Bis-coumarins; non-cytotoxic selective urease inhibitors and antiglycation agents

© 2019 Elsevier Inc. The current study is concerned with the identification of lead molecules based on the bis-coumarin scaffold having selective urease inhibitory and antiglycation activities. For that purpose, bis-coumarins (1-44) were synthesized and structurally characterized by different spectroscopic techniques. Eight derivatives 4, 8-10, 14, 17, 34, and 40 demonstrated urease inhibition in the range of IC50 = 4.4 ± 0.21–115.6 ± 2.13 μM, as compared to standard thiourea (IC50 = 21.3 ± 1.3 μM). Especially, compound 17 (IC50 = 4.4 ± 0.21 μM) was found to be five-fold more potent than the standard. Kinetic studies were also performed on compound 17 in order to identify the mechanism of inhibition. Kinetic studies revealed that compound 17 is a competitive inhibitor. Antiglycation activity was evaluated using glycation of bovine serum albumin by methylglyoxal in vitro. Compounds 2, 11-13, 16, 17, 19–22, 35, 37, and 42 showed good to moderate antiglycation activities with IC50 values of 333.63–919.72 μM, as compared to the standard rutin (IC50 = 294.46 ± 1.5 μM). Results of both assays showed that the compounds with urease inhibitory activity did not show any antiglycation potential, and vice versa. Only compound 17 showed dual inhibition potential. All compounds were also evaluated for cytotoxicity. Compounds 17, 19, and 37 showed a weak toxicity towards 3 T3 mouse fibroblast cell line. All other compounds were found to be non-cytotoxic. Urease inhibition is an approach to treat infections caused by ureolytic bacteria whereas inhibition of glycation of proteins is a strategy to avoid late diabetic complications. Therefore, these compounds may serve as leads for further research

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Febrile Neutropenia Risk Assesment and Granulocyte-Colony Stimulating Factor Support in Patients with Diffuse Large B Cell Lymphoma Receiving R-CHOP Regimens

Osteopontin (OPN), a multifunctional acidic glycoprotein, expressed by osteoblasts within the endosteal region of the bone marrow (BM) suppresses the proliferation of hemopoietic stem and progenitor cells and also regulates their lodgment within the BM after transplantation. Herein we demonstrate that OPN cleavage fragments are the most abundant forms of this protein within the BM. Studies aimed to determine how hemopoietic stem cells (HSCs) interact with OPN revealed for the first time that murine and human HSCs express \u3b19\u3b21 integrin. The N-terminal thrombin cleavage fragment of OPN through its binding to the \u3b19\u3b2 1 and \u3b14\u3b21 integrins plays a key role in the attraction, retention, regulation, and release of hemopoietic stem and progenitor cells to, in, and from their BM niche. Thrombin-cleaved OPN (trOPN) acts as a chemoattractant for stem and progenitor cells, mediating their migration in a manner that involves interaction with \u3b19\u3b2 1 and \u3b14\u3b21 integrins. In addition, in the absence of OPN, there is an increased number of white blood cells and, specifically, stem and progenitor cells in the peripheral circulation

Anemia and erythropoiesis-stimulating agent administration in patients with non-Hodgkin lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone ± rituximab chemotherapy: results from an observational study

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) ± rituximab [(± R)CHOP] is the current standard of care for aggressive non-Hodgkin lymphoma (NHL). Anemia resulting from chemotherapy can be treated with erythropoiesis-stimulating agents (ESAs). As part of the observational IMPACT NHL study, data were collected on ESA use and anemia-related outcomes in 1829 adults receiving (± R)CHOP-14 or (± R)CHOP-21. Overall, 33% of patients were anemic during chemotherapy. Older age, lower baseline hemoglobin (Hb), worse performance status, more advanced disease stage, and use of CHOP-14 were significant predictors of transfusion and anemia in logistic regression models. ESAs were received by 404 patients, usually in response to low or declining Hb levels. Most patients (65%) had Hb 9-11 g/dL at ESA initiation, and 89% (Kaplan-Meier percentage) achieved Hb 10-12 g/dL. In conclusion, two-thirds of anemic patients with NHL receiving (± R)CHOP initiated ESA treatment at Hb 9-11 g/dL, and most achieved target Hb levels (10-12 g/dL)

Synthesis, in vitro and in silico screening of 2-amino-4-aryl-6-(phenylthio) pyridine-3,5-dicarbonitriles as novel ? -glucosidase inhibitors

Inhibition of α-glucosidase enzyme is of prime importance for the treatment of diabetes mellitus (DM). Apart of many organic scaffolds, pyridine based compounds have previously been reported for wide range of bioactivities. The current study reports a series of pyridine based synthetic analogues for their α-glucosidase inhibitory potential assessed by in vitro, kinetics and in silico studies. For this purpose, 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles 1-28 were synthesized and subjected to in vitro screening. Several analogs, including 1-3, 7, 9, 11-14, and 16 showed many folds increased inhibitory potential in comparison to the standard acarbose (IC50 = 750 ± 10 µM). Interestingly, compound 7 (IC50 = 55.6 ± 0.3 µM) exhibited thirteen-folds greater inhibition strength than the standard acarbose. Kinetic studies on most potent molecule 7 revealed a competitive type inhibitory mechanism. In silico studies have been performed to examine the binding mode of ligand (compound 7) with the active site residues of α-glucosidase enzyme

Effects of Annealing on TiN Thin Film Growth by DC Magnetron Sputtering

We have reviewed the deposition of titanium nitride (TiN) thin films on stainless steel substrates by a DC magnetron sputtering method and annealing at different annealing temperatures of 500, 600, and 700°C for 120 min in nitrogen/argon atmospheres. Effects of annealing temperatures on the structural and the optical properties of TiN films were investigated using X-ray diffraction (XRD), atomic force microscope (AFM), field emission scanning electron microscopy (FESEM), and UV-VIS spectrophotometer. Our experimental studies reveal that the annealing temperature appreciably affected the structures, crystallite sizes, and reflection of the films. By increasing the annealing temperature to 700°C crystallinity and reflection of the film increase. These results suggest that annealed TiN films can be good candidate for tokamak first wall due to their structural and optical properties