Evaluation of doxorubicin and β-lapachone analogs as anticancer agents, a biological and computational study.

We have conducted an experimental and computational evaluation of new doxorubicin (4a-c) and β-lapachone (5a-c) analogs. These novel anticancer analogs were previously synthesized, but had not been tested or characterized until now. We have evaluated their antiproliferative and DNA cleavage inhibition properties using breast (MCF-7 and MDA-MB-231) and prostate (PC3) cancer cell lines.

Protein N-glycans in Healthy and Sclerotic Glomeruli in Diabetic Kidney Disease.

Background: Diabetes is expected to directly impact renal glycosylation, yet to date, there has not been a comprehensive evaluation of alterations in N-glycan composition in the glomeruli of patients with diabetic kidney disease (DKD).

Methods: We used untargeted mass spectrometry imaging to identify N-glycan structures in healthy and sclerotic glomeruli in FFPE sections from needle biopsies of five patients with DKD and three healthy kidney samples. Regional proteomics was performed on glomeruli from additional biopsies from the same patients to compare the abundances of enzymes involved in glycosylation.

Pragmatic Trial of Hospitalization Rate in Chronic Kidney Disease.

Background: Despite the availability of effective therapies for patients with chronic kidney disease, type 2 diabetes, and hypertension (the kidney-dysfunction triad), the results of large-scale trials examining the implementation of guideline-directed therapy to reduce the risk of death and complications in this population are lacking.

Methods: In this open-label, cluster-randomized trial, we assigned 11,182 patients with the kidney-dysfunction triad who were being treated at 141 primary care clinics either to receive an intervention that used a personalized algorithm (based on the patient's electronic health record [EHR]) to identify patients and practice facilitators to assist providers in delivering guideline-based interventions or to receive usual care. The primary outcome was hospitalization for any cause at 1 year.

Defining the molecular correlate of arteriolar hyalinosis in kidney disease progression by integration of single cell transcriptomic analysis and pathology scoring.

Arteriolar hyalinosis in kidneys is an independent predictor of cardiovascular disease, the main cause of mortality in chronic kidney disease (CKD). The underlying molecular mechanisms of protein accumulation in the subendothelial space are not well understood. Using single cell transcriptomic data and whole slide images from kidney biopsies of patients with CKD and acute kidney injury in the Kidney Precision Medicine Project, the molecular signals associated with arteriolar hyalinosis were evaluated.

Extended BODIPYs as Red-NIR Laser Radiation Sources with Emission from 610 nm to 750 nm.

Herein, we report the synthetic access to a set of π-extended BODIPYs featuring a penta-arylated (phenyl and/or thiophene) dipyrrin framework. We take advantage of the full chemoselective control of 8-methylthio-2,3,5,6-tetrabromoBODIPY when we conduct the Liebeskind-Srogl cross-coupling (LSCC) to functionalize exclusively the -position, followed by the tetra-Suzuki reaction to arylate the halogenated sites. All these laser dyes display absorption and emission bands in the red edge of the visible spectrum reaching the near-infrared with thiophene functionalization.

Synthesis of Fluorescent Pyrrolo[1,2-]pyrimidines from Fischer Carbene Complexes as Building Blocks.

A novel synthetic methodology is reported for the synthesis of fluorescent pyrrolo[1,2-]pyrimidines. Fischer carbene complexes served as the synthetic platform for (3+3) cyclization to form the heterocyclic moiety. The reaction process furnished two products, their ratio being modulated by the metal, base, and solvent.

Synthesis of Polysubstituted Symmetrical BODIPYs via Fischer Carbene Complexes: Theoretical, Photophysical and Electrochemical Evaluation.

A series of new symmetrical highly substituted BODIPYs 6 a-l was synthesized through a prefunctionalization approach in 35 %-89 % yields from the pyrrole core. This strategy allowed modulation of the substituents at the different positions based on the choice of Fischer's alkynyl carbenes, oxazolones and aldehydes used as precursors. The substituent variation at positions 2, 6, 3 and 5 had the greatest effect on the modulation of their photophysical properties such as absorption (λ ) and emission (λ ) wavelengths, extinction coefficient (ϵ), quantum yields (ϕ), Stokes shifts (Δν), fluorescence decay, radiative (k ) and non-radiative (k ) constants and the CIE 1931 coordinates.

Chalcones, a Privileged Scaffold: Highly Versatile Molecules in [4+2] Cycloadditions.

Chalcones are aromatic ketones found in nature as the central core of many biological compounds. They have a wide range of biological activity and are biogenetic precursors of other important molecules such as flavonoids. Their pharmacological relevance makes them a privileged scaffold, advantageous for seeking alternative therapies in medicinal chemistry.

6-Amino-3-Methyl-4-(2-nitrophenyl)-1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile Shows Antihypertensive and Vasorelaxant Action via Calcium Channel Blockade.

Several 4-pyran derivatives were designed and synthesized previously as vasorelaxant agents for potential antihypertensive drugs. In this context, the objective of the present investigation was to determine the functional mechanism of vasorelaxant action of 6-amino-3-methyl-4-(2-nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1: ) and its antihypertensive effect. Thus, compound 1: showed significant vasorelaxant action on isolated aorta rat rings pre-contracted with serotonin or noradrenaline, and the effect was not endothelium-dependent.

Effect of the substituents of new coumarin-imidazo[1,2-]heterocyclic-3-acrylate derivatives on nonlinear optical properties: a combined experimental-theoretical approach.

A series of new coumarin-imidazo[1,2-]heterocyclic-3-acrylate derivatives 7a-h were synthesized by the Heck reaction between the corresponding 3-(imidazo[1,2-]pyrimidines)-(2-yl)-2-chromen-2-ones 4a-e and methyl acrylate in 45-87% yields. The effect of the distinct substituents on third-order nonlinear optical properties was examined, experimentally measuring their nonlinear refractive indexes by the -scan technique. Density functional theory and time-dependent density functional theory were utilized with the B3LYP, CAM-B3LYP, PBE (PBEPBE), and M062X functionals on Gaussian09 software to calculate the vertical excitation, relaxation of the brightest excited states, conformation, HOMO-LUMO gaps, oscillator strength, polarizability, and hyperpolarizabilities of all derivatives.

Association of Inflammatory Biomarkers with Immunosuppression Management and Outcomes in Kidney Transplant Recipients with COVID-19.

Background: Kidney transplant recipients with coronavirus disease 2019 (COVID-19) are at increased risk for adverse outcomes, such as acute kidney injury (AKI), intensive care unit (ICU) admission, and death. The association of inflammatory biomarkers with outcomes and the impact of changes in immunosuppression on biomarker levels are unknown.

Methods: We investigated factors associated with a composite of AKI, ICU admission, or death, and whether immunosuppression changes correlated with changes in inflammatory biomarkers and outcomes in kidney transplant recipients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction.

Accounting for quality improvement during the conduct of embedded pragmatic clinical trials within healthcare systems: NIH Collaboratory case studies.

Embedded pragmatic clinical trials (ePCTs) and quality improvement (QI) activities often occur simultaneously within healthcare systems (HCSs). Embedded PCTs within HCSs are conducted to test interventions and provide evidence that may impact public health, health system operations, and quality of care. They are larger and more broadly generalizable than QI initiatives, and may generate what is considered high-quality evidence for potential use in care and clinical practice guidelines.

Rationale and design of the Kidney Precision Medicine Project.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes.

Organocatalytic Cascade Reactions for the Diversification of Thiopyrano-Piperidone Fused Rings Utilizing Trienamine Activation.

An aminocatalytic privileged diversity-oriented synthesis (ApDOS) strategy utilizing trienamine catalysis for the construction of diverse and complex thiopyrans-piperidone fused rings through a thia-Diels-Alder/nucleophilic ring-closing sequence by using dithioamides as activated heterodienophiles is reported. Following this strategy, a super cascade reaction to assemble nine fused rings can be achieved by employing a bis-dithioamide. Additionally, by linking an indole moiety on the dithioamide, a Pictet-Spengler type reaction can be promoted once the cascade sequence has been achieved, leading to more complex penta- hexa- and heptacyclic fused ring derivatives in a one-pot process.

Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies.

Coumarin-hydroxamic acid derivatives - were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30-87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds , , , and the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 μM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites.

Systematic Review and Meta-Analysis of Native Kidney Biopsy Complications.

Background And Objectives: Native kidney biopsies are commonly performed in the diagnosis of acute kidney diseases and CKD. Because of the invasive nature of the procedure, bleeding-related complications are not uncommon. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases-sponsored Kidney Precision Medicine Project requires that all participants undergo a kidney biopsy; therefore, the objective of this analysis was to study complication rates of native kidney biopsies performed using automated devices under kidney imaging.

Selective synthesis of trisubstituted pyrroles through the reactions of alkynyl Fischer carbene complexes with oxazolones.

An efficient and simple synthesis of novel trisubstituted 1H-pyrroles 4a-qvia 1,3-dipolar cycloaddition of Δ3-trifluoromethyloxazolones 2a-d with both chromium and tungsten alkynyl Fischer carbene complexes (1a-h) is described. An unexpected and unreported -CF3 group elimination process was observed in the pyrrole structure. Our experimental and theoretical data suggested that the metal fragment may be responsible for this phenomenon.