Disruption Of Basement Membrane Research Articles

Ameliorative effects of sinapic acid against vancomycin-induced testicular oxidative damage, apoptosis, inflammation, testicular histopathologic disorders and decreased epididymal sperm quality

In this study, it was aimed to determine the effect of sinapic acid (SNP), a polyphenol with antioxidant, anti-inflammatory and antibacterial properties, on testicular damage caused by vancomycin (VCM), a widely used antibiotic against gram positive bacteria. A total of 35 male Sprague Dawley rats were used in the study, divided into five groups: control, VCM, SNP, VCM + SNP 10, and VCM + SNP 20. Following a week of oral administration, the rats were euthanized under sevoflurane anesthesia. While the VCM group had a significant increase in MDA levels, the SNP administration inhibited the increase in MDA levels. VCM led to a significant decrease in GSH levels, SOD, CAT, and GPx activity in the testicular tissue of rats, while SNP administration increased these antioxidant levels. SNP administration decreased the mRNA expression levels of VCM induced Nrf-2, HO-1, and NQO1 in testicular tissue while increasing the levels of MAPK14, MAPK15, JNK, P53, Apaf-1, Caspase-3, Caspase-6, Caspase-9, and Beclin-1 mRNA transcript levels. The VCM group showed a significant increase in Bax and NF-κB levels in testicular tissue, while Bcl-2 levels decreased. VCM significantly decreased sperm motility and increased the percentage of damaged sperm in rats. Histopathological results revealed that VCM caused disruption of basement membranes and disorganization of seminiferous tubules, but SNP administration preserved testicular histology. As a result, VCM increased oxidative stress, apoptosis, and autophagy in the testicular tissue of rats, altered testicular histopathology, and decreased sperm quality, while SNP decreased these effects.

The Impairment of Endothelial Autophagy Accelerates Renal Senescence by Ferroptosis and NLRP3 Inflammasome Signaling Pathways with the Disruption of Endothelial Barrier.

Autophagy is a cellular process that degrades damaged cytoplasmic components and regulates cell death. The homeostasis of endothelial cells (ECs) is crucial for the preservation of glomerular structure and function in aging. Here, we investigated the precise mechanisms of endothelial autophagy in renal aging. The genetic deletion of Atg7 in the ECs of Atg7flox/flox;Tie2-Cre mice accelerated aging-related glomerulopathy and tubulointerstitial fibrosis. The EC-specific Atg7 deletion in aging mice induced the detachment of EC with the disruption of glomerular basement membrane (GBM) assembly and increased podocyte loss resulting in microalbuminuria. A Transwell co-culture system of ECs and kidney organoids showed that the iron and oxidative stress induce the disruption of the endothelial barrier and increase vascular permeability, which was accelerated by the inhibition of autophagy. This resulted in the leakage of iron through the endothelial barrier into kidney organoids and increased oxidative stress, which led to ferroptotic cell death. The ferritin accumulation was increased in the kidneys of the EC-specific Atg7-deficient aging mice and upregulated the NLRP3 inflammasome signaling pathway. The pharmacologic inhibition of ferroptosis with liproxstatin-1 recovered the disrupted endothelial barrier and reversed the decreased expression of GPX4, as well as NLRP3 and IL-1β, in endothelial autophagy-deficient aged mice, which attenuated aging-related renal injury including the apoptosis of renal cells, abnormal structures of GBM, and tubulointerstitial fibrosis. Our data showed that endothelial autophagy is essential for the maintenance of the endothelial barrier during renal aging and the impairment of endothelial autophagy accelerates renal senescence by ferroptosis and NLRP3 inflammasome signaling pathways. These processes may be attractive therapeutic targets to reduce cellular injury from renal aging.

Disorganisation of basement membrane zone architecture impairs melanocyte residence in vitiligo.

The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin β1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Linking Basement Membrane and Slit Diaphragm in Drosophila Nephrocytes.

The glomerular basement membrane and the slit diaphragm are essential parts of the filtration barrier. How these layers collaborate remains unclear. The podocyte-like nephrocytes in Drosophila harbor both a slit diaphragm and a basement membrane, serving as a model to address this critical question. Basement membrane components and matrix receptors were silenced using RNAi in nephrocytes. Slit diaphragms were analyzed by immunofluorescence followed by automated quantification. Tracer endocytosis was applied for functional readouts. Immunofluorescence indicated a significant reduction of slit diaphragm density upon loss of laminin and collagen IV components. This was accompanied by reduced expression of fly nephrin and shallower membrane invaginations. Tracer studies revealed that the basement membrane defines properties of the nephrocyte filtration barrier. Acute enzymatic disruption of the basement membrane via collagenase rapidly caused slit diaphragm mislocalization and disintegration, which was independent of cell death. Loss of matrix-interacting receptors, particularly integrins mys and mew, phenocopied basement membrane disruption. Integrins and nephrin co-localized at the slit diaphragm in nephrocytes in a mutually dependent manner, interacting genetically. Human integrin α3 interacted physically with nephrin. The glomerular basement membrane model in Drosophila nephrocytes reveals that matrix receptor-mediated cues ensure correct positioning of the slit diaphragm and the overall filtration barrier architecture.

2.Cerebrovascular neuropathology in the brains of people with Down syndrome

AbstractBackgroundPeople with Down syndrome (DS) are at genetic risk of developing early‐onset Alzheimer’s disease (AD). By age 40 years, virtually all people with DS develop beta amyloid plaques and tau neurofibrillary tangles, typically followed by the development of AD dementia over a decade later. Despite having a low frequency of vascular risk factors (i.e., hypertension, atherosclerosis), people with DS show an age‐related progression of cerebral amyloid angiopathy (CAA), white matter hyperintensities, microbleeds, micro infarcts, and enlarged perivascular spaces by neuroimaging. Interestingly, the incidence of CAA at autopsy is significantly higher in people with DS than patients with late onset AD. Our main objective is to investigate the cerebrovascular pathology in DS autopsy cases.MethodFree floating 30 µm thick sections from the occipital cortex of DS cases with or without AD pathology (DSAD and DS, respectively, n = 5/group) were compared to age matched cognitively normal controls (n = 5). Sections were immunostained for collagen IV (basement membranes) and for fibrinogen (protein extravasation).ResultPreliminary results show that compared to controls, DSAD brains have impaired vascular integrity, observed as reduced collagen IV basement membrane labeling and evidence of protein extravasation which may reflect microbleeds observed using in vivo neuroimaging.ConclusionOur preliminary data suggest a disruption of blood vessel basement membranes observed as losses in collagen IV immunostaining in DSAD brains. Moreover, fibrinogen extravasation was consistently observed in DSAD brains. We are currently characterizing the age of onset of collagen IV disruption/losses and fibrinogen leakage into the brain parenchyma in the context of an AT(N) framework to understand when in AD progression, cerebrovascular pathology evolves in DS.

Targeting senescent dermal fibroblasts responsible for hyperactive melanocytes in melasma

Targeting senescent dermal fibroblasts responsible for hyperactive melanocytes in melasma

Basement membrane product, endostatin, as a link between inflammation, coagulation and vascular permeability in COVID-19 and non-COVID-19 acute respiratory distress syndrome.

Immune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro. In our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters. We observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort. The cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology.

Potentially Important Markers in Thyroid Neoplasia: Claudin-1 and MMP-7

ABSTRACT Background: Thyroid carcinomas are the most common malignant endocrine tumors, and various immunohistochemical markers are tested in routine practice to reduce diagnostic differences, as well as to elucidate carcinogenesis and detect malignancy. Disruption of basement membranes and the extracellular matrix is an important step in tumor carcinogenesis and progression. The claudin and matrix metalloproteinase families are also thought to be effective in this process. Aim: In this retrospective study, the comparative expression of claudin-1 and MMP-7 immunomarkers in normal tissues and thyroid neoplasia were investigated. Materials and Methods: Immunohistochemical staining was performed for claudin-1 and matrix metalloproteinase 7 (MMP-7) in 112 sections, including 24 follicular adenomas, 22 follicular carcinomas, 24 medullary carcinomas, 24 papillary carcinomas, and 18 single dominant nodules from thyroid lesions. Results: A significant staining difference for claudin-1 was observed in follicular carcinoma and medullary carcinoma, papillary carcinoma, and single dominant nodules compared to normal thyroid tissue. A statistically significant staining difference was observed for MMP-7 in follicular adenoma, medullary carcinoma, and papillary carcinoma compared to normal thyroid tissue. Conclusions: These results indicate that claudin-1 and MMP-7 are important in the diagnosis, differential diagnosis, and carcinogenesis of follicular adenoma, follicular carcinoma, medullary carcinoma, papillary carcinoma, and single dominant nodules.

HAM/TSP Pathogenesis: The Transmigration Activity of HTLV-1-Infected T Cells into Tissues.

Slowly progressive spastic paraparesis with bladder dysfunction, the main clinical feature of human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by inflammatory cytokines, etc., induced under the interaction between infiltrated HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ cytotoxic T cells, has been considered implicated for the induction of chronic inflammation. As this bystander mechanism is triggered conceivably by the transmigration of HTLV-1-infected CD4+ T cells to the spinal cord, heightened transmigrating activity of HTLV-1-infected CD4+ T cells to the spinal cord might play a crucial role as the first responder in the development of HAM/TSP. This review evaluated the functions of HTLV-1-infected CD4+ T cells in HAM/TSP patients as the prerequisite for the acquisition of the activity such as adhesion molecule expression changes, small GTPases activation, and expression of mediators involved in basement membrane disruption. The findings suggest that HTLV-1-infected CD4+ T cells in HAM/TSP patients have enough potential to facilitate transmigration into the tissues. Future HAM/TSP research should clarify the molecular mechanisms leading to the establishment of HTLV-1-infected CD4+ T cells as the first responder in HAM/TSP patients. In addition, a regimen with an inhibitory activity against the transmigration of HTLV-1-infected CD4+ T cells into the spinal cord might be recommended as one of the therapeutic strategies against HAM/TSP patients.

Spatiotemporal microvascular changes following contusive spinal cord injury.

Microvascular integrity is disrupted following spinal cord injury (SCI) by both primary and secondary insults. Changes to neuronal structures are well documented, but little is known about how the capillaries change and recover following injury. Spatiotemporal morphological information is required to explore potential treatments targeting the microvasculature post-SCI to improve functional recovery. Sprague-Dawley rats were given a T10 moderate/severe (200 kDyn) contusion injury and were perfuse-fixed at days 2, 5, 15, and 45 post-injury. Unbiased stereology following immunohistochemistry in four areas (ventral and dorsal grey and white matter) across seven spinal segments (n = 4 for each group) was used to calculate microvessel density, surface area, and areal density. In intact sham spinal cords, average microvessel density across the thoracic spinal cord was: ventral grey matter: 571 ± 45 mm-2, dorsal grey matter: 484 ± 33 mm-2, ventral white matter: 90 ± 8 mm-2, dorsal white matter: 88 ± 7 mm-2. Post-SCI, acute microvascular disruption was evident, particularly at the injury epicentre, and spreading three spinal segments rostrally and caudally. Damage was most severe in grey matter at the injury epicentre (T10) and T11. Reductions in all morphological parameters (95-99% at day 2 post-SCI) implied vessel regression and/or collapse acutely. Transmission electron microscopy (TEM) revealed disturbed aspects of neurovascular unit fine structure at day 2 post-SCI (n = 2 per group) at T10 and T11. TEM demonstrated a more diffuse and disrupted basement membrane and wider intercellular clefts at day 2, suggesting a more permeable blood spinal cord barrier and microvessel remodelling. Some evidence of angiogenesis was seen during recovery from days 2 to 45, indicated by increased vessel density, surface area, and areal density at day 45. These novel results show that the spinal cord microvasculature is highly adaptive following SCI, even at chronic stages and up to three spinal segments from the injury epicentre. Multiple measures of gross and fine capillary structure from acute to chronic time points provide insight into microvascular remodelling post-SCI. We have identified key vascular treatment targets, namely stabilising damaged capillaries and replacing destroyed vessels, which may be used to improve functional outcomes following SCI in the future.

Transcriptomic analysis predicts the risk of progression of premalignant lesions in human tongue

The 5-year survival rate for patients with oral squamous cell carcinomas (SCC), including tongue SCC, has not significantly improved over the last several decades. Oral potentially malignant disorders (OPMD), including oral dysplasias, are oral epithelial disorders that can develop into oral SCCs. To identify molecular characteristics that might predict conversion of OPMDs to SCCs and guide treatment plans, we performed global transcriptomic analysis of human tongue OPMD (n = 9) and tongue SCC (n = 11) samples with paired normal margin tissue from patients treated at Weill Cornell Medicine. Compared to margin tissue, SCCs showed more transcript changes than OPMDs. OPMDs and SCCs shared some altered transcripts, but these changes were generally greater in SCCs than OPMDs. Both OPMDs and SCCs showed altered signaling pathways related to cell migration, basement membrane disruption, and metastasis. We suggest that OPMDs are on the path toward malignant transformation. Based on patterns of gene expression, both OPMD and tongue SCC samples can be categorized into subclasses (mesenchymal, classical, basal, and atypical) similar to those seen in human head and neck SCC (HNSCC). These subclasses of OPMDs have the potential to be used to stratify patient prognoses and therapeutic options for tongue OPMDs. Lastly, we identified a gene set (ELF5; RPTN; IGSF10; CRMP1; HTR3A) whose transcript changes have the power to classify OPMDs and SCCs and developed a Firth logistic regression model using the changes in these transcripts relative to paired normal tissue to validate pathological diagnosis and potentially predict the likelihood of an OPMD developing into SCC, as data sets become available.

LHX2 in germ cells control tubular organization in the developing mouse testis

In the gonads of mammalian XY embryos, the organization of cords is the hallmark of testis development. This organization is thought to be controlled by interactions of the Sertoli cells, endothelial and interstitial cells with little or no role of germ cells. Challenging this notion, herein we show that the germ cells play an active role in the organization of the testicular tubules. We observed that the LIM-homeobox gene, Lhx2 is expressed in the germ cells of the developing testis between E12.5-E15.5. In Lhx2 knockout-fetal testis there was altered expression of several genes not just in germ cells but also in the supporting (Sertoli) cells, endothelial cells, and interstitial cells. Further, loss of Lhx2 led to disrupted endothelial cell migration and expansion of interstitial cells in the XY gonads. The cords in the developing testis of Lhx2 knockout embryos are disorganized with a disrupted basement membrane. Together, our results show an important role of Lhx2 in testicular development and imply the involvement of germ cells in the tubular organization of the differentiating testis. The preprint version of this manuscript is available at https://doi.org/10.1101/2022.12.29.522214

Nontuberculous mycobacteria otomastoiditis with facial palsy.

Nontuberculous mycobacteria otomastoiditis with facial palsy.

Human Papillary and Reticular Fibroblasts Show Distinct Functions on Tumor Behavior in 3D-Organotypic Cultures Mimicking Melanoma and HNSCC.

Human dermis can be morphologically divided into the upper papillary and lower reticular dermis. Previously, we demonstrated that papillary (PFs) and reticular (RFs) fibroblasts show distinct morphology and gene expression profiles. Moreover, they differently affect tumor invasion and epithelial-to-mesenchymal transition (EMT) in in vitro 3D-organotypic cultures of cutaneous squamous cell carcinoma (cSCC). In this study, we examined if these distinct effects of PFs and RFs can be extrapolated in other epithelial/non-epithelial tumors such as melanoma and head and neck squamous cell carcinoma (HNSCC). To this end, 3D-Full-Thickness Models (FTMs) were established from melanoma (AN and M14) or HNSCC cell lines (UM-SCC19 and UM-SCC47) together with either PFs or RFs in the dermis. The interplay between tumor cells and different fibroblasts was investigated. We observed that all the tested tumor cell lines showed significantly stronger invasion in RF-FTMs compared to PF-FTMs. In addition, RF-FTMs demonstrated more tumor cell proliferation, EMT induction and basement membrane disruption. Interestingly, RFs started to express the cancer-associated fibroblast (CAF) biomarker α-SMA, indicating reciprocal interactions eventuating in the transition of RFs to CAFs. Collectively, in the melanoma and HNSCC FTMs, interaction of RFs with tumor cells promoted EMT and invasion, which was accompanied by differentiation of RFs to CAFs.

Pathological MAPK activation-mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib.

Lymphangiectasia, an anomalous dilation of lymphatic vessels first described in the 17th century, is frequently associated with chylous effusion, respiratory failure, and high mortality in young patients, yet the underlying molecular pathogenesis and effective treatments remain elusive. Here, we identify an unexpected causal link between MAPK activation and defective development of the lymphatic basement membrane that drives lymphangiectasia. Human pathological tissue samples from patients diagnosed with lymphangiectasia revealed sustained MAPK activation within lymphatic endothelial cells. Endothelial KRASG12D–mediated sustained MAPK activation in newborn mice caused severe pulmonary and intercostal lymphangiectasia, accumulation of chyle in the pleural space, and complete lethality. Pathological activation of MAPK in murine vasculature inhibited the Nfatc1-dependent genetic program required for laminin interactions, collagen crosslinking, and anchoring fibril formation, driving defective development of the lymphatic basement membrane. Treatment with ravoxertinib, a pharmacological inhibitor of MAPK, reverses nuclear-to-cytoplasmic localization of Nfatc1, basement membrane development defects, lymphangiectasia, and chyle accumulation, ultimately improving survival of endothelial KRAS mutant neonatal mice. These results reveal defective lymphatic basement membrane assembly and composition as major causes of thoracic lymphangiectasia and provide a potential treatment.

Riehl's Melanosis: A Multimodality, In Vivo, Real-Time Skin Imaging Study with Cellular Resolution Optical Coherence Tomography and Advanced Skin Diagnosis System in a Tertiary Medical Center.

Background: Riehl’s melanosis is a psychologically devastating hyperpigmentary disorder that typically occurs on the face and neck. The study of Riehl’s melanosis is limited due to its rarity, variable morphology, and lack of noninvasive diagnostic tools. Recent advances in skin imaging analysis and diagnostic systems improve diagnostic accuracy and enable the noninvasive, real-time evaluation of pigmentary disease. A comprehensive study of Riehl’s melanosis clinical morphology with multimodality and in vivo skin imaging systems has yet to be reported. Objectives: To investigate the clinical features and in vivo advanced skin imaging findings of Riehl’s melanosis. Methods: We retrospectively investigated the clinical characteristics, dermoscopic, and histopathological features of Riehl’s melanosis. We further utilized multimodality skin imaging analysis systems, including a cellular resolution optical coherence tomography (OCT) and new skin diagnosis system, to investigate the features of Riehl’s melanosis. In addition, we compared OCT findings with histopathological features and clinical assessment. Results: We evaluated 30 patients with Riehl’s melanosis at a tertiary medical center from 2010 to 2022. The average age was 47.7 ± 12.3 (mean ± SD) years, predominantly female patients (female: n = 23; male: n = 7). Cellular resolution OCT imaging from lesion skin shows increased melanocyte capping, disrupted basement membrane, telangiectatic blood vessels, and melanophages in the dermis. The advanced skin diagnosis system captured subclinical erythema of the skin, highlighting the inflammatory nature of the disease. The results correlated well with histopathological findings. Limitations: This is a single-center, cross-sectional study. Conclusions: We highlight the features of Riehl’s melanosis through a novel cellular resolution OCT and photographic skin diagnosis system. A multimodality skin diagnosis system can serve as a real-time, in vivo, noninvasive method for evaluating pigmentary disorders.

Synthesis, formulation, evaluation of insecticidal activity of chromen derivatives against cotton leafworm Spodoptera littoralis (Lepidoptera: Noctuidae) and their mode of action under laboratory conditions

The toxicity of benzothiazole derivatives obtained from 2-cyanomethyl benzothiazole against cotton leafworm Spodoptera littoralis 2nd and 4th instar larvae has been documented. The main objective of this research was to formulate two previously reported chromen derivatives and test their biological activity against cotton leafworm S. littoralis 2nd and 4th instar larvae under laboratory conditions. According to the standard method, two chromen derivatives with two distinct substituents (salicylaldehyde and 2-hydroxy-1-naphthaldehyde) were synthesized. Their physical and chemical properties were evaluated, and both were formulated as 10 and 9.5 percent dustable powder formulations. Both formulae were then evaluated in the laboratory on cotton leafworm S. littoralis 2nd and 4th instar larvae for mortality and developmental effect percentage. Formulation (F2) was more efficient than formulation (F3) in both cases and for both stages. Furthermore, when comparing the developmental effects on the 2nd and 4th instar larvae, the 4th instar larvae demonstrated marked tolerance. Both stages were unable to complete their life cycle. Histopathological analysis of samples from the affected stages was performed to assess the mode of action of these formulations on 4th instar larvae at their LC50 values. Experimental data showed that Formulation (F3) resulted in epidermal cells separated from the cuticular layer, necrosis, ruptured columnar cells with pyknotic nuclei, disrupted basement membrane, and weak epicuticle necrosis and separation. In comparison, formulation (F2) revealed a midgut with vacuoles, damaged columnar, muscle cell necrosis, and a ruined peritrophic matrix. Thus, the cotton leafworm S. littoralis could be combated with the newly prepared formulations (F2) and (F3).

GSPE Protects against Bleomycin-Induced Pulmonary Fibrosis in Mice via Ameliorating Epithelial Apoptosis through Inhibition of Oxidative Stress.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause which leads to alveolar epithelial cell apoptosis followed by basement membrane disruption and accumulation of extracellular matrix, destroying the lung architecture. Oxidative stress is involved in the development of alveolar injury, inflammation, and fibrosis. Oxidative stress-mediated alveolar epithelial cell (AEC) apoptosis is suggested to be a key process in the pathogenesis of IPF. Therefore, the present study investigated whether grape seed proanthocyanidin extract (GSPE) could inhibit the development of pulmonary fibrosis via ameliorating epithelial apoptosis through the inhibition of oxidative stress. We found that GSPE significantly ameliorated the histological changes and the level of collagen deposition in bleomycin (BLM)-induced lungs. Moreover, GSPE attenuated lung inflammation by reducing the total number of cells in bronchoalveolar lavage (BAL) fluid and decreasing the expression of IL-6. We observed that the levels of H2O2 leading to oxidative stress were increased following BLM instillation, which significantly decreased with GSPE treatment both in vivo and in vitro. These findings showed that GSPE attenuated BLM-induced epithelial apoptosis in the mouse lung and A549 alveolar epithelial cell through the inhibition of oxidative stress. Furthermore, GSPE could attenuate mitochondrial-associated cell apoptosis via decreasing the Bax/Bcl-2 ratio. The present study demonstrates that GSPE could ameliorate bleomycin-induced pulmonary fibrosis in mice via inhibition of epithelial apoptosis through the inhibition of oxidative stress.

Association between matrix metalloproteinases-2 and -9 gene polymorphism with basement membrane disruption in oral lichen planus: A case-control pilot study

ObjectivesThis study investigated genetic polymorphism of matrix metalloproteinases (MMP) −2 and −9 in oral lichen planus (OLP) and their association with the basement membrane status. Study designThis case-control study involved genotyping of peripheral blood sample of 32 OLP patients and 106 ethnically matched controls. Single nucleotide polymorphisms (SNP) that were assessed in the groups were- MMP9 rs3918242, MMP9 rs17576 and MMP2 rs865094. Basement membrane status of the OLP biopsy samples was microscopically assessed and recorded following Periodic acid Schiff staining. ResultsMMP9 rs3918242 showed significant genotypic and allelic associations between OLP subjects and controls. It was also significantly associated with intact basement membranes in OLP cases with increased frequency of ‘TT’ genotype and ‘T’ allele. No association was found with regard to MMP9 rs17576 and MMP2 rs865094. ConclusionBiallelic substitution at the promoter region of MMP9 (rs3918242) gene may be associated with increased risk of development of OLP. It may be involved in compromising the integrity of the basement membrane junction.

Disruption of the glomerular basement membrane associated with nutcracker syndrome and double inferior vena cava in Noonan syndrome: a case report

BackgroundNutcracker syndrome (NCS) is characterized by compression of the left renal vein (LRV) between the aorta and the superior mesenteric artery. While rare, NCS was reported to be accompanied by double inferior vena cava (IVC). We herein report a case of Noonan syndrome (NS) with double IVC who presented with macrohematuria and proteinuria.Case presentationThe patient was a 23-year-old man, who had been diagnosed with NS due to RIT1 mutation, after showing foamy macrohematuria 3 weeks previously. A physical examination revealed low-set ears and a webbed neck. A urinalysis showed hematuria and proteinuria, and urinary sediments showed more than 100 isomorphic red blood cells per high-power field. His proteinuria and albuminuria concentrations were 7.1 and 4.5 g/g⋅Cr, respectively. Three-dimensional contrast-enhanced computed tomography (CT) showed double IVC and narrowing of the LRV after interflow of the left IVC. The aortomesenteric angle on a sagittal reconstruction of the CT image was 14.7°. Cystoscopy revealed a flow of macrohematuria from the left ureteral opening. On Doppler ultrasonography, there was scant evidence to raise the suspicion of the nutcracker phenomenon. Since severe albuminuria continued, a left kidney biopsy was performed. Light microscopy showed red blood cells in Bowman’s space and the tubular lumen. Electron microscopy revealed disruption of the glomerular basement membrane (GBM). Vulnerability of the GBM was suspected and a genetic analysis revealed a heterozygous mutation at c.4793 T > G (p.L1598R) in the COL4A3 gene. Screening for coagulation disorders revealed the factor VIII and von Willebrand factor (vWF) values were low, at 47.6 and 23%, respectively. A multimer analysis of vWF showed a normal multimer pattern and he was diagnosed with von Willebrand disease type 1. As the bleeding tendency was mild, replacement of factor VIII was not performed. His macrohematuria and proteinuria improved gradually without treatment, and his urinalysis results have been normal for more than 6 months.ConclusionsThe present case showed macrohematuria and proteinuria due to NCS in NS with double IVC and von Willebrand disease type 1. The macrohematuria and proteinuria originated from glomerular hemorrhage because of vulnerability of the GBM due to COL4A3 mutation.