Destruction Of Extracellular Matrix Research Articles

Exploring Salivary Epithelial Dysfunction in Sjögren's Disease.

Sjögren's Disease (SjD) is an autoimmune disease of the exocrine tissues. Etiological events result in the loss of epithelial homeostasis alongside extracellular matrix (ECM) destruction within the salivary and lacrimal glands, followed by immune cell infiltration. In this review, we have assessed the current understanding of epithelial-mesenchymal transition (EMT)-associated changes within the salivary epithelium potentially involved in salivary dysfunction and SjD pathogenesis. We performed a PubMed literature review pertaining to the determination of pathogenic events that lead to EMT-related epithelial dysfunction and signaling in SjD. Molecular patterns of epithelial dysfunction in SjD salivary glands share commonalities with EMT mediating wound healing. Pathological changes altering salivary gland integrity and function may precede direct immune involvement while perpetuating MMP9-mediated ECM destruction, inflammatory mediator expression, and eventual immune cell infiltration. Dysregulation of EMT-associated factors is present in the salivary epithelium of SjD and may be significant in initiating and perpetuating the disease. In this review, we further highlight the gap regarding mechanisms that drive epithelial dysfunction in salivary glands in the early or subclinical pre-lymphocytic infiltration stages of SjD.

Пространственное распределение протеогликанов суставного хряща бедренных мыщелков и тибиального плато при экспериментальном остеоартрозе у крыс

Introduction. Very few works have studied the spatial distribution of proteoglycans of the articular cartilage of femoral condyles (FCs) and the tibial plateau (TP) in normal and experimental osteoarthritis (OA). The aim of the paper was to analyze the spatial distribution of lubricin and aggrecan in the articular cartilage of FCs and the TP in normal and experimental OA in rats. Materials and methods. We divided 15 male Wistar rats (weight 250–300 g) into three groups: intact, undergone sham surgery, and having experimental OA. Sham surgery was done with intra-articular injection of saline solution, and experimental OA was modeled by intra-articular injection of medical talc. We performed morphological and immunohistochemical studies using antibodies to Aggrecan and Lubricin to assess the spatial distribution of proteoglycans. Results. After 3 weeks in the group with OA, the thickness of the articular cartilage of FCs and the TP was 15% greater and 11% less, respectively, in comparison with that in the intact rats (p<0.05). In the intact group, the numerical density of chondrocytes of the superficial zone of the articular cartilage of the TP was 2.6 times higher compared to that of FCs; after 3 weeks, the group with OA showed the opposite trend. A similar pattern was in the middle and deep zones. Immunohistochemistry revealed the presence of intense staining on lubricin of isogenic groups of chondrocytes and extracellular matrix (ECM) of the middle zone of the articular cartilage of the TP in experimental OA. Conclusion. In experimental OA, we observed interstitial growth in the articular cartilage of FCs and signs of ECM destruction in superficial and middle zones of the articular cartilage of the TP. In experimental OA, the distribution of lubricin synthesis changes. For the middle zone chondrocytes, localized close to the surface zone, the color on lubricin is characteristic. Keywords: morphology, articular cartilage, aggrecan, lubricin, femoral condyles, tibial plateau, osteoarthritis, rat

Comparative Toxicological Effects of Perfluorooctane Sulfonate and Its Alternative 6:2 Chlorinated Polyfluorinated Ether Sulfonate on Earthworms.

High levels of 6:2 chlorinated polyfluorinated ether sulfonate (F-53B), which is a substitute for perfluorooctane sulfonate (PFOS), are detected in various environmental matrices, wildlife, and humans. Chlorinated polyfluorinated ether sulfonate has received increased attention due to its potential risk to ecosystems. However, its toxicity in the soil organisms remains unclear. In the present study, a comparative investigation was conducted on the toxicities of 6:2 Chlorinated polyfluorinated ether sulfonate (F-53B) and PFOS to the earthworm Eisenia. fetida. F-53B was significantly more acutely toxic to earthworms than PFOS, with median lethal concentrations of 1.43 and 1.83 mmol/kg dry soil (~816 and 984 mg/kg dry soil), respectively. Although both F-53B and PFOS, at 0.4 mmol/kg dry soil (=228 and 215 mg/kg dry soil) caused oxidative stress in earthworms, as evidenced by increased superoxide dismutase, peroxidase, and catalase activities as well as malondialdehyde level, the stress caused by F-53B was higher than that caused by PFOS. In transcriptomic and metabolomic studies, negative effects of PFOS and F-53B were observed on several metabolic processes in earthworms, including protein digestion and amino acid absorption, lipid metabolism, and the immune response. Compared with PFOS, F-53B exhibited a weaker disruption of lipid metabolism, comparable potency for toxicity to the immune response, and a stronger potency in extracellular matrix destruction along with apoptosis and ferroptosis induction. Hence, our data suggest that F-53B is more toxic than PFOS to earthworms. The findings provide some new insights into the potential toxicity of F-53B to soil organisms. Environ Toxicol Chem 2024;43:170-181. © 2023 SETAC.

Luteolin alleviates renal ischemia-reperfusion injury in streptozotocin induced diabetic rats by inhibiting metalloenzymes expression

Abstract Diabetes patients are more prone to acute kidney injury (AKI). Endopeptidases known as matrix metalloproteinases (MMPs) cause extracellular matrix destruction and are responsible for ischemic organ damage. Diabetic nephropathy (DN) affects almost one third of all diabetic patients. MMP-2 and MMP-9 lead to the breakdown of the basement membrane of the glomeruli and thereby the advancement of ischemic injury in diabetes. In addition, histone deacetylase-2 (HDAC-2) is the primary regulator of important signalling processes in the diabetic kidney. A possible treatment approach for diabetic kidney preservation is the flavonoid luteolin (LT), which has anti-inflammatory and antioxidant effects. Our aim was to investigate the renoprotective potential of LT in diabetes by modulating MMP-2, MMP-9 and HDAC-2 activity. The expression of MMP-2, MMP-9 and HDAC-2 were statistically higher in streptozotocin-induced diabetic rat renal homogenate after renal ischemic reperfusion injury. These changes were reversed with 2 weeks of pre-treatment with LT (50 mg/kg po). In diabetic rats, pre-treatment with LT significantly reduced oxidative stress, inflammation and fibrosis compared to control animals. Preventive LT prior to renal ischemia showed improvement in body weight, kidney weight/body weight ratio, reversal of renal injury and biochemical changes with lower activity of malondialdehyde (MDA), myeloperoxidase (MPO), hydroxyproline (HP), pathological damage and fibrosis in renal tissue. Our data imply that LT prevents DN in rats by inhibiting MMP-2, MMP-9 and HDAC-2 expression, as well as by lowering the indices of oxidative stress, pro-inflammatory factors and fibrosis.

Integrated transcriptomic and proteomic profiling reveals the key molecular signatures of brain endothelial reperfusion injury.

Reperfusion therapy after ischemic stroke often causes brain microvascular injury. However, the underlying mechanisms are unclear. Transcriptomic and proteomic analyses were performed on human cerebral microvascular endothelial cells following oxygen-glucose deprivation (OGD) or OGD plus recovery (OGD/R) to identify molecules and signaling pathways dysregulated by reperfusion. Major findings were further validated in a mouse model of cerebral ischemia and reperfusion. Transcriptomic analysis identified 390 differentially expressed genes (DEGs) between the OGD/R and OGD group. Pathway analysis indicated that these genes were mostly associated with inflammation, including the TNF signaling pathway, TGF-β signaling pathway, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and NF-κB signaling pathway. Proteomic analysis identified 201 differentially expressed proteins (DEPs), which were primarily associated with extracellular matrix destruction and remodeling, impairment of endothelial transport function, and inflammatory responses. Six genes (DUSP1, JUNB, NFKBIA, NR4A1, SERPINE1, and THBS1) were upregulated by OGD/R at both the mRNA and protein levels. In mice with cerebral ischemia and reperfusion, brain TNF signaling pathway was activated by reperfusion, and inhibiting TNF-α with adalimumab significantly attenuated reperfusion-induced brain endothelial inflammation. In addition, the protein level of THBS1 was substantially upregulated upon reperfusion in brain endothelial cells and the peri-endothelial area in mice receiving cerebral ischemia. Our study reveals the key molecular signatures of brain endothelial reperfusion injury and provides potential therapeutic targets for the treatment of brain microvascular injury after reperfusion therapy in ischemic stroke.

Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects. This study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein. We exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin. Digoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells. These findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.

Regulation of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by destruction and progressive expansion of the abdominal aortic wall. An AAA is typically defined as an enlargement of the abdominal aorta with diameter ≥3 cm or ≥50% greater than the suprarenal diameter. The pathological changes associated with AAA include inflammatory cell infiltration, extracellular matrix (ECM) destruction and remodeling, and vascular smooth muscle cell loss. The matrix metalloproteinase (MMP) family of proteins plays an important role in initiation and progression of AAA. Since understanding the regulation of MMP-2 and MMP-9 in AAA is essential for treatment of AAA, this review summarized the regulatory mechanisms of MMPs to provide a reference for exploring novel therapeutic approaches.

The endothelium in lung fibrosis: a core signaling hub in disease pathogenesis?

Pulmonary fibrosis is a progressive chronic lung disease characterized by excessive deposition of extracellular matrix and structural destruction, associated with a severe five year mortality rate. The onset of the disease is thought to be triggered by chronic damage to the alveolar epithelium. Since the pulmonary endothelium is an important component of the alveolar-capillary niche, it is also affected by the initial injury. In addition to ensuring proper gas exchange, the endothelium has critical functional properties, including regulation of vascular tone, inflammatory responses, coagulation and maintenance of vascular homeostasis and integrity. Recent single-cell analyses have shown that shifts in endothelial cell subtypes occur in pulmonary fibrosis. Furthermore, the increased vascular remodeling associated with pulmonary fibrosis leads to deteriorated outcomes for patients, underscoring the importance of the vascular bed in pulmonary fibrosis. To date, the causes and consequences of endothelial and vascular involvement in pulmonary fibrosis are poorly understood. Therefore, it is of great importance to investigate the involvement of endothelial cells and the vascular system in the pathogenesis of the disease. In this review, we will outline the current knowledge on the role of the pulmonary vasculature in pulmonary fibrosis, in terms of abnormal cellular interactions, hyperinflammation, vascular barrier disorders and an altered basement membrane composition. Finally, we will summarize recent advances in extensive therapeutic research and discuss the significant value of novel therapies targeting the endothelium.

The role of flavonoids in the regulation of epithelial-mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis.

One of the hallmarks of cancer is metastasis, a process that entails the spread of cancer cells to distant regions in the body, culminating in tumor formation in secondary organs. Importantly, the proinflammatory environment surrounding cancer cells further contributes to cancer cell transformation and extracellular matrix destruction. During metastasis, front-rear polarity and emergence of migratory and invasive features are manifestations of epithelial-mesenchymal transition (EMT). A variety of transcription factors (TFs) are implicated in the execution of EMT, the most prominent belonging to the Snail Family Transcriptional Repressor (SNAI) and Zinc Finger E-Box Binding Homeobox (ZEB) families of TFs. These TFs are regulated by interaction with specific microRNAs (miRNAs), as miR34 and miR200. Among the several secondary metabolites produced in plants, flavonoids constitute a major group of bioactive molecules, with several described effects including antioxidant, antiinflammatory, antidiabetic, antiobesogenic, and anticancer effects. This review scrutinizes the modulatory role of flavonoids on the activity of SNAI/ZEB TFs and on their regulatory miRNAs, miR-34, and miR-200. The modulatory role of flavonoids can attenuate mesenchymal features and stimulate epithelial features, thereby inhibiting and reversing EMT. Moreover, this modulation is concomitant with the attenuation of signaling pathways involved in diverse processes as cell proliferation, cell growth, cell cycle progression, apoptosis inhibition, morphogenesis, cell fate, cell migration, cell polarity, and wound healing. The antimetastatic potential of these versatile compounds is emerging and represents an opportunity for the synthesis of more specific and potent agents.

Evidence that enolase-phosphatase 1 exacerbates early cerebral ischemia injury and blood–brain barrier breakdown by enhancing extracellular matrix destruction and inhibiting the interaction between ADI1 and MT1-MMP

Enolase-phosphatase 1 (ENOPH1) is a newly identified enzyme associated with stress responses and cell proliferation. Our previous study found that ENOPH1 mediates cerebral microvascular endothelial cell apoptosis under cerebral ischemia conditions. In this study, we systematically provide mechanistic insights into the regulation of ENOPH1 in blood–brain barrier (BBB) dysfuction induced by early ischemia. ENOPH1 knockout mice (ENOPH1 KO) and wild type (WT) mice were exposed to transient middle cerebral artery occlusion (tMCAO) for 90 min followed by 3 h of reperfusion in vivo, and brain microvascular endothelial cell lines (bEnd.3 cells) were exposed to oxygen-glucose deprivation (OGD) in vitro. BEnd.3 cells were transfected with ENOPH1 shRNA to knockdown ENOPH1 expression. Brain ischemic damage and nerve function was assessed with 2, 3, 5-triphenyltetrazolium chloride (TTC) staining and neurological scores. BBB permeability and tight junction (TJ) protein and adherens junction (AJ) proteins expression were analyzed by FITC-dextran staining, western blotting and coimmunofluorescence. The MMP-2/9 activity was analyzed by gelatin zymography. Differential protein expression was assessed by quantitative proteomics. The interaction between ADI1 and MT1-MMP was measured by coimmunoprecipitation assay and coimmunofluorescence. Knockout of ENOPH1 ameliorated cerebral ischemic injury, decreased BBB permeability, inhibited the activity of MMP-2/9, upregulated the expression of TJ/AJ proteins and reversed extracellular matrix destruction after ischemia in vivo. Mechanistic studies have shown that ENOPH1 silencing enhanced the interaction between ADI1 and MT1-MMP by promoting the nuclear translocation of ADI1 to inhibit MT1-MMP in bEnd.3 cells after OGD and decreasing the expression of Tnc and Fn1 to inhibit ECM degradation. Our results reveal that ENOPH1 increases the activity of MMP-2/9, then promotes TJ protein and extracellular matrix degradation, and eventually destroys the stability of the BBB. Therefore, ENOPH1 is a new therapeutic target for ischemic stroke.

A static magnetic field enhances the repair of osteoarthritic cartilage by promoting the migration of stem cells and chondrogenesis.

To investigate the therapeutic effects of static magnetic field (SMF) and its regulatory mechanism in the repair of osteoarthritic cartilage. Fourteen-week-old female C57BL/6 mice were randomly divided into the sham operation group and the osteoarthritis (OA) groups with and without SMF application. SMF was applied at 200​mT for two consecutive weeks. Changes in knee cartilage were examined by histomorphometry, and the chondrogenesis and migration of endogenous stem cells were assessed. The expression of SRY-related protein 9 (SOX9), Collagen type II (COL2), matrix metallopeptidase 13 (MMP13), stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4), Piezo1 and other genes was evaluated, and the mechanism of SMF's action was tested using the CXCR4 inhibitor, AMD3100, and Piezo1 siRNA. SMF significantly decreased the OARSI scores after induction of OA. SMF was beneficial to chondrogenesis by elevating SOX9. In the OA mouse model, an increase in MMP13 with a decrease in COL2 led to the destruction of the cartilage extracellular matrix, which was suppressed by SMF. SMF promoted the migration of cartilage-derived stem/progenitor cells and bone marrow-derived mesenchymal stem cells (MSCs). It increased SDF-1 and CXCR4, while the CXCR4 inhibitor significantly suppressed the beneficial effects of SMF. The application of Piezo1 siRNA inhibited the SMF-induced increase of CXCR4. SMF enhanced chondrogenesis and improved cartilage extracellular matrices. It activated the Piezo1-mediated SDF-1/CXCR4 regulatory axis and promoted the migration of endogenous stem cells. Collectively, it attenuated the pathological progression of cartilage destruction in OA mice. The findings in this study provided convincing evidence that SMF could enhance cartilage repair and improve OA symptoms, suggesting that SMF could have clinical value in the treatment of OA.

Periodontal Disease: Correlation with Histological and Immunological Parameters

Abstract Periodontal disease is inflammatory pathological conditions in the gingiva and dental support structures that usually results in extracellular matrix and connective tissue destruction. During periodontitis, inflammatory cells facilitate collagen and connective tissue loss, affects the number and activity of fibroblasts and its production of local collagen networks. Aim of this study was to evaluate collagen density and accumulation of collagen producing fibroblast and macrophages in affected tissue of periodontal disease. Histological and immunohistochemical analyzes were performed on paraffin embedded tissue sections of gingival biopsies, obtained from 30 patients with diagnosis of periodontal disease and 10 healthy donors. Tissue sections of gingival of patients with periodontal disease had significantly decreased collagen volume density and visible fragmentation and lysis of the collagen fibers, decreased number of fibroblasts, accompanied with increased accumulation of macrophages. Presented data implicate that macrophages accumulation may be the cause of enzyme mediated collagen destruction

Identification of pathological-related and diagnostic potential circular RNAs in Stanford type A aortic dissection.

Stanford type A aortic dissection (TAAD) is one of the lethal macrovascular diseases caused by the invasion of blood into the media layer of ascending aortic wall. Inflammation, smooth muscle dysfunction, and extracellular matrix (ECM) degradation were regarded as the major pathology in affected tissue. However, the expression pattern and its regulation especially through circular RNAs (circRNAs) as an overall characteristic of TAAD molecular pathology remain unclear. We employed CIRCexplorer2 to identify circRNAs based on the RNA sequencing (RNA-seq) data of human ascending aortic tissues to systematically assess the role of circRNA in the massive alterations of gene expression in TAAD aortas. The key circRNAs were determined by LASSO model and functionally annotated by competing endogenous RNAs (ceRNA) network and co-analysis with mRNA profile. The expression level and diagnostic capability of the 4 key circRNAs in peripheral serum were confirmed by real-time polymerase chain reaction (RT-PCR). The 4 key circRNAs, namely circPTGR1 (chr9:114341075-114348445[-]), circNOX4 (chr11:89069012-89106660[-]), circAMN1 (chr12:31854796-31862359[-]) and circUSP3 (chr15:63845913-63855207[+]), demonstrated a high power to discriminate between TAAD and control tissues, suggesting that these molecules stand for a major difference between the tissues at gene regulation level. Functionally, the ceRNA network of circRNA-miRNA-mRNA predicted by the online databases, combining gene set enrichment analysis (GSEA) and cell component prediction, revealed that the identified circRNAs covered all the aspects of primary TAAD pathology, centralized with increasing inflammatory factors and cells, and ECM destruction and loss of vascular inherent cells along with the circRNAs. Importantly, we validated the high concentration and diagnostic capability of the 4 key circRNAs in the peripheral serum in TAAD patients. This study reinforces the vital status of circRNAs in TAAD and the possibility of serving as promising diagnostic biomarkers.

Development of Inhalable Spray Dried Nitrofurantoin Formulations for the Treatment of Emphysema

A central characteristic of emphysematous progression is the continuous destruction of the lung extracellular matrix (ECM). Current treatments for emphysema have only addressed symptoms rather than preventing or reversing the loss of lung ECM. Nitrofurantoin (NF) is an antibiotic that has the potential to induce lung fibrosis as a side effect upon oral administration. Our study aims to repurpose NF as an inhalable therapeutic strategy to upregulate ECM expression, thereby reversing the disease progression within the emphysematous lung. Spray-dried (SD) formulations of NF were prepared in conjunction with a two-fluid nozzle (2FN) and three-fluid nozzle (3FN) using hydroxypropyl methylcellulose (HPMC) and NF at 1:1 w/w. The formulations were characterized for their physicochemical properties (particle size, morphology, solid-state characteristics, aerodynamic behaviour, and dissolution properties) and characterized in vitro with efficacy studies on human lung fibroblasts. The 2FN formulation displayed a mass mean aerodynamic diameter (MMAD) of 1.8 ± 0.05 µm and fine particle fraction (FPF) of 87.4 ± 2.8% with significantly greater deposition predicted in the lower lung region compared to the 3FN formulation (MMAD: 4.4 ± 0.4 µm; FPF: 40 ± 5.8%). Furthermore, drug dissolution studies showed that NF released from the 2FN formulation after 3 h was significantly higher (55.7%) as compared to the 3FN formulation (42.4%). Importantly, efficacy studies in human lung fibroblasts showed that the 2FN formulation induced significantly enhanced ECM protein expression levels of periostin and Type IV Collagen (203.2% and 84.2% increase, respectively) compared to untreated cells, while 3FN formulations induced only a 172.5% increase in periostin and a 38.1% increase in type IV collagen. In conclusion, our study highlights the influence of nozzle choice in inhalable spray-dried formulations and supports the feasibility of using SD NF prepared using 2FN as a potential inhalable therapeutic agent to upregulate ECM protein production.

Tumor extracellular matrix-targeted nanoscavengers reverse suppressive microenvironment for cocktail therapy

Extracellular matrix (ECM) is not only a natural bulwark to shield solid tumor cells from therapeutic agents and cytotoxic T lymphocytes (CTLs), but also one of the key factors that cause tumor hypoxic environment, severely hindering photodynamic reactions and immune responses. In this work, multifunctional nanoscavengers (ECMT NS) consisting of digestive enzyme chymotrypsin, catalase, calcium peroxide nanoparticles, photosensitizer chlorin e6, and tumor ECM-targeting CLT1 peptide are rationally designed with several benefits for enhanced cocktail calcium ion/photodynamic/immune therapy. The scavengers can effectively “clear” tumor ECM via digestive proteolytic enzyme- and reactive oxygen species-mediated pathways, deepening tumor penetration of the scavengers and CTLs. Thanks to the ECM destruction and oxygen self-supply capability of ECMT NS, the hypoxia in tumors is attenuated, thus improving photodynamic therapeutic efficiency and downregulating immunosuppressive factors. Moreover, the combination of calcium ion overload and photodynamic therapy enriches damage-associated molecular patterns, which promotes CTL activation to inhibit abscopal tumor growth and lung metastasis. The presented ECM destruction strategy provides a solution to overcome the tumor suppressive microenvironment.

Plasma Elevations of Extracellular Matrix Collagens Are Predictive of Unfavorable Outcome after Trauma

INTRODUCTION: The extracellular matrix is critical for intracellular communication, but the association between extracellular matrix integrity after trauma and clinical outcomes remains unexplored. Collagen type-6 alpha-3 chain (COL6A3) and collagen type-18 alpha-1 chain (COL18A1) are increased in patients’ plasma after hemorrhagic shock. We hypothesized that these increased concentrations of COL6A3 and COL18A1 are associated with adverse outcomes after severe injury. METHODS: Blood was collected from severely injured patients at a Level I trauma center as part of the COMBAT study. Plasma proteomics were performed using targeted liquid chromatography coupled with mass spectrometry. Spearman correlations, Mann-Whitney tests, and multiple linear regression were used to analyze association among injury, COL6A3, and COL18A1 levels, and outcomes. RESULTS: Patients with greater shock (lower base excess) on emergency department (ED) arrival had higher ED COL18A1 and 24-hour COL6A3 (both Spearman R –0.28, p < 0.05). Independently of NISS and base excess, higher ED COL18A1 and higher 24-hour COL6A3 were each associated with fewer ICU- and ventilator-free days (all p < 0.05, Figure 1). The effect of 24-hour COL6A3 on ICU-free days and ventilator-free days was also independent of ED COL18A1 (p < 0.05). Additionally, patients who developed ARDS had higher 24-hour COL6A3 (p < 0.05).CONCLUSION: Plasma measures of COL18A1 on ED arrival and COL6A3 at 24 hours are independent predictors of unfavorable outcome after injury. These collagen chains in the plasma are indicators of extracellular matrix destruction, and further study is needed to elucidate their potential role in inflammomodulatory signaling that mediates adverse outcomes.

Aortic Cellular Diversity and Quantitative Genome-Wide Association Study Trait Prioritization Through Single-Nuclear RNA Sequencing of the Aneurysmal Human Aorta.

Mural cells in ascending aortic aneurysms undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore this biology, we analyzed the transcriptional features of thoracic aortic tissue. Single-nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm, and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. We sequenced 71 689 nuclei from human thoracic aortas and identified 14 clusters, aligning with 11 cell types, predominantly vascular smooth muscle cells (VSMCs) consistent with aortic histology. With unbiased methodology, we found 7 vascular smooth muscle cell and 6 fibroblast subclusters. Differentially expressed genes analysis revealed a vascular smooth muscle cell group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. Differentially expressed genes were used to prioritize genes at aortic diameter and distensibility genome-wide association study loci highlighting the genes JUN, LTBP4 (latent transforming growth factor beta-binding protein 1), and IL34 (interleukin 34) in fibroblasts, ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4), and GLRX in vascular smooth muscle cells, as well as LRP1 in macrophage populations. Using nuclear RNA sequencing, we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single-nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.

Endogenous advanced glycation end products in the pathogenesis of chronic diabetic complications.

Diabetes is a common metabolic illness characterized by hyperglycemia and is linked to long-term vascular problems that can impair the kidney, eyes, nerves, and blood vessels. By increasing protein glycation and gradually accumulating advanced glycation end products in the tissues, hyperglycemia plays a significant role in the pathogenesis of diabetic complications. Advanced glycation end products are heterogeneous molecules generated from non-enzymatic interactions of sugars with proteins, lipids, or nucleic acids via the glycation process. Protein glycation and the buildup of advanced glycation end products are important in the etiology of diabetes sequelae such as retinopathy, nephropathy, neuropathy, and atherosclerosis. Their contribution to diabetes complications occurs via a receptor-mediated signaling cascade or direct extracellular matrix destruction. According to recent research, the interaction of advanced glycation end products with their transmembrane receptor results in intracellular signaling, gene expression, the release of pro-inflammatory molecules, and the production of free radicals, all of which contribute to the pathology of diabetes complications. The primary aim of this paper was to discuss the chemical reactions and formation of advanced glycation end products, the interaction of advanced glycation end products with their receptor and downstream signaling cascade, and molecular mechanisms triggered by advanced glycation end products in the pathogenesis of both micro and macrovascular complications of diabetes mellitus.

Matrix Metalloproteinases Expression Is Associated with SARS-CoV-2-Induced Lung Pathology and Extracellular-Matrix Remodeling in K18-hACE2 Mice.

The COVID-19 pandemic caused by the SARS-CoV-2 infection induced lung inflammation characterized by cytokine storm and fulminant immune response of both resident and migrated immune cells, accelerating alveolar damage. In this work we identified members of the matrix metalloprotease (MMPs) family associated with lung extra-cellular matrix (ECM) destruction using K18-hACE2-transgenic mice (K18-hACE2) infected intranasally with SARS-CoV-2. Five days post infection, the lungs exhibited overall alveolar damage of epithelial cells and massive leukocytes infiltration. A substantial pulmonary increase in MMP8, MMP9, and MMP14 in the lungs post SARS-CoV-2 infection was associated with degradation of ECM components including collagen, laminin, and proteoglycans. The process of tissue damage and ECM degradation during SARS-CoV-2 lung infection is suggested to be associated with activity of members of the MMPs family, which in turn may be used as a therapeutic intervention.

Polymorphism rs652438 of gene &lt;i&gt;mmp12&lt;/i&gt; and oxidative DNA damage in bronchial asthma: An experimental non-randomised study

Background. Personalised medicine is an avenue to create technologies for individual prognosis of the disease onset and development. The identification of individual gene haplotypes is prerequisite to detecting predispositions to multifactorial diseases. The level of serum 8-oxoguanine is an indicator of genotoxic stress underlying many pathologies.Objectives. A study of associations of mmp12 gene’s polymorphic variant rs652438 and the nature of genome oxidative damage in bronchial asthma.Methods. Genotyping of polymorphic variant rs652438 of gene mmp12 was performed using TaqMan-probe real-time PCR assays. The gene variant association with disease was assessed by odds ratio. The degree of DNA oxidative damage was estimated by 8-oxoguanine serum concentrations determined in monoclonal antibody-based enzyme immunoassays. The StatPro software package with StatTools (Palisade Corporation, USA) was used for statistical data processing.Results. The haplotype and allele frequencies were established for polymorphic locus rs652438 of the mmp12 gene in the control and bronchial asthma cohorts. Heterozygotes were shown to differ significantly; the estimate was 2.3-fold higher in the control vs. bronchial asthma (BA) cohort (p &lt; 0.05). The AA and GG haplotype frequencies did not differ significantly. The minor allele G odds ratio (OR = 0.362, CI 95% 0.134–0.975) suggests its protective effect. This may be associated with a lowering activity of the encoded macrophage metalloelastase enzyme, which results in a poorer extracellular matrix destruction in the bronchial tree. The baseline 8-oxoG levels in the control and BA samples were 6.4 and 9.4 ng/mL, respectively (U = 25, Ucut-off = 23; p &gt;0.05). An in vitro electromagnetic exposure of varying frequency leads to a significant oxidative genomic damage in both cohorts and an earlier reparative depletion in bronchial asthma vs. control.Conclusion. A protective effect of minor allele G against pathology has been demonstrated. Adaptations to oxidative genomic stress in bronchial asthma manifest by an impaired resistance to in vitro high-intensity electromagnetic exposures.