Docking and QSAR Studies of Camptothecin Derivatives as Inhibitor of DNA Topoisomerase-I

Camptothecin (CPT) is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme Topoisomerase-I (Topo-I) and has shown remarkable anticancer activity in preliminary clinical trials. The major limitation is its low solubility and high adverse reaction. In the studied work, we performed molecular docking of CPT derivatives against Topo-I and developed the quantitative structure activity relationship (QSAR) model for anticancer activity screening. For QSAR, we used CPT and other anticancer drugs with its IC50 values. We used a total of forty seven anticancer drugs as training set and eight compounds as test set and thirty derivatives of CPT as query set. Total of fifty two chemical descriptors were used for the quantitative data calculation. Only four showed good correlation with the experimental activity. Forward feed regression method was used for development of multiple linear regression (MLR) QSAR model. Model showed acceptable regression coefficient (r2) 0.89 (i.e., 89% of correlation) and cross validation coefficient (rCV2) 0.86 (i.e., 86 % of prediction accuracy). After drug likeness test, ten compounds namely, MSB3a, MSB3b, MSB19, MSB22L, MSB22M, MSB22O, MSB22R, MSB25D, MSB37G and MSB39D, showed promising predicted anticancer activity and drug likeness properties. Out of ten, only six compounds namely, MSB19, MSB22L, MSBM, MSB22O, MSB22R and MSB37D indicate two times more activity than the parent CPT compound. In molecular docking studies, all the identified active CPT derivatives showed high binding affinity with Topo-I. QSAR study indicates that connectivity index, electron affinity, mol.wt. & ether group count highly contribute to inhibitory activity of CPT derivatives. These results can offer useful references for directing the molecular design of Topo-I inhibitor with improved anticancer activity.
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Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P \u3c 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 μM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ−4.7 mmHg and Δ−8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P \u3e 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD

MMP9 mediates acute hyperglycemia-induced human cardiac stem cell death by upregulating apoptosis and pyroptosis in vitro

Providing a conducive microenvironment is critical to increase survival of transplanted stem cells in regenerative therapy. Hyperglycemia promotes stem cell death impairing cardiac regeneration in the diabetic heart. Understanding the molecular mechanisms of high glucose-induced stem cell death is important for improving cardiac regeneration in diabetic patients. Matrix metalloproteinase-9 (MMP9), a collagenase, is upregulated in the diabetic heart, and ablation of MMP9 decreases infarct size in the non-diabetic myocardial infarction heart. In the present study, we aim to investigate whether MMP9 is a mediator of hyperglycemia-induced cell death in human cardiac stem cells (hCSCs) in vitro. We created MMP9−/− hCSCs to test the hypothesis that MMP9 mediates hyperglycemia-induced oxidative stress and cell death via apoptosis and pyroptosis in hCSCs, which is attenuated by the lack of MMP9. We found that hyperglycemia induced oxidative stress and increased cell death by promoting pyroptosis and apoptosis in hCSCs, which was prevented in MMP9−/− hCSCs. These findings revealed a novel intracellular role of MMP9 in mediating stem cell death and provide a platform to assess whether MMP9 inhibition could improve hCSCs survival in stem cell therapy at least in acute hyperglycemic microenvironment

Effects of passive and active leg movements to interrupt sitting in mild hypercapnia on cardiovascular function in healthy adults

Prolonged sitting in a mild hypercapnic environment impairs peripheral vascular function. The effects of sitting interruptions using passive or active skeletal muscle contractions are still unclear. Therefore, we sought to examine the vascular effects of brief periods (2 min every half hour) of passive and active lower limb movement to interrupt prolonged sitting with mild hypercapnia in adults. Fourteen healthy adults (24 ± 2 yr) participated in three experimental visits sitting for 2.5 h in a mild hypercapnic environment (CO2 = 1,500 ppm): control (CON, no limb movement), passive lower limb movement (PASS), and active lower limb movement (ACT) during sitting. At all visits, brachial and popliteal artery flow-mediated dilation (FMD), microvascular function, plasmatic levels of nitrate/nitrite and endothelin-1, and heart rate variability were assessed before and after sitting. Brachial and popliteal artery FMDs were reduced in CON and PASS (P \u3c 0.05) but were preserved (P \u3e 0.05) in ACT. Microvascular function was blunted in CON (P \u3c 0.05) but was preserved in PASS and ACT (P \u3e 0.05). In addition, total plasma nitrate/nitrite was preserved in ACT (P \u3e 0.05) but was reduced in CON and PASS (P \u3c 0.05), and endothelin-1 levels were decreased in ACT (P \u3c 0.05). Both passive and active movement induced a greater ratio between the low-frequency and high-frequency bands for heart rate variability (P \u3c 0.05). For the first time, to our knowledge, we found that brief periods of passive leg movement can preserve microvascular function, but that an intervention that elicits larger increases in shear rate, such as low-intensity exercise, is required to fully protect both macrovascular and microvascular function and circulating vasoactive substance balance

Reduced regional brain cortical thickness in patients with heart failure.

AimsAutonomic, cognitive, and neuropsychologic deficits appear in heart failure (HF) subjects, and these compromised functions depend on cerebral cortex integrity in addition to that of subcortical and brainstem sites. Impaired autoregulation, low cardiac output, sleep-disordered-breathing, hypertension, and diabetic conditions in HF offer considerable potential to affect cortical areas by loss of neurons and glia, which would be expressed as reduced cortical thicknesses. However, except for gross descriptions of cortical volume loss/injury, regional cortical thickness integrity in HF is unknown. Our goal was to assess regional cortical thicknesses across the brain in HF, compared to control subjects.Methods and resultsWe examined localized cortical thicknesses in 35 HF and 61 control subjects with high-resolution T1-weighted images (3.0-Tesla MRI) using FreeSurfer software, and assessed group differences with analysis-of-covariance (covariates; age, gender; p<0.05; FDR). Significantly-reduced cortical thicknesses appeared in HF over controls in multiple areas, including the frontal, parietal, temporal, and occipital lobes, more markedly on the left side, within areas that control autonomic, cognitive, affective, language, and visual functions.ConclusionHeart failure subjects show reduced regional cortical thicknesses in sites that control autonomic, cognitive, affective, language, and visual functions that are deficient in the condition. The findings suggest chronic tissue alterations, with regional changes reflecting loss of neurons and glia, and presumably are related to earlier-described axonal changes. The pathological mechanisms contributing to reduced cortical thicknesses likely include hypoxia/ischemia, accompanying impaired cerebral perfusion from reduced cardiac output and sleep-disordered-breathing and other comorbidities in HF

Combined anthocyanins and bromelain supplement improves endothelial function and skeletal muscle oxygenation status in adults: a double-blind placebo-controlled randomised crossover clinical trial

Anthocyanins and bromelain have gained significant attention due to their antioxidative and anti-inflammatory properties. Both have been shown to improve endothelial function, blood pressure (BP) and oxygen utility capacity in humans; however, the combination of these two and the impacts on endothelial function, BP, total antioxidant capacity (TAC) and oxygen utility capacity have not been previously investigated. The purpose of this study was to investigate the impacts of a combined anthocyanins and bromelain supplement (BE) on endothelial function, BP, TAC, oxygen utility capacity and fatigability in healthy adults. Healthy adults (n 18, age 24 (SD 4) years) received BE or placebo in a randomised crossover design. Brachial artery flow-mediated dilation (FMD), BP, TAC, resting heart rate, oxygen utility capacity and fatigability were measured pre- and post-BE and placebo intake. The BE group showed significantly increased FMD, reduced systolic BP and improved oxygen utility capacity compared with the placebo group (P \u3c 0·05). Tissue saturation and oxygenated Hb significantly increased following BE intake, while deoxygenated Hb significantly decreased (P \u3c 0·05) during exercise. Additionally, TAC was significantly increased following BE intake (P \u3c 0·05). There were no significant differences for resting heart rate, diastolic BP or fatigability index. These results suggest that BE intake is an effective nutritional therapy for improving endothelial function, BP, TAC and oxygen utility capacity, which may be beneficial to support vascular health in humans