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Background/Objectives: Fat and inflammation confound current magnetic resonance imaging (MRI) methods for assessing fibrosis in liver disease. Sodium or amide proton transfer-weighted MRI methods may be more specific for assessing liver fibrosis. The purpose of this study was to determine the feasibility of sodium and amide proton transfer-weighted MRI in individuals with liver disease and to determine if either method correlated with clinical markers of fibrosis. Methods: T₁ and T₂ relaxation maps, proton density fat fraction maps, liver shear stiffness maps, amide proton transfer-weighted (APTw) images, and sodium images were acquired at 3T. Image data were extracted from regions of interest placed in the liver. ANOVA tests were run with disease status, age, and body mass index as independent factors; significance was set to p < 0.05. Post-hoc t-tests were run when the ANOVA showed significance. Results: A total of 36 participants were enrolled, 34 of whom were included in the final APTw analysis and 24 in the sodium analysis. Estimated liver tissue sodium concentration differentiated participants with liver disease from those without, whereas amide proton transfer-weighted MRI did not. Estimated liver tissue sodium concentration negatively correlated with the Fibrosis-4 score, but amide proton transfer-weighted MRI did not correlate with any clinical marker of disease. Conclusions: Amide proton-weighted imaging was not different between groups. Estimated liver tissue sodium concentrations did differ between groups but did not provide additional information over conventional methods. Full article

Background and Objectives: This study aimed to explore the risk factors of histopathological crescent formation in pediatric IgA vasculitis nephritis (IgAVN). Materials and Methods: Enrolled patients with biopsy-proven IgAVN from Zhejiang University’s hospital were split into two groups: 377 with no crescents on histopathology (Group 1) and 364 with crescentic nephritis (Group 2). Collected data included clinical features, lab indicators, histopathological grading, and factors causing glomerular sclerosis. Logistic regression was used to assess factors affecting crescent formation in IgAVN. Double-immunofluorescence assay was used to detect TGF-β1, MCP-1, α-SMA, Collagen I, and FN1 in kidney biopsy specimens. The relationship between kidney fibrosis factors and histopathological grade were analyzed using Chi-square and Pearson tests. Results: A total of 741 patients with IgAVN were included in the study. Univariate logistic regression identified potential factors related to crescent formation, including age, gender, clinical classification, hematuria grade, 24 h urine protein level, peripheral white blood cells (WBCs), serum albumin, Cystatin-C, APTT, and PT. Multivariate analysis revealed statistical significance for age, 24 h urine protein, and WBCs across pathological grades (p < 0.05). Mantel–Haenszel Chi-square tests indicated a linear relationship between IgAVN pathological grade and α-SMA, TGF-β1, MCP-1, and FN1. Pearson correlation analysis confirmed a positive correlation between pathological grade and these markers. Conclusions: Age, 24 h urinary protein, and blood WBCs are identified as risk factors for histopathological crescent formation in children with IgAVN. Additionally, a higher pathological grade is associated with more pronounced fibrosis indicators. Full article

Background: Pulmonary fibrosis (PF), the end-stage manifestation of interstitial lung disease, is defined by excessive extracellular matrix deposition and alveolar destruction. Activated fibroblasts, the primary matrix producers, rely heavily on dysregulated glucose metabolism for their activation. While Salt Inducible Kinase 2 (SIK2) regulates glycolytic pathways in oncogenesis, its specific contributions to fibroblast activation and therapeutic potential in PF pathogenesis remain undefined. This study elucidates the functional role of SIK2 in PF and assesses its viability as a therapeutic target. Methods: SIK2 expression/localization in fibrosis was assessed by Western blot and immunofluorescence. Fibroblast-specific Sik2 KO mice evaluated effects on bleomycin-induced fibrosis. SIK2’s role in fibroblast activation and glucose metabolism impact (enzyme expression, metabolism assays, metabolites) were tested. SIK2 inhibitors were screened and evaluated therapeutically in fibrosis models. Results: It demonstrated significant SIK2 upregulation, specifically within activated fibroblasts of fibrotic lungs from both PF patients and murine models. Functional assays demonstrated that SIK2 is crucial for fibroblast activation, proliferation, and migration. Mechanistically, SIK2 enhances fibroblast glucose metabolism by increasing the expression of glycolysis-related enzymes. Additionally, this study demonstrated that the SIK2 inhibitor YKL06-061 effectively inhibited PF in both bleomycin and FITC-induced PF mouse models with the preliminary safety profile. Furthermore, we identified a novel therapeutic application for the clinically approved drug fostamatinib, demonstrating it inhibits fibroblast activation via SIK2 targeting and alleviates PF in mice. Conclusions: Our findings highlight SIK2 as a promising therapeutic target and provide compelling preclinical evidence for two distinct anti-fibrotic strategies with significant potential for future PF treatment. Full article

Cystic fibrosis (CF), the most common hereditary lung disease in Caucasians, is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR). We evaluated CFTR function using a newly developed Ussing chamber system, the Multi Trans Epithelial Current Clamp (MTECC), in an in vitro model of human airway epithelia. Air–liquid interface (ALI) cultures were established from nasal brushings of healthy controls (HC) and CF patients with biallelic CFTR variants. ALI layer thickness was similar between groups (HC: 62 ± 13 µm; CF: 55 ± 9 µm). Immunofluorescence showed apical CFTR expression in HC, but reduced or absent signal in CF cultures. MTECC enabled continuous measurement of transepithelial resistance (Rt), potential difference (PD), and conductance (G_t). G_t was significantly reduced in CF cultures compared to HC (0.825 ± 0.024 vs. −0.054 ± 0.016 mS/cm²), indicating impaired cAMP-inducible ion transport by CFTR. Treatment of CF cultures with elexacaftor, tezacaftor, and ivacaftor (Trikafta^®) increased G_t, reflecting partial restoration of CFTR function. These findings demonstrate the utility of MTECC in detecting functional differences in CFTR activity and support its use as a platform for evaluating CFTR-modulating therapies. Our model may contribute to the development of personalized treatment strategies for CF patients. Full article

Background: Atrial fibrosis is a key contributor to atrial cardiomyopathy and can be assessed invasively using mean left atrial voltage (MLAV) from electroanatomical mapping. However, the invasive nature of this procedure limits its clinical applicability. Machine learning (ML), particularly regression tree-based models, may offer a non-invasive approach for predicting MLAV using clinical and echocardiographic data, improving non-invasive atrial fibrosis characterisation beyond current dichotomous classifications. Methods: We prospectively included and followed 113 patients with paroxysmal or persistent atrial fibrillation (AF) undergoing pulmonary vein isolation (PVI) with ultra-high-density voltage mapping (uHDvM), from whom MLAV was estimated. Standardised two-dimensional transthoracic echocardiography was performed before ablation, and clinical and echocardiographic variables were analysed. A regression tree model was constructed using the Classification and Regression Trees—CART-algorithm to identify key predictors of MLAV. Results: The regression tree model exhibited moderate predictive accuracy (R² = 0.63; 95% CI: 0.55–0.71; root mean squared error = 0.90; 95% CI: 0.82–0.98), with indexed minimum LA volume and passive emptying fraction emerging as the most influential variables. No significant differences in AF recurrence-free survival were found among MLAV tertiles or model-based generated groups (log-rank p = 0.319 and p = 0.126, respectively). Conclusions: We present a novel ML-based regression tree model for non-invasive prediction of MLAV, identifying minimum LA volume and passive emptying fraction as the most significant predictors. This model offers an accessible, non-invasive tool for refining atrial cardiomyopathy characterisation by reflecting the fibrotic substrate as a continuum, a crucial advancement over existing dichotomous approaches to guide tailored therapeutic strategies. Full article

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by vascular abnormalities, immune dysfunction, and progressive fibrosis. One of the most common manifestations of SSc is interstitial lung disease (ILD), known by a progressive course leading to significant morbidity and mortality. Aim: to investigate autoantibodies, cytokines, and genetic markers in SSc-ILD through a systematic review and analysis of a Kazakh cohort of SSc-ILD patients. Methods: A PubMed search over the past 10 years was performed with “SSc-ILD”, “autoantibodies”, “cytokines”, and “genes”. Thirty patients with SSc were assessed for lung involvement, EScSG score, and modified Rodnan skin score. IL-6 was measured by ELISA, antinuclear factor on HEp-2 cells by indirect immunofluorescence, and specific autoantibodies by immunoblotting. Genetic analysis was performed using a 120-gene AmpliSeq panel on the Ion Proton platform. Results: The literature review identified 361 articles, 26 addressed autoantibodies, 20 genetic variants, and 12 cytokine profiles. Elevated levels of IL-6, TGF-β, IL-33, and TNF-α were linked to SSc. Based on the results of the systemic review, we created a preliminary immunogenic panel for SSc-ILD with following analysis in Kazakh patients with SSc (n = 30). Fourteen of them (46.7%) demonstrated signs of ILD and/or lung hypertension, with frequent detection of antibodies such as Scl-70, U1-snRNP, SS-A, and genetic variants in SAMD9L, REL, IRAK1, LY96, IL6R, ITGA2B, AIRE, TREX1, and CD40 genes. Conclusions: Current research confirmed the presence of the broad range of autoantibodies and variations in IRAK1, TNFAIP3, SAMD9L, REL, IRAK1, LY96, IL6R, ITGA2B, AIRE, TREX1, CD40 genes in of Kazakhstani cohort of SSc-ILD patients. Full article

Biofilms are structured communities of microorganisms encased in a self-produced extracellular matrix, and they represent one of the most widespread forms of microbial life on Earth. Their presence poses serious challenges in both environmental and clinical settings. In natural and industrial systems, biofilms contribute to water contamination, pipeline corrosion, and biofouling. Clinically, biofilm-associated infections are responsible for approximately 80% of all microbial infections, including endocarditis, osteomyelitis, cystic fibrosis, and chronic sinusitis. A particularly critical concern is their colonization of medical devices, where biofilms can lead to chronic infections, implant failure, and increased mortality. Implantable devices, such as orthopedic implants, cardiac pacemakers, cochlear implants, urinary catheters, and hernia meshes, are highly susceptible to microbial attachment and biofilm development. These infections are often recalcitrant to conventional antibiotics and frequently necessitate surgical revision. In the United States, over 500,000 biofilm-related implant infections occur annually, with prosthetic joint infections alone projected to incur revision surgery costs exceeding USD 500 million per year—a figure expected to rise to USD 1.62 billion by 2030. To address these challenges, surface modification of medical devices has emerged as a promising strategy to prevent bacterial adhesion and biofilm formation. This review focuses on recent advances in chemical surface functionalization using non-antibiotic agents, such as enzymes, chelating agents, quorum sensing quenching factors, biosurfactants, oxidizing compounds and nanoparticles, designed to enhance antifouling and mature biofilm eradication properties. These approaches aim not only to prevent device-associated infections but also to reduce dependence on antibiotics and mitigate the development of antimicrobial resistance. Full article

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic ciliopathy resulting from loss-of-function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA–B-Raf–MEK–ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-κB-driven inflammation and fibrosis; and the TWEAK/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-κB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD’s complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD. Full article

Pulmonary hypertension (PH) is a serious pulmonary vascular disease. Vascular remodeling, metabolic reprogramming, inflammation, and fibrosis are all major pathogenic mechanisms in PH. MicroRNAs (miRNAs) are small RNAs, about 20–24 nucleotides long, that play important regulatory roles in biological processes, and in recent years, miRNAs have been found to potentially play a regulatory role in the pathogenesis of PH, and also serve as biomarkers and therapeutic agents for PH. However, there is still a long way to go from these experimental findings to their implementation in clinical practice. This study reviews the potential role of miRNAs in the pathogenesis of PH and suggests future applications of miRNAs in PH. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with limited therapeutic options and increasing global incidence, with a median survival of only 2–5 years. The clinical utility of macrophage polarization to regulate the progression of pulmonary fibrosis remains understudied. This study determined the efficacy of nintedanib and pexidartinib (PLX3397) combination therapy for treating IPF. Combination treatment effectively inhibited the progression of radiation-induced pulmonary fibrosis (RIPF) and prolonged survival in bleomycin-treated mice. Micro-CT analysis revealed a significant tissue repair efficacy. The therapy significantly normalized the abnormal vascular structure observed during RIPF and bleomycin-induced pulmonary fibrosis progression and was accompanied by a decrease in the M2 population. Polarized M1 macrophages enhanced normalized tube formation of irradiated endothelial cells (ECs) in vitro; M2 macrophages increased adhesion in irradiated ECs and abnormal tube formation. Single-cell RNA sequencing data from patients with IPF further supports colony stimulating factor (CSF) 1 upregulation in macrophages and downregulation of capillary EC markers. This study highlights a promising combination strategy to overcome the therapeutic limitations of monotherapy with nintedanib for the treatment of IPF. Full article

Diabetes-related pathophysiological processes contribute to endothelial dysfunction, arterial stiffening (AS), hypertension, vascular remodeling, and impaired myocardial perfusion. This study aimed to assess the relationship between arterial wall parameters and sST2 concentration as potential risk factors in type 2 diabetes (T2DM) and investigate sex-related differences. To achieve this, we enrolled 100 patients with suspected or exacerbated coronary artery disease (CAD) and divided them into a T2DM group (n = 58) and a control group (n = 42). Endothelial reactivity (lnRHI), ABI, sST2 levels, and carotid–femoral (cfPWV) and carotid–radial pulse wave velocity (crPWV) were assessed. Coronary angiography was performed in every patient, and epicardial flow and myocardial perfusion were evaluated using QuBE and FLASH. Our results showed that the coronary angiographic findings were similar in both groups. However, T2DM patients had a significantly higher central AS (cfPWV 10.8 ± 2 vs. 9.9 ± 2.7 m/s, p < 0.05) and vascular age (70.0 ± 12.3 vs. 61.3 ± 15.4 years, p < 0.05), while peripheral AS, RHI, and ABI showed no differences. CfPWV correlated with renal function; higher HbA1c and sST2 levels were additionally associated with advanced vascular age. Notably, central AS and vascular age were higher in men with T2DM but not in women. These findings indicate that T2DM patients exhibit increased central AS and vascular aging, influenced by sST2 levels, suggesting fibrosis as a target for precision medicine in T2DM. Full article

Background: Accumulating evidence indicates that SARS-CoV-2 infection results in long-term multiorgan complications, with the kidney being a primary target. This study aimed to characterize the long-term transcriptomic changes in the kidney following coronavirus infection using a murine model of MHV-1-induced SARS-like illness and to evaluate the therapeutic efficacy of SPIKENET (SPK). Methods: A/J mice were infected with MHV-1. Renal tissues were collected and subjected to immunofluorescence analysis and Next Generation RNA Sequencing to identify differentially expressed genes associated with acute and chronic infection. Bioinformatic analyses, including PCA, volcano plots, and GO/KEGG pathway enrichment, were performed. A separate cohort received SPK treatment, and comparative transcriptomic profiling was conducted. Gene expression profile was further confirmed using real-time PCR. Results: Acute infection showed the upregulation of genes involved in inflammation and fibrosis. Long-term MHV-1 infection led to the sustained upregulation of genes involved in muscle regeneration, cytoskeletal remodeling, and fibrotic responses. Notably, both expression and variability of SLC22 and SLC22A8, key proximal tubule transporters, were reduced, suggesting a loss of segment-specific identity. Further, SLC12A1, a critical regulator of sodium reabsorption and blood pressure, was downregulated and is associated with the onset of polyuria and hydronephrosis. SLC transporters exhibited expression patterns consistent with tubular dysfunction and inflammation. These findings suggest aberrant activation of myogenic pathways and structural proteins in renal tissues, consistent with a pro-fibrotic phenotype. In contrast, SPK treatment reversed the expression of most genes, thereby restoring the gene profiles to those observed in control mice. Conclusions: MHV-1-induced long COVID is associated with persistent transcriptional reprogramming in the kidney, indicative of chronic inflammation, cytoskeletal dysregulation, and fibrogenesis. SPK demonstrates robust therapeutic potential by normalizing these molecular signatures and preventing long-term renal damage. These findings underscore the relevance of the MHV-1 model and support further investigation of SPK as a candidate therapy for COVID-19-associated renal sequelae. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder associated with metabolic risk factors such as obesity, type 2 diabetes, and cardiovascular disease. If left untreated, the accumulation of excess hepatic fat can lead to inflammation, fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure. Capsaicin (CAP), the primary pungent compound in chili peppers, has previously been shown to prevent weight gain in high-fat diet (HFD)-induced obesity models. In this study, we investigated the potential of dietary CAP to prevent HFD-induced MASLD. Methods: C57BL/6 mice were fed an HFD (60% kcal from fat) with or without 0.01% CAP supplementation for 26 weeks. We evaluated CAP’s effects on hepatic fat accumulation, inflammation, and mitochondrial function to determine its role in preventing MASLD. Results: CAP acts as a potent and selective agonist of the transient receptor potential vanilloid 1 (TRPV1) channel. We confirmed TRPV1 expression in the liver and demonstrated that CAP activates hepatic TRPV1, thereby preventing steatosis, improving insulin sensitivity, reducing inflammation, and enhancing fatty acid oxidation. These beneficial effects were observed in wild-type but not in TRPV1 knockout mice. Mechanistically, CAP-induced TRPV1 activation promotes calcium influx and activates AMPK, which leads to SIRT1-dependent upregulation of PPARα and PGC-1α, enhancing mitochondrial biogenesis and lipid metabolism. Conclusions: Our findings suggest that dietary CAP prevents MASLD through TRPV1 activation. TRPV1 signaling represents a promising therapeutic target for the prevention and management of MASLD in individuals with metabolic disorders. Full article

Background: Inherited thrombophilia is increasingly recognized as a contributing factor to placental vascular pathology and adverse pregnancy outcomes. While the clinical implications are well-established, fewer studies have systematically explored the histopathological changes associated with specific genetic mutations in thrombophilic pregnancies. Materials and Methods: This retrospective observational study included two cohorts of placental samples collected between September 2020 and September 2024 at a tertiary maternity hospital. Group 1 included women diagnosed with hereditary thrombophilia, and Group 2 served as controls without known maternal pathology. Placentas were examined macroscopically and histologically, with pathologists blinded to group allocation. Histological lesions were classified according to the Amsterdam Consensus and quantified using a composite score (0–5) based on five key vascular features. Results: Placental lesions associated with maternal vascular malperfusion—including infarctions, intervillous thrombosis, stromal fibrosis, villous stasis, and acute atherosis—were significantly more frequent in the thrombophilia group (p < 0.05 for most lesions). A combination of well-established thrombophilic mutations (Factor V Leiden, Prothrombin G20210A) and other genetic polymorphisms with uncertain clinical relevance (MTHFR C677T, PAI-1 4G/4G) showed moderate-to-strong correlations with histopathological markers of placental vascular injury. A composite histological score ≥3 was significantly associated with thrombophilia (p < 0.001). Umbilical cord abnormalities, particularly altered coiling and hypertwisting, were also more prevalent in thrombophilic cases. Conclusions: Thrombophilia is associated with distinct and quantifiable placental vascular lesions, even in pregnancies without overt clinical complications. The use of a histological scoring system may aid in the retrospective identification of thrombophilia-related placental pathology and support the integration of genetic and histologic data in perinatal risk assessment. Full article

Chronic nasopharyngeal and otic disorders in children represent a significant clinical challenge due to their multifactorial etiology, variable presentation, and frequent resistance to standard therapies. Although often approached from a symptomatic or anatomical perspective, these conditions are deeply rooted in histological and molecular alterations that sustain inflammation, impair mucosal function, and promote recurrence. This narrative review synthesizes the current knowledge on the normal histology of the nasopharynx, Eustachian tube, and middle ear, and explores key pathophysiological mechanisms, including epithelial remodeling, immune cell infiltration, cytokine imbalance, and tissue fibrosis. Special emphasis is placed on the role of immunohistochemistry in defining inflammatory phenotypes, barrier dysfunction, and remodeling pathways. The presence of biofilm, epithelial plasticity, and dysregulated cytokine signaling are also discussed as contributors to disease chronicity. These findings have direct implications for diagnosis, therapeutic stratification, and postoperative monitoring. By integrating histological, immunological, and molecular data, clinicians can better characterize disease subtypes, anticipate treatment outcomes, and move toward a more personalized and biologically informed model of pediatric ENT care. Full article