Exploring Quinazoline Nitro-Derivatives as Potential Antichagasic Agents: Synthesis and In Vitro Evaluation.

is a protozoan parasite that causes Chagas disease in humans. The current antichagasic drugs nifurtimox and benznidazole have inconveniences of toxicity; therefore, the search for alternative therapeutic strategies is necessary. The present study reports the synthesis, drug-likeness predictions, and in vitro anti-trypanosome activity of a series of 14 quinazoline 2,4,6-triamine derivatives.

Compounds Consisting of Quinazoline, Ibuprofen, and Amino Acids with Cytotoxic and Anti-Inflammatory Effects.

In this research work, a series of 16 quinazoline derivatives bearing ibuprofen and an amino acid were designed as inhibitors of epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) and cyclooxygenase-2 (COX-2) with the intention of presenting dual action in their biological behavior. The designed compounds were synthesized and assessed for cytotoxicity on epithelial cancer cells lines (AGS, A-431, MCF-7, MDA-MB-231) and epithelial non-tumorigenic cell line (HaCaT). From this evaluation, derivative 6 was observed to exhibit higher cytotoxic potency (IC) than gefitinib (reference drug) on three cancer cell lines (0.

Synthesis of Quinazolin-2,4,6-triamine Derivatives as Non-purine Xanthine Oxidase Inhibitors and Exploration of Their Toxicological Potential.

In this work, a new set of quinazolin-2,4,6-triamine derivatives were synthesized to explore their potential biological activity as xanthine oxidase (XO) inhibitors, superoxide scavengers and screening of their toxicological profile. Among all the synthesized compounds, B1 exhibited better inhibitory activity against bovine xanthine oxidase (bXO) than allopurinol (IC =1.56 μM and IC =6.

Anti-Oxidative Therapy in Diabetic Nephropathy.

Chronic kidney disease is generally progressive and currently has no reliable treatment to reverse a decline in kidney function or to slow the progression of the disease. Diabetic nephropathy is one of the leading causes of end-stage kidney failure. Kidney damage in diabetic nephropathy is largely attributed to the increased oxidative stress, affecting its metabolic activity, metabolic pathways, and hemodynamic pathways.

Dysregulation of β-Cell Proliferation in Diabetes: Possibilities of Combination Therapy in the Development of a Comprehensive Treatment.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia as a result of insufficient insulin levels and/or impaired function as a result of autoimmune destruction or insulin resistance. While Type 1 DM (T1DM) and Type 2 DM (T2DM) occur through different pathological processes, both result in β-cell destruction and/or dysfunction, which ultimately lead to insufficient β-cell mass to maintain normoglycemia. Therefore, therapeutic agents capable of inducing β-cell proliferation is crucial in treating and reversing diabetes; unfortunately, adult human β-cell proliferation has been shown to be very limited (~0.

Multisensory Integration: Is Medial Prefrontal Cortex Signaling Relevant for the Treatment of Higher-Order Visual Dysfunctions?

In the mammalian brain, information processing in sensory modalities and global mechanisms of multisensory integration facilitate perception. Emerging experimental evidence suggests that the contribution of multisensory integration to sensory perception is far more complex than previously expected. Here we revise how associative areas such as the prefrontal cortex, which receive and integrate inputs from diverse sensory modalities, can affect information processing in unisensory systems processes of down-stream signaling.

Integrated Metabolomics and Proteomics Analyses in the Local Milieu of Islet Allografts in Rejection versus Tolerance.

An understanding of the immune mechanisms that lead to rejection versus tolerance of allogeneic pancreatic islet grafts is of paramount importance, as it facilitates the development of innovative methods to improve the transplant outcome. Here, we used our established intraocular islet transplant model to gain novel insight into changes in the local metabolome and proteome within the islet allograft's immediate microenvironment in association with immune-mediated rejection or tolerance. We performed integrated metabolomics and proteomics analyses in aqueous humor samples representative of the graft's microenvironment under each transplant outcome.

In Silico Characterization of Masitinib Interaction with SARS-CoV-2 Main Protease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a global health problem. Despite the current implementation of COVID-19 vaccination schedules, identifying effective antiviral drug treatments for this disease continues to be a priority. A recent study showed that masitinib (MST), a tyrosine kinase inhibitor, blocks the proteolytic activity of SARS-CoV-2 main protease (M ).

Parallel Multi-Omics in High-Risk Subjects for the Identification of Integrated Biomarker Signatures of Type 1 Diabetes.

Background: Biomarkers are crucial for detecting early type-1 diabetes (T1D) and preventing significant β-cell loss before the onset of clinical symptoms. Here, we present proof-of-concept studies to demonstrate the potential for identifying integrated biomarker signature(s) of T1D using parallel multi-omics.

Methods: Blood from human subjects at high risk for T1D (and healthy controls; = 4 + 4) was subjected to parallel unlabeled proteomics, metabolomics, lipidomics, and transcriptomics.

A machine learning approach to predict pancreatic islet grafts rejection versus tolerance.

The application of artificial intelligence (AI) and machine learning (ML) in biomedical research promises to unlock new information from the vast amounts of data being generated through the delivery of healthcare and the expanding high-throughput research applications. Such information can aid medical diagnoses and reveal various unique patterns of biochemical and immune features that can serve as early disease biomarkers. In this report, we demonstrate the feasibility of using an AI/ML approach in a relatively small dataset to discriminate among three categories of samples obtained from mice that either rejected or tolerated their pancreatic islet allografts following transplant in the anterior chamber of the eye, and from naïve controls.

Design, Synthesis and Evaluation of 2,4-Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors.

Microtubules are highly dynamic polymers composed of α- and β-tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β-tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well-known tubulin-depolymerizing agents that have close binding sites in the β-tubulin.

Longitudinal proteomics analysis in the immediate microenvironment of islet allografts during progression of rejection.

The applicability and benefits of pancreatic islet transplantation are limited due to various issues including the need to avoid immune-mediated rejection. Here, we used our experimental platform of allogeneic islet transplant in the anterior chamber of the eye (ACE-platform) to longitudinally monitor the progress of rejection in mice and obtain aqueous humor samples representative of the microenvironment of the graft for accurately-timed proteomic analyses. LC-MS/MS-based proteomics performed on such mass-limited samples (~5 μL) identified a total of 1296 proteins.

Genotoxicity assessment of four novel quinazoline-derived trypanocidal agents in the Drosophila wing somatic mutation and recombination test.

Chagas disease, caused by the protozoan Trypanosoma cruzi, has increased in the world due to migration, travelling and climate change; at present, the principal problem is that common trypanocidal agents have resulted in toxic or inconvenient side effects. We tested for genotoxicity in the standard (ST) and high bioactivation (HB) crosses of Drosophila wing somatic mutation and recombination test, four novel trypanocidal agents derived from 2, 4, 6-triaminquinazoline (TAQ): 2,4-diamino-6 nitro-1,3 diazonaftalene (S-1QN2-1), 2,4-diacetamino-6-amino 1,3 diazonaftalene (D-1), N6-(4,methoxybenzyl)quinazoline-2,4,6-triamine (GHPM) and N6-[4-(trifluoromethoxy)benzyl]quinazoline-2,4,6-triamine (GHPMF) at 1.9, 3.

Evaluation of New Benzimidazole Derivatives as Cysticidal Agents: In Vitro, in Vivo and Docking Studies.

Based on our previous research on cysticidal drugs, we report the synthesis and evaluation of three new benzimidazole derivatives. In these compounds, the amido group was used as a bioisosteric replacement of the ester group. The molecular docking on β-tubulin revealed that the derivatives interacted through hydrogen bonding with N165, E198 and V236.

Feasibility of Localized Metabolomics in the Study of Pancreatic Islets and Diabetes.

(1) Background: Disruption of insulin production by native or transplanted pancreatic islets caused by auto/allo-immunity leads to hyperglycemia, a serious health condition and important therapeutic challenge due to the lifelong need for exogeneous insulin administration. Early metabolic biomarkers can prompt timely interventions to preserve islet function, but reliable biomarkers are currently lacking. We explored the feasibility of "localized metabolomics" where initial biomarker discovery is made in aqueous humor samples for further validation in the circulation.

Correction to: In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice.

Unfortunately there is a mistake in the presentation of the affiliations in this paper.

In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice.

Aims/hypothesis: Autoimmune attack against the insulin-producing beta cells in the pancreatic islets results in type 1 diabetes. However, despite considerable research, details of the type 1 diabetes immunopathology in situ are not fully understood mainly because of difficult access to the pancreatic islets in vivo.

Methods: Here, we used direct non-invasive confocal imaging of islets transplanted in the anterior chamber of the eye (ACE) to investigate the anti-islet autoimmunity in NOD mice before, during and after diabetes onset.

Operational immune tolerance towards transplanted allogeneic pancreatic islets in mice and a non-human primate.

Aims/hypothesis: Patients with autoimmune type 1 diabetes transplanted with pancreatic islets to their liver experience significant improvement in quality of life through better control of blood sugar and enhanced awareness of hypoglycaemia. However, long-term survival and efficacy of the intrahepatic islet transplant are limited owing to liver-specific complications, such as immediate blood-mediated immune reaction, hypoxia, a highly enzymatic and inflammatory environment and locally elevated levels of drugs including immunosuppressive agents, all of which are injurious to islets. This has spurred a search for new islet transplant sites and for innovative ways to achieve long-term graft survival and efficacy without life-long systemic immunosuppression and its complications.

Systematic search for benzimidazole compounds and derivatives with antileishmanial effects.

Leishmaniasis is a neglected tropical disease that currently affects 12 million people, and over 1 billion people are at risk of infection. Current chemotherapeutic approaches used to treat this disease are unsatisfactory, and the limitations of these drugs highlight the necessity to develop treatments with improved efficacy and safety. To inform the rational design and development of more efficient therapies, the present study reports a chemoinformatic approach using the ChEMBL database to retrieve benzimidazole as a target scaffold.

Effect of Arginase-1 Inhibition on the Incidence of Autoimmune Diabetes in NOD Mice.

Metabolism of the amino acid L-arginine is implicated in many physiological and pathophysiological processes including autoimmune conditions such as type 1 diabetes (T1D). Alternate arginine metabolism through the citrulline-nitric oxide (NO) or the ornithine pathways can lead to proinflammatory or immune regulatory effects, respectively. In this report, we blocked the arginine-ornithine metabolic pathway by inhibiting the enzyme arginase-1 with Nω-hydroxy-nor-arginine (nor-NOHA) to make arginine more available to the alternate citrulline pathway for augmented NO production and increased incidence of autoimmune T1D in female non-obese diabetic (NOD) mice.

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies.

Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by . Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT.

Synthesis and biological evaluation of 2-methyl-1H-benzimidazole-5-carbohydrazides derivatives as modifiers of redox homeostasis of Trypanosoma cruzi.

Twelve novel benzimidazole derivatives were synthesized and their in vitro activities against epimastigotes of Trypanosoma cruzi were evaluated. Two derivatives (6 and 7), which have 4-hydroxy-3-methoxyphenyl moiety in their structures, proved to be the most active in inhibiting the parasite growth. Compound 6 showed a trypanocidal activity higher than benznidazole (IC=5µM and 7.

Correlation between plasma levels of arginine and citrulline in preterm and full-term neonates: Therapeutical implications.

Background: Preterm neonates exhibit several deficiencies that endanger their lives. Understanding those disturbances will provide tools for the management of preterm neonates. The present work focuses on arginine and citrulline which has been flagged among the biochemical landmarks of prematurity.

Dehydroepiandrosterone increases the number and dendrite maturation of doublecortin cells in the dentate gyrus of middle age male Wistar rats exposed to chronic mild stress.

Aging increases the vulnerability to stress and risk of developing depression. These changes have been related to a reduction of dehydroepiandrosterone (DHEA) levels, an adrenal steroid with anti-stress effects. Also, adult hippocampal neurogenesis decreases during aging and its alteration or impaired is related to the development of depression.

Incident Management Systems and Building Emergency Management Capacity during the 2014-2016 Ebola Epidemic - Liberia, Sierra Leone, and Guinea.

Establishing a functional incident management system (IMS) is important in the management of public health emergencies. In response to the 2014-2016 Ebola virus disease (Ebola) epidemic in West Africa, CDC established the Emergency Management Development Team (EMDT) to coordinate technical assistance for developing emergency management capacity in Guinea, Liberia, and Sierra Leone. EMDT staff, deployed staff, and partners supported each country to develop response goals and objectives, identify gaps in response capabilities, and determine strategies for coordinating response activities.