Search

• Disorganized smooth muscle, fibrosis and fewer endometrial glands are characteristics of uterine scars. • Glandular structure could be responsible for healing defects after caesarean section. • Uterine scar defects have a fibroblastic highly collagenic stromal reaction. • No correlation was found between biomechanical characteristics and histology. The rate of caesarean section (CS) is increasing worldwide. Defects in uterine healing have a major gynaecological and obstetric impact (uterine rupture, caesarean scar defect, caesarean scar pregnancy, placenta accreta spectrum). The complex process of cellular uterine healing after surgery, and specifically after CS, remains poorly understood in contrast to skin wound healing. This literature review on uterine wound healing was mainly based on histological observations, particularly after CS. The primary objective of the review was to examine the effects of CS on uterine tissue at the cellular level, based on histological observations. The secondary objectives were to describe the biomechanical characteristics and the therapies used to improve scar tissue after CS. This review was performed using PRISMA criteria, and PubMed was the data source. The study included all clinical and animal model studies with CS and histological analysis of the uterine scar area (macroscopic, microscopic, immunohistochemical and biomechanical). Twenty studies were included: 10 human and 10 animal models. In total, 533 female humans and 511 female animals were included. Review articles, meeting abstracts, case series, case reports, and abstracts without access to full-text were excluded. The search was limited to studies published in English. No correlation was found between cutaneous and uterine healing. The histology of uterine scars is characterized by disorganized smooth muscle, fibrosis with collagen fibres and fewer endometrial glands. As for skin healing, the initial inflammation phase and mediation of some growth factors (particularly connective tissue growth factor, vascular endothelial growth factor, platelet-derived growth factor, tumour necrosis factor α and tumour necrosis factor β) seem to be essential. This initial phase has an impact on the subsequent phases of proliferation and maturation. Collagen appears to play a key role in the initial granulation tissue to replace the loss of substance. Subsequent maturation of the scar tissue is essential, with a decrease in collagen and smooth muscle restoration. Unlike skin, the glandular structure of uterine tissue could be responsible for the relatively high incidence of healing defects. Uterine scar defects after CS are characterized by an atrophic disorganized endometrium with atypia and a fibroblastic highly collagenic stromal reaction. Concerning immunohistochemistry, one study found a decrease in tumour necrosis factor β in uterine scar defects. No correlation was found between biomechanical characteristics (particularly uterine strength) and the presence of a collagenous scar after CS. Based on the findings of this review, an illustration of current understanding about uterine healing is provided. There is currently no validated prevention of caesarean scar defects. Various treatments to improve uterine healing after CS have been tested, and appeared to have good efficacy in animal studies: alpha lipoic acid, growth factors, collagen scaffolds and mesenchymal stem cells. Further prospective studies are needed. [ABSTRACT FROM AUTHOR]

We investigated the effects of zoledronate (ZA) and compressive force, separately and in combination, on the proliferation and differentiation of human gingival fibroblasts (HGFs) to verify the mechanism underlying medication-related osteonecrosis of the jaw (MRONJ). The addition of 100 µM ZA markedly inhibited cell proliferation. Expression of type I collagen, fibroblast growth factor 2, and connective tissue growth factor genes, was decreased by ZA and compressive force. Similar results were observed for collagen expression by using Sirius red staining. These results, together with clinical findings that MRONJ is more common in cases with excessive mechanical stress on the oral mucosa, suggest that bisphosphonates such as ZA and mechanical stress may act in conjunction as risk factors for the development of MRONJ by affecting homeostasis of the oral mucosal tissues, including HGFs. [ABSTRACT FROM AUTHOR]

The polymerase delta interacting protein 2 (Poldip2) is a nuclear-encoded mitochondrial protein required for oxidative metabolism. Under hypoxia, Poldip2 expression is repressed by an unknown mechanism. Therefore, low levels of Poldip2 are required to maintain glycolytic metabolism. The Cellular Communication Network Factor 2 (CCN2, Connective tissue growth factor, CTGF) is a profibrogenic molecule highly expressed in cancer and vascular inflammation in advanced atherosclerosis. Because CCN2 is upregulated under hypoxia and is associated with glycolytic metabolism, we hypothesize that Poldip2 downregulation is responsible for the upregulation of profibrotic signaling under hypoxia. Here, we report that Poldip2 is repressed under hypoxia by a mechanism that requires the activation of the enhancer of zeste homolog 2 repressive complex (EZH2) downstream from the Cyclin-Dependent Kinase 2 (CDK2). Importantly, we found that Poldip2 repression is required for CCN2 expression downstream of metabolic inhibition of the ubiquitin-proteasome system (UPS)-dependent stabilization of the serum response factor. Pharmacological or gene expression inhibition of CDK2 under hypoxia reverses Poldip2 downregulation, the inhibition of the UPS, and the expression of CCN2, collagen, and fibronectin. Thus, our findings connect cell cycle regulation and proteasome activity to mitochondrial function and fibrotic responses under hypoxia. [Display omitted] • In hypoxia, Poldip2 is repressed by EZH2-mediated signaling downstream of the cell cycle. • Poldip2 expression under hypoxia controls the activity of the Ubiquitin proteasome system. • Cell cycle regulation controls pro-fibrotic signaling under hypoxia. • Poldip2 deficiency exacerbates hypoxia-induced vascular hypoxia. [ABSTRACT FROM AUTHOR]

Connective tissue growth factor (Ctgf) is a matricellular protein with diverse biological function. It is regarded as a central regulator of tissue fibrosis and collagen synthesis in mammals. However, its roles in fish remain elusive. Here, a ctgf gene was cloned (NcCtgf), characterized and functionally studied in the chu's croaker (Nibea coibor). NcCtgf encoded a protein containing 346 amino acids, 38 conserved cysteine residues, 4 functional domains and a signal peptide. NcCtgf shared highest identity (99.4 %) to the Larimichthys crocea Ctgf protein. Phylogenetic tree revealed that NcCtgf clustered with the teleost Ctgfa and Ctgf of higher vertebrates, instead of teleost Ctgfb. NcCtgf was expressed with higher level in gonad, spleen, gill and swimming bladder than other tissues, and was up-regulated in swim bladder synchronously with collagen I genes by hydroxyproline and TGF-β1 treatment. NcCtgf knockdown/overexpression inhibited/promoted collagen synthesis in swim bladder cell, respectively. Notably, NcCtgf protein could be secreted to cell culture medium and up-regulated collagen I expression in swim bladder cell. These findings indicate NcCtgf plays vital roles in collagen synthesis in swim bladder of Nibea coibor , and provide basis for further understanding of ctgf evolution and exploring new approach for enhancing collagen deposition in fish products during aquaculture. [ABSTRACT FROM AUTHOR]

Our previous research revealed that androgen receptor (AR) activation reduces endothelial cell proliferation via non-genomic pathways. We hypothesized that AR activation might also affect endothelial cell migration, a critical step in angiogenesis. Our data demonstrates that treatment of human umbilical vein endothelial cells (HUVECs) with AR agonists, metribolone (R1881) or dihydrotestosterone (DHT), results in a dose-dependent reduction in migration, which can be reversed by AR antagonists or AR knockdown. Mechanistically, R1881 inhibits HUVEC migration by suppressing RhoA activity through the cSrc/FAK/paxillin pathway and promoting RhoA degradation via RhoA-p27 complex formation, ultimately resulting in RhoA ubiquitination. Transfection with constitutively active RhoA-V14 rescues the inhibitory effect of R1881 on HUVEC migration. Furthermore, R1881 elevates intracellular vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) levels but reduces VEGF secretion from HUVECs. This reduction is attributed to the formation of VEGF-CTGF complexes in the cytosol induced by R1881. Transfection with RhoA-V14 reduces CTGF levels and VEGF-CTGF complex formation, leading to enhanced VEGF secretion. Pre-treatment with WP631, a CTGF inhibitor, mitigates the R1881-induced reduction in VEGF secretion and HUVECs migration. In vivo assessments using zebrafish angiogenesis and mouse matrigel plug assays validate the anti-angiogenic effects of R1881. These findings provide insight into the molecular mechanisms through which AR activation modulates endothelial cell migration and angiogenesis. [Display omitted] • This study is the first to demonstrate that AR activation inhibits endothelial cell migration, revealing a novel regulatory role in vascular biology. • AR agonists like metribolone (R1881) and DHT inhibit endothelial migration dose-dependently, confirming a key pathway for therapeutic exploration. • We uncover that AR regulates migration via RhoA suppression and degradation through cSrc/FAK/paxillin, offering new mechanistic insights. • AR activation's anti-angiogenic effects are validated in vivo, highlighting its potential as a novel target in vascular disease treatment. • AR significantly reshapes VEGF signaling through VEGF-CTGF complexes, providing fresh insights into hormone-driven angiogenesis regulation. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent inflammatory joint diseases characterized by synovitis, cartilage, and bone destruction. Fibroblast-like synoviocytes (FLSs) of the synovial membrane are a decisive factor in arthritis, making them a target for future therapies. Developing novel strategies targeting FLSs requires advanced in vitro joint models that accurately replicate non-diseased joint tissue. This study aims to identify a cell source reflecting physiological synovial fibroblasts. Therefore, we newly compared the phenotype and metabolism of "healthy" knee-derived FLSs from patients with ligament injuries (trauma-FLSs) to mesenchymal stromal cells (MSCs), their native precursors. We differentiated MSCs into fibroblasts using connective tissue growth factor (CTGF) and compared selected protein and gene expression patterns to those obtained from trauma-FLSs and OA-FLSs. Based on these findings, we explored the potential of an MSC-derived synovial tissue model to simulate a chronic inflammatory response akin to that seen in arthritis. We have identified MSCs as a suitable cell source for synovial tissue engineering because, despite metabolic differences, they closely resemble human trauma-derived FLSs. CTGF-mediated differentiation of MSCs increased HAS2 expression, essential for hyaluronan synthesis. It showed protein expression patterns akin to OA-FLSs, including markers of ECM components and fibrosis, and enzymes leading to a shift in metabolism towards increased fatty acid oxidation. In general, cytokine stimulation of MSCs in a synovial tissue model induced pro-inflammatory and pro-angiogenic gene expression, hyperproliferation, and increased glucose consumption, reflecting cellular response in human arthritis. We conclude that MSCs can serve as a proxy to study physiological synovial processes and inflammatory responses. In addition, CTGF-mediated mesenchymal-to-fibroblast transition resembles OA-FLSs. Thus, we emphasize MSCs as a valuable cell source for tools in preclinical drug screening and their application in tissue engineering. • Human knee-derived FLSs from trauma patients exhibit a stem cell-like phenotype similar to human bone marrow-derived MSCs. • MSCs did not differ substantially in protein expression from trauma-FLSs. • Stimulation with CTGF leads to activation of MSCs and their differentiation into a profibrotic fibroblast phenotype. • Mimicking the 3D geometry of the synovial membrane supports the arrangement of MSCs in a lining layer-like structure. [ABSTRACT FROM AUTHOR]

The cerebral ischemia was one of the most common causes of disability and death worldwide. Basic fibroblast growth factor (bFGF) was reported to have neuroprotective function as well as promoting angiogenesis in the ischemic brain, but the targeting delivery of bFGF to ischemic brain was still difficult. In present study, a specific peptide was used to modify bFGF to construct recombinant CFBP-bFGF, and CFBP-bFGF could specifically deliver to ischemic brain through binding with the upregulated protein-connective tissue growth factor (CTGF). When CFBP-bFGF was used in rats with cerebral ischemia by intravenous injection, local concentration of the bFGF in ischemic brain was significantly increased. In addition, enhanced neurons survival, increased angiogenesis, decreased neuroinflammation were observed, that improved the motor functional recovery of cerebral ischemic injury. These results demonstrated that the targeting delivery of CFBP-bFGF would be a potential therapeutic approach for cerebral ischemia. The targeted delivery scheme illustration of the CFBP-bFGF, specially bonded with CTGF highly expressed in the ischemia brain. [Display omitted] • CFBP-bFGF could specifically deliver to ischemic brain through targeting upregulated connective tissue growth factor. • CFBP-bFGF improved the motor functional recovery of cerebral ischemic injury. • CFBP-bFGF enhanced neurons survival, promoted angiogenesis, decreased neuroinflammation. [ABSTRACT FROM AUTHOR]

Understanding how weight loss interventions in older adults with obesity impact aging biology can lay the foundation for targeted, 'geroscience-based' interventions. This study examines the association between changes in the senescence-associated secretory phenotypes (SASP) and changes in function in response to a weight loss intervention. We conducted a post-hoc biomarker analysis on adults aged ≥ 65 years with body mass index [BMI] ≥30 kg/m2 enrolled in a six-month, non-randomized telemedicine-delivered weight loss intervention. We assessed 16 SASP cytokines using serum samples collected pre-and post-intervention. Clinical outcomes include anthropometric and physical function measurements. A weight loss responder was defined as a loss of ≥5 % of body weight. Mean age was 73.2 ± 3.9 years (73 % female), and BMI was 36.5 ± 5.2 kg/m2. Responders lost 7.6 ± 2.5 %, while non-responders lost 2.0 ± 2.3 % of weight (n = 16 per group, p < 0.001). We observed several significant associations between SASP cytokines and physical function and anthropometric measurement outcomes in age- and sex-adjusted linear models. These included grip strength and Interleukin-8 (IL-8) (b = 9.07) and Insulin-like Growth Factor 1 (IGF-1) (b = 2.6); gait speed and Thymus and Activation-Regulated Chemokine (TARC) (b = 0.46) and IL-7(b = 61 0.11); weight IL-6 (b = -6.77) and IL-15 (b = -2.53); BMI and IL-15 (b = -0.95); waist-to-hip ratio and osteopontin (b = -0.07) (p < 0.05 for all). Our pilot data demonstrated an association between changes in select SASP biomarkers and increased functional ability with intentional weight loss in older adults with obesity. However, findings must be replicated in prospective randomized trials with a control group and additional SASP biomarkers. [ABSTRACT FROM AUTHOR]