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Cyclin-dependent kinase 9 (CDK9) is a transcription-associated protein involved in controlling the cell cycle and is often deregulated in stress conditions. CDK9 is being studied as a well-known druggable target for developing effective therapeutics against a wide range of cancer, cardiac dysfunction and inflammatory diseases. Owing to the significance of CDK9 in the etiology of hematological and solid malignancies, its structure, biological activity, regulation and its pharmacological inhibition are being explored for therapeutic management of cancer. We employed a structure-based virtual high-throughput screening of bioactive compounds from the IMPPAT database to discover potential bioactive inhibitors of CDK9. The preliminary results were obtained from the Lipinski criteria, ADMET parameters and sorting compounds without any PAINS patterns. Subsequently, binding affinity and selectivity analyses were used to find effective CDK9 hits. This screening resulted in the identification of two natural compounds, Glabrene and Guggulsterone with high affinity and specificity for the CDK9 binding site. Both compounds exhibit drug-like characteristics, as projected by ADMET analysis, physicochemical data and PASS evaluation. Both compounds preferentially bind to the ATP-binding pocket of CDK9 and interact with functionally important residues. Further, the dynamics and consistency of CDK9 interaction with Glabrene and Guggulsteron were evaluated through all-atom molecular dynamic (MD) simulations which suggested the stability of both complexes. The results might be deployed to introduce novel CDK9 inhibitors that may treat life-threatening diseases, including cancer.Communicated by Ramaswamy H. Sarma. more...

Huperzine A (HupA), an alkaloid found in the club moss

Shahd E Sharaf,1,2 Safaa Alsanosi,1 Abdullah R Alzahrani,1,2 Saeed S Al-Ghamdi,1,2 Sharaf E Sharaf,2– 4 Nahla Ayoub1,2 1Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; 2Saudi Toxicology Society, Umm Al-Qura University, Makkah, Saudi Arabia; 3Pharmaceutical Chemistry Department, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia; 4Clinical Research Administration, Executive Administration of Research and Innovation, King Abdullah Medical City in the Holy Capital, Makkah, Saudi ArabiaCorrespondence: Sharaf E SharafPharmaceutical Chemistry Department, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia, Tel +966532660411Email sesharaf@uqu.edu.saIntroduction: Bee venom acupuncture therapy (BVT) is an alternative therapy used worldwide by patients with different chronic diseases due to its therapeutic effects on conditions such as rheumatoid arthritis (RA). Previous studies have illustrated the clinical effects of BVT on RA, but such a study has yet to be performed in Saudi Arabia (SA). It is important to evaluate BVT awareness among citizens of SA to measure the feasibility of conducting clinical trials of BVT in patients with RA in SA. This study aims to measure the knowledge, attitude, and practice (KAP) of BVT on RA and other chronic diseases in SA. This will help determine whether patients with RA have sufficient knowledge to be enrolled in clinical trials.Patients and Methods: A cross-sectional study of 180 patients with RA in SA was conducted using a KAP questionnaire on BVT. Individuals completed an online questionnaire using the Survey Monkey website. Data were obtained by self-completion of the online KAP questionnaire regarding BVT.Results: A total of 180 patients with RA and other chronic diseases, with a mean age of 45 years (18– 70 years), participated in the study. The results of the questionnaire showed that 55% of the participants demonstrated a good knowledge of BVT treatment; however, they also reported a poor attitude (55%) and practice (55%). Participants with RA demonstrated higher severity of disease (80%) than those with other chronic diseases. Participants with RA showed better KAP responses towards BVT than those with other chronic diseases. Participants with school education only and those who were beekeepers demonstrated significantly better KAP responses (P < 0.05) compared to participants who had received university education and those who were not beekeepers, respectively.Conclusion: Participants with strong RA knowledge may prove that patients from SA can be enrolled in BVT clinical trials. The participants’ poor attitudes and practices may be due to BVT being expensive and unavailable in many cities in SA.Keywords: bee venom acupuncture therapy, rheumatoid arthritis, knowledge, attitude, practice, Saudi Arabia more...

Background: Diagnosed cases with hypertension (HT) are elevating worldwide and in Saudi Arabia (SA). HT self-management amid patients is important for controlling the disease and its complications. The aim of this study is to perform an HT KAP evaluation amid patients with HT in SA. Subjects and methods: This Cross-sectional study was performed between January and April 2021. An administered validated online survey was presented to the patients via the Survey Monkey website-link. Data collectors contacted possible patients in several sites comprising; hospitals, shopping malls, and leisure-centers. The associations amid categorical variables were assessed via the chi-square test application. The Pearson correlation coefficient (r) measured potential correlations between the patients’ KAP and outcome variables. Results: This study surveyed 410 patients with HT with mean systolic blood pressure (SBP) of 144.1 mmHg ± 15.4 and diastolic blood pressure (DBP) 90.2 mmHg ± 10.2, mean age 56 ± 11 years, range 18–80 years. Generally, 73% of patients showed good HT knowledge and 78% showed good HT attitude, whereas 77% revealed poor HT practice. Significant positive linear correlations were found amid attitude versus (with) knowledge (r= 0.40, P more...

Introduction: Obesity is a chronic disease that is increasing in Saudi Arabia (SA) and globally. Obesity self-management among individuals is essential for managing obesity and its complications. This study aimed to conduct an obesity knowledge, attitude, and practice (KAP) assessment and prevalence of used pharmaceutical anti-obesity medications among individuals with obesity in SA. Subjects and methods: This cross-sectional study was conducted between January and April 2021. The participants completed a validated online administered questionnaire using the Survey Monkey website. Potential participants were approached in governmental hospitals, leisure centers, and shopping malls. The chi-square test was used to assess associations between categorical variables. In addition, correlations between the participants' KAP and outcome variables were measured using the Pearson correlation coefficient (r). Results: In all, 410 obese individuals (mean age 40±14 years, range 18–80 years) were surveyed. Overall, 68% of participants reported good obesity knowledge, and 63% reported a good attitude, while 72% reported poor practice. In addition, there were significant positive linear correlations between knowledge and attitude (r=0.44, P more...

Death-associated protein kinase 3 (DAPK3) is a serine/threonine protein kinase that regulates apoptosis, autophagy, transcription, and actin cytoskeleton reorganization. DAPK3 induces morphological alterations in apoptosis when overexpressed, and it is considered a potential drug target in antihypertensive and anticancer drug development. In this article, we report new findings from a structure-guided virtual screening for discovery of phytochemicals that could modulate the elevated expression of DAPK3, and with an eye to anticancer drug discovery. We used the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT), a curated database, as part of the methodology. The potential initial hits were identified based on their physicochemical properties and binding affinity toward DAPK3. Subsequently, various filters for drug likeness followed by interaction analysis and molecular dynamics (MD) simulations for 100 nsec were performed to explore the conformational sampling and stability of DAPK3 with the candidate molecules. Notably, the data from all-atom MD simulations and principal component analysis suggested that DAPK3 forms stable complexes with ketanserin and rotenone. In conclusion, this study supports the idea that ketanserin and rotenone bind to DAPK3, and show stability, which can be further explored as promising scaffolds in drug development and therapeutics innovation in clinical contexts such as hypertension and various types of cancer. more...

Neuronal damage in iron-sensitive brain regions occurs as a result of iron dyshomeostasis. Increased iron levels and iron-related pathogenic triggers are associated with neurodegenerative diseases, including Alzheimer’s disease (AD). Ferritin is a key player involved in iron homeostasis. Major pathological hallmarks of AD are amyloid plaques, neurofibrillary tangles (NFTs) and synaptic loss that lead to cognitive dysfunction and memory loss. Natural compounds persist in being the most excellent molecules in the area of drug discovery because of their different range of therapeutic applications. Bryostatins are naturally occurring macrocyclic lactones that can be implicated in AD therapeutics. Among them, Bryostatin 1 regulates protein kinase C, a crucial player in AD pathophysiology, thus highlighting the importance of bryostatin 1 in AD management. Thus, this study explores the binding mechanism of Bryotstain 1 with ferritin. In this work, the molecular docking calculations revealed that bryostatin 1 has an appreciable binding potential towards ferritin by forming stable hydrogen bonds (H-bonds). Molecular dynamics simulation studies deciphered the binding mechanism and conformational dynamics of ferrritin–bryostatin 1 system. The analyses of root mean square deviation, root mean square fluctuations, Rg, solvent accessible surface area, H-bonds and principal component analysis revealed the stability of the ferritin–bryostatin 1 docked complex throughout the trajectory of 100 ns. Moreover, the free energy landscape analysis advocated that the ferritin–bryostatin 1 complex stabilized to the global minimum. Altogether, the present work delineated the binding of bryostatin 1 with ferritin that can be implicated in the management of AD. Communicated by Ramaswamy H. Sarma more...

Nonalcoholic fatty liver disease (NAFLD) is characterized by low-circulating concentration of high-density lipoprotein cholesterol (HDL-C) and raised triacylglycerol (TAG). Exercise reduces hepatic fat content, improves insulin resistance and increases clearance of very-low-density lipoprotein-1 (VLDL1). However, the effect of exercise on TAG and HDL-C metabolism is unknown. We randomized male participants to 16 wk of supervised, moderate-intensity aerobic exercise ( n = 15), or conventional lifestyle advice ( n = 12). Apolipoprotein A-I (apoA-I) and VLDL-TAG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes (1-[13C]-leucine and 1,1,2,3,3-2H5 glycerol) pre- and postintervention. Participants underwent MRI/spectroscopy to assess changes in visceral fat. Results are means ± SD. At baseline, there were no differences between exercise and control groups for age (52.4 ± 7.5 vs. 52.8 ± 10.3 yr), body mass index (BMI: 31.6 ± 3.2 vs. 31.7 ± 3.6 kg/m2), and waist circumference (109.3 ± 7.5 vs. 110.0 ± 13.6 cm). Percentage of liver fat was 23.8 (interquartile range 9.8–32.5%). Exercise reduced body weight (101.3 ± 10.2 to 97.9 ± 12.2 kg; P < 0.001) and hepatic fat content [from 19.6%, interquartile range (IQR) 14.6–36.1% to 8.9% (4.4–17.8%); P = 0.001] and increased the fraction HDL-C concentration (measured following ultracentrifugation) and apoA-I pool size with no change in the control group. However, plasma and VLDL1-TAG concentrations and HDL-apoA-I fractional catabolic rate (FCR) and production rate (PR) did not change significantly with exercise. Both at baseline (all participants) and after exercise there was an inverse correlation between apoA-I pool size and VLDL-TAG and -apoB pool size. The modest effect of exercise on HDL metabolism may be explained by the lack of effect on plasma and VLDL1-TAG. more...

Context Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear. Objective To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes. Design Randomized, double-blind, cross-over study. Setting Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Patients Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)]. Interventions Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies. Main Outcome Measures Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion. Results Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60–480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0–240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0–360min (P = 0.006) were lower with lixisenatide than with placebo. Conclusions Lixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance., Using stable isotopes, lixisenatide acutely slowed gastric emptying, lowering postprandial TAG levels. A more prolonged effect of reduced chylomicron TAG was from increased clearance. more...