Proapoptotic Bcl-2 inhibitor as host directed therapy for pulmonary tuberculosis.

establishes within host cells by inducing anti-apoptotic Bcl-2 family proteins, triggering necrosis, inflammation, and fibrosis. Here, we demonstrate that navitoclax, an orally bioavailable, small-molecule Bcl-2 inhibitor, significantly improves pulmonary tuberculosis (TB) treatments as a host-directed therapy. Addition of navitoclax to standard TB treatments at human equipotent dosing in mouse models of TB, inhibits Bcl-2 expression, leading to improved bacterial clearance, reduced tissue damage / fibrosis and decreased extrapulmonary bacterial dissemination.

Dynamic PET reveals compartmentalized brain and lung tissue antibiotic exposures of tuberculosis drugs.

Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic F-pretomanid positron emission tomography (PET) in eight human subjects to visualize F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements.

Dynamic PET Reveals Compartmentalized Brain and Lung Tissue Antibiotic Exposures.

Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we performed first-in-human dynamic F-pretomanid positron emission tomography (PET) studies in eight human subjects for three-dimensional, multi-compartmental visualization of antibiotic concentration-time exposures (area under the curve - AUC), demonstrating preferential brain (AUC 2.25) versus lung (AUC 0.

Multi-functionalization of reduced graphene oxide nanosheets for tumor theragnosis: Synthesis, characterization, enzyme assay, in-silico study, radiolabeling and in vivo targeting evaluation.

Background: In this study, a combination of nanotechnology, organic synthesis and radiochemistry were utilized in order to design an efficient nano-system conjugated with a suitable radionuclide and an antitumor agent for possible application as tumor theragnostic agent.

Method: Four novel compounds (3 and 4a-c) bearing tetrahydroquinazoline-7-sulfonohydrazide or 1,2,3,4-tetrahydroquinazoline-7-sulfonamide scaffold were designed. Then, docking study predicted that the compounds can be considered as potential inhibitors for PARP-1.

New phenothiazine conjugates as apoptosis inducing agents: Design, synthesis, In-vitro anti-cancer screening and I-radiolabeling for in-vivo evaluation.

Phenothiazines (PTZs) are a group of compounds characterized by the presence of the 10H-dibenzo-[b,e]-1,4-thiazine system. PTZs used in clinics as antipsychotic drugs with other diverse biological activities. The current aim of the study is to investigate and understand the effect of potent PTZs compounds using a group of In-vitro and In-vivo assays.

Novel substituted 1,8-naphthyridines: Design, synthesis, radiolabeling, and evaluation of apoptosis and topoisomerase II inhibition.

A series of seventeen 1,8-naphthyridine derivatives (5a-5q) conjugated at N to various substituted phenyl rings were designed and synthesized as potential topoisomerase II (Topo II) inhibitors. The antiproliferative activity of the target compounds against three cancer cell lines showed that compounds 5g and 5p had the highest antiproliferative activity. In addition, 5p and 5g displayed a high selectivity index (SI) for cancer cells when tested on WI38 normal cells, whereby compound 5p showed the highest SI.

Tailoring of Selenium-Plated Novasomes for Fine-Tuning Pharmacokinetic and Tumor Uptake of Quercetin: In Vitro Optimization and In Vivo Radiobiodistribution Assessment in Ehrlich Tumor-Bearing Mice.

Quercetin (QRC) is a bioflavonoid with anti-inflammatory, antioxidant, and anticancer activities, yet QRC poor bioavailability has hampered its clinical implementation. The aim of the current work was to harness novasomes (NOVs), free fatty acid enriched vesicles, as a novel nano-cargo for felicitous QRC delivery with subsequent functionalization with selenium (SeNOVs), to extend the systemic bio-fate of NOVs and potentiate QRC anticancer efficacy through the synergy with selenium. QRC-NOVs were primed embedding oleic acid, Brij 35, and cholesterol adopting thin-film hydration technique according to Box-Behnken design.

Extraction, purification and radioiodination of Khellin as cancer theranostic agent.

Khellin was successfully extracted from Ammi visnaga fruits with a recovery percent of 96.15%. Next radio-iodination of Khellin was successfully achieved with a high yield.

Discovery of New Coumarin-Based Lead with Potential Anticancer, CDK4 Inhibition and Selective Radiotheranostic Effect: Synthesis, 2D & 3D , Molecular Dynamics, In Vitro Cytotoxicity, Radioiodination, and Biodistribution Studies.

Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolyl-based derivatives were synthesized. A quantitative structure activity relationship ( model with high predictive power r = 0.92, and RMSE = 0.

"Tau Protein Targeting Via Radioiodinated Azure A For Brain Theranostics: Radiolabeling, Molecular Docking, in vitro And in vivo Biological Evaluation".

Azure-A is one of the phenothiazines (PTZs) derivatives which for decades have been used as antipsychotic drugs due to good lipophilic characteristics which enable them to pass through the blood brain barrier (BBB), besides the important property of enabeling investigation of the pathological forms of aggregated tau protein found in the neurons of the central nervous system. Radioiodination of Azure-A was carried out via an electrophilic substitution reaction using chloramine-T as oxidizing agent. The influence of various reaction parameters and conditions on radioiodination efficiency was investigated, and a high radiochemical yield of 92.

Immunohistochemistry of Janus Kinase 1 (JAK1) Expression in Vitiligo.

Background: Vitiligo is a chronic autoimmune disease in which the destruction of melanocytes causes white spots on the affected skin. Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-signal transducer and activator of transcription pathway. The aim of the present study is to explore the possible role of JAK1 in the pathogenesis of vitiligo using immunohistochemical methods.

Radioiodination and biological distribution of a new s-triazine derivative for tumor uptake evaluation.

A newly synthesized s-triazine derivative 1,1',1″-(((1,3,5-triazine-2,4,6-triyl) tris (azanediyl)) tris (benzene-4,1-diyl))tris (ethan-1-one), (1), was synthesized as a part of an ongoing research for development of novel s-triazine-based radiopharmaceuticals. In-vitro cell viability assay against different human cancer cell lines showed very promising inhibitory activity of the synthesized compound. This finding encouraged the radioiodination of 1 to study the degree of its localization in tumor site for evaluating the possibility of its use as a tumor imaging agent.

Development, Potential Anticancer Activity and the Receptor Profile of Different Functionalized 1,3,5-Triazine Derivatives.

1,3,5-Triazine-based compounds form a privileged class of compounds in the medicinal chemistry field as they are versatile synthetic scaffolds possessing wide spectra of biological effects including potential anticancer activity. 1,3,5-Triazine compounds explored for anticancer activities have been reported to act by various mechanisms on several molecular targets in human cells such as methyltransferase (DNMT), heat shock protein 90 (Hsp90) and phosphoinositide 3-kinase (PI3K). This review focuses on the synthetic strategies for current developments of 1,3,5-triazine-based anticancer agents and discuses the docking studies that confirm their unique binding modes in the targeted receptors active sites.