Deep generative models for ligand-based de novo design applied to multi-parametric optimization.

Multi-parameter optimization (MPO) is a major challenge in new chemical entity (NCE) drug discovery. Recently, promising results were reported for deep learning generative models applied to de novo molecular design, but, to our knowledge, until now no report was made of the value of this new technology for addressing MPO in an actual drug discovery project. In this study, we demonstrate the benefit of applying AI technology in a real drug discovery project.

Procollagen C-Proteinase Enhancer-1 (PCPE-1) deficiency in mice reduces liver fibrosis but not NASH progression.

Background And Aims: Nonalcoholic Steatohepatitis (NASH) is a major cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma resulting ultimately in increased liver-related mortality. Fibrosis is the main driver of mortality in NASH. Procollagen C-Proteinase Enhancer-1 (PCPE-1) plays a key role in procollagen maturation and collagen fibril formation.

Deficiency of Procollagen C-Proteinase Enhancer 1 in Mice has No Major Impact on Cardiac Collagen and Function Under Basal Conditions.

Maturation of fibrillar collagen is known to play a crucial role in the pathophysiology of myocardial fibrosis. Procollagen C-proteinase enhancer 1 (PCPE1) has a key role in procollagen maturation and collagen fibril formation. The phenotype of both male and female PCPE1 knock-out mice was investigated under basal conditions to explore the potential of PCPE1 as a therapeutic target in heart failure.

Aging increases circulating BH without modifying BH levels and impairs peripheral vascular function in healthy adults.

Little is known about the mechanisms of aging on vascular beds and its relationship with tetra and di-hydrobiopterin (BH and BH) levels. This observational clinical study analyzed the impact of aging on plasma and platelet biopterins, cutaneous blood flow (CBF), and coronary flow reserve (CFR) in healthy adults. The study enrolled healthy adults in 3 age groups: 18-30, 50-59, and 60-70 years (n = 25/group).

S62798, a potent TAFIa inhibitor, accelerates endogenous fibrinolysis in a murine model of pulmonary thromboembolism.

Enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Venous thrombosis and thromboembolism risks are associated with increased plasma levels of TAFI (Thrombin Activatable Fibrinolysis Inhibitor) as well as its active form TAFIa. A new TAFIa inhibitor, namely S62798 has been identified.

Phosphinanes and Azaphosphinanes as Potent and Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa).

Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure-activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors.

Vascular dysfunctions in the isolated aorta of double-transgenic hypertensive mice developing aortic aneurysm.

Angiotensin-II and oxidative stress are involved in the genesis of aortic aneurysms, a phenomenon exacerbated by endothelial nitric oxide synthase (eNOS) deletion or uncoupling. The purpose of this work was to study the endothelial function in wild-type C57BL/6 (BL) and transgenic mice expressing the h-angiotensinogen and h-renin genes (AR) subjected to either a control, or a high-salt diet plus a treatment with a NO-synthase inhibitor, N-ω-nitro-L-arginine-methyl-ester (L-NAME; BLSL and ARSL). BLSL showed a moderate increase in blood pressure, while ARSL became severely hypertensive.

Preserved regulation of renal perfusion pressure by small and intermediate conductance KCa channels in hypertensive mice with or without renal failure.

The purpose of this study was to assess, in the murine kidney, the mechanisms underlying the endothelium-dependent control of vascular tone and whether or not, in a severe model of hypertension and renal failure, KCa channels contribute to its regulation. Wild-type (BL) and double-transgenic female mice expressing human angiotensinogen and renin (AR) genes received either control or a high-salt diet associated to a nitric oxide (NO) synthase inhibitor treatment (BLSL and ARSL). Changes in renal perfusion pressure (RPP) were measured in isolated perfused kidneys.

Chronic reduction of nitric oxide level in adult spontaneously hypertensive rats induces aortic stiffness similar to old spontaneously hypertensive rats.

Introduction: Age and hypertension are two major determinants of arterial stiffness, as well as endothelial dysfunction. The present study was designed to test whether a chronic reduction of endogenous nitric oxide (NO) produces arterial stiffening close to that observed in old spontaneously hypertensive rats (SHR), and also to study the effect of an acute or a chronic decrease in blood pressure (BP) on aortic distensibility.

Methods: BP, aortic stiffness, endothelial dysfunction and remodelling were measured in male adult (20-week-old) SHR, in adult SHR treated with a nonspecific NO synthase inhibitor L-NAME (SHR/L-NAME) for 2 weeks, in adult SHR/L-NAME cotreated with perindopril (1 mg/kg/day) and in old SHR (55-week-old).

(Pro)renin promotes fibrosis gene expression in HEK cells through a Nox4-dependent mechanism.

The (pro)renin receptor (PRR) has recently been demonstrated to bind equally well renin and its precursor, prorenin, leading to a similar intracellular signaling independent of angiotensin II. In this study, we report that human embryonic kidney cells (HEK) exposed to renin or prorenin for 24 h in the presence of a blocking concentration of the angtiotensin-converting enzyme inhibitor perindoprilate increased superoxide anion production as measured by luminescence (lucigenin) and electron spin resonance spectroscopy (hydroxylamine radical transition). Also, both renin and prorenin increased Nox4 expression while Nox2, p47(phox), and p67(phox) remained unchanged.

Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells.

Introduction: Plasminogen Activator Inhibitor-1 (PAI-1) is the most potent endogenous inhibitor of fibrinolysis which is implicated in the pathogenesis of myocardial infarction and metabolic syndrome. The formation of reactive oxygen species (ROS) plays an important role in the pathology of vascular disorders and has been shown to increase PAI-1 expression by endothelial cells. Growing evidence indicates that NADPH oxidase and in particular the constitutively active Nox4-p22(phox) complexes are major sources of ROS in endothelial cells.

Distinct role of nox1, nox2, and p47phox in unstimulated versus angiotensin II-induced NADPH oxidase activity in human venous smooth muscle cells.

Human saphenous veins (SV) are used for coronary bypass surgery despite the higher rate of graft failure observed as compared to arteries. A higher production of reactive oxygen species (ROS) in SV than in internal mammary artery (IMA) has been incriminated as possibly implicated in graft failure. NADPH oxidase, involved in vascular ROS production, was therefore characterized in human smooth muscle cells from SV.

Different flavonoids present in the micronized purified flavonoid fraction (Daflon 500 mg) contribute to its anti-hyperpermeability effect in the hamster cheek pouch microcirculation.

Aim: This study evaluated microcirculatory effects of the flavonoid substances that constitute the micronized purified flavonoid fraction (MPFF) (Daflon 500 mg) in comparison to diosmin.

Methods And Results: In groups of 3 male hamsters, oral treatment with MPFF or diosmin (15 min before anesthesia) did not alter blood pressure. At 10 or 30 mg/kg, both MPFF and diosmin significantly decreased the leaky sites caused by ischemia/reperfusion (I/R) (30 min) in the hamster cheek pouch; the effect was significantly higher with MPFF (39+/-1% and 52+/-1%, respectively) than diosmin (18+/-1% and 37+/-3%, respectively).

Altered TP receptor function in isolated, perfused kidneys of nondiabetic and diabetic ApoE-deficient mice.

Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A(2)) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded.

Comparison of extracellular matrix in skin and saphenous veins from patients with varicose veins: does the skin reflect venous matrix changes?

Varicose vein disease is a frequently occurring pathology with multifactorial causes and a genetic component. An intense remodelling of the varicose vein wall has been described and could be at the origin of its weakness and altered elasticity. We have described previously a dysregulation of collagen synthesis in cultured smooth muscle cells from saphenous veins and in dermal fibroblasts from the skin of patients with varicose veins, suggesting a systemic defect in their connective tissue.

Decreased production of collagen Type III in cultured smooth muscle cells from varicose vein patients is due to a degradation by MMPs: possible implication of MMP-3.

An alteration of extracellular matrix is involved in varicose veins. We have previously shown that collagen III production, but not its mRNA expression, is decreased in cultured smooth muscle cells (SMC) from varicose veins, involving an over-production of collagen I. In this study, the mechanisms involved in this collagen III reduction are explored.

Role of NADPH oxidase-mediated superoxide production in the regulation of E-selectin expression by endothelial cells subjected to anoxia/reoxygenation.

Objective: Anoxia followed by reoxygenation (A/R) increases endothelial cell superoxide (O2-) generation which is implicated in E-selectin overexpression. The mechanisms which govern these processes are not fully understood and therefore the goal of our study was to determine the functional importance of NADPH oxidase in the regulation of E-selectin expression in human umbilical veins endothelial cells (HUVECs) submitted to A/R.

Methods: O2- production was estimated using lucigenin chemiluminescence and formazan accumulation.

Chronic venous insufficiency: dysregulation of collagen synthesis.

Varicose vein disease is a common condition. Its pathology is not well characterized. A disorganization of smooth muscle cells and extracellular matrix components in the venous wall have been described.

Synthesis of collagen is dysregulated in cultured fibroblasts derived from skin of subjects with varicose veins as it is in venous smooth muscle cells.

Background: The dilatation and tortuosity observed in varicose veins provide evidence for progressive venous wall remodeling associated with abnormalities of smooth muscle cells and extracellular matrix. The present study was designed to examine if the phenotypic modulations observed in the venous smooth muscle cells of patients with varicose veins were also present in their dermal fibroblasts.

Methods And Results: Collagen type I (collagen I), type III (collagen III), and type V (collagen V) were compared in dermal fibroblasts derived from the skin of control subjects and patients with varicose veins.

Imbalance in the synthesis of collagen type I and collagen type III in smooth muscle cells derived from human varicose veins.

Varicose veins have a thickening wall. Their smooth muscle cells are disorganized as regards proliferation and production of extracellular matrix protein. An imbalance between the synthesis of collagen type I protein (collagen I) and collagen type III protein (collagen III) could explain the lack of elasticity of varicose veins.

S17834, a new inhibitor of cell adhesion and atherosclerosis that targets nadph oxidase.

microdant stress is involved in the events that accompany endothelial cell expression of adhesion molecules and leukocyte adherence in many disease states, including atherosclerosis. A recently discovered benzo(b)pyran-4-one derivative, S17834 (10 to 50 micromol/L), reduced tumor necrosis factor-stimulated vascular cell adhesion molecule-1 (VCAM) mRNA accumulation and protein expression in human umbilical vein endothelial cells. Intercellular cell adhesion molecule-1 and E-selectin were also inhibited by S17834, but platelet endothelial cell adhesion molecule-1 was not.

Histochemical evidence for inducible nitric oxide synthase in advanced but non-ruptured human atherosclerotic carotid arteries.

In response to cytokine stimulation, the inducible isoform of the nitric oxide synthase (iNOS) produces large amounts of nitric oxide with potential consequences in the pathophysiology of atherosclerosis. Previous investigations have demonstrated the presence of iNOS in human atherosclerotic lesions. The goal of this study was to evaluate the occurrence of the expression of iNOS in ruptured versus non-ruptured human carotid atherosclerotic plaques.

TGF-(beta)1 maintains hematopoietic immaturity by a reversible negative control of cell cycle and induces CD34 antigen up-modulation.

Somatic stem cells are largely quiescent in spite of their considerable proliferative potential. Transforming growth factor-(beta)1 (TGF-(beta)1) appears to be a good candidate for controlling this quiescence. Indeed, various mutations in the TGF-beta signalling pathway are responsible for neoplasic proliferation of primitive stem/progenitor cells in human tissues of various origins.

Abnormal deposition of extracellular matrix proteins by cultured smooth muscle cells from human varicose veins.

The aim of the present study was to verify whether the modifications of the extracellular matrix, described in varicose veins, are also present in cultures of smooth muscle cells from human varicose veins. The accumulation of collagen type III and fibronectin was determined by immunofluorescence in cultures of smooth muscle cells at passage 2-3 during the proliferation phase. After 5 days of culture, the immunostaining of both collagen type III and fibronectin was weaker in cells from varicose than in those of control veins while the expression of collagen type III and fibronectin messenger ribonucleic acids was not significantly different.