Anticancer screening of medicinal plant phytochemicals against Cyclin-Dependent Kinase-2 (CDK2): An in-silico approach

Background: Cyclin-Dependent Kinase-2 (CDK2) is a member of serine/threonine protein kinases family and plays an important role in regulation of various eukaryotic cell division events. Over-expression of CDK2 during cell cycle may lead to several cellular functional aberrations including diverse types of cancers (lung cancer, primary colorectal carcinoma, ovarian cancer, melanoma and pancreatic carcinoma) in humans. Medicinal plants phytochemicals which have anticancer potential can be used as an alternative drug resource.Methods: This study was designed to find out anticancer phytochemicals from medicinal plants which could inhibit CDK2 with the help of molecular docking technique. Molecular Operating Environment (MOE v2009) software was used to dock 2300 phytochemicals in this study.Results: The outcome of this study shows that four phytochemicals Kushenol T, Remangiflavanone B, Neocalyxins A and Elenoside showed the lowest S-score (-17.83, -17.57, -17.26, -17.17 respectively) and binds strongly with all eight active residues Tyr15, Lys33, Ileu52, Lys56, Leu78, phe80, Asp145 and Phe146 of CDK2 binding site. These phytochemicals could successfully inhibit the CDK2.Conclusion: These phytochemicals can be considered as potential anticancer agents and used in drug development against CDK2. We anticipate that this study would pave way for phytochemical based novel small molecules as more efficacious and selective anti-cancer therapeutic compounds

Insights into the mechanisms of arsenic-selenium interactions and the associated toxicity in plants, animals, and humans: a critical review

This review highlights arsenic (As) and selenium (Se) sources in the environment, their uptake in the soil-plant system, interactions between these metals and the associated toxicity in major biological compartments, which may assist in addressing the hazardous impacts associated with As and Se contamination. The interaction between As and Se is a critical factor for a detailed systematic understanding of the transportation, environmental fate, and associated toxicological effects of these metalloids in plants, animals, and humans. Arsenic and Se induce cytotoxicity and genotoxicity through the generation of reactive oxygen species (ROS). Compared to arsenite (AsIII), methylated arsenicals, including methylarsonous acid (MAsIII) and dimethylarsinous acids (DMAsIII), exhibit more cytotoxic and genotoxic potential to inhibit more potent enzymes and activate the protein AP˗1, which is a critical marker of genetic stability. Methylated AsIII and its associated metabolites are well-known potential carcinogens that induce toxicity by blocking Se metabolism pathway. The imbalance of Se compounds can lead to the generation of ROS, which can inhibit or decrease genomic stability. The As and Se nexus also affect cellular signaling through activation of transcription factors such as NFκB and AP-1

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

A Review on the Status of Mercury Pollution in Pakistan: Sources and Impacts

Mercury (Hg) contamination in environmental matrices and associated human exposure has been recognized as a critical long-lasting issue worldwide. However, studies are still elusive that summarized the overall status of Hg pollution and its impacts on public health in Pakistan. Hence, this review encompasses the environmental prevalence, potential sources, and human exposure tendencies to Hg contamination in Pakistan. Reviewed literature revealed jolting levels of Hg in various environmental samples, such as dust, soil, water, and air collected from the residential and industrial areas. Inhalation of Hg via dust particle was identified as the primary pathway for human exposure, while atmospheric deposition and gold mining are identified as the two primary sources of Hg contamination in the environment. Considering human exposure, the highest bioaccumulation of Hg was ranged from 5885 to 8698 mu g/kg in hair samples collected from the residents of the Kashmir Valley, Pakistan. However, in the lower Himalayan regions, including Islamabad and Swabi, the concentration of Hg in hair samples was reported at 1085 mu g/kg, slightly beyond WHO devised reference dose (RfD) of Hg (1000 mu g/kg). This review revealed the worst scenario of Hg contamination in human biomatrices and environmental compartments in Pakistan, which needed immediate rehabilitation measures

Elucidating various geochemical mechanisms drive fluoride contamination in unconfined aquifers along the major rivers in Sindh and Punjab, Pakistan

The present study aims to investigate the spatial distribution and associated various geochemical mechanisms responsible for fluoride (F-) contamination in groundwater of unconfined aquifer system along major rivers in Sindh and Punjab, Pakistan. The concentration of F (-) in groundwater samples ranged from 0.1 to 3.9 mg/L (mean = 1.0 mg/L) in Sindh and 0.1-10.3 mg/L (mean = 1.0 mg/L) in Punjab, respectively with 28.9% and 26.6% of samples exhibited F- contamination beyond WHO permissible limit value (1.5 mg/L). The geochemical processes regulated F- concentration in unconfined aquifer mainly in Sindh and Punjab were categorized as follows: 1) minerals weathering that observed as the key process to control groundwater chemistry in the study areas, 2) the strong correlation between F- and alkaline pH, which provided favorable environmental conditions to promote F- leaching through desperation or by ion exchange process, 3) the 72.6% of samples from Sindh and Punjab were dominated by Na+- Cl- type of water, confirmed that the halite dissolution process was the major contributor for F- enrichment in groundwater, 4) dolomite dissolution was main process frequently observed in Sindh, compared with Punjab, 5) the arid climatic conditions promote evaporation process or dissolution of evaporites or both were contributing to the formation of saline groundwater in the study area, 6) the positive correlation observed between elevated F- and fluorite also suggested that the fluorite dissolution also played significant role for leaching of F- in groundwater from sediments, and 7) calcite controlled Ca2+ level and enhanced the dissolution of F-bearing minerals and drive F- concentration in groundwater. In a nut shell, this study revealed the worst scenarios of F- contamination via various possible geochemical mechanisms in groundwater along major rivers in Sindh and Punjab, Pakistan, which need immediate attention of regulatory authorities to avoid future hazardous implications. (C) 2019 Elsevier Ltd. All rights reserved

Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population

Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

BackgroundTranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding.MethodsWe did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.FindingsBetween July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).InterpretationWe found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial.</div