Discovery of a brain penetrant SGK1 inhibitor using a ligand- and structure-based virtual screening methodology.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is an underexplored kinase involved in several neurodegenerative diseases. Although SGK1 inhibitors are not available on the market, the absence of side effects in two SGK1 knockout mouse models supports the development of brain-penetrant SGK1 inhibitors to explore their therapeutic potential. Through a combined ligand- and target-based virtual screening using the ECBL, we identified a small heterocyclic molecule with SGK1 inhibitory activity (IC = 0.

Activating Mutations Promotes Osteoblastic Bone Metastases in Medullary Thyroid Cancer.

Unlabelled: Development of bone metastases increases mortality in patients with medullary thyroid cancer (MTC), with ∼50% survival at 5 years after diagnosis, but the underlying mechanisms are unknown. We show that patient-derived MTC cells ( mutant TT cells and mutant MZCRC1 cells) promote an osteoblastic phenotype due to reduced bone resorption. Mechanistically, activated RET increases the expression of osteoprotegerin (OPG), an inhibitor of bone resorption, leading to decreased osteoclast differentiation.

Novel neuroglobin boosters as a therapeutic strategy for traumatic brain injury.

Neuroglobin (Ngb) induction offers a promising strategy for mitigating traumatic brain injury (TBI) damage due to its intrinsic antioxidant properties and capacity to alleviate oxidative stress. In this study, we employed high-throughput bioinformatics analysis to identify specific compounds that modulate Ngb-related mechanisms, followed by in vitro evaluation of their effects in astrocyte cultures. Among the compounds screened, A1 and A4 emerged as the most potent Ngb inducers.

Management of Local Skin Reactions Caused by 5-FU 4% Cream for the Treatment of Actinic Keratosis: A Delphi Consensus.

Introduction: Treatments such as 4% 5-fluorouracil (5-FU) cream have demonstrated strong efficacy in lesion clearance of actinic keratosis; however, local skin reactions (LSR) during treatment remain a significant challenge, potentially affecting patient adherence.

Objective: We sought to build consensus on management of LSR associated with 4% 5-FU using the Delphi methodology.

Methods: Twenty-eight expert dermatologists participated in a 3-round Delphi process.

The ROCK Inhibitor Fasudil and Sertraline Share Morphological and Molecular Effects in the Hippocampus of Chronically Stressed Rats: Exploring Common Antidepressant Pathways by Network Pharmacology.

Despite the widespread use of selective serotonin reuptake inhibitors like sertraline, the intricate molecular mechanisms underlying major depression and the therapeutic efficacy of these treatments remain not fully elucidated. Building on our preliminary findings, this study investigates the antidepressant effects of fasudil, a Rho-associated protein kinase (ROCK) inhibitor typically utilized as a vasodilator and antispasmodic, and compares its effects with those of sertraline using a chronic restraint stress model in rats. Specifically, we examined the effects of chronic administration on dendritic spine density, key molecular survival pathways, and miRNA levels in the hippocampus.

Identification of druggable binding sites and small molecules as modulators of TMC1.

Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via mechano-electrical transducer (MET) channels, composed of TMC1/2 proteins. However, the therapeutic use of ototoxic drugs, such as aminoglycosides and cisplatin, which can enter hair cells through MET channels, often leads to profound auditory and vestibular dysfunction. To date, our understanding of how small-molecule modulators interact with TMCs remains limited, hampering the discovery of novel drugs.

Phase IIa randomized placebocontrolled clinical trial to evaluate the efficacy of bromhexine in combination with standard therapy in the early treatment of COVID-19 in primary care patients.

Unlabelled: The continuous appearance of SARS-CoV-2 variants with both increased transmission and immune evading potential, in addition to the reluctance of some populations to be vaccinated, supports the search for alternative treatments to protect against the viral infection consequences. Bromhexine is a well-known, over-the counter, expectorant which have garnered interest for the potential prevention and treatment of COVID-19.

Aim: To evaluate the efficacy of oral bromhexine in patients with mild to moderate symptomatic active SARS-CoV-2 infection.

Emotion Forecasting: A Transformer-Based Approach.

Background: Monitoring the emotional states of patients with psychiatric problems has always been challenging due to the noncontinuous nature of clinical assessments, the effect of the health care environment, and the inherent subjectivity of evaluation instruments. However, mental states in psychiatric disorders exhibit substantial variability over time, making real-time monitoring crucial for preventing risky situations and ensuring appropriate treatment.

Objective: This study aimed to leverage new technologies and deep learning techniques to enable more objective, real-time monitoring of patients.

MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers.

MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since reliable clinical biomarkers are unavailable. In recent years, advancements in high-throughput sequencing strategies have led to the identification of novel ALS biomarkers, facilitating earlier diagnosis and assessment of treatment efficacy.

Influence of Social Determinants of Health on Presentation and Outcomes of Primary Congenital Glaucoma.

Purpose: Assess the effect of social determinants of health on presentation and outcomes in primary congenital glaucoma (PCG).

Design: Retrospective case series.

Subjects: Patients with PCG presenting between 2011 and 2023 with > 3 months follow-up.

Dose-dependent ventricular lesion formation using a novel large-area pulsed field ablation catheter: A preclinical feasibility study.

Background: Pulsed field ablation (PFA) has shown promising data in terms of safety and procedural efficiency for pulmonary vein isolation. Large-area focal PFA catheter designs might be suitable to deliver deep and durable lesions in ventricular myocardium.

Objective: We aimed to investigate the dose-response of a novel large-area focal 3-dimensional (3D)-enabled map-and-ablate PFA catheter for ventricular ablation in a chronic preclinical swine model.

Lesion Formation in Cardiac Pulsed-Field Ablation: Acute to Chronic Cellular Level Changes.

As pulsed-field ablation (PFA) emerges as a promising therapy for atrial arrhythmias, an understanding of the cellular injury to cardiac tissue is critical to evaluating and interpreting results for each PFA system. This review aims to detail the mechanism of cell death for PFA, compare the cell death mechanism to thermal ablation modalities, clarify common histology markers, detail the progression of PFA lesions from the acute, to subacute, to chronic maturation states, and discuss clinical indicators of PFA lesions.

Phase I trial of hydroxychloroquine to enhance palbociclib and letrozole efficacy in ER+/HER2- breast cancer.

Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2-negative metastatic breast cancer (ER+/HER2- MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses.

Impedimetric Sensor for SARS-CoV-2 Spike Protein Detection: Performance Assessment with an ACE2 Peptide-Mimic/Graphite Interface.

The COVID-19 pandemic has prompted the need for the development of new biosensors for SARS-CoV-2 detection. Particularly, systems with qualities such as sensitivity, fast detection, appropriate to large-scale analysis, and applicable in situ, avoiding using specific materials or personnel to undergo the test, are highly desirable. In this regard, developing an electrochemical biosensor based on peptides derived from the angiotensin-converting enzyme receptor 2 (ACE2) is a possible answer.

Intragastric administration of short chain fatty acids greatly reduces voluntary ethanol intake in rats.

Alcohol use disorder (AUD) represents a public health crisis with few FDA-approved medications for its treatment. Growing evidence supports the key role of the bidirectional communication between the gut microbiota and the central nervous system (CNS) during the initiation and progression of alcohol use disorder. Among the different protective molecules that could mediate this communication, short chain fatty acids (SCFAs) have emerged as attractive candidates, since these gut microbiota-derived molecules have multi-target effects that could normalize several of the functional and structural parameters altered by chronic alcohol abuse.

From Rangelands to Cropland, Land-Use Change and Its Impact on Soil Organic Carbon Variables in a Peruvian Andean Highlands: A Machine Learning Modeling Approach.

Unlabelled: Andean highland soils contain significant quantities of soil organic carbon (SOC); however, more efforts still need to be made to understand the processes behind the accumulation and persistence of SOC and its fractions. This study modeled SOC variables-SOC, refractory SOC (RSOC), and the C isotope composition of SOC (δC)-using machine learning (ML) algorithms in the Central Andean Highlands of Peru, where grasslands and wetlands ("bofedales") dominate the landscape surrounded by Junin National Reserve. A total of 198 soil samples (0.

Coronary Spasm Due to Pulsed Field Ablation: A State-of-the-Art Review.

With the ever-growing population of patients undergoing cardiac ablation with pulsed electric fields, there is a need to understand secondary effects from the therapy. Coronary artery spasm is one such effect that has recently emerged as the subject of further investigation in electrophysiology literature. This review aims to elucidate the basic anatomy underlying vascular spasm due to pulsed electric fields and the effects of irreversible electroporation on coronary arteries.

AlzyFinder: A Machine-Learning-Driven Platform for Ligand-Based Virtual Screening and Network Pharmacology.

Alzheimer's disease (AD), a prevalent neurodegenerative disorder, presents significant challenges in drug development due to its multifactorial nature and complex pathophysiology. The AlzyFinder Platform, introduced in this study, addresses these challenges by providing a comprehensive, free web-based tool for parallel ligand-based virtual screening and network pharmacology, specifically targeting over 85 key proteins implicated in AD. This innovative approach is designed to enhance the identification and analysis of potential multitarget ligands, thereby accelerating the development of effective therapeutic strategies against AD.

Identification of Antioxidant Methyl Derivatives of -Carbonyl Hydroquinones That Reduce Caco-2 Cell Energetic Metabolism and Alpha-Glucosidase Activity.

α-glucosidase, a pharmacological target for type 2 diabetes mellitus (T2DM), is present in the intestinal brush border membrane and catalyzes the hydrolysis of sugar linkages during carbohydrate digestion. Since α-glucosidase inhibitors (AGIs) modulate intestinal metabolism, they may influence oxidative stress and glycolysis inhibition, potentially addressing intestinal dysfunction associated with T2DM. Herein, we report on a study of an -carbonyl substituted hydroquinone series, whose members differ only in the number and position of methyl groups on a common scaffold, on radical-scavenging activities (ORAC assay) and correlate them with some parameters obtained by density functional theory (DFT) analysis.

Repurposing the Open Global Health Library for the discovery of novel Mpro destabilizers with scope as broad-spectrum antivirals.

The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear and phenotype.

Global 30-Day Morbidity and Mortality of Primary Bariatric Surgery Combined with Another Procedure: The BLEND Study.

Background: No robust data are available on the safety of primary bariatric and metabolic surgery (BMS) alone compared to primary BMS combined with other procedures.

Objectives: The objective of this study is to collect a 30-day mortality and morbidity of primary BMS combined with cholecystectomy, ventral hernia repair, or hiatal hernia repair.

Setting: This is as an international, multicenter, prospective, and observational audit of patients undergoing primary BMS combined with one or more additional procedures.