Non-invasive candidate protein signature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response.

Background And Aims: A reduction in hepatic venous pressure gradient (HVPG) is the most accurate marker for assessing the severity of portal hypertension and the effectiveness of intervention treatments. This study aimed to evaluate the prognostic potential of blood-based proteomic biomarkers in predicting HVPG response amongst cirrhotic patients with portal hypertension due to Hepatitis C virus (HCV) and had achieved sustained virologic response (SVR).

Methods: The study comprised 59 patients from two cohorts.

Efficacy and safety of MAS825 (anti-IL-1β/IL-18) in COVID-19 patients with pneumonia and impaired respiratory function.

MAS825, a bispecific IL-1β/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium-glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks.

Metabolic adaptation characterizes short-term resistance to weight loss induced by a low-calorie diet in overweight/obese individuals.

Background: Low-calorie diet (LCD)-induced weight loss demonstrates response heterogeneity. Physiologically, a decrease in energy expenditure lower than what is predicted based on body composition (metabolic adaptation) and/or an impaired capacity to increase fat oxidation may hinder weight loss. Understanding the metabolic components that characterize weight loss success is important for optimizing weight loss strategies.

Glucosuric, renal and haemodynamic effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2, in patients with chronic kidney disease: A randomized trial.

Aim: To investigate the glucosuric, renal and haemodynamic effects of licogliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, in patients with chronic kidney disease (CKD).

Methods: This multiple-dose, parallel-group, phase II mechanistic study randomized 53 participants (aged 18-78 years, body mass index ≤ 50 kg/m ) with varying degrees of CKD or normal renal function to treatment with licogliflozin (50 mg once daily) or placebo for 7 days. The effects of licogliflozin on 24-h urinary glucose excretion (UGE ), renal function, haemodynamics, pharmacokinetics and safety were assessed.

Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors.

Target-engagement pharmacodynamic (PD) biomarkers are valuable tools in the prioritization of drug candidates, especially for novel, first-in-class mechanisms whose robustness to alter disease outcome is unknown. Methionine aminopeptidase 2 (MetAP2) is a cytosolic metalloenzyme that cleaves the N-terminal methionine from nascent proteins. Inhibition of MetAP2 leads to weight loss in obese rodents, dogs and humans.

Basal insulin peglispro increases lipid oxidation, metabolic flexibility, thermogenesis and ketone bodies compared to insulin glargine in subjects with type 1 diabetes mellitus.

Aims: When treated with basal insulin peglispro (BIL), patients with type 1 diabetes mellitus (T1DM) exhibit weight loss and lower prandial insulin requirements versus insulin glargine (GL), while total insulin requirements remain similar. One possible explanation is enhanced lipid oxidation and improved ability to switch between glucose and lipid metabolism with BIL. This study compared the effects of BIL and GL on glucose and lipid metabolism in subjects with T1DM.

Reduced skeletal muscle secreted frizzled-related protein 3 is associated with inflammation and insulin resistance.

Objective: To investigate the role of secreted frizzled-related protein 3 (Sfrp3) in insulin sensitivity (ISi) and β-cell function in humans across a spectrum of glucose homeostasis.

Methods: Subjects included those with normal glucose homeostasis (NGT; n = 18), prediabetes (PD; n = 11), or type 2 diabetes (T2D; n=12). Serum and skeletal muscle (SkM) Sfrp3 levels were measured by ELISA and qPCR, respectively, and insulin signaling pathway was assessed by Western blot.

Inhibition of JNK mitochondrial localization and signaling is protective against ischemia/reperfusion injury in rats.

To build upon recent findings that mitochondrial JNK signaling is inhibited by selectively blocking the interaction between JNK and Sab, we utilized a cell-permeable peptide to demonstrate that ischemia/reperfusion (I/R) injury could be protected in vivo and that JNK mitochondrial signaling was the mechanism by which reactive oxygen species (ROS) generation, mitochondrial dysfunction, and cardiomyocyte cell death occur. We also demonstrated that 5 mg/kg SR-3306 (a selective JNK inhibitor) was able to protect against I/R injury, reducing infarct volume by 34% (p < 0.05) while also decreasing I/R-induced increases in the activity of creatine phosphokinase and creatine kinase-MB.

Small Molecule c-jun-N-terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson's Disease.

There are currently no drugs to treat neurodegeneration in Parkinson's disease (PD) and all existing medications only treat symptoms, lose efficacy over time, and produce untoward side effects. In the current work, we report the first highly selective, orally bioavailable, c-jun-N-terminal kinase (JNK) inhibitor for protection of dopaminergic neurons in vitro and in vivo. At 300 nM this compound showed statistically significant protection of primary dopaminergic neurons exposed to 1-methyl-4-phenylpyridinium (MPP(+)), had pharmacokinetic properties in rodents consistent with twice daily (b.

Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors.

Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications.

Discovery of Potent and Selective Urea-Based ROCK Inhibitors and Their Effects on Intraocular Pressure in Rats.

A series of urea-based Rho kinase (ROCK) inhibitors were designed and evaluated. The discovered compounds had excellent enzyme and cellular potency, high kinase selectivity, high aqueous solubility, good porcine corneal penetration, and appropriate DMPK profiles for topical applications as antiglaucoma therapeutics.

Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway.

Bone morphogenetic protein (BMP) signaling regulates embryonic development of many organ systems and defective BMP signaling has been implicated in adult disorders of many of these systems. However, its relevance in cardiac disease has not been reported. Here we demonstrate for the first time that Bmp4 activity promotes cellular apoptosis following ischemia-reperfusion (I/R) injury induced myocardial infarction (MI).

Nasal vaccination with troponin reduces troponin specific T-cell responses and improves heart function in myocardial ischemia-reperfusion injury.

Myocardial ischemia with subsequent reperfusion (MI/R) can lead to significant myocardial damage. Ischemia initiates inflammation at the blood-microvascular endothelial cell interface and contributes significantly to both acute injury and repair of the damaged tissue. We have found that MI/R injury in mice is associated with a cellular immune response to troponin.

Secreted frizzled related protein 2 protects cells from apoptosis by blocking the effect of canonical Wnt3a.

We have demonstrated that mesenchymal stem cells overexpressing the survival gene Akt can confer paracrine protection to ischemic myocytes both in vivo and in vitro through the release of secreted frizzled related protein 2 (Sfrp2). However, the mechanisms mediating these effects of Sfrp2 have not been fully elucidated. In this study, we studied rat cardiomyoblasts subjected to hypoxia reoxygenation (HR) injury to test the hypothesis that Sfrp2 exerts anti-apoptotic effect by antagonizing pro-apoptotic properties of specific Wnt ligands.

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway.

Heme-oxygenase-1 (HO-1), a stress-inducible protein, is an important cytoprotective agent against ischemia/reperfusion (I/R) injury. However, the role of downstream mediators involved in HO-1-induced cytoprotection is not clear. In the current study we investigated the role of biliverdin reductase, an enzyme involved in the conversion of HO-1-derived biliverdin into bilirubin and the PI3K/Akt pathway in mediating the cytoprotective effects of HO-1 against hypoxia and reoxygenation (H/R) injury in vitro and in vivo.

Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction.

We reported previously that predelivery of heme oxygenase-1 (HO-1) gene to the heart by adeno-associated virus-2 (AAV-2) markedly reduces ischemia and reperfusion (I/R)-induced myocardial injury. However, the effect of preemptive HO-1 gene delivery on long-term survival and prevention of postinfarction heart failure has not been determined. We assessed the effect of HO-1 gene delivery on long-term survival, myocardial function, and left ventricular (LV) remodeling 1 yr after myocardial infarction (MI) using echocardiographic imaging, pressure-volume (PV) analysis, and histomorphometric approaches.

Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair.

Stem cell therapy has emerged as a promising tool for the treatment of a variety of diseases. Previously, we have shown that Akt-modified mesenchymal stem cells mediate tissue repair through paracrine mechanisms. Using a comprehensive functional genomic strategy, we show that secreted frizzled related protein 2 (Sfrp2) is the key stem cell paracrine factor that mediates myocardial survival and repair after ischemic injury.

Chronic recurrent myocardial ischemic injury is significantly attenuated by pre-emptive adeno-associated virus heme oxygenase-1 gene delivery.

Objectives: We assessed the hypothesis that overexpression of the antioxidant enzyme heme oxygenase (HO)-1 may protect against chronic recurrent ischemia/reperfusion injury.

Background: Multiple and recurring episodes of myocardial ischemia can result in significant myocardial damage, including myocyte death, fibrosis, and wall thinning, leading to impaired ventricular function and cardiac failure.

Methods: In this study we used a closed-chest rodent model of chronic recurring myocardial ischemia and reperfusion to investigate the efficacy of pre-emptive gene therapy in overexpressing the antioxidant enzyme HO-1, using adeno-associated virus (AAV)-2 as the delivery vector.

Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function.

We reported previously that predelivery of the anti-oxidant gene heme oxygenase-1 (HO-1) to the heart by adeno associated virus (AAV) markedly reduces injury after acute myocardial infarction (MI). However, the effect of HO-1 gene delivery on postinfarction recovery has not been investigated. In the current study, we assessed the effect of HO-1 gene delivery on post-MI left ventricle (LV) remodeling and function using echocardiographic imaging and histomorphometric approaches.

Therapeutic potential of endothelial progenitor cells in cardiovascular diseases.

Endothelial dysfunction and cell loss are prominent features in cardiovascular disease. Endothelial progenitor cells (EPCs) originating from the bone marrow play a significant role in neovascularization of ischemic tissues and in re-endothelialization of injured blood vessels. Several studies have shown the therapeutic potential of EPC transplantation in rescue of tissue ischemia and in repair of blood vessels and bioengineering of prosthetic grafts.

Genetic therapies for cardiovascular diseases.

Recent advances in understanding the molecular and cellular basis of cardiovascular diseases, together with the availability of tools for genetic manipulation of the cardiovascular system, offer possibilities for new treatments. Gene therapies have demonstrated potential usefulness for treating complex cardiovascular diseases, such as hypertension, atherosclerosis and myocardial ischemia, in various animal models. Some of these experimental therapies are now undergoing clinical evaluation in patients with cardiovascular disease.

Endothelium-targeted gene and cell-based therapies for cardiovascular disease.

Most common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its predominant role in the pathogenesis of cardiovascular disease, the vascular endothelium is an attractive therapeutic target. The identification of promoter sequences capable of rendering endothelial-specific transgene expression together with the recent development of vectors with enhanced tropism for endothelium may offer opportunities for the design of new strategies for modulation of endothelial function.

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury.

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1).