Relaxin's induction of metalloproteinases is associated with the loss of collagen and glycosaminoglycans in synovial joint fibrocartilaginous explants

Diseases of specific fibrocartilaginous joints are especially common in women of reproductive age, suggesting that female hormones contribute to their etiopathogenesis. Previously, we showed that relaxin dose-dependently induces matrix metalloproteinase (MMP) expression in isolated joint fibrocartilaginous cells. Here we determined the effects of relaxin with or without β-estradiol on the modulation of MMPs in joint fibrocartilaginous explants, and assessed the contribution of these proteinases to the loss of collagen and glycosaminoglycan (GAG) in this tissue. Fibrocartilaginous discs from temporomandibular joints of female rabbits were cultured in medium alone or in medium containing relaxin (0.1 ng/ml) or β-estradiol (20 ng/ml) or relaxin plus β-estradiol. Additional experiments were done in the presence of the MMP inhibitor GM6001 or its control analog. After 48 hours of culture, the medium was assayed for MMPs and the discs were analyzed for collagen and GAG concentrations. Relaxin and β-estradiol plus relaxin induced the MMPs collagenase-1 and stromelysin-1 in fibrocartilaginous explants – a finding similar to that which we observed in pubic symphysis fibrocartilage, but not in articular cartilage explants. The induction of these proteinases by relaxin or β-estradiol plus relaxin was accompanied by a loss of GAGs and collagen in joint fibrocartilage. None of the hormone treatments altered the synthesis of GAGs, suggesting that the loss of this matrix molecule probably resulted from increased matrix degradation. Indeed, fibrocartilaginous explants cultured in the presence of GM6001 showed an inhibition of relaxin-induced and β-estradiol plus relaxin-induced collagenase and stromelysin activities to control baseline levels that were accompanied by the maintenance of collagen or GAG content at control levels. These findings show for the first time that relaxin has degradative effects on non-reproductive synovial joint fibrocartilaginous tissue and provide evidence for a link between relaxin, MMPs, and matrix degradation

Mice Lacking Gpr37 Exhibit Decreased Expression of the Myelin-Associated Glycoprotein Mag and Increased Susceptibility to Demyelination

GPR37 is an orphan G protein-coupled receptor that is predominantly expressed in the brain and found at particularly high levels in oligodendrocytes. GPR37 has been shown to exert effects on oligodendrocyte differentiation and myelination during development, but the molecular basis of these actions is incompletely understood and moreover nothing is known about the potential role(s) of this receptor under demyelinating conditions. To shed light on the fundamental biology of GPR37, we performed proteomic studies comparing protein expression levels in the brains of mice lacking GPR37 and its close relative GPR37-like 1 (GPR37L1). These studies revealed that one of the proteins most sharply decreased in the brains of Gpr37/Gpr37L1 double knockout mice is the myelin-associated glycoprotein MAG. Follow-up Western blot studies confirmed this finding and demonstrated that genetic deletion of Gpr37, but not Gpr37L1, results in strikingly decreased brain expression of MAG. Further in vitro studies demonstrated that GPR37 and MAG form a complex when expressed together in cells. As loss of MAG has previously been shown to result in increased susceptibility to brain insults, we additionally assessed Gpr37-knockout (Gpr37−/−) vs. wild-type mice in the cuprizone model of demyelination. These studies revealed that Gpr37−/− mice exhibit dramatically increased loss of myelin in response to cuprizone, yet do not show any increased loss of oligodendrocyte precursor cells or mature oligodendrocytes. These findings reveal that loss of GPR37 alters oligodendrocyte physiology and increases susceptibility to demyelination, indicating that GPR37 could be a potential drug target for the treatment of demyelinating diseases such as multiple sclerosis

A comprehensive evaluation of polygenic score and genotype imputation performances of human SNP arrays in diverse populations

publishedVersio

Quantitative Proteomics Reveal an Altered Pattern of Protein Expression in Brain Tissue from Mice Lacking Gpr37 and Gpr37l1

GPR37 and GPR37L1 are glia-enriched G protein-coupled receptors that have been implicated in several neurological and neurodegenerative diseases. To gain insight into the potential molecular mechanisms by which GPR37 and GPR37L1 regulate cellular physiology, proteomic analyses of whole mouse brain tissue from wild-type (WT) versus GPR37/GPR37L1 double knockout (DKO) mice were performed in order to identify proteins regulated by the absence versus presence of these receptors (data are available via ProteomeXchange with identifier PXD015202). These analyses revealed a number of proteins that were significantly increased or decreased by the absence of GPR37 and GPR37L1. One of the most decreased proteins in the DKO versus WT brain tissue was S100A5, a calcium-binding protein, and the reduction of S100A5 expression in KO brain tissue was validated via Western blot. Coexpression of S100A5 with either GPR37 or GPR37L1 in HEK293T cells did not result in any change in S100A5 expression but did robustly increase secretion of S100A5. To dissect the mechanism by which S100A5 secretion was enhanced, cells coexpressing S100A5 with the receptors were treated with different pharmacological reagents. These studies revealed that calcium is essential for the secretion of S100A5 downstream of GPR37 and GPR37L1 signaling, as treatment with BAPTA-AM, an intracellular Ca2+ chelator, reduced S100A5 secretion from transfected HEK293T cells. Collectively, these findings provide a panoramic view of proteomic changes resulting from loss of GPR37 and GPR37L1 and also impart mechanistic insight into the regulation of S100A5 by these receptors, thereby shedding light on the functions of GPR37 and GPR37L1 in brain tissue

Polyphasic evaluation and cytotoxic investigation of isolated cyanobacteria with an emphasis on potent activities of a Scytonema strain

DATA AVAILABILITY STATEMENT : The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.Cyanobacteria are phototrophic organisms widely found in most types of natural habitats in the tropical regions of the world. In this study, we isolated and identified cyanobacterial strains from paddy soil in Hanoi (Vietnam) and investigated their cytotoxic activities. Five isolated cyanobacterial strains showed distinctive profiles of gene sequences (rRNA 16S and rbcL), phylogenetic placements, and morphological characteristics. Based on the polyphasic evaluation, they were classified as Scytonema bilaspurense NK13, Hapalosiphon welwitschii MD2411, Aulosira sp. XN1103, Desikacharya sp. NS2000, and Desmonostoc sp. NK1813. The cytotoxic screening revealed that the extract of strain Scytonema bilaspurense NK13 exhibited potent cytotoxic activities against four human cell lines of HeLa cells, OVCAR-8 cells, HaCaT cells, and HEK-293T cells, with IC50 values of 3.8, 34.2, 21.6, and 0.6μg/mL, respectively. This is the first time a well-classified Scytonema strain from tropical habitat in Southeast Asia has been recognized as a potential producer of cytotoxic compounds.The Vietnam National University, Hanoi (VNU).http://www.frontiersin.org/Microbiologyam2023BiochemistryGeneticsMicrobiology and Plant Patholog

Understanding the barriers to integrating maternal and mental health at primary health care in Vietnam

The prevalence of common perinatal mental disorders in Vietnam ranges from 16.9% to 39.9%, and substantial treatment gaps have been identified at all levels. This paper explores constraints to the integration of maternal and mental health services at the primary healthcare level and the implications for the health system’s responsiveness to the needs and expectations of pregnant women with mental health conditions in Vietnam. As part of the RESPONSE project, a three-phased realist evaluation study, we present Phase One findings which employed systematic and scoping literature reviews, and qualitative data collection (focus groups and interviews) with key health system actors, in Bac Giang province, Vietnam, to understand the barriers to maternal mental healthcare provision, utilisation, and integration strategies. A four-level framing of the barriers to integrating perinatal mental health services in Vietnam was used in reporting findings, which comprised individual, socio-cultural, organisational, and structural levels. At the socio-cultural and structural levels, these barriers included: cultural beliefs about the holistic notion of physical and mental health, stigma towards mental health, biomedical approach to healthcare services, absence of comprehensive mental health policy, and a lack of mental health workforce. At the organisational level, there was absence of clinical guidelines on the integration of mental health in routine antenatal visits, a shortage of staff, and poor health facilities. Finally, at the provider level, a lack of knowledge and training on mental health was identified. The integration of mental health into routine antenatal visits at the primary care level has the potential help to reduce stigma towards mental health and improve health system responsiveness by providing services closer to the local level, offering prompt attention, better choice of services, and better communication while ensuring privacy and confidentiality of services. This can improve the demand for mental health services and help reduce the delay of care-seeking

Twenty-first-century projections of shoreline change along inlet-interrupted coastlines

Sandy coastlines adjacent to tidal inlets are highly dynamic and widespread landforms, where large changes are expected due to climatic and anthropogenic influences. To adequately assess these important changes, both oceanic (e.g., sea-level rise) and terrestrial (e.g., fluvial sediment supply) processes that govern the local sediment budget must be considered. Here, we present novel projections of shoreline change adjacent to 41 tidal inlets around the world, using a probabilistic, reduced complexity, system-based model that considers catchment-estuary-coastal systems in a holistic way. Under the RCP 8.5 scenario, retreat dominates (90% of cases) over the twenty-first century, with projections exceeding 100 m of retreat in two-thirds of cases. However, the remaining systems are projected to accrete under the same scenario, reflecting fluvial influence. This diverse range of response compared to earlier methods implies that erosion hazards at inlet-interrupted coasts have been inadequately characterised to date. The methods used here need to be applied widely to support evidence-based coastal adaptation

Realist evaluation to improve health systems responsiveness to neglected health needs of vulnerable groups in Ghana and Vietnam: Study protocol

Background Socio-economic growth in many low and middle-income countries has resulted in more available, though not equitably accessible, healthcare. Such growth has also increased demands from citizens for their health systems to be more responsive to their needs. This paper shares a protocol for the RESPONSE study which aims to understand, co-produce, implement and evaluate context-sensitive interventions to improve health systems responsiveness to health needs of vulnerable groups in Ghana and Vietnam. Methods We will use a realist mixed-methods theory-driven case study design, combining quantitative (household survey, secondary analysis of facility data) and qualitative (in-depth interviews, focus groups, observations and document and literature review) methods. Data will be analysed retroductively. The study will comprise three Phases. In Phase 1, we will understand actors’ expectations of responsive health systems, identify key priorities for interventions, and using evidence from a realist synthesis we will develop an initial theory and generate a baseline data. In Phase 2, we will co-produce jointly with key actors, the context-sensitive interventions to improve health systems responsiveness. The interventions will seek to improve internal (i.e. intra-system) and external (i.e. people-systems) interactions through participatory workshops. In Phase 3, we will implement and evaluate the interventions by testing and refining our initial theory through comparing the intended design to the interventions’ actual performance. Discussion The study’s key outcomes will be: (1) improved health systems responsiveness, contributing to improved health services and ultimately health outcomes in Ghana and Vietnam and (2) an empirically-grounded and theoretically-informed model of complex contexts-mechanisms-outcomes relations, together with transferable best practices for scalability and generalisability. Decision-makers across different levels will be engaged throughout. Capacity strengthening will be underpinned by in-depth understanding of capacity needs and assets of each partner team, and will aim to strengthen individual, organisational and system level capacities

Drug-Related Problems in Coronary Artery Diseases

Coronary artery disease (CAD) remains the leading cause of mortality among cardiovascular diseases, responsible for 16% of the world’s total deaths. According to a statistical report published in 2020, the global prevalence of CAD was estimated at 1655 per 100,000 people and is predicted to exceed 1845 by 2030. Annually, in the United States, CAD accounts for approximately 610,000 deaths and costs more than 200 billion dollars for healthcare services. Most patients with CAD need to be treated over long periods with a combination of drugs. Therefore, the inappropriate use of drugs, or drug-related problems (DRPs), can lead to many consequences that affect these patients’ health, including decreased quality of life, increased hospitalization rates, prolonged hospital stays, increased overall health care costs, and even increased risk of morbidity and mortality. DRPs are common in CAD patients, with a prevalence of over 60%. DRPs must therefore be noticed and recognized by healthcare professionals. This chapter describes common types and determinants of DRPs in CAD patients and recommends interventions to limit their prevalence