Collagen Turnover Research Articles

Biomarkers of collagen turnover and wound healing in chronic thromboembolic pulmonary hypertension patients before and after pulmonary endarterectomy

BackgroundIn chronic thromboembolic pulmonary hypertension (CTEPH), fibrotic remodeling of tissue and thrombi contributes to disease progression. Removal of the thromboembolic mass by pulmonary endarterectomy (PEA) improves hemodynamics and right ventricular function, but the roles of different collagens before as well as after PEA are not well understood. MethodsIn this study, hemodynamics and 15 different biomarkers of collagen turnover and wound healing were evaluated in 40 CTEPH patients at diagnosis (baseline) and 6 and 18 months after PEA. Baseline biomarker levels were compared with a historical cohort of 40 healthy subjects. ResultsBiomarkers of collagen turnover and wound healing were increased in CTEPH patients compared with healthy controls, including a 35-fold increase in the PRO-C4 marker of type IV collagen formation and a 55-fold increase in the C3M marker of type III collagen degradation. PEA reduced pulmonary pressures to almost normal levels 6 months after the procedure, with no further improvement at 18 months. There were no changes in any of the measured biomarkers after PEA. ConclusionsBiomarkers of collagen formation and degradation are increased in CTEPH suggesting a high collagen turnover. While PEA effectively reduces pulmonary pressures, collagen turnover is not significantly modified by surgical PEA.

Eco synthesized chitosan/zinc oxide nanocomposites as the next generation of nano-delivery for antibacterial, antioxidant, antidiabetic potential, and chronic wound repair

The present research work aimed at synthesizing chitosan-coated Zinc oxide nanocomposites (NS-CS/ZnONCs) by a bio-inspired method using an aqueous extract of Nigella sativa (NS) seeds and employing a quality-by-design approach (Box-Behnken design). The biosynthesized NS-CS/ZnONCs were physicochemically characterized and subjected to their in-vitro and in-vivo therapeutic potential. The zeta potential value of −11.2 mV and −12.6 mV indicated the stability of NS-mediated synthesized zinc oxide nanoparticles (NS-ZnONPs) and NS-CS/ZnONCs, respectively. The particle size of NS-ZnONPs and NS-CS/ZnONCs were 288.1 nm and 130.2 nm, respectively, with PDI of 0.198 and 0.158. NS-ZnONPs and NS-CS/ZnONCs showed superior radical scavenging abilities, excellent α-amylase, and α-glucosidase inhibitory activities. Also, NS-ZnONPs and NS-CS/ZnONCs demonstrated effective antibacterial activity against selected pathogens. Furthermore, NS-ZnONPs and NS-CS/ZnONCs demonstrated significant (p < 0.001) wound closure with 93.00 ± 0.43 % and 95.67 ± 0.43 % on the 15th day of treatment at the dose of 14 mg/wound, compared to 93.42 ± 0.58 % of standard. Collagen turnover was represented by hydroxyproline, which was shown to be significantly (p < 0.001) higher in the NS-ZnONPs (60.70 ± 1.44 mg/g of tissue) and NS-CS/ZnONCs (66.10 ± 1.23 mg/g of tissue) treatment groups than in the control group (47.7 ± 0.81 mg/g of tissue). Thus the NS-ZnONPs and NS-CS/ZnONCs could effectively develop promising drugs to inhibit pathogens and chronic tissue repair.

A META-ANALYSIS OF OSTEOARTHRITIS SYNOVIAL BIOMARKERS

Establishing disease biomarkers has been a long-sought after goal to improve Osteoarthritis (OA) diagnosis, prognosis, clinical and pharmaceutical interventions. Given the role of the synovium in contributing to OA, a meta-analysis was performed to determine significant synovial biomarkers in human OA tissue, compared to non-OA patients. Outcomes will direct future research on marker panels for OA disease modelling in vitro/in vivo, aiding clinical research into OA disease targets.A PRISMA compliant search of databases was performed to identify potential biomarker studies analysing human, OA, synovial samples compared to non-OA/healthy participants. The Risk of Bias In Non-Randomised Studies of Interventions (ROBINS-I) tool assessed methodological quality, with outcome analysed by Grading of Recommendations Assessment, Development and Evaluation (GRADE). Meta-analyses were conducted for individual biomarkers using fixed or random effect models, as appropriate. Where three or more studies included a specific biomarker, Forest Plot comparisons were generated.3230 studies were screened, resulting in 34 studies encompassing 25 potential biomarkers (1581 OA patients and 695 controls). Significant outcomes were identified for thirteen comparisons. Eleven favoured OA (IL-6, IL-10, IL-13, IP-10, IL-8, CCL4, CCL5, PIICP, TIMP1, Leptin and VEGF), two favoured non-OA controls (BMP-2 and HA). Notably, PIICP showed the largest effect (SMD 6.11 [3.50, 8.72], p &lt;0.00001, I2 99%), and TIMP1 resulted critically important (0.95 [0.65, 1.25], p &lt;0.00001, I2 82%). Leptin and CCL4 showed lower effects (SMD 0.81 [0.33, 1.28], p =0.0009; 0.59 [0.32, 0.86], p &lt;0.0001, respectively).Thirteen significant synovial biomarkers showed links with OA bioprocesses including collagen turnover, inflammatory mediators and ECM components. Limitations arose due to bias risk from incomplete or missing data, publication bias of inconclusive results, and confounding factors from patient criteria. These findings suggest markers of potential clinical viability for OA diagnosis and prognosis that could be correlated with specific disease stages.

Metalloproteinases and Hypertrophic Cardiomyopathy: A Systematic Review.

Hypertrophic cardiomyopathy (HCM) is a genetic condition determined by an altered collagen turnover of the extracellular matrix. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are abnormally released in patients with HCM. The purpose of this systematic review was to thoroughly summarize and discuss the existing knowledge of MMPs profile in patients with HCM. All studies meeting the inclusion criteria (detailed data regarding MMPs in patients with HCM) were selected, after screening the literature from July 1975 to November 2022. Sixteen trials that enrolled a total of 892 participants were included. MMPs-particularly MMP2-levels were found higher in HCM patients compared to healthy subjects. MMPs were used as biomarkers after surgical and percutaneous treatments. Understanding the molecular processes that control the cardiac ECM's collagen turnover allows for a non-invasive evaluation of HCM patients through the monitoring of MMPs and TIMPs.

Autoreactivity against Denatured Type III Collagen Is Significantly Decreased in Serum from Patients with Cancer Compared to Healthy Controls.

Autoantibodies have the potential as cancer biomarkers as they may associate with the outcome and immune-related adverse events (irAEs) following immunotherapy. Cancer and other fibroinflammatory diseases, such as rheumatoid arthritis (RA), are associated with excessive collagen turnover leading to collagen triple helix unfolding and denaturation with exposure of immunodominant epitopes. In this study, we aimed to investigate the role of autoreactivity against denatured collagen in cancer. A technically robust assay to quantify autoantibodies against denatured type III collagen products (anti-dCol3) was developed and then measured in pretreatment serum from 223 cancer patients and 33 age-matched controls. Moreover, the association between anti-dCol3 levels and type III collagen degradation (C3M) and formation (PRO-C3) was investigated. Anti-dCol3 levels were significantly lower in patients with bladder (p = 0.0007), breast (p = 0.0002), colorectal (p < 0.0001), head and neck (p = 0.0005), kidney (p = 0.005), liver (p = 0.030), lung (p = 0.0004), melanoma (p < 0.0001), ovarian (p < 0.0001), pancreatic (p < 0.0001), prostate (p < 0.0001), and stomach cancers (p < 0.0001) compared to controls. High anti-dCol3 levels were associated with type III collagen degradation (C3M, p = 0.0002) but not type III collagen formation (PRO-C3, p = 0.26). Cancer patients with different solid tumor types have downregulated levels of circulating autoantibodies against denatured type III collagen compared to controls, suggesting that autoreactivity against unhealthy type III collagen may be important for tumor control and eradication. This autoimmunity biomarker may have the potential for studying the close relationship between autoimmunity and cancer.

Abstract 1341: Non-invasive biomarkers quantifying collagens essential for embryogenesis are elevated in the circulation of solid tumor patients and may guide drug development

Abstract Background Collagen remodeling is an essential part of embryogenesis and defines tissue structure and function in adulthood. The 28 different collagens are all important for maintaining tissue homeostasis and are deregulated in cancer. The abundant, major collagens, such as type I collagen, serve a structural role, whereas the less abundant, minor collagens serve a more regulatory role. Fibroblasts are the primary source of collagens and different cancer-associated fibroblast (CAF) subtypes, such as myCAFs or iCAFs, have been attributed important roles in cancer and are the target of novel therapies. Emerging evidence suggests minor collagens may be aberrantly expressed in cancer and linked to specific fibroblast subtypes, suggesting novel biomarker potential. This study aimed to evaluate the association between different CAF subtypes and collagen expression. Methods We investigated collagen expression in pancreatic cells and CAF subtypes in a publicly available single-cell RNA-Seq dataset (GSA: CRA001160). 24 samples were from patients with pancreatic ductal adenocarcinoma (PDAC) as this is one of the most collagen rich tumor types, and 11 samples were from pancreatic cysts, bile duct- or duodenal-tumors. In addition, we generated a collagen turnover profile using a panel of immunoassays to measure specific collagen fragments in the serum of 220 patients with various solid tumor types and 33 healthy controls. The included immunoassays measured collagen epitopes associated with either formation, degradation, or other modifications of collagens. Results Based on the single-cell RNA-Seq dataset, fibroblasts were the primary source of collagens. Major collagens, including COL1A1, COL3A1, COL4A1, and COL6A1, were highly expressed in both healthy fibroblasts and PDAC CAFs, whereas minor collagens such as COL8A1, COL10A1, COL11A1, and COL12A1 were exclusively expressed in CAFs. When further examining the CAF subtypes, major collagens were expressed in all CAF subtypes, with high expression in myCAFs and iCAFs. In contrast, the minor collagens were exclusively expressed in the myCAFs. When measuring these collagens in serum, the minor collagens were elevated across all cancer types when compared to healthy control serum. Contrastingly, the major collagens were not elevated in any cancers or only elevated in a few cancer types. Conclusions Collagens in general are highly expressed in cancer. However, minor collagens may be more cancer-specific than major collagens. Our findings also suggest that minor collagens may be specific to certain subtypes of CAFs. These collagens can be quantified in blood, making them promising actionable biomarkers that may guide drug development aimed at targeting CAFs. Citation Format: Jeppe Thorlacius-Ussing, Christina Jensen, Emilie Madsen, Morten Karsdal, Nicholas Willumsen. Non-invasive biomarkers quantifying collagens essential for embryogenesis are elevated in the circulation of solid tumor patients and may guide drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1341.

A bio-polymeric scaffold incorporated with p-Coumaric acid enhances diabetic wound healing by modulating MMP-9 and TGF-β3 expression

Diabetic wounds lead to severe health complications as the tissue regeneration process fails predominantly due to prolonged inflammation, reactive oxygen species generation, and imbalance in collagen turnover. Modern wound dressings that can aid in wound management thus improving the public healthcare system, is the present need. This study aims to fabricate an effective wound dressing using plant polyphenol to treat chronic wounds as polyphenols possess excellent wound-healing ability. The collagen scaffold enriched with the polyphenol, p-Coumaric acid, was fabricated by freeze-drying method (Col-OxP3-Ca) and examined for its wound-healing ability by in vitro and in vivo analyses. Col-OxP3-Ca scaffold exhibited 85% antioxidant activity, biocompatibility in fibroblast cells, enhanced cell proliferation and migration rate. The diabetic excision wound treated with Col-OxP3-Ca scaffold healed within 21 days and a well-developed epidermis, blood vessels, hair follicle formation, fewer inflammatory cells and collagen deposition was observed in histological analysis. The immunohistochemical results depicted the enhanced expression of TGF-β3 and lessened expression of the MMP-9 in Col-OxP3-Ca scaffold treatment group. p-Coumaric acid shortened the inflammatory stage, enhanced angiogenesis, tissue regeneration and balanced collagen turnover during healing. From this, we can accomplish that the Col-OxP3-Ca wound dressing could be an outstanding alternative to treat chronic wounds.

Prediction of coronary artery disease using urinary proteomics.

Coronary artery disease (CAD) is multifactorial, caused by complex pathophysiology, and contributes to a high burden of mortality worldwide. Urinary proteomic analyses may help to identify predictive biomarkers and provide insights into the pathogenesis of CAD. Urinary proteome was analysed in 965 participants using capillary electrophoresis coupled with mass spectrometry. A proteomic classifier was developed in a discovery cohort with 36 individuals with CAD and 36 matched controls using the support vector machine. The classifier was tested in a validation cohort with 115 individuals who progressed to CAD and 778 controls and compared with two previously developed CAD-associated classifiers, CAD238 and ACSP75. The Framingham and SCORE2 risk scores were available in 737 participants. Bioinformatic analysis was performed based on the CAD-associated peptides. The novel proteomic classifier was comprised of 160 urinary peptides, mainly related to collagen turnover, lipid metabolism, and inflammation. In the validation cohort, the classifier provided an area under the receiver operating characteristic curve (AUC) of 0.82 [95% confidence interval (CI): 0.78-0.87] for the CAD prediction in 8 years, superior to CAD238 (AUC: 0.71, 95% CI: 0.66-0.77) and ACSP75 (AUC: 0.53 and 95% CI: 0.47-0.60). On top of CAD238 and ACSP75, the addition of the novel classifier improved the AUC to 0.84 (95% CI: 0.80-0.89). In a multivariable Cox model, a 1-SD increment in the novel classifier was associated with a higher risk of CAD (HR: 1.54, 95% CI: 1.26-1.89, P < 0.0001). The new classifier further improved the risk reclassification of CAD on top of the Framingham or SCORE2 risk scores (net reclassification index: 0.61, 95% CI: 0.25-0.95, P = 0.001; 0.64, 95% CI: 0.28-0.98, P = 0.001, correspondingly). A novel urinary proteomic classifier related to collagen metabolism, lipids, and inflammation showed potential for the risk prediction of CAD. Urinary proteome provides an alternative approach to personalized prevention.

Earlier proteoglycan turnover promotes higher efficiency matrix remodeling in MRL/MpJ tendons.

While most mammalian tissue regeneration is limited, the Murphy Roths Large (MRL/MpJ) mouse has been identified to regenerate several tissues, including tendon. Recent studies have indicated that this regenerative response is innate to the tendon tissue and not reliant on a systemic inflammatory response. Therefore, we hypothesized that MRL/MpJ mice may also exhibit a more robust homeostatic regulation of tendon structure in response to mechanical loading. To assess this, MRL/MpJ and C57BL/6J flexor digitorum longus tendon explants were subjected to stress-deprived conditions in vitro for up to 14 days. Explant tendon health (metabolism, biosynthesis, and composition), matrix metalloproteinase (MMP) activity, gene expression, and tendon biomechanics were assessed periodically. We found a more robust response to the loss of mechanical stimulus in the MRL/MpJ tendon explants, exhibiting an increase in collagen production and MMP activity consistent with previous in vivo studies. This greater collagen turnover was preceded by an early expression of small leucine-rich proteoglycans and proteoglycan-degrading MMP-3, promoting efficient regulation and organization of newly synthesized collagen and allowing for more efficient overall turnover in MRL/MpJ tendons. Therefore, mechanisms of MRL/MpJ matrix homeostasis may be fundamentally different from that of B6 tendons and may indicate better recovery from mechanical microdamage in MRL/MpJ tendons. We demonstrate here the utility of the MRL/MpJ model in elucidating mechanisms of efficient matrix turnover and its potential to shed light on new targets for more effective treatments for degenerative matrix changes brought about by injury, disease, or aging.

Degradation of collagen I by activated C1s in periodontal Ehlers-Danlos Syndrome.

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, lack of attached gingiva and thin and fragile gums leading to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. pEDS is caused by heterozygous missense mutations in C1R and C1S genes of the classical complement C1 complex. Previously we showed that pEDS pathogenic variants trigger intracellular activation of C1r and/or C1s, leading to extracellular presence of activated C1s. However, the molecular link relating activated C1r and C1s proteases to the dysregulated connective tissue homeostasis in pEDS is unknown. Using cell- and molecular-biological assays, we identified activated C1s (aC1s) as an enzyme which degrades collagen I in cell culture and in in vitro assays. Matrix collagen turnover in cell culture was assessed using labelled hybridizing peptides, which revealed fast and comprehensive collagen protein remodeling in patient fibroblasts. Furthermore, collagen I was completely degraded by aC1s when assays were performed at 40°C, indicating that even moderate elevated temperature has a tremendous impact on collagen I integrity. This high turnover is expected to interfere with the formation of a stable ECM and result in tissues with loose compaction a hallmark of the EDS phenotype. Our results indicate that pathogenesis in pEDS is not solely mediated by activation of the complement cascade but by inadequate C1s-mediated degradation of matrix proteins, confirming pEDS as a primary connective tissue disorder.

Increased Fibrosis in White Adipose Tissue of Male and Female bGH Transgenic Mice Appears Independent of TGF-β Action.

Fibrosis is a pathological state caused by excess deposition of extracellular matrix proteins in a tissue. Male bovine growth hormone (bGH) transgenic mice experience metabolic dysfunction with a marked decrease in lifespan and with increased fibrosis in several tissues including white adipose tissue (WAT), which is more pronounced in the subcutaneous (Sc) depot. The current study expanded on these initial findings to evaluate WAT fibrosis in female bGH mice and the role of transforming growth factor (TGF)-β in the development of WAT fibrosis. Our findings established that female bGH mice, like males, experience a depot-dependent increase in WAT fibrosis, and bGH mice of both sexes have elevated circulating levels of several markers of collagen turnover. Using various methods, TGF-β signaling was found unchanged or decreased-as opposed to an expected increase-despite the marked fibrosis in WAT of bGH mice. However, acute GH treatments in vivo, in vitro, or ex vivo did elicit a modest increase in TGF-β signaling in some experimental systems. Finally, single nucleus RNA sequencing confirmed no perturbation in TGF-β or its receptor gene expression in any WAT cell subpopulations of Sc bGH WAT; however, a striking increase in B lymphocyte infiltration in bGH WAT was observed. Overall, these data suggest that bGH WAT fibrosis is independent of the action of TGF-β and reveals an intriguing shift in immune cells in bGH WAT that should be further explored considering the increasing importance of B cell-mediated WAT fibrosis and pathology.

Global deletion of CCL2 has adverse impacts on recovery of skeletal muscle fiber size and function and is muscle specific.

Timely and complete recovery of muscle mass and function following a bout of physical disuse are critical components of returning to normal activities of daily living and lifestyle. Proper cross talk between the muscle tissue and myeloid cells (e.g., macrophages) throughout the recovery period from disuse atrophy plays a significant role in the complete resolution of muscle size and function. Chemokine C-C motif ligand 2 (CCL2) has a critical function of recruiting macrophages during the early phase of muscle damage. However, the importance of CCL2 has not been defined in the context of disuse and recovery. Here, we utilized a mouse model of whole body CCL2 deletion (CCL2KO) and subjected them to a period of hindlimb unloading followed by reloading to investigate the importance of CCL2 on the regrowth of muscle following disuse atrophy using ex vivo muscle tests, immunohistochemistry, and fluorescence-activated cell sorting approaches. We show mice that lack CCL2 display an incomplete recovery of gastrocnemius muscle mass, myofiber cross-sectional area, and EDL muscle contractile characteristics during the recovery from disuse atrophy. The soleus and plantaris had limited impact as a result of CCL2 deficiency suggesting a muscle-specific effect. Mice that lack CCL2 have decreased skeletal muscle collagen turnover, which may be related to defects in muscle function and stiffness. In addition, we show that the recruitment of macrophages to gastrocnemius muscle was dramatically reduced in CCL2KO mice during the recovery from disuse atrophy, which likely precipitated poor recovery of muscle size and function and aberrant collagen remodeling.NEW & NOTEWORTHY We provide evidence that the whole body loss of CCL2 in mice has adverse impacts on whole body function and skeletal muscle-specific contractile characteristics and collagen content. These defects in muscle function worsened during the recovery from disuse atrophy and corresponded with decreased recovery of muscle mass. We conclude that the absence of CCL2 decreased recruitment of proinflammatory macrophages to the muscle during the regrowth phase following disuse atrophy resulting in impaired collagen remodeling events and full resolution of muscle morphology and function.

Effect of mechanical tension on fibroblast transcriptome profile and regulatory mechanisms of myocardial collagen turnover.

Excess deposition of extracellular matrix in the myocardium is a predictor of reduced left ventricular function. Although reducing the hemodynamic load is known to improve myocardial fibrosis, the mechanisms underlying the reversal of the fibrosis have not been elucidated. We focused on the elasticity of myocardial tissue, which is assumed to influence the fibroblast phenotype. Normal and fibrotic myocardium were cultured in 16 kPa and 64 kPa silicone gel-coated dishes supplemented with recombinant TGFβ protein, respectively. Matrix-degrading myocardium was cultured in 64 kPa silicone gel-coated dishes with recombinant TGFβ protein and then in 16 kPa silicone gel-coated dishes. Cardiac fibroblasts were cultured in this three-part in vitro pathological models and compared. Fibroblasts differentiated into activated or matrix-degrading types in response to the pericellular environment. Comprehensive gene expression analysis of fibroblasts in each in vitro condition showed Selenbp1 to be one of the genes responsible for regulating differentiation of fibroblasts. In vitro knockdown of Selenbp1 enhanced fibroblast activation and inhibited conversion to the matrix-degrading form. In vivo knockdown of Selenbp1 resulted in structural changes in the left ventricle associated with progressive tissue fibrosis and left ventricular diastolic failure. Selenbp1 is involved in regulating fibroblast differentiation and appears to be one of the major molecules regulating collagen turnover in cardiac fibrosis.

Single collagen fibrils isolated from high stress and low stress tendons show differing susceptibility to enzymatic degradation by the interstitial collagenase matrix metalloproteinase-1 (MMP-1)

Bovine forelimb flexor and extensor tendons serve as a model for examining high stress, energy storing and low stress, positional tendons, respectively. Previous research has shown structural differences between the collagen fibrils of these tissues. The nanoscale collagen fibrils of flexor tendons are smaller in size, more heavily crosslinked, and respond differently to mechanical loading. Meanwhile, energy storing tendons undergo less collagen turnover compared to positional tendons and are more commonly injured. These observations raise the question of whether collagen fibril structure influences the collagen degradation processes necessary for remodelling. Atomic force microscopy was used to image dry collagen fibrils before and after 5-hour exposure to matrix metalloproteinase-1 (MMP-1) to detect changes in fibril size. Collagen fibrils from three tissue types were studied: bovine superficial digital flexor tendons, matched-pair bovine lateral digital extensor tendons, and rat tail tendons. Compared to control fibrils exposed only to buffer, a significant decrease in fibril cross-sectional area (CSA) following MMP-1 exposure was observed for bovine extensor and rat tail fibrils, with larger fibrils experiencing a greater magnitude of CSA decrease in both fibril types. Fibrils from bovine flexor tendons, on the other hand, showed no decrease in CSA when exposed to MMP-1. The result did not appear to be linked to the small size of flexor fibrils, as equivalently sized extensor fibrils were readily degraded by the enzyme. Increased proteolytic resistance of collagen fibrils from high stress tendons may help to explain the longevity of collagen within these tissues in vivo.

Serum and Urine Biomarkers Related to Kidney Fibrosis Predict Kidney Outcome in Czech Patients with IgA Nephropathy.

We evaluated biomarkers related to kidney fibrosis for the outcome of patients with IgA nephropathy (IgAN). Clinical parameters (estimated glomerular filtration rate, hypertension, proteinuria) and histological findings were assessed in 134 patients with IgAN at the time of diagnosis and followed up prospectively (mean follow-up time, 56.5 months). We measured biomarkers of collagen and laminin turnover in serum and urine collected at the time of kidney biopsy using a novel enzyme-linked immunosorbent assay. Linear discriminant analysis and logistic regression models were used to predict the patient's kidney outcome. Five serum and urine biomarkers of laminin and collagen turnover (sLG1M, sPRO-C3, sPRO-C6, uPRO-C6/Cr, uC3M/Cr) could significantly differentiae IgAN patients with a worse prognosis. Clinical parameters (glomerular filtration rate (GFR), proteinuria) distinguished patients at risk of IgAN progression with a specificity of 87.3% and a sensitivity of 45.2% (area under the curve-AUC 0.751). The addition of the biomarkers significantly increased the prognostic ability with a specificity of 85.1% and a sensitivity of 73.3% (AUC 0.905). We have identified three serum (sLG1M, sPRO-C3, sPRO-C6) and two urinary markers (uPRO-C6/Cr, u-C3M /Cr) that significantly improve the prognostic ability of markers of kidney function to identify an IgAN patient's risk of progressing to ESKD.

Intestinal Barrier Dysfunction and Microbial Translocation in Patients with First-Diagnosed Atrial Fibrillation.

According to the leaky gut concept, microbial products (e.g., lipopolysaccharide, LPS) enter the circulation and mediate pro-inflammatory immunological responses. Higher plasma LPS levels have been reported in patients with various cardiovascular diseases, but not specifically during early atrial fibrillation (AF). We studied data and blood samples from patients presenting with first-diagnosed AF (FDAF) (n = 80) and 20 controls. Circulating biomarkers that are suggestive of mucosal inflammation (zonulin, mucosal adhesion molecule MAdCAM-1) and intestinal epithelium damage (intestinal fatty acid binding protein, IFABP) were increased in the plasma of patients with FDAF when compared to patients with chronic cardiovascular diseases but without AF. Surrogate plasma markers of increased intestinal permeability (LPS, CD14, LPS-binding protein, gut-derived LPS-neutralising IgA antibodies, EndoCAbs) were detected during early AF. A reduced ratio of IgG/IgM EndoCAbs titres indicated chronic endotoxaemia. Collagen turnover biomarkers, which corresponded to the LPS values, suggested an association of gut-derived low-grade endotoxaemia with adverse structural remodelling. The LPS concentrations were higher in FDAF patients who experienced a major adverse cardiovascular event. Intestinal barrier dysfunction and microbial translocation accompany FDAF. Improving gut permeability and low-grade endotoxaemia might be a potential therapeutic approach to reducing the disease progression and cardiovascular complications in FDAF.

Interrelationship Between Inflammatory Biomarkers and Collagen Remodeling Proteins in Atrial Fibrillation.

Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia worldwide. Inflammation and structural remodeling of the left atrium are thought to be involved in the pathogenesis of AF. This study explores collagen remodeling and inflammatory biomarkers in AF patients compared to healthy controls to discern their role in AF. Plasma samples were collected from AF patients undergoing first AF ablation (n = 72) and compared with commercially available human plasma samples from healthy subjects (n = 62). The collagen remodeling biomarkers and inflammatory biomarkers in the AF patients and control population were quantified using sandwich ELISA kits. GraphPad prism was used to perform statistical analyses. There was a statistically significant elevation in all the collagen remodeling biomarkers and inflammatory biomarkers in the AF patients compared to healthy controls. Spearman correlation analysis demonstrated significant correlations between inflammatory and collagen remodeling biomarkers, and among the collagen biomarkers. Of note, CRP was found to be correlated with TIMP-1, ICTP and PIIINP. IL6 and TIMP-1 were also found to be intercorrelated. Furthermore, correlations were noted among the different collagen remodeling peptides, and between TNFα and IL6, two of the inflammatory markers explored in this study. The elevation of the inflammatory biomarkers and collagen remodeling proteins in AF patients is suggestive of inflammation and increased collagen turnover. The association between inflammatory biomarkers and collagen remodeling proteins may contribute to their regulation and role in the remodeling process.

Pomegranate Peel Extract Reduces Diabetes-induced Collagen Turnover and Biochemical Imbalance in Rat Lung

Diabetes causes lung function disorders. However, pulmonary collagen turnover under diabetes has not been well studied. The purpose of this study was to investigate collagen turnover in lung and to evaluate protective effect of pomegranate peel extract (PPE). Diabetes model in rat was induced by alloxan (250 mg/kg, i.p.). PPE treated rats received 100 mg/kg of PPE for 30 days. PPE was characterized by Gas chromatography–mass spectrometry (GC-MS). Hydroxyproline was determined by colourimetric assay kit, total collagen using ELISA kit and by histopathological assay. Collagenases (MMP-1,-8,-13) wereanalyzed by fluorometric method. Antioxidant enzyme activities and inflammatory marker C-reactive protein (CRP) were evaluated. Diabetes decreases SOD activity and increases CRP level by 33% (p &lt; 0.05) and 125% (p &lt; 0.01), respectively, when compared to the control group. PPE abrogated diabetesinduced SOD activity and CRP level disturbance. Collagenase activity was lower in diabetes and PPE group by 38% (p &lt; 0.05) and 34% (p &lt; 0.05), respectively, when compared to control. Diabetes increased significantly collagen and hydroxyproline by 32% (p &lt; 0.05) and 192% (p &lt; 0.01), respectively, and restored at similar level than controls in PPE group. Lung histopathological assay showed distended alveoli and peribronchial inflammatory cell infiltration in diabetic group. Compared to diabetic, PPE limits inflammatory cell infiltration in lung tissue. Diabetes causes ECM imbalance and enhances inflammation in lung wall, which can be abrogated by PPE.

Remodeling of the uterine artery during and early after pregnancy in the mouse.

Pregnancy associates with dramatic changes in maternal cardiovascular physiology that ensure that the utero-placental circulation can support the developing fetus. Particularly striking is the marked flow-induced remodeling of uterine arteries during pregnancy and their recovery following birth. Whereas details are available in the literature on alterations in hemodynamics within and changes in the dimensions of uterine arteries during and following pregnancy in mice, we report here the first biaxial biomechanical phenotyping of these arteries during this dynamic period of growth and remodeling (G&R). To gain additional insight into the measured G&R, we also use a computational constrained mixture model to describe and predict findings, including simulations related to complications that may arise during pregnancy. It is found that dramatic pregnancy-induced remodeling of the uterine artery is largely, but not completely, reversed in the postpartum period, which appears to be driven by increases in collagen turnover among other intramural changes. By contrast, data on the remodeling of the ascending aorta, an elastic artery, reveal modest changes that are fully recovered postpartum. There is strong motivation to continue biomechanical studies on this critical aspect of women's health, which has heretofore not received appropriate consideration from the biomechanics community.

17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice.

Estrogen signaling is protective against chronic liver diseases, although men and a subset of women are contraindicated for chronic treatment with 17β-estradiol (17β-E2) or combination hormone replacement therapies. We sought to determine if 17α-estradiol (17α-E2), a naturally occurring diastereomer of 17β-E2, could attenuate liver fibrosis. We evaluated the effects of 17α-E2 treatment on collagen synthesis and degradation rates using tracer-based labeling approaches in male mice subjected to carbon tetrachloride (CCl4)-induced liver fibrosis. We also assessed the effects of 17α-E2 on markers of hepatic stellate cell (HSC) activation, collagen cross-linking, collagen degradation, and liver macrophage content and polarity. We found that 17α-E2 significantly reduced collagen synthesis rates and increased collagen degradation rates, which was mirrored by declines in transforming growth factor β1 (TGF-β1) and lysyl oxidase-like 2 (LOXL2) protein content in liver. These improvements were associated with increased matrix metalloproteinase 2 (MMP2) activity and suppressed stearoyl-coenzyme A desaturase 1 (SCD1) protein levels, the latter of which has been linked to the resolution of liver fibrosis. We also found that 17α-E2 increased liver fetuin-A protein, a strong inhibitor of TGF-β1 signaling, and reduced proinflammatory macrophage activation and cytokines expression in the liver. We conclude that 17α-E2 reduces fibrotic burden by suppressing HSC activation and enhancing collagen degradation mechanisms. Future studies will be needed to determine if 17α-E2 acts directly in hepatocytes, HSCs, and/or immune cells to elicit these benefits.