Repurposing of 8-Hydroxyquinoline-Based Butyrylcholinesterase and Cathepsin B Ligands as Potent Nonpeptidic Deoxyribonuclease I Inhibitors.

A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 µM and 50 nM, respectively, while two nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 and 20 µM. Selected derivatives were screened for various co-target binding affinities at dopamine D2 and D3 , histamine H3 and H4 receptors and inhibition of 5-lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non-peptide DNase I inhibitors. The present study demonstrates that 8-hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.

Purine adducts as a presumable missing link for aristolochic acid nephropathy-related cellular energy crisis, potential anti-fibrotic prevention and treatment.

Aristolochic acid nephropathy is a progressive exposome-induced disease characterized by tubular atrophy and fibrosis culminating in end-stage renal disease and malignancies. The molecular mechanisms of the energy crisis as a putative cause of fibrosis have not yet been elucidated. In light of the fact that aristolochic acid forms DNA and RNA adducts by covalent binding of aristolochic acid metabolites to exocyclic amino groups of (deoxy)adenosine and (deoxy)guanosine, we hypothesize here that similar aristolochic acid adducts may exist with other purine-containing molecules. We also provide new insights into the aristolochic acid-induced energy crisis and presumably a link between already known mechanisms. In addition, an overview of potential targets in fibrosis treatment is provided, which is followed by recommendations on possible preventive measures that could be taken to at least postpone or partially alleviate aristolochic acid nephropathy.

1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors.

Herein we report an assessment of 24 1,2,3,4-tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC50 values below 200 µM. The most potent was 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2) (IC50 =134.35±11.38 µM) exhibiting slightly better IC50 value compared to three other active compounds, 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-phenylethan-1-one (15) (IC50 =147.51±14.87 µM), 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (18) (IC50 =149.07±2.98 µM) and 2-[6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (22) (IC50 =148.31±2.96 µM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC-5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.

Synthesis and analysis of 4-oxothiazolidines as potential dual inhibitors of deoxyribonuclease I and xanthine oxidase.

In this study, seven new 4-oxothiazolidine derivatives were synthesized and assayed, along 7 known derivatives, for inhibitory properties against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. Among tested compounds, (5Z)-Ethyl-2-(2-(cyanomethylene)-4-oxothiazolidin-5-yliden)acetate (6) exhibited inhibitory activity against both enzymes (DNase I IC50 = 67.94 ± 5.99 µM; XO IC50 = 98.98 ± 13.47 µM), therefore being the first reported dual inhibitor of DNase I and XO. Observed DNase I inhibition qualifies compound 6 as the most potent small organic DNase I inhibitor reported so far. Derivatives of 2-alkyliden-4-oxothiazolidinone (1) inhibited DNase I below 200 µM, while the other tested 4-oxothiazolidine derivatives remained inactive against both enzymes. The molecular docking and molecular dynamics simulations into the binding sites of DNase I and XO enzyme allowed us to clarify the binding modes of this 4-oxothiazolidine derivative, which might aid future development of dual DNase I and XO.

Deoxyribonuclease I Inhibitory Properties, Molecular Docking and Molecular Dynamics Simulations of 1-(Pyrrolidin-2-yl)propan-2-one Derivatives.

Deoxyribonuclease I (DNase I) inhibitory properties of two 1-(pyrrolidin-2-yl)propan-2-one derivatives were examined in vitro. Determined IC50 values of 1-[1-(4-methoxyphenyl)pyrrolidin-2-yl]propan-2-one (1) (192.13±16.95 µM) and 1-[1-(3,4,5-trimethoxyphenyl)pyrrolidin-2-yl]propan-2-one (2) (132.62±9.92 µM) exceed IC50 value of crystal violet, used as a positive control, 1.89- and 2.73-times, respectively. Compounds are predicted to be nontoxic and to have favorable pharmacokinetic profiles, with high gastrointestinal absorption and blood-brain barrier permeability. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, Glu 78, Arg 111, Pro 137, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Determined inhibitory properties along with predicted ADMET profiles and observed interactions would be beneficial for the discovery of new active 1-(pyrrolidin-2-yl)propan-2-one-based inhibitors of DNase I.

Predictive Markers for Malignant Urothelial Transformation in Balkan Endemic Nephropathy: A Case-Control Study.

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease frequently accompanied by urothelial carcinoma (UC). In light of the increased UC incidence and the markers observed in BEN patients with developed UC, the aim of the current case-control study is to assess survivin, p53 protein, growth factors and receptors (VEGF, VEGFR1, IGF I, IGF-1R and IGFBP5), tumor marker (TF)/CD142, circulating soluble Fas receptor and neopterin, as potentially predictive markers for UC in patients with BEN (52 patients), compared to healthy, age-matched subjects (40). A threefold increase was registered in both circulating and urinary survivin level in BEN patients. Especially noticeable was the ratio of U survivin/U Cr level five times the ratio of BEN patients associated with standard renal markers in multivariate regression models. The concentrations of VEGF, VEGFR1, (TF)/CD142, (sFas) were not significantly different in BEN patients, while urinary/plasma level demonstrated a significant decrease for VEGF. The levels of IGF I, IGFBP5 and IGF-1R were significantly reduced in the urine of BEN patients. Plasma concentration of neopterin was significantly higher, while urinary neopterin value was significantly lower in BEN patients compared to healthy controls, which reflected a significantly lower urine/plasma ratio and low local predictive value. As BEN is a slow-progressing chronic kidney disease, early detection of survivin may be proposed as potential predictor for malignant alteration and screening tool in BEN patients without the diagnosis of UC.

DPP-4 Inhibitors in the Prevention/Treatment of Pulmonary Fibrosis, Heart and Kidney Injury Caused by COVID-19-A Therapeutic Approach of Choice in Type 2 Diabetic Patients?

Since the outbreak of SARS-CoV-2 virus more than 12,500,000 cases have been reported worldwide. Patients suffering from diabetes and other comorbidities are particularly susceptible to severe forms of the COVID-19, which might result in chronic complications following recovery. Dipeptidyl peptidase-4 inhibitors exert beneficial effects in prevention/treatment of pulmonary fibrosis, heart, and kidney injury, and since they may be a long-term consequence caused by COVID-19, it is reasonable to expect that DPP-4 inhibitors might be beneficial in alleviating long-term consequences of COVID-19. With that in mind, we would like to voice our concerns over chronic implications following recovery from COVID-19, especially not only in diabetic but also in non-diabetic patients, and to indicate that some preventive measures could be undertaken by application of DPP-4 inhibitors.

[Oral health related knowledge and health behavior of parents and school children].

INTRODUCTION: The family provides the background for developing behaviors, attitudes and knowledge related to oral health of children. The aim of this study was to compare oral health behavior of parents and their children and to asses the impact of parental behavior on children's oral health. MATERIAL AND METHODS: This cross-sectional study included 99 parent--child pairs (12 to 15 years old). Data on oral health behavior, knowledge and attitudes regarding oral hygiene, fluorides and nutrition of parents and their children were collected by questionnaires. The parental dental health was assessed according to self-reported data on tooth loss and prosthodontic rehabilitation, while the dental status of children was determined by clinical examination. RESULTS: The parents reported the use of dental floss (p < 0.001) and mouth rinses (p < 0.05) more often than their children and they had better knowledge on fluorides. Approximately one third of parents thought they should not control sugar consumption of their child. There was a statistically significant correlation between parental oral hygiene and their habit to control the child in brushing with the child's oral health status. CONCLUSION: Oral health education activities directed towards the prevention of risk factors for developing caries should involve both parents and their children, because parental behavior is a significant predictor of children's oral health.