Search Results (405)

Asthma is characterized by persistent airway epithelial dysfunction and remodelling of the reticular basement membrane (RBM). In healthy airways, the RBM is primarily composed of the extracellular matrix (ECM) proteins laminin and collagen-IV, but in remodelled asthmatic airways, the RBM has increased deposition of collagen-I, -III and fibronectin. Here, we systematically compared the effects of collagen-I, -III, -IV, fibronectin, laminin, and bovine serum albumin (BSA) control on bronchial epithelial cells (BECs) from six healthy controls and seven individuals with asthma. Epithelial attachment, spreading and barrier function were assessed in real time over 72 h using electrical cell–substrate impedance sensing. Cell culture supernatants were analyzed for release of epithelial cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-6, IL-8, and IL-11 using ELISA. BECs from both control and asthma donors had faster cell attachment, spreading, and barrier formation on collagen-I, -III, -IV, and fibronectin compared to laminin and BSA. BECs from both control and asthma donors cultured on collagen -I and -III produced more TSLP, but had no effect on IL-6, IL-8, and IL-11 expression. In summary, remodelling of the RBM in asthma may promote epithelial barrier formation whilst simultaneously enhancing epithelial-derived Th2 inflammation through increased TSLP release. Full article

Background: Alport syndrome is a hereditary disorder caused by defects in the type IV collagen network. Although exon variants are primarily associated with Alport syndrome, the clinical significance of intronic variants remains incompletely characterized. The aim of this study was to characterize the clinical and molecular features of a familial case of Alport syndrome associated with the intronic variant c.1588-2A>G and to assess its impact using in silico tools. Case description: Two affected siblings presented with hematuria, proteinuria, and renal biopsy demonstrated focal global and segmental glomerulosclerosis, findings consistent with Alport syndrome. Whole-exome sequencing was subsequently performed in patients. The variant (NM_033380.2, c.1588-2A>G) in intron 23 of the COL4A5 gene was identified in both probands. SpliceAI analysis demonstrated a complete loss of the canonical acceptor site and a high probability of cryptic site activation. Conclusion: The evidence suggests a likely pathogenic role of the COL4A5 c.1588-2A>G variant in Alport syndrome. Full article

Background: Sugaya type III rotator cuff re-tears are characterized by preserved tendon continuity with reduced thickness and are often associated with persistent pain and functional impairment. Bioinductive collagen implants may enhance tendon healing, but clinical evidence in this population remains limited. This study aimed to evaluate the clinical and radiologic outcomes of arthroscopic repair with bioinductive collagen implant augmentation in patients with Sugaya type III re-tears. Methods: This retrospective case series (Level IV) included 15 patients (mean age 61.7 years) with MRI-confirmed Sugaya type III re-tears. An a priori power analysis based on a large effect size (Cohen’s d = 0.80) indicated that a sample size of 15 would provide 80% power to detect clinically meaningful changes in the primary endpoint. Clinical outcomes were assessed preoperatively and at 6 and 12 months postoperatively using VAS, ASES, SANE, and WORC scores. MRI was used to evaluate changes in supraspinatus tendon thickness. Non-parametric statistical analysis with Bonferroni correction was applied. Results: The median VAS pain score improved from 6.5 (IQR, 6.0–7.0) preoperatively to 2.8 (IQR, 2.0–3.5) at 6 months and to 2.1 (IQR, 1.5–2.8) at 12 months (adjusted p < 0.001). The median ASES score increased from 45.0 (IQR, 39.0–51.0) to 78.0 (IQR, 72.0–85.0), with a median improvement of 33 points. SANE and WORC scores also showed significant improvements. Supraspinatus tendon thickness increased from 4.8 mm (IQR, 3.7–5.7) to 6.9 mm (IQR, 5.4–8.3) at 12 months (adjusted p < 0.001). No graft failure was observed on follow-up MRI. Conclusions: Arthroscopic repair with bioinductive collagen implant augmentation may be associated with short-term improvements in pain, function, and tendon thickness in patients with Sugaya type III re-tears. Given the small sample size and lack of a control group, these findings should be interpreted cautiously, and further prospective comparative studies are needed. Full article

The non-collagenous domain 1 of the α3 chain of type IV collagen (α3(IV)NC1) is the primary autoantigen in anti-glomerular basement membrane (anti-GBM) disease. We previously developed a modified antigen-specific peptide, m-P14, derived from the nephritogenic epitope α3_127–148, which ameliorated experimental anti-GBM nephritis. However, its short half-life limits clinical translation. This study evaluated a butyrate-conjugated derivative (m-P14-BA) to improve pharmacokinetic properties while preserving therapeutic efficacy. M-P14-BA and m-P14 were administered to α3_127–148 immunized Wistar Kyoto rats in early and late treatment settings. Renal injury parameters and intrarenal inflammation were assessed, and pharmacokinetic profiles were evaluated following intraperitoneal administration in beagle dogs. M-P14-BA reduced proteinuria, crescent formation, glomerular IgG deposition, complement activation, and inflammatory cell infiltration, with overall efficacy comparable to m-P14 in early treatment settings. In late treatment settings, m-P14-BA was associated with a significant improvement in blood urea nitrogen levels and modest reductions in proteinuria and histopathological injury. Butyrate conjugation markedly improved pharmacokinetics, prolonging plasma elimination half-life by approximately 2.8-fold and increasing systemic exposure nearly fourfold. These pharmacokinetic improvements were associated with maintained therapeutic efficacy at a reduced dose, with 10 mg/kg m-P14-BA achieving effects broadly similar to those observed with 30 mg/kg m-P14. In summary, butyrate conjugation improves the pharmacokinetic profile of an antigen-specific therapeutic peptide while preserving therapeutic activity, suggesting a potential strategy to enhance the translational feasibility of peptide-based immunotherapy in anti-GBM disease. Full article

Persistent microscopic hematuria in children is often considered benign, yet recent evidence shows that a substantial proportion of affected individuals have underlying glomerular disease, particularly collagen IV-related nephropathies. We report a case of autosomal dominant Alport syndrome (ADAS) diagnosed just before discontinuation of long-term follow-up in a young woman initially presumed to have benign familial hematuria. The proband had persistent microscopic hematuria from early childhood, with normal renal function and no extrarenal manifestations. Her mother also had microscopic hematuria without kidney impairment, and the absence of accessible family history reinforced the assumption of benign familial hematuria. At age 42, the mother developed sensorineural hearing loss, and around the same time, the family learned that the maternal grandfather was undergoing dialysis for end-stage renal disease of unknown etiology. These findings prompted genetic testing, which identified a heterozygous pathogenic COL4A4 frameshift variant (c.2317_2318del; p.Arg773GlyfsTer14) in both the mother and the proband, confirming ADAS. This case illustrates the phenotypic variability of ADAS within a single family and highlights the limitations of relying solely on clinical features or incomplete family history. In contemporary practice, persistent glomerular hematuria warrants long-term follow-up and a low threshold for molecular testing of COL4A3-COL4A5, even in the absence of overt clinical signs. Earlier genetic evaluation would likely have enabled a timelier diagnosis in this case. This report underscores the importance of reassessing presumed benign hematuria and integrating genetic testing into the diagnostic approach for children and young adults with persistent microscopic hematuria. Full article

Chronic exposure to fine particulate matter (${\mathrm{PM}}_{2.5}$) derived from residential wood combustion is a major environmental health concern in southern Chile and other cold-climate regions. Although ${\mathrm{PM}}_{2.5}$ has been linked to adverse reproductive outcomes, it remains unclear whether sustained exposure induces pregestational uterine alterations that compromise reproductive competence before the first pregnancy. This study evaluated the effects of chronic wood smoke-derived ${\mathrm{PM}}_{2.5}$ exposure on uterine morphology and molecular markers in nulliparous rats. A two-generation exposure model was used to assess cumulative effects. Second-generation (G2) female Sprague Dawley rats continuously exposed from conception were housed in filtered air (FA, control; $n=12$) or ${\mathrm{PM}}_{2.5}$-containing ambient air (NFA; $n=12$) until reproductive maturity (82 days). Uterine horns were analyzed by histology, planimetry, immunohistochemistry, immunofluorescence, and second harmonic generation microscopy. Markers of hypoxia, inflammation, extracellular matrix remodeling, angiogenesis, proliferation, apoptosis, and DNA repair were quantified. Chronic ${\mathrm{PM}}_{2.5}$ exposure increased hypoxia-inducible factor 1$\alpha$, tumor necrosis factor-$\alpha$, vascular endothelial growth factor A, and collagen types I, III, and IV, while transforming growth factor-$\beta$ expression and Ki-67-positive proliferating cells were reduced. Exposed rats showed increased apoptosis and decreased nuclear expression of ${\mathrm{O}}^6$-methylguanine-DNA methyltransferase, indicating impaired DNA repair capacity. Second harmonic generation imaging demonstrated increased collagen deposition with marked fibrillar disorganization. These findings indicate that chronic wood smoke-derived ${\mathrm{PM}}_{2.5}$ exposure induces hypoxia-driven structural and molecular alterations in the uterus of nulliparous rats before first pregnancy, including extracellular matrix remodeling, inflammatory imbalance, angiogenic dysregulation, reduced proliferation, and compromised DNA repair, suggesting early disruption of uterine homeostasis and increased susceptibility to adverse reproductive outcomes. Full article

Introduction. The superficial musculoaponeurotic system (SMAS) is fundamental for facial soft tissue support and surgical rejuvenation. Although its morphology in the midface and neck is well characterized, the structure of its cranial extension to the forehead remains a subject of terminological uncertainty. The aim of this study was to conduct a detailed histological and immunohistochemical examination of the forehead supporting structures to characterize their morphology and propose an expanded, region-specific classification of the SMAS. Material and methods. Full-thickness tissue specimens (n = 30) were obtained from five standardized facial regions (parotid, buccal, temporal, frontal, and cervical) from 12 male and 18 female body donors (aged 25–70 years). Specimens were processed for histological analysis using hematoxylin and eosin, van Gieson staining, and Masson’s trichrome. Immunohistochemical staining for S100 protein was used to identify neural structures. Morphometric analysis was performed on digitized sections to quantify interseptal distances and the depth of superficial nerve trunks. Results. The analysis confirmed the established SMAS types (I–V) in the cheek, parotid gland, and neck, confirming the validity of the method. Two distinct, sequentially arranged structures were identified on the forehead, proposed as new types. Type VI (neurovascular arborization) is a discrete fan-shaped structures with a central collagen core surrounding a neurovascular bundle, showing positive S100 staining. These structures, spaced approximately 2.2 mm apart, function as true retaining ligaments. Type VII (fibroseptal) SMAS patterns is vertically oriented, purely fibrous septa (retinacula cutis) connecting the aponeurosis to the dermis, devoid of neural elements, and spaced approximately 9.2 mm apart. Importantly, the superficial nerve trunks were located at an average depth of only 1.09 mm (range: 0.57–1.97 mm) from the skin surface. Conclusion. This study identified two novel SMAS patterns in the forehead—neurovascular arborization (type VI) and fibroseptal (type VII)—supporting the expanded functional seven-type classification of the SMAS. The extremely superficial location of the forehead nerves (average 1.1 mm) defines a critical “danger zone” for aesthetic procedures. These findings provide a refined anatomical basis for improving the precision and safety of both surgical and minimally invasive facial procedures. Full article

Background/Objectives: X-linked Alport syndrome (XLAS) arises from pathogenic variants in COL4A5. Truncating variants are generally classified as severe, but whether clinically meaningful heterogeneity exists within this group remains unclear. This study aimed to establish a novel Col4a5 knock-in mouse model based on a clinical variant and to determine whether truncating mutation position influences disease severity. Methods: A de novo COL4A5 frameshift variant, c.2440delG, was identified in a patient with severe early-onset XLAS. A Col4a5-G814fs knock-in mouse was generated by CRISPR/Cas9 on the C57BL/6J inbred mouse strain background and compared with the established Col4a5-G5X nonsense model using survival analysis, serial functional measurements, kidney histopathology, transmission electron microscopy, and RNA sequencing. Results: The Col4a5-G814fs knock-in mouse was successfully generated and showed loss of glomerular α5(IV) collagen chain expression. Compared with G5X mice, G814fs mice exhibited shorter survival (median 141 vs. 161.5 days, p = 0.0004), earlier onset of proteinuria, and more severe kidney functional decline. By 16 weeks, G814fs mice also showed more severe glomerular basement membrane abnormalities and more extensive glomerulosclerosis. RNA sequencing revealed a shared inflammatory gene signature in both models, together with selective upregulation of genes related to the PPAR signaling pathway and fatty acid metabolism in G814fs kidneys. Conclusions: This study reports a novel de novo COL4A5 frameshift variant and establishes the first Col4a5-G814fs knock-in mouse model. Direct comparison with the G5X model shows that distinct truncating COL4A5 mutations can be associated with substantially different disease severity, providing a useful platform for future mechanistic and therapeutic studies in XLAS. Full article

Background and Objectives: Peripheral nerve adaptation to different pathological conditions is accompanied by the remodelling of the nerve’s extracellular matrix (ECM). Ischemic conditions caused by peripheral vascular disease are known to affect the function of peripheral nerves; however, the morphological changes to their ECM remain insufficiently examined and understood. Bearing in mind that alterations in collagen I, collagen IV, and laminin content may compromise peri- and endoneurial integrity, the aim of our study was to analyse whether peripheral vascular disease (PVD) induces distinct ECM alterations in the human sural nerve compared with the adaptive remodelling observed in ageing. Materials and Methods: The study aimed to determine the amount of type I and IV collagen and laminin in the perineurium and endoneurium of human peripheral nerves from patients with PVD and to compare the results with those of the age-matched controls. Twenty human sural nerves were harvested from cadavers and amputated limbs—10 from each—and were further distributed into two age groups: below and over 75 years of age. The sural nerve tissue samples were stained immunohistochemically for collagen I, collagen IV, and laminin. We measured the percentage content of these ECM components in the perineurium and endoneurium. For morphometric analysis, we used ImageJ software v1.54d. Results: Perineurial collagen type I and laminin were decreased in the older PVD group, relative to both the younger PVD and the older age group. Within the endoneurium, the expression of collagen type IV was higher in older PVD patients, while both collagen type I and laminin were deposited in lower amounts in the same group compared with the younger PVD group. Conclusions: These findings suggest that age-related ECM remodelling in the peripheral nerve may be impaired under ischemic conditions in older adults, with implications for surgical grafting strategies or neural conduit therapies aimed at promoting functional regeneration. Full article

Oligomeric species of alpha-synuclein (α-syn) in saliva and phosphorylated α-syn deposits in the skin are established molecular biomarkers for Parkinson’s disease (PD). However, existing research has yet to fully explore the diagnostic potential of non-phosphorylated α-syn and other cutaneous morphometric parameters, such as variations in collagen type IV within the dermis and epidermis or α-syn expression in melanocytes. This study aims to evaluate and compare the diagnostic utility of these skin morphometric parameters in differentiating 32 PD patients from 19 healthy subjects (HSs), while also examining their correlation with salivary α-syn oligomer levels. Skin biopsies were analyzed via immunofluorescence and confocal microscopy, while salivary oligomeric α-syn was quantified through competitive ELISA. Results revealed a significant reduction in α-syn-positive fibres in PD patients compared to HSs (0.91; <0.0001). Conversely, the collagen staining area and the number of α-syn-positive melanocytes were significantly increased in the skin of PD patients. Specifically, the collagen type IV staining area was significantly higher in the dermis and surrounding the sweat glands of PD patients, demonstrating optimal diagnostic power (0.9448; <0.0001). Similarly, the increase in α-syn-positive melanocytes in PD patients showed robust diagnostic potential (0.84; <0.001). Salivary α-syn oligomers accurately discriminated between PD and HS groups. Furthermore, significant correlations were found between collagen type IV and melanocyte morphometric parameters and various clinical scores in PD. Our findings highlight how multimodal morphometric analysis of the skin can enhance diagnostic accuracy in PD, supporting the use of salivary and cutaneous biomarkers as complementary tools that may reflect distinct aspects of PD pathology. Full article

Steroid-resistant nephrotic syndrome (SRNS) in childhood frequently reflects monogenic podocytopathies in which immunosuppression is ineffective. Biallelic variants in MYO1E, encoding the class I myosin Myo1E, cause a distinctive form of focal segmental glomerulosclerosis (FSGS) often accompanied by “Alport-like” multilamination of the glomerular basement membrane (GBM). Early recognition has therapeutic and prognostic implications. A previously healthy 4-year-old boy presented with generalized edema and nephrotic-range proteinuria. Glucocorticoids induced no remission; sequential calcineurin inhibition (cyclosporine, then tacrolimus) and a single dose of ofatumumab yielded only transient, partial reductions in proteinuria. A first biopsy elsewhere showed FSGS with nonspecific IgM/C3 trapping; electron microscopy (EM) was not performed. At age 10, repeat biopsy with EM revealed ~30% segmental foot-process effacement, focal GBM thickening (to 1740 nm), irregular lamina densa multilamination, and lamellar duplications without immune-complex deposits—features highly suggestive of hereditary GBM disease. Targeted sequencing identified compound-heterozygous MYO1E variants segregating in trans: a canonical splice-donor change (c.2785+1G>A) and a frameshift (c.3094_3097del; p.Thr1032Profs*73). Each parent was an unaffected heterozygous carrier; the sibling was negative. Supportive therapy with ramipril was continued. At last follow-up (January 2025), renal function was normal (serum creatinine 0.5 mg/dL; creatinine clearance 122 mL/min) with stable sub-nephrotic proteinuria (0.52 g/day; 16 mg/m² per hour) and normotension. This case broadens clinicopathologic recognition of MYO1E-associated nephropathy and highlights the teaching point that Alport-like GBM changes are not pathognomonic for type IV collagen disorders but may signal defects in podocyte cytoskeletal anchoring. Full article

Aging is associated with changes in intramuscular collagen structure and metabolism, which may impair mechanical adaptability and regenerative capacity. We investigated the effects of aging and repeated passive stretching on intramuscular collagen remodeling in the tibialis anterior muscles of mice. The tibialis anterior muscles of young and aged mice were exposed to repeated passive stretching, and the localization of collagen and collagen-related factors was evaluated. Baseline gene expression of collagens I and IV was significantly reduced in aged muscles and was not restored by stretching. Repeated passive stretching increased the area and intensity of collagen I immunoreactivity in both young and aged mice but produced little change in collagen IV. Stretch-induced dynamic changes in lysyl oxidase-positive cells in the extracellular matrix (ECM) were evident in young mice but were markedly attenuated in aged mice. In addition, matrix metalloproteinases (MMP2 and MMP9) mRNA and protein expressions did not differ between groups. No significant age- or stretch-dependent changes were observed in the localization of advanced glycation end products. These findings suggest that although the increase in fibrillar collagen in response to stretching is maintained with aging, the regulatory mechanisms controlling ECM stabilization, particularly those related to cross-linking dynamics, may be impaired. Full article

Thin, dry skin is characterized by impaired barrier integrity, loss of dermal density, and accelerated aging driven by intrinsic and extrinsic factors. Biomimetic collagen peptides mimic native collagen sequences, stimulating fibroblasts to enhance synthesis while limiting matrix metalloproteinase-mediated degradation. This study evaluated the clinical efficacy and safety of a multi-ingredient cosmetic product for thin, dry, aging skin, formulated as a dual-purpose body and face serum lotion containing 0.1% biomimetic collagen tripeptide (Tripeptide-29) along with Niacinamide, Citrullus lanatus fruit extract, and Selaginella lepidophylla extract. In this prospective, single-center study, 47 healthy women, aged 36–65 years with Fitzpatrick skin types I–IV, applied the formula twice daily to the face and body over four weeks. Objective measurements—including elasticity, wrinkle depth and volume, hydration, trans-epidermal water loss (TEWL), and texture—were collected weekly alongside clinical grading and self-assessments. Significant improvements were observed across all parameters, with facial dryness decreasing immediately (−74.6%) and continuing to week 4 (−93.7%), hydration increasing up to 72.5%, softness improving up to 37.7%, roughness decreasing up to 37.9%, and TEWL reductions indicating strengthened barrier function. Desquamation improved by 75.5% by week 3, and no adverse effects occurred. The serum lotion demonstrated robust, well-tolerated benefits for enhancing multiple markers of thin, dry, aging skin. Full article

This study aimed to investigate the effect and underlying mechanism of Taxus cuspidata seed oil (TCSO) on carbon tetrachloride (CCl₄)-induced hepatic fibrosis in mice. A mouse model of hepatic fibrosis was established by CCl₄ induction, and the model mice were subsequently treated orally with high dose or low dose TCSO for eight weeks. The degree of liver fibrosis and the mechanism of action were assessed through organ indices, serum biochemical markers, oxidative stress levels, histopathological examination, and molecular biological analyses. The results demonstrated that TCSO significantly reduced serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Concurrently, it decreased the concentrations of liver fibrosis markers, including procollagen III (PC III), collagen IV (IV-C), hyaluronic acid (HA), and laminin (LN), and reduced hepatic collagen deposition. Furthermore, TCSO enhanced the activities of the antioxidants superoxide dismutase (SOD) and glutathione (GSH) while inhibiting the production of the lipid peroxidation product malondialdehyde (MDA), and it ameliorated histopathological alterations in liver tissue. Additionally, TCSO markedly downregulated the expression of key fibrogenic proteins, such as transforming growth factor-β1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), and tissue inhibitor of metalloproteinases-1 (TIMP-1), thereby effectively suppressing the progression of hepatic fibrosis. In conclusion, TCSO ameliorates hepatic fibrosis in mice by reducing hepatotoxic enzyme activity and collagen deposition, enhancing antioxidant capacity, and downregulating the expression of fibrosis-related proteins. Full article

Background/Objectives: Aneurysms develop secondary to progressive weakening of arterial walls and remain a major cause of morbidity and mortality worldwide. Collagen, particularly fibrillar types I and III, is the primary tensile load-bearing component of arteries, yet its specific role in aneurysm formation, progression, and rupture is incompletely defined. This narrative review synthesizes current evidence on collagen structure, regulation, and degradation in aneurysm pathophysiology, highlighting cerebral aneurysms within the broader context of aneurysms as a whole. Methods: Searches of PubMed, MEDLINE, Embase, and Google Scholar were performed to identify all English-language studies published prior to January 2026. Search terms included “cerebral aneurysm”, “collagen”, “extracellular matrix”, “vascular remodeling”, and “aneurysm rupture”. Included studies evaluated collagen structure or content, extracellular matrix remodeling, matrix metalloproteinases, or biomechanical properties of the aneurysm wall in experimental or human models. Results: The literature search identified 348 records, of which 87 studies published between 1999 and 2025 met the inclusion criteria and were synthesized in this review. Collagen types I and III form the primary tensile scaffold of intracranial arteries, while basement membrane and regulatory collagens (e.g., types IV, V, and VI) modulate fibril organization, endothelial stability, and mechanical homeostasis. Research demonstrates that endothelial dysfunction, nitric oxide dysregulation, oxidative stress, and matrix metalloproteinase activation are key pathways driving collagen fragmentation and degradation. Genetic and epigenetic disturbances in collagen and related extracellular matrix pathways further increase aneurysm susceptibility. Conclusions: Collagen dysregulation appears to be a final common pathway through which hemodynamic, inflammatory, hormonal, and genetic insults converge to weaken intracranial arterial walls. However, existing evidence is dominated by animal and aortic models, and in vivo tools, such as Magnetic Resonance Imaging with collagen-sensitive sequences and Positron Emission Tomography Tracers, to quantify collagen integrity in cerebral aneurysms are lacking. Future efforts should prioritize human-focused studies, advanced collagen-sensitive imaging, biomarker development, and targeted strategies to preserve or restore collagen structure as potential means to improve aneurysm risk stratification, prevention, and treatment. Full article