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.

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.

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.

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.

Background/Objectives: The Reelin–Dab1 signaling pathway, known for its crucial role in neurodevelopment, particularly in neuronal migration and the formation of cortical layers, has been a subject of extensive research. However, its involvement in gastrointestinal organogenesis is a relatively unexplored area. Our study investigates the expression patterns of Dab1, Reelin, PGP9.5, and Sox2 during stomach development in yotari (Dab1−/−) mice and aims to shed light on how Dab1 inactivation affects epithelial–mesenchymal signaling dynamics, thereby contributing to a deeper understanding of this pathway’s non-neural functions. Methods: Embryonic stomach tissues from yotari and wild-type mice, collected at developmental stages E13.5 and E15.5, were examined by immunofluorescenceto evaluate the difference in expression of Dab1, Reelin, PGP9.5, and Sox2. Semi-quantitative scoring and quantitative image analysis were used to assess protein localization and intensity within epithelial and mesenchymal compartments. Results: Dab1 expression was significantly increased in both the epithelium and mesenchyme of yotari mice at E13.5 and E15.5. Reelin expression in the epithelium showed a visible but statistically non-significant decrease in yotari at E15.5, while mesenchymal expression remained low and significantly lower than controls. PGP9.5 expression was significantly reduced in yotari epithelium at E13.5, then strongly upregulated at E15.5. Mesenchymal PGP9.5 remained consistently high. Sox2 showed no statistically significant changes but increased semi-quantitatively in yotari epithelium and mesenchyme at E15.5. These findings highlight compartment-specific disruptions and potential compensatory mechanisms following Dab1 inactivation. Conclusions: Our findings indicate that Dab1 deficiency leads to distinct molecular changes in epithelial and mesenchymal compartments of the developing stomach. The Reelin–Dab1 axis appears critical for epithelial–mesenchymal coordination, while PGP9.5 and Sox2 upregulation in yotari mice may represent potential compensatory responses that could support epithelial integrity, although this remains speculative without functional validation.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the third most common congenital anomaly and a significant public health concern. It is the predominant cause of chronic renal disease in pediatric populations and the principal reason for kidney replacement therapy in individuals under 20, as well as the fourth leading cause in adults. Five candidate genes, including EDA2R, PCDH9, and TRAF7 were identified as potential contributors to CAKUT. These genes had not been previously prioritized in CAKUT research, and our prior studies have demonstrated that the proteins encoded by these candidate genes display dysregulated expression across various CAKUT subgroups. Our research examined the expression patterns of EDA2R, PCDH9, and TRAF7 in yotari (Dab1−/−) mice at two embryonic stages (E13.5 and E15.5) and two postnatal stages (P4 and P14) to ascertain the potential correlation between Reelin–Dab1 signaling, previously linked to CAKUT phenotypes, and the aforementioned proteins through molecular and morphological analyses. All three observed proteins exhibited the highest area percentage at E13.5, with a trend of decline into postnatal stages, during which specific changes in protein expression were noted between the cortex and medulla of yotari mice compared to wild-type mice. For TRAF7, a statistically significant difference in area percentage at E13.5 was observed, indicating a link with Reelin–Dab1 signaling and a potentially critical role in the pathophysiology of CAKUT, also marked by our prior study.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric renal failure, but the molecular mechanisms driving these conditions are not yet fully understood. Fibroblast Growth Factor 23 (FGF23) and its co-receptor α-KLOTHO play crucial roles in regulating calcium and phosphate homeostasis in adult kidneys, but their roles in kidney development and the pathogenesis of CAKUT remain unclear. Because of that, we analyzed the spatial and temporal expression of FGF23 and α-KLOTHO in normal fetal kidney development and CAKUT using an immunofluorescence technique. Our results demonstrate a dynamic pattern of FGF23 and α-KLOTHO expression in healthy kidney development, with FGF23 levels decreasing and α-KLOTHO levels increasing with gestational age. Also, we showed that FGF23 expression was significantly reduced in horseshoe (HKs) and duplex kidneys (DKs), while α-KLOTHO expression remained unchanged across all CAKUT conditions. Based on our results, we suggest that altered FGF23 expression in CAKUT contributes to disease pathogenesis and may represent a potential therapeutic target.