Combined Effect of Omega-3 Fatty Acid and Vitamin D 3 on Oxidized LDL-C and Non-HDL-C Levels in People With Vitamin D Deficiency: A Randomized Controlled Trial.

ABSTRACT: The present randomized clinical trial (RCT) was conducted on Jordanian participants with vitamin D deficiency (VDD) with no other medical conditions, to evaluate the combined effect of 1,25-dihydroxy vitamin D 3 (Vit.D 3 ) and omega-3 fatty acid (n-3FA) supplements (D+) on oxidized low-density lipoprotein (Ox-LDL) and non-high-density lipoprotein cholesterol (non-HDL-C) levels as common predictors of cardiovascular diseases (CVDs). Participants were randomized into 4 groups as follows: a control group (C) that received no supplementations, a Vit.D 3 group that received 50,000 IU of Vit.D 3 every week, an n-3FA group that received 300 mg of omega-3 fatty acid every day, and a D+ group that received a combination of both supplements, with the same dosage administered by the previous groups but with a 4-6-hour time interval between Vit.D 3 and n-3FA administration to avoid any possible interaction. All supplementations were administered orally for 8 weeks. Forty-seven participants were allocated to each group. Twenty-six in the control group, 37 participants in the Vit.D 3 group, 37 participants in the n-3FA group, and 46 participants in the D+ group completed the study to the end. The D+ supplementations significantly increased non-HDL-C (118.99 ± 60.98 to 155.26 ± 43.36 mg/dL, P << 0.05) but decreased Ox-LDL-C levels (69.29 ± 37.69 to 52.81 ± 17.30 pg/mL, P = 0.03). The stepwise regression showed that the serum LDL-C level was the main independent variable involved in the elevation of non-HDL levels (R 2 = 0.837) observed at the end of the trial in the D+ group. The groups that were supplemented with either Vit.D 3 alone or n-3FA alone had an insignificant decrease in the level of Ox-LDL-C. In conclusion, despite the observed hyperlipidemic effect, the combination treatment is recommended by the research team because the decrease in Ox-LDL may offset the hyperlipidemic effect.

In Vitro and In Vivo Evaluation of Casein as a Drug Carrier for Enzymatically Triggered Dissolution Enhancement from Solid Dispersions.

Due to its unique properties, such as biodegradability, biocompatibility, high amphiphilic property, and micelle formation, casein (CS) has been increasingly studied for drug delivery. We used CS as a drug carrier in solid dispersions (SDs) and evaluated the effect of its degradation by trypsin on drug dissolution from the dispersions. SDs of CS and mefenamic acid (MA) were prepared by physical mixing, kneading, and coprecipitation methods. In comparison to pure MA, the dispersions were evaluated for drug-protein interaction, loss of drug crystalinity, and drug morphology by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Drug dissolution from the dispersions was evaluated in simulated intestinal fluid as enzyme free and trypsin-enriched media. Furthermore, in vivo drug absorption of MA from CS-MA coprecipitate was evaluated in rats, in comparison with a reference SD of polyethylene glycol and MA (PEG-MA SD). Relative to other CS preparations, CS-MA coprecipitate showed the highest loss of drug crystallinity, drug micronization, and CS-MA interaction. CS remarkably enhanced the dissolution rate and extent of MA from the physical and kneaded mixtures. However, the highest dissolution enhancement was obtained when MA was coprecipitated with CS. Trypsin that can hydrolyze CS during dissolution resulted in further enhancement of MA dissolution from the physical and kneaded mixtures. However, a corresponding retardation effect was obtained for the coprecipitate. In correlation with in vitro drug release, CS-MA coprecipitate also showed significantly higher MA bioavailability in rats than PEG-MA SD.

Identification of novel inhibitors for Pim-1 kinase using pharmacophore modeling based on a novel method for selecting pharmacophore generation subsets.

Targeting Proviral integration-site of murine Moloney leukemia virus 1 kinase, hereafter called Pim-1 kinase, is a promising strategy for treating different kinds of human cancer. Headed for this a total list of 328 formerly reported Pim-1 kinase inhibitors has been explored and divided based on the pharmacophoric features of the most active molecules into 10 subsets projected to represent potential active binding manners accessible to ligands within the binding pocket of Pim-1 kinase. Discovery Studio 4.1 (DS 4.1) was employed to detect potential pharmacophoric active binding manners anticipated by Pim-1 Kinase inhibitors. The pharmacophoric models were then allowed to compete within Quantitative Structure Activity Relationship (QSAR) framework with other 2D descriptors. Accordingly Genetic algorithm and multiple linear regression investigation were engaged to find the finest QSAR equation that has the best predictive power r262(2) = 0.70, F = 119.14, rLOO(2) = 0.693, rPRESS(2) against 66 external test inhibitors = 0.71 q(2) = 0.55. Three different pharmacophores appeared in the successful QSAR equation this represents three different binding modes for inhibitors within the Pim-1 kinase binding pocket. Pharmacophoric models were later used to screen compounds within the National Cancer Institute database. Several low micromolar Pim-1 Kinase inhibitors were captured. The most potent hits show IC50 values of 0.77 and 1.03 µM. Also, upon analyzing the successful QSAR Equation we found that some polycyclic aromatic electron-rich structures namely 6-Chloro-2-methoxy-acridine can be considered as putative hits for Pim-1 kinase inhibition.

Combining docking-based comparative intermolecular contacts analysis and k-nearest neighbor correlation for the discovery of new check point kinase 1 inhibitors.

Check point kinase 1 (Chk1) is an important protein in G2 phase checkpoint arrest required by cancer cells to maintain cell cycle and to prevent cell death. Therefore, Chk1 inhibitors should have potential as anti-cancer therapeutics. Docking-based comparative intermolecular contacts analysis (dbCICA) is a new three-dimensional quantitative structure activity relationship method that depends on the quality and number of contact points between docked ligands and binding pocket amino acid residues. In this presented work we implemented a novel combination of k-nearest neighbor/genetic function algorithm modeling coupled with dbCICA to select critical ligand-Chk1 contacts capable of explaining anti-Chk1 bioactivity among a long list of inhibitors. The finest set of contacts were translated into two valid pharmacophore hypotheses that were used as 3D search queries to screen the National Cancer Institute's structural database for new Chk1 inhibitors. Three potent Chk1 inhibitors were discovered with IC50 values ranging from 2.4 to 69.7 µM.

The use of docking-based comparative intermolecular contacts analysis to identify optimal docking conditions within glucokinase and to discover of new GK activators.

Glucokinase (GK) is involved in normal glucose homeostasis and therefore it is a valid target for drug design and discovery efforts. GK activators (GKAs) have excellent potential as treatments of hyperglycemia and diabetes. The combined recent interest in GKAs, together with docking limitations and shortages of docking validation methods prompted us to use our new 3D-QSAR analysis, namely, docking-based comparative intermolecular contacts analysis (dbCICA), to validate docking configurations performed on a group of GKAs within GK binding site. dbCICA assesses the consistency of docking by assessing the correlation between ligands' affinities and their contacts with binding site spots. Optimal dbCICA models were validated by receiver operating characteristic curve analysis and comparative molecular field analysis. dbCICA models were also converted into valid pharmacophores that were used as search queries to mine 3D structural databases for new GKAs. The search yielded several potent bioactivators that experimentally increased GK bioactivity up to 7.5-folds at 10 µM.

Preparation and in vitro characterization of glibenclamide-loaded alginate hexyl-amide beads: a novel drug delivery system to improve the dissolution rate.

OBJECTIVE: This investigation aimed to synthesize amphiphilic hexyl amidic derivative of alginate to be used in the preparation of glibenclamide-loaded release system of improved dissolution rate. MATERIALS AND METHODS: Hexyl amine was associated to the activated carboxylic acid moieties of alginate to synthesize alginate hexyl amide polymer (AHAP). This polymer in comparison to alginate was used in different concentrations for preparing beads containing glibenclamide by an ionic gelation using Ca(++) as gelling ion. The prepared beads were characterized by DSC, FTIR and scanning electron microscope. The swelling behavior, drug loading capacity and release behavior were studied. RESULTS AND DISCUSSION: The results showed that the prepared AHAP beads were smaller in size and more spherical. The surface was highly corrugated with much and wider pore size. The beads showed a high drug loading capacity and efficacy that was affected by the polymer concentration. The drug release rate from AHAP beads reached 100% after 4, 8 and 12 hours in comparison to 75.3%, 73.2% and 69.2% from alginate beads at 3%, 2% and 1% polymer concentrations, respectively. CONCLUSION: It can thus be concluded that the amphiphilic AHAP-based bead is a simple and efficient delivery system of promising industrial significance for the improvement of the dissolution rate.

Elaborate ligand-based modeling coupled with QSAR analysis and in silico screening reveal new potent acetylcholinesterase inhibitors.

Inhibition of the enzyme acetylcholinesterase (AChE) has been shown to alleviate neurodegenerative diseases prompting several attempts to discover and optimize new AChE inhibitors. In this direction, we explored the pharmacophoric space of 85 AChE inhibitors to identify high quality pharmacophores. Subsequently, we implemented genetic algorithm-based quantitative structure-activity relationship (QSAR) modeling to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation among training compounds (r2(68)=0.94, F-statistic=125.8, r2 LOO=0.92, r2 PRESS against 17 external test inhibitors = 0.84). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within AChE binding pocket. The successful pharmacophores were comparable with crystallographically resolved AChE binding pocket. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute list of compounds. Twenty-four low micromolar AChE inhibitors were identified. The most potent gave IC50 value of 1.0 µM.

Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and In Vitro Validation as New CETP Inhibitors.

BACKGROUND: Hyperlipidemia, a cardiovascular disease risk factor, is characterized by a rise in low-density lipoprotein (LDL), triglycerides and total cholesterol, and a decrease in high-density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) enables the transfer of cholesteryl ester from HDL to LDL and very low-density lipoprotein. OBJECTIVE: CETP inhibition is a promising approach to prevent and treat cardiovascular diseases. By inhibiting lipid transport activity, it increases HDL levels and decreases LDL levels. METHOD: Herein, diaryl sulfonamides 6a-6g and 7a-7g were prepared, and the structure of these compounds was fully determined using different spectroscopic techniques. RESULTS: These compounds underwent biological evaluation in vitro and showed different inhibitory activities against CETP; 100% inhibitory activity was observed for compounds 7a-7g, while activities of compounds 6a-6g ranged up to 42.6% at 10 µM concentration. Pharmacophore mapping agreed with the bioassay results where the four aromatic ring compounds 7a-7g possessed higher fit values against Hypo4/8 and the shape-complemented Hypo4/8 in comparison to compounds 6a-6g. CONCLUSION: Docking of the synthesized compounds using libdock and ligandfit engines revealed that compounds 7a-7g formed п-п stacking and hydrophobic interactions with the binding pocket, while compounds 6a-6g missed these hydrophobic interactions with amino acids Leu206, Phe265, and Phe263.

The effect of omega-3 supplements on the serum levels of ACE/ACE2 ratio as a potential key in cardiovascular disease: A randomized clinical trial in participants with vitamin D deficiency.

Objective: The aim of this randomized controlled clinical trial was to determine the effect of the omega-3 fatty acid supplementations 300 mg per day for 8 weeks on the serum levels of ACE/ACE2 ratio in Jordanian participants with vitamin D deficiency (VDD). Methods: The physical and clinical characteristic of individuals in both intervention and control randomized controlled clinical trial were measured and analyzed. The comparisons between the two groups and the changes in each group before and after taking omega-3 doses were studied through independent t test and paired t test, respectively. Possible factors that have a role in the changes were determined by multivariate stepwise regression. Follow-up period lasted 10 weeks. Results: The sample consisted of 82 participants with VDD and a mean age of 37.85 ± 9.85 years. Omega-3 Supplements resulted in a significant decrease in serum ACE levels, ACE/ACE2 ratio and serum 25-hydroxy vitamin D (25OHD). While the change in serum ACE2 levels and serum triglycerides levels were insignificant. Also, a significant increase in serum LDL levels were observed. Conclusion: It is possible that taking high doses of omega-3 fatty acid supplementations have positive effects on the heart and circulatory system and could protect from COVID-19 or decrease disease severity, in connection with a decrease in the ACE/ACE 2 ratio. On the other hand, omega-3 supplement may have negative effect on cardiovascular system due to the significant increase in serum LDL levels.

The Effect of Weekly 50,000 IU Vitamin D3 Supplements on the Serum Levels of Selected Cytokines Involved in Cytokine Storm: A Randomized Clinical Trial in Adults with Vitamin D Deficiency.

This research aimed to evaluate the effects of high-dose cholecalciferol (VD3) supplements (50,000 IU/week) on selected circulating cytokines associated with cytokine storms in adults with vitamin D deficiency. This clinical trial, based in Jordan, included 50 participants receiving vitamin D3 supplements (50,000 IU/week) for 8 weeks; the exact number was assigned to the control group. Interleukin-6 (IL-6), interleukin-1ß (IL-1ß), interleukin-10 (IL-10), tumor necrotic factor-α (TNF-α), and leptin were measured in serum at baseline and 10 weeks (wash out: 2 weeks). Our results revealed that vitamin D3 supplementation significantly increased the serum levels of 25OHD, IL-6, IL-10, IL-1ß, and leptin compared with baseline. In contrast, the serum level of TNF-α insignificantly increased in the group receiving vitamin D3 supplementation. Although the observations of this trial may refer to a potential negative effect of VD3 supplementation during cytokine storms, further trials are required to clarify the potential benefits of VD3 supplement during cytokine storms.

The association of coffee consumption rate with serum 25-hydroxyvitamin D, non-HDL levels, and TC/HDL ratio in females with vitamin D deficiency.

OBJECTIVES: The purpose of this study was to evaluate the association of coffee consumption rate with serum 25-hydroxyvitamin D, non-high-density lipoprotein cholesterol levels, and total cholesterol to high-density lipoprotein cholesterol ratio in females with vitamin D deficiency. METHODS: This retrospective cross-sectional study was carried out by studying the records of 270 Jordanian females aged 18-65 years with varying degrees of vitamin D deficiency. Following completion of the questionnaire regarding their anthropometric characteristics and coffee consumption rate during the preceding 3 months, the participants were required to provide blood samples for analysis to measure 25-hydroxyvitamin D and lipid profile levels including non-high-density lipoprotein cholesterol and total cholesterol to high-density lipoprotein cholesterol ratio. RESULTS: The current study demonstrated that coffee consumption rate and vitamin D deficiency were significantly positively connected with the total cholesterol to high-density lipoprotein cholesterol ratio (p = .003) in women with vitamin D deficiency. In addition, vitamin D deficiency alone correlated positively with non-high-density lipoprotein cholesterol levels and the total cholesterol to high-density lipoprotein cholesterol ratio (p = .010) and (p = .002), respectively. CONCLUSION: Higher coffee consumption rate among women with vitamin D deficiency significantly elevated total cholesterol to high-density lipoprotein cholesterol ratio that may increase woman's risk of hyperlipidemia.

Docking-based comparative intermolecular contacts analysis as new 3-D QSAR concept for validating docking studies and in silico screening: NMT and GP inhibitors as case studies.

The significant role played by docking algorithms in drug discovery combined with their serious pitfalls prompted us to envisage a novel concept for validating docking solutions, namely, docking-based comparative intermolecular contacts analysis (dbCICA). This novel approach is based on the number and quality of contacts between docked ligands and amino acid residues within the binding pocket. It assesses a particular docking configuration on the basis of its ability to align a set of ligands within a corresponding binding pocket in such a way that potent ligands come into contact with binding site spots distinct from those approached by low-affinity ligands and vice versa. In other words, dbCICA evaluates the consistency of docking by assessing the correlation between ligands' affinities and their contacts with binding site spots. Optimal dbCICA models can be translated into valid pharmacophore models that can be used as 3-D search queries to mine structural databases for new bioactive compounds. dbCICA was implemented to search for new inhibitors of candida N-myristoyl transferase as potential antifungal agents and glycogen phosphorylase (GP) inhibitors as potential antidiabetic agents. The process culminated in five selective micromolar antifungal leads and nine GP inhibitory leads.

Ligand-based modelling followed by synthetic exploration unveil novel glycogen phosphorylase inhibitory leads.

Glycogen phosphorylase (GP) is a valid anti-diabetic target. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory GP leads via combining pharmacophore modeling, QSAR analysis and in silico screening, followed by synthetic exploration of active hits. Virtual screening identified six low micromolar inhibitory leads from the National Cancer Institute (NCI) list of compounds. The most potent hits exhibited anti-GP IC(50) values of 3.2 and 4.1 µM. Synthetic exploration of hit 59 (IC(50)=4.1 µM) yielded 25 lead inhibitors with the best illustrating IC(50) of 3.0 µM. Interestingly, we prepared several novel mixed oxalyl amide anti-GP leads employing new chemical reaction involving succinic acid-based adducts.

The Effect of Omega-3 Supplements on The Serum Levels Of ACE/ACE2 Ratio As A Potential Key in Cardiovascular Disease: A Randomized Clinical Trial in Participants with Vitamin D Deficiency

Objective: The aim of this randomized controlled clinical trial was to determine the effect of the omega-3 fatty acid supplementations 300 mg per day for 8 weeks on the serum levels of ACE/ACE2 ratio in Jordanian participants with vitamin D deficiency (VDD). Methods: The physical and clinical characteristic of individuals in both intervention and control randomized controlled clinical trial were measured and analyzed. The comparisons between the two groups and the changes in each group before and after taking omega-3 doses were studied through independent t test and paired t test, respectively. Possible factors that have a role in the changes were determined by multivariate stepwise regression. Follow-up period lasted 10 weeks. Results: The sample consisted of 82 participants with VDD and a mean age of 37.85 ± 9.85 years. Omega-3 Supplements resulted in a significant decrease in serum ACE levels, ACE/ACE2 ratio and serum 25-hydroxy vitamin D (25OHD). While the change in serum ACE2 levels and serum triglycerides levels were insignificant. Also, a significant increase in serum LDL levels were observed. Conclusion: It is possible that taking high doses of omega-3 fatty acid supplementations have positive effects on the heart and circulatory system and could protect from COVID-19 or decrease disease severity, in connection with a decrease in the ACE/ACE 2 ratio. On the other hand, omega-3 supplement may have negative effect on cardiovascular system due to the significant increase in serum LDL levels. (AU)

Research advances in kinase enzymes and inhibitors for cardiovascular disease treatment.

The targeting of protein kinases has great future potential for the design of new drugs against cardiovascular diseases (CVDs). Enormous efforts have been made toward achieving this aim. Unfortunately, kinase inhibitors designed to treat CVDs have suffered from numerous limitations such as poor selectivity, bad permeability and toxicity. So, where are we now in terms of discovering effective kinase targeting drugs to treat CVDs? Various drug design techniques have been approached for this purpose since the discovery of the inhibitory activity of Staurosporine against protein kinase C in 1986. This review aims to provide context for the status of several emerging classes of direct kinase modulators to treat CVDs and discuss challenges that are preventing scientists from finding new kinase drugs to treat heart disease.

Discovery of potent adenosine A2a antagonists as potential anti-Parkinson disease agents. Non-linear QSAR analyses integrated with pharmacophore modeling.

Adenosine A2A receptor antagonists are of great interest in the treatment for Parkinson's disease. In this study, we combined extensive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent Adenosine A2A antagonists. Genetic function algorithm (GFA) joined with k nearest neighbor (kNN) analyses were applied to build predictive QSAR models. Successful pharmacophores were complemented with exclusion spheres to improve their receiver operating characteristic curve (ROC) profiles. Best QSAR models and their associated pharmacophore hypotheses were validated by identification of several novel Adenosine A2A antagonist leads retrieved from the National Cancer Institute (NCI) structural database. The most potent hit illustrated IC50 value of 545.7 nM.

Ligand-based modeling followed by in vitro bioassay yielded new potent glucokinase activators.

Glucokinase (GK) has received recent interest as a valid antidiabetic target. With this in mind, we applied a computational workflow based on combining pharmacophore modeling and QSAR analysis followed by in silico screening toward the discovery of novel GK activators. Virtual screening identified 10 promising bioactivators from the National Cancer Institute (NCI) list of compounds. The most potent NCI hit illustrated 6.3-fold GK activation at 10 µM. These results demonstrated that our virtual screening protocol was able to identify novel GK activator leads for subsequent development into potential antidiabetic agents.