be used as a marker for invasiveness and further investigated due to its predictive potential.

Background and objectives: Melanocytic nevi are among the most common skin lesions, yet their relationship with the peripheral nervous system has remained understudied. Given the neural crest origin of melanocytes and Schwann cells, and the neurotrophic signaling capabilities of pigment cells, this study aimed to investigate the density of nerve fibers within nevi and assess how it varies with respect to histological subtype and anatomical location. Materials and Methods: A total of 90 nevi were analyzed, including junctional, compound, and intradermal types, distributed across the head, trunk, and limbs. Immunofluorescence staining for the pan-neuronal marker PGP 9.5 and for CGRP were performed and nerve fiber density was quantified. Statistical evaluation using two-way ANOVA revealed that both nevus type and anatomical site significantly influenced the degree of total innervation. Results: Junctional nevi demonstrated the highest total nerve fiber density, significantly exceeding that of compound and intradermal nevi. Likewise, nevi located on the head exhibited a significantly greater density of PGP 9.5-positive nerve fibers compared to those on the trunk and limbs. No significant correlation was observed between nevus type and location, suggesting that both factors contribute independently to the differences in innervation. CGRP-positive innervation was uniform regardless of the histological type of nevus and anatomical location. Conclusions: These findings likely reflect the facts that junctional nevi reside at the dermo-epidermal junction, where nerve fibers are most abundant, while the skin of the head and neck is well known to be more richly innervated than other regions. In contrast, analysis of CGRP-positive fibers suggests that the heterogeneity detected with PGP 9.5 is primarily driven by other neuronal populations. The results support the hypothesis of a dynamic relationship between nevi and the peripheral nervous system, potentially mediated by neurotrophic factors. Understanding this interaction may provide insight into nevus biology, sensory symptoms reported in some lesions, and the evolving role of nerves in the tumor microenvironment.

Obesity, a global health concern defined by excessive adiposity and persistent metabolic imbalance, has far-reaching implications that extend beyond standard metabolic and cardiovascular comorbidities. While the association between obesity and reproductive dysfunction is well-established, the precise molecular mechanisms underlying these associations remain incompletely understood, particularly as regards the distinction between obesity-specific effects and those mediated by dietary components or metabolic syndrome. The present review integrates currently available knowledge on the mechanisms through which obesity impairs reproductive function in both sexes, from gametogenesis to postnatal development. In males, obesity drives testicular inflammation, disrupts spermatogenesis, impairs sperm motility and DNA integrity, and alters key signaling pathways, with oxidative stress and metabolic endotoxemia as central mediators. In females, obesity induces ovarian dysfunction, alters steroidogenesis, compromises oocyte quality and disrupts follicular environments, leading to reduced fertility and adverse pregnancy outcomes. However, the relative contribution of obesity-induced inflammation vs. direct lipotoxic effects remains poorly characterized in both sexes. The present review further examines the impact of parental obesity on fertilization capacity, placental function and in utero development, highlighting sex-specific and intergenerational effects mediated by mitochondrial dysfunction and epigenetic modifications. Notably, maternal obesity impairs placental and fetal organ development, increases the risk of metabolic and reproductive disorders in offspring, and alters key developmental signaling pathways. While some studies suggest that lifestyle interventions and antioxidant therapies may partially reverse obesity-induced reproductive impairments, significant gaps remain in understanding the precise molecular mechanisms and potential for therapeutic rescue. By synthesizing findings from animal models and human studies, the present review highlights the pivotal role of oxidative stress as a mechanistic link between obesity and reproductive dysfunction. It emphasizes the need for further research to inform clinical strategies aimed at mitigating these adverse outcomes.

Lung development is governed by tightly regulated signaling mechanisms, including endocytosis-mediated pathways critical for epithelial–mesenchymal communication and tissue remodeling. This study investigated the effects of Dab1 deficiency on the expression of endocytic and signaling-related proteins, Megalin, Cubilin, Caveolin-1, GIPC1, and Dab2IP, during embryonic lung development in yotari mice. Using immunofluorescence and quantitative image analysis, protein expressions were compared between yotari and wild-type embryos at gestational days E13.5 and E15.5. Results showed significantly reduced expression of Caveolin-1 in the yotari epithelium across both stages, along with diminished mesenchymal levels of Megalin and GIPC1 at E13.5. Cubilin and Dab2IP expression patterns showed no statistically significant differences, although developmental and compartmental shifts were observed. These findings suggest that Dab1 deficiency selectively disrupts endocytic and signaling scaffolds crucial for branching morphogenesis and alveolar maturation. The altered spatiotemporal expression of these proteins underscores the essential role of Dab1 in regulating lung epithelial–mesenchymal dynamics and maintaining developmental homeostasis during critical stages of organogenesis.