Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights.

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays.

Novel Agonists of Adenosine Receptors in Animal Model of Acute Myocardial Infarction.

Background And Purpose: Current treatments for acute myocardial infarction (AMI) include pain relief and attempts to improve survival. This study investigated the effects of two new ligands of the adenosine receptor, LASSBio-1027 and LASSBio-1860, on cardiac function in an experimental model of AMI.

Methods: AMI was induced in Wistar rats by ligating the anterior descending coronary arteries.

Perspectives on Stem Cell Therapy in Diabetic Neuropathic Pain.

Diabetes mellitus-related morbidity and mortality are primarily caused by long-term complications such as retinopathy, nephropathy, cardiomyopathy, and neuropathy. Diabetic neuropathy (DN) involves the progressive degeneration of axons and nerve fibers due to chronic exposure to hyperglycemia. This metabolic disturbance leads to excessive activation of the glycolytic pathway, inducing oxidative stress and mitochondrial dysfunction, ultimately resulting in nerve damage.

Antihypertensive Effect of New Agonist of Adenosine Receptor in Spontaneously Hypertensive Rats.

Background: Systemic arterial hypertension is a risk factor for cardiac, renal, and metabolic dysfunction. The search for new strategies to prevent and treat cardiovascular diseases led to the synthesis of new N-acylhydrazones to produce antihypertensive effect. Adenosine receptors are an alternative target to reduce blood pressure because of their vasodilatory action and antioxidant properties, which may reduce oxidative stress characteristic of systemic arterial hypertension.

Antinociceptive Effect of the Combination of a Novel α4β2* Agonist with Donepezil in a Chronic Pain Model.

Chronic pain presents a major challenge in contemporary medicine, given the limited effectiveness and numerous adverse effects linked to available treatments. Recognizing the potential of the cholinergic pathway as a therapeutic target, the present work evaluates the antinociceptive activity of a combination of Cris-104, a novel α4β2* receptor agonist, and donepezil, a central anticholinesterase agent. Isobolographic analysis revealed that equimolar combination was approximately 10 times more potent than theoretically calculated equipotent additive dose.

A Novel Hyaluronic Acid Filling Technique for Restoring Volume of the Labia Majora.

Vulvar rejuvenation, which includes both functional and aesthetic aspects, has received a lot of attention in recent years. Despite the fact that surgical interventions have proven to be effective, the development of minimally invasive techniques for restoring volume and tissue function remains a top priority. This case study describes a novel method for vulvar volumization and collagen stimulation of the labia majora using a hyaluronic acid filling technique.

Diabetes-Induced Cardiac Autonomic Neuropathy: Impact on Heart Function and Prognosis.

Cardiovascular autonomic neuropathy (CAN) is a severe complication of the advance stage of diabetes. More than 50% of diabetic patients diagnosed with peripheral neuropathy will have CAN, with clinical manifestations including tachycardia, severe orthostatic hypotension, syncope, and physical exercise intolerance. Since the prevalence of diabetes is increasing, a concomitant increase in CAN is expected and will reduce quality of life and increase mortality.

Heart Failure in Menopause: Treatment and New Approaches.

Aging is an important risk factor for the development of heart failure (HF) and half of patients with HF have preserved ejection fraction (HFpEF) which is more common in elderly women. In general, sex differences that lead to discrepancies in risk factors and to the development of cardiovascular disease (CVD) have been attributed to the reduced level of circulating estrogen during menopause. Estrogen receptors adaptively modulate fibrotic, apoptotic, inflammatory processes and calcium homeostasis, factors that are directly involved in the HFpEF.

Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls.

Mesenchymal Stem Cell Therapy in Diabetic Cardiomyopathy.

The incidence and prevalence of diabetes mellitus (DM) are increasing worldwide, and the resulting cardiac complications are the leading cause of death. Among these complications is diabetes-induced cardiomyopathy (DCM), which is the consequence of a pro-inflammatory condition, oxidative stress and fibrosis caused by hyperglycemia. Cardiac remodeling will lead to an imbalance in cell survival and death, which can promote cardiac dysfunction.

Crossroads between Estrogen Loss, Obesity, and Heart Failure with Preserved Ejection Fraction.

The prevalence of obesity and heart failure with preserved ejection fraction (HFpEF) increases significantly in postmenopausal women. Although obesity is a risk factor for left ventricular diastolic dysfunction (LVDD), the mechanisms that link the cessation of ovarian hormone production, and particularly estrogens, to the development of obesity, LVDD, and HFpEF in aging females are unclear. Clinical, and epidemiologic studies show that postmenopausal women with abdominal obesity (defined by waist circumference) are at greater risk for developing HFpEF than men or women without abdominal obesity.

Design and Synthesis In Silico Drug-like Prediction and Pharmacological Evaluation of Cyclopolymethylenic Homologous of LASSBio-1514.

Acylhydrazones are still an important framework to the design of new bioactive compounds. As treatment of chronic pain represents a clinical challenge, we decided to modify the structure of LASSBio-1514 (), previously described as anti-inflammatory and analgesic prototype. Applying the homologation as a strategy for molecular modification, we designed a series of cyclopentyl- (-), cyclobutyl- (-), and cyclopropylacylhydrazones (-) that were synthetized and evaluated in murine models of inflammation and pain.

Mesenchymal Stem Cells Therapies on Fibrotic Heart Diseases.

Stem cell therapy is a promising alternative approach to heart diseases. The most prevalent source of multipotent stem cells, usually called somatic or adult stem cells (mesenchymal stromal/stem cells, MSCs) used in clinical trials is bone marrow (BM-MSCs), adipose tissue (AT-MSCs), umbilical cord (UC-MSCs) and placenta. Therapeutic use of MSCs in cardiovascular diseases is based on the benefits in reducing cardiac fibrosis and inflammation that compose the cardiac remodeling responsible for the maintenance of normal function, something which may end up causing progressive and irreversible dysfunction.

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a cardiovascular disease caused by extensive vascular remodeling in the lungs, which ultimately leads to death in consequence of right ventricle (RV) failure. While current drugs for PH therapy address the sustained vasoconstriction, no agent effectively targets vascular cell proliferation and tissue inflammation. Rho-associated protein kinases (ROCKs) emerged in the last few decades as promising targets for PH therapy, since ROCK inhibitors demonstrated significant anti-remodeling and anti-inflammatory effects.

Antinociceptive Effect of Lodenafil Carbonate in Rodent Models of Inflammatory Pain and Spinal Nerve Ligation-Induced Neuropathic Pain.

Introduction: New therapeutic alternatives for pain relief include the use of phosphodiesterase-5 (PDE5) inhibitors, which could prevent the transmission of painful stimuli by neuron hyperpolarization via nitric oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. The present work investigated the antinociceptive activity of a new PDE5 inhibitor, lodenafil carbonate, in inflammatory and neuropathic pain models.

Methods And Results: Although no effect was detected on neurogenic phase of formalin test in mice, oral administration of lodenafil carbonate dose-dependently reduced reactivity in the inflammatory phase (200.

Estrogen Receptors: Therapeutic Perspectives for the Treatment of Cardiac Dysfunction after Myocardial Infarction.

Estrogen receptors (ER) mediate functions beyond their endocrine roles, as modulation of cardiovascular, renal, and immune systems through anti-inflammatory and anti-apoptotic effects, preventing necrosis of cardiomyocytes and endothelial cells, and attenuating cardiac hypertrophy. Estradiol (E2) prevents cardiac dysfunction, increases nitric oxide synthesis, and reduces the proliferation of vascular cells, yielding protective effects, regardless of gender. Such actions are mediated by ER (ER-alpha (ERα), ER-beta (ERβ), or G protein-coupled ER (GPER)) through genomic or non-genomic pathways, which regulate cardiovascular function and prevent tissue remodeling.

Therapeutic Benefit of the Association of Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O) for three weeks plus a weekly i.

New Benzofuran -Acylhydrazone Reduces Cardiovascular Dysfunction in Obese Rats by Blocking TNF-Alpha Synthesis.

Introduction: Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran -acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC.

Methods: Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study.

Reduction of cardiac and renal dysfunction by new inhibitor of DPP4 in diabetic rats.

Background: Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM.

G-Protein-Coupled Estrogen Receptor Agonist G1 Improves Diastolic Function and Attenuates Cardiac Renin-Angiotensin System Activation in Estrogen-Deficient Hypertensive Rats.

This study was aimed to clarify differences in how specific agonists of the 3 estrogen receptors (ERs) influence diastolic function and the renin-angiotensin system (RAS) after ovariectomy (OVX) in 24 female spontaneously hypertensive rat (SHR) undergoing bilateral OVX at 12 weeks of age. Eight weeks after surgery, rats were randomized (n = 6/group) to receive equipotent, daily treatments of one of the ER agonists (ERα agonist, propyl pyrazole trisphenol 94 μg/kg; ERβ agonist, diarylpropionitrile 58 μg/kg; G-protein-coupled estrogen receptor [GPER] agonist, G1 100 μg/kg), or vehicle (peanut oil). After 4 weeks of treatment, left ventricular function/structure and systemic/intracardiac pressure measurements were obtained by echocardiography and a fluid-filled catheter attached to a pressure transducer, respectively.

Effects of the FGF receptor-1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension.

Background And Purpose: Pulmonary arterial hypertension (PAH) is a progressive disease associated with high morbidity and mortality, despite advances in medical therapy. We compared the effects of infigratinib (NVP-BGJ398), a new FGF receptor-1 inhibitor, with or without the PDE-5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF-β (Smads-1/2/4) and transcription factor of endothelial-mesenchymal transition (Twist-1) in established experimental PAH. Types I and III pro-collagen and TGF-β expressions in lung fibroblasts were analysed in vitro after the different treatments.

Human Mesenchymal Stem Cell Therapy Reverses Su5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice.

Pulmonary arterial hypertension (PAH) is a disease characterized by an increase in pulmonary vascular resistance and right ventricular (RV) failure. We aimed to determine the effects of human mesenchymal stem cell (hMSC) therapy in a SU5416/hypoxia (SuH) mice model of PAH. C57BL/6 mice (20-25 g) were exposure to 4 weeks of hypoxia combined vascular endothelial growth factor receptor antagonism (20 mg/kg SU5416; weekly injections; PAH mice).

Novel agonist of αβ* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain.

Objective: To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}piperidine), a novel selective αβ* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models.

Materials And Methods: Hot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods.