Association between Low Adiponectin Level and Cardiovascular Complications in Diabetic and non Diabetic Patients with End Stage Renal Disease

Introduction: Adiponectin is a collagen-like protein synthesized by adipose tissue that has anti-inflammatory and anti-atherogenic properties. We aimed to evaluate adiponectin levels in end stage renal disease (ESRD) patients with and without diabetes mellitus and its relation to the presence of cardiovascular complications (CVC). Methods: The study included 20 healthy subjects who served as controls (group I), 20 non-diabetic ESRD patients without CVC (group IIA), 20 non-diabetic ESRD patients with CVC (group IIB), 20 diabetic ESRD patients without CVC (group IIIA) and 20 diabetic ESRD patients with CVC (group IIIB). Evaluation included mean arterial blood pressure (MABP), body mass index (BMI), fasting plasma glucose, fasting plasma insulin, homeostasis model assessment for insulin resistance (HOMA-IR), lipid profile, and serum adiponectin levels. Results: Adiponectin level in the control group was 6.4±1.2 mcg/ml, and was significantly lower than both group II and III (

Proposed mechanism for the antitrypanosomal activity of Quercetin and Myricetin isolated from hypericum Afrum lam: Phytochemistry, in vitro testing and modeling studies

The in vitro activity of L. donovani (promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells) and T. brucei, from the fractions obtained from the hydroalcoholic extract of the aerial part of Hypericum afrum and the isolated compounds, has been evaluated. The chloroform, ethyl acetate and n-butanol extracts showed significant antitrypanosomal activity towards T. brucei, with IC50 values of 12.35, 13.53 and 12.93 µg/mL and with IC90 values of 14.94, 19.31 and 18.67 µg/mL, respectively. The phytochemical investigation of the fractions led to the isolation and identification of quercetin (1), myricitrin (2), biapigenin (3), myricetin (4), hyperoside (5), myricetin-3-O-β-D-galactopyranoside (6) and myricetin-3’-O-β-D-glucopyranoside (7). Myricetin- 3’-O-β-D-glucopyranoside (7) has been isolated for the first time from this genus. The chemical structures were elucidated by using comprehensive one- and two-dimensional nuclear magnetic resonance (1D and 2D NMR) spectroscopic data, as well as high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). These compounds have also been evaluated for their antiprotozoal activity. Quercetin (1) and myricetin (4) showed noteworthy activity against T. brucei, with IC50 and IC90 values of 7.52 and 5.71 µM, and 9.76 and 7.97 µM, respectively. The T. brucei hexokinase (TbHK1) enzyme was further explored as a potential target of quercetin and myricetin, using molecular modeling studies. This proposed mechanism assists in the exploration of new candidates for novel antitrypanosomal drugs

Computationally assisted lead optimization of novel potent and selective mao-b inhibitors

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and-B. Compounds 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c–4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson’s Disease and other neurological disorders

Fluorescence Spectrometric Determination of Drugs Containing α-Methylene Sulfone/Sulfonamide Functional Groups Using N1-Methylnicotinamide Chloride as a Fluorogenic Agent

A simple spectrofluorometric method has been developed, adapted, and validated for the quantitative estimation of drugs containing α-methylene sulfone/sulfonamide functional groups using N1-methylnicotinamide chloride (NMNCl) as fluorogenic agent. The proposed method has been applied successfully to the determination of methyl sulfonyl methane (MSM) (1), tinidazole (2), rofecoxib (3), and nimesulide (4) in pure forms, laboratory-prepared mixtures, pharmaceutical dosage forms, spiked human plasma samples, and in volunteer's blood. The method showed linearity over concentration ranging from 1 to 150 μg/mL, 10 to 1000 ng/mL, 1 to 1800 ng/mL, and 30 to 2100 ng/mL for standard solutions of 1, 2, 3, and 4, respectively, and over concentration ranging from 5 to 150 μg/mL, 10 to 1000 ng/mL, 10 to 1700 ng/mL, and 30 to 2350 ng/mL in spiked human plasma samples of 1, 2, 3, and 4, respectively. The method showed good accuracy, specificity, and precision in both laboratory-prepared mixtures and in spiked human plasma samples. The proposed method is simple, does not need sophisticated instruments, and is suitable for quality control application, bioavailability, and bioequivalency studies. Besides, its detection limits are comparable to other sophisticated chromatographic methods

Chronic pain in hemodialysis patients: Role of bone mineral metabolism

Background: Pain is one of the most common complaints in clinical practice because it is a symptom for a myriad of physical and mental problems. The high prevalence of pain in the chronic kidney disease (CKD) population is particularly concerning because pain has been shown to adversely affect quality of life. The aim of this study was to evaluate the prevalence and possible causes of chronic pain in patients with end stage renal disease on long-term hemodialysis (HD).Methods: We prospectively enrolled 100 patients who were undergoing maintenance HD for at least 6 months or more. Pain was evaluated using the Brief Pain Inventory (BPI). Data collected on each participant included age, gender, body mass index (BMI), time on dialysis and biochemical findings.Results: The average age was 42.06 years ranged from 22 to 58 years; the average duration on dialysis was 4.97 years. 52 patients were males and 48 were females. Although 52% of patients experienced chronic pain, only 25% described the pain as severe, 28% described pain as moderate while 52% of patients described as mild. Musculoskeletal pain was the most frequent form of chronic pain reported by patients who were on HD (54%). Malnutrition and high CRP were highly statistically associated with chronic pain (p< 0.001). High statistical significant correlation was found between lower calcium, lower 25(OH) D3 levels, higher parathyroid hormone (PTH) levels and experienced chronic pain (p< 0.001).Conclusion: Chronic pain is highly experienced in long-term hemodialysis patients. Malnutrition, high CRP and disturbed bone mineral metabolism are highly correlated with the incident of this pain

Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast

Treatment failures with artemisinin combination therapies (ACTs) threaten global efforts to eradicate malaria. They highlight the importance of identifying drug targets and new inhibitors and of studying how existing antimalarial classes work. Here, we report the successful development of a heterologous expression-based compound-screening tool. The validated drug target Plasmodium falciparum ATPase 6 (PfATP6) and a mammalian orthologue (sarco/endoplasmic reticulum calcium ATPase 1a [SERCA1a]) were functionally expressed in Saccharomyces cerevisiae, providing a robust, sensitive, and specific screening tool. Whole-cell and in vitro assays consistently demonstrated inhibition and labeling of PfATP6 by artemisinins. Mutations in PfATP6 resulted in fitness costs that were ameliorated in the presence of artemisinin derivatives when studied in the yeast model. As previously hypothesized, PfATP6 is a target of artemisinins. Mammalian SERCA1a can be mutated to become more susceptible to artemisinins. The inexpensive, low-technology yeast screening platform has identified unrelated classes of druggable PfATP6 inhibitors. Resistance to artemisinins may depend on mechanisms that can concomitantly address multitargeting by artemisinins and fitness costs of mutations that reduce artemisinin susceptibility

Association of adiponectin with cardiovascular events in diabetic and non-diabetic hemodialysis patients

Adiponectin is a novel collagen-like protein synthesized by white adipose tissue. Its levels are decreased in obesity, type-2 diabetes and insulin-resistant states, and are increased in chronic renal failure. It has anti-inflammatory and anti-atherogenic properties. This study was planned to evaluate the levels of adiponectin in uremic patients with and without diabetes and to find any relationship between adiponectin levels and some cardiovascular risk factors, and to determine the possible predictive value of adiponectin for cardiovascular complications (CVC). The study included 100 subjects, 20 of them were healthy subjects and served as the control group (group I), 40 were uremic non-diabetic patients (group II) (half of them were without CVC, group IIA, and the other half were patients with CVC, group IIB) and, lastly, 40 uremic diabetic patients (group III) (half of them were without CVC, group IIIA, and the other half were patients with CVC, group IIIB). All subjects were subjected to complete clinical examination, including determination of mean arterial blood pressure (MABP), body mass index (BMI), waist to hip ratio, routine laboratory investigations, fasting plasma glucose, fasting plasma insulin, lipid profile (cholesterol, TG, LDL, HDL), determination of insulin resistance by homeostasis model assessment index (HOMA-IR) and estimation of serum levels of adiponectin. There was a significant increase in serum adiponectin levels in all the uremic patients (group II and group III) when compared with the control (group I) group, P <0.01; also, serum adiponectin levels were significantly decreased in uremic diabetic patients (group III) when compared with uremic non-diabetic patients (group II), P <0.01; but this was still higher than in the controls. The patients with CVC, whether uremic non-diabetic (group IIB) or uremic diabetic (group IIIB), had a significant decrease in serum adiponectin levels when compared with patients without CVC (group IIA and group IIIA), P <0.01. Serum adiponectin has a significant positive correlation with HDL and a significant negative correlation with MABP, BMI, plasma insulin, HOMA-IR, LDL, TG and choles-terol in all the patients. Therefore, it can be concluded that adiponectin levels in uremic patients, whether diabetic or non-diabetic, may be a good indicator of cardiovascular disease risk

Potential Pro-Inflammatory Effect of Vitamin E Analogs through Mitigation of Tetrahydrocannabinol (THC) Binding to the Cannabinoid 2 Receptor

Vitamin E acetate, which is used as a diluent of tetrahydrocannabinol (THC), has been reported as the primary causative agent of e-cigarette, or vaping, product use-associated lung injury (EVALI). Here, we employ in vitro assays, docking, and molecular dynamics (MD) computer simulations to investigate the interaction of vitamin E with the membrane-bound cannabinoid 2 receptor (CB2R), and its role in modulating the binding affinity of THC to CB2R. From the MD simulations, we determined that vitamin E interacts with both CB2R and membrane phospholipids. Notably, the synchronized effect of these interactions likely facilitates vitamin E acting as a lipid modulator for the cannabinoid system. Furthermore, MD simulation and trajectory analysis show that when THC binds to CB2R in the presence of vitamin E, the binding cavity widens, facilitating the entry of water molecules into it, leading to a reduced interaction of THC with CB2R. Additionally, the interaction between THC and vitamin E in solution is stabilized by several H bonds, which can directly limit the interaction of free THCs with CB2R. Overall, both the MD simulations and the in vitro dissociation assay results indicate that THC binding to CB2R is reduced in the presence of vitamin E. Our study discusses the role of vitamin E in limiting the effect of THCs and its implications on the reported pathology of EVALI

Structurally Modified Bioactive Peptide Inhibits SARS-CoV-2 Lentiviral Particles Expression

Coronavirus disease 2019 (COVID-19), the current global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Various pharmaceuticals are being developed to counter the spread of the virus. The strategy of repurposing known drugs and bioactive molecules is a rational approach. A previously described molecule, Ile-Arg-Trp (IRW), is a bioactive tripeptide that exhibits an ability to boost angiotensin converting enzyme-2 (ACE2) expression in animals and cells. Given the importance of SARS-CoV-2 S receptor binding domain (RBD)-ACE2 interaction in SARS-CoV-2 pathophysiology, we synthesized various IRW analogs intending to mitigate the RBD-ACE-2 interaction. Herein, we describe two analogs of IRW, A9 (Acetyl-Ile-Arg-Trp-Amide) and A14 (Formyl-Ile-Arg-Trp-Amide) which lowered the SARS-CoV-2 S RBD-ACE2 (at 50 &micro;M) in vitro. The free energy of binding suggested that A9 and A14 interacted with the SARS-CoV-2 S RBD more favorably than ACE2. The calculated MMGBSA &Delta;G of spike binding for A9 was &minus;57.22 kcal/mol, while that of A14 was &minus;52.44 kcal/mol. A14 also inhibited furin enzymatic activity at various tested concentrations (25, 50, and 100 &micro;M). We confirmed the effect of the two potent analogs using SARS-CoV-2 spike protein overexpressing cells. Both peptides lowered the protein expression of SARS-CoV-2 spike protein at the tested concentration (50 &micro;M). Similarly, both peptides, A9 and A14 (50 &micro;M), also inhibited pseudotyped lentiviral particles with SARS-CoV-2 Spike in ACE2 overexpressing cells. Further, the molecular dynamics (MD) calculations showed the interaction of A9 and A14 with multiple residues in spike S1 RBD. In conclusion, novel peptide analogs of ACE2 boosting IRW were prepared and confirmed through in vitro, cellular, and computational evaluations to be potential seed candidates for SARS-CoV-2 host cell binding inhibition