Vascular Adhesion Protein-1 Determines the Cellular Properties of Endometrial Pericytes

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible adhesion molecule and a primary amine oxidase involved in immune cell trafficking. Leukocyte extravasation into tissues is mediated by adhesion molecules expressed on endothelial cells and pericytes. Pericytes play a major role in the angiogenesis and vascularization of cycling endometrium. However, the functional properties of pericytes in the human endometrium are not known. Here we show that pericytes surrounding the spiral arterioles in midluteal human endometrium constitutively express VAP-1. We first characterize these pericytes and demonstrate that knockdown of VAP-1 perturbed their biophysical properties and compromised their contractile, migratory, adhesive and clonogenic capacities. Furthermore, we show that loss of VAP-1 disrupts pericyte-uterine natural killer cell interactions in vitro. Taken together, the data not only reveal that endometrial pericytes represent a cell population with distinct biophysical and functional properties but also suggest a pivotal role for VAP-1 in regulating the recruitment of innate immune cells in human endometrium. We posit that VAP-1 could serve as a potential biomarker for pregnancy pathologies caused by a compromised perivascular environment prior to conception

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Adipokines and the Metabolic Aspects of the Polycystic Ovary Syndrome

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age associated with a number of adverse metabolic sequealae. These women have an increased risk of insulin resistance and hyperinsulinemia, an increased risk of glucose intolerance and type 2 diabetes mellitus, dyslipidemia, subclinical atherosclerosis and vascular dysfunction, independent of BMI. With the epidemic of obesity, the PCOS phenotype is becoming ever more so prevalent and represents a clear and present health issue that needs to be addressed urgently. The studies describe for the first time the expression of visfatin and Retinol-Binding Protein 4 (RBP4) as well as adiponectin receptors, in corresponding sc and om human adipose tissues at both mRNA and protein levels. Also, it was shown that there was significant upregulation of visfatin and RBP4 as well as adiponectin receptors gene expression and protein in both these adipose tissue depots in overweight women with PCOS, including significantly higher circulatin visfatin and RBP4 levels, compared with matched controls. Furthermore, in isolated sc adipocytes, visfatin and RBP4 mRNA as well as adiponectin receptor(s) expression was significantly higher in age, BMI and WHR matched overweight PCOS women. Leptin was found to regulate om adipose tissue visfatin protein production and secretion, exhibiting a 'biphasic' response with a peak at leptin 10-9 M; a dose which is of physiological relevance in both mice and humans; returning to baseline with higher doses of leptin. This was true even in experiments conducted with C57BLIKs db/db mice, which lacked the membrane bound long leptin receptor (OB-Rb); thus highlighting the possible role of the membrane bound short leptin receptor (OBRa) in leptin induced visfatin protein production. Also, the apparent diminished response to higher doses of leptin with respect to visfatin production may be partly explained by the concurrent significant increase in the secretion of the soluble leptin receptor (SLR) at higher doses ofleptin. Binding ofleptin with SLR decreases the bioavailability of leptin to membrane bound leptin receptors and as a consequence, attenuates leptin's biological actions. Finally, when omental adipose tissues were subjected to leptin treatment in the presence of inhibitors of MAPK and PI3K, there was a significant decrease in leptin induced visfatin protein production and secretion. The MAPK and PI3K signalling pathways are known to functionally signal through both the short (OB-Ra) as well as the long (OB-Rb) leptin receptors. Leptin and visfatin may therefore playa coordinated role in various bodily functions, for example adipogenesis. Furthermore, the studies provide novel evidence that testosterone and 17~-estradiol increase both AdipoRl and AdipoR2 mRNA and protein levels; also, that 17~-estradiol significantly increases RBP4 secretion and up-regulates RBP4 mRNA expression and protein levels in human sc and om adipose tissue explants. Finally, HEK-293 cells were found to be suitable to further study and clarify the signalling pathways of both AdipoRl and AdipoR2. The temporal differences observed with respect to the activation ofAMPK between globular adiponectin and full length adiponectin forms the basis of further studies looking into the regulation of glucose and lipid metabolism, the molecular causes of diabetes and atherosclerosis, and the development of anti-diabetic and anti-atherosclerotic drugs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Proteomics Studies in Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis

Gestational Diabetes Mellitus (GDM) is the most common metabolic complication during pregnancy and is associated with serious maternal and fetal complications such as pre-eclampsia and stillbirth. Further, women with GDM have approximately 10 times higher risk of diabetes later in life. Children born to mothers with GDM also face a higher risk of childhood obesity and diabetes later in life. Early prediction/diagnosis of GDM leads to early interventions such as diet and lifestyle, which could mitigate the maternal and fetal complications associated with GDM. However, no biomarkers identified to date have been proven to be effective in the prediction/diagnosis of GDM. Proteomic approaches based on mass spectrometry have been applied in various fields of biomedical research to identify novel biomarkers. Although a number of proteomic studies in GDM now exist, a lack of a comprehensive and up-to-date meta-analysis makes it difficult for researchers to interpret the data in the existing literature. Thus, we undertook a systematic review and meta-analysis on proteomic studies and GDM. We searched MEDLINE, EMBASE, Web of Science and Scopus from inception to January 2022. We searched Medline, Embase, CINHAL and the Cochrane Library, which were searched from inception to February 2021. We included cohort, case-control and observational studies reporting original data investigating the development of GDM compared to a control group. Two independent reviewers selected eligible studies for meta-analysis. Data collection and analyses were performed by two independent reviewers. The PROSPERO registration number is CRD42020185951. Of 120 articles retrieved, 24 studies met the eligibility criteria, comparing a total of 1779 pregnant women (904 GDM and 875 controls). A total of 262 GDM candidate biomarkers (CBs) were identified, with 49 CBs reported in at least two studies. We found 22 highly replicable CBs that were significantly different (nine CBs were upregulated and 12 CBs downregulated) between women with GDM and controls across various proteomic platforms, sample types, blood fractions and time of blood collection and continents. We performed further analyses on blood (plasma/serum) CBs in early pregnancy (first and/or early second trimester) and included studies with more than nine samples (nine studies in total). We found that 11 CBs were significantly upregulated, and 13 CBs significantly downregulated in women with GDM compared to controls. Subsequent pathway analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatics resources found that these CBs were most strongly linked to pathways related to complement and coagulation cascades. Our findings provide important insights and form a strong foundation for future validation studies to establish reliable biomarkers for GDM

Circulating C1q complement/TNF-related protein (CTRP) 1, CTRP9, CTRP12 and CTRP13 concentrations in Type 2 diabetes mellitus: In vivo regulation by glucose.

OBJECTIVES The C1q complement/TNF-related protein (CTRP) superfamily, which includes the adipokine adiponectin, has been shown in animal models to have positive metabolic and cardiovascular effects. We sought to investigate circulating CTRP1, CTRP9, CTRP12 and CTRP13 concentrations in persons with type 2 diabetes mellitus (T2DM), with age and BMI matched controls, and to examine the effects of a 2 hour 75g oral glucose tolerance test (OGTT) on serum CTRP1, CTRP9, CTRP12 and CTRP13 levels in persons with T2DM. DESIGN Cross-sectional study [newly diagnosed T2DM (n = 124) and control (n = 139) participants]. Serum CTRP1, CTRP9, CTRP12 and CTRP13 were measured by ELISA. RESULTS Systolic and diastolic blood pressure, total cholesterol (TCH), Low-density lipoprotein (LDL)-cholesterol, triglycerides, TCH/High-density lipoprotein (HDL) ratio, triglycerides/HDL ratio, glucose, insulin, homeostatic model assessment-insulin resistance (HOMA-IR), C-reactive protein and endothelial lipase were significantly higher, whereas leptin and adiponectin were significantly lower in T2DM participants. Serum CTRP1 were significantly higher and CTRP12 significantly lower in T2DM participants. Age, diastolic blood pressure, glucose and CTRP12 were predictive of serum CTRP1; leptin was predictive of serum CTRP9; glucose and CTRP1 were predictive of serum CTRP12; endothelial lipase was predictive of serum CTRP13. Finally, serum CTRP1 were significantly higher and CTRP12 significantly lower in T2DM participants after a 2 hour 75g OGTT. CONCLUSIONS Our data supports CTRP1 and CTRP12 as potential novel biomarkers for the prediction and early diagnosis of T2DM. Furthermore, pharmacological agents that target CTRP1 and CTRP12 could represent a new strategy in the treatment of T2DM

Soluble Vascular Adhesion Protein 1 (sVAP-1) as a biomarker for pregnancy complications: A pilot study.

BackgroundVascular adhesion protein 1 (VAP-1) has been implicated in a wide range of clinical conditions. Moreover, serum levels are associated with disease prediction and progression in several clinical studies. There is a paucity of data on VAP-1 and pregnancy. Given the emerging role of VAP-1 in pregnancy, the aim of this study was to examine sVAP-1 as an early biomarker of pregnancy complications, especially hypertension during pregnancy. The objectives of the study are to associate sVAP-1 levels with other pregnancy complications, patient demographics and blood tests performed throughout pregnancy.MethodsWe conducted a pilot study in a cohort of pregnant women (gestational week lower than 20 at the time of recruitment) attending their first antenatal ultrasound scan at the Leicester Royal Infirmary (LRI, UK). Data were both prospectively generated (from blood sample analysis) and retrospectively collected (from hospital records).ResultsFrom July and October 2021, a total of 91 participants were enrolled. Using ELISA (enzyme-linked immunosorbent assay), we found reduced serum levels of sVAP-1 in pregnant women with either pregnancy induced hypertension (PIH) (310 ng/mL) or GDM (366.73 ng/mL) as compared to controls (427.44 ng/mL and 428.34 ng/mL, respectively). No significant difference was found between women with FGR compared to controls (424.32 ng/mL vs 424.52 ng/mL), and patients with any pregnancy complications compared to healthy pregnancies (421.28 ng/mL vs 428.34 ng/mL).ConclusionFurther studies are needed to establish whether or not sVAP-1 might be considered as an early, non-invasive, and affordable biomarker to screen women who will develop PIH or GDM. Our data will aid sample size calculations for such larger studies