Molecular docking, pharmacokinetic prediction and molecular dynamics simulations of tankyrase inhibitor compounds with the protein glucokinase, induced in the development of diabetes.

GCK is a protein that plays a crucial role in the sensing and regulation of glucose homeostasis, which associates it with disorders of carbohydrate metabolism and the development of several pathologies, including gestational diabetes. This makes GCK an important therapeutic target that has aroused the interest of researchers to discover GKA that are simultaneously effective in the long term and free of side effects. TNKS is a protein that interacts directly with GCK; recent studies have shown that it inhibits GCK action, which affects glucose detection and insulin secretion. This justifies our choice of TNKS inhibitors as ligands to test their effects on the GCK-TNKS complex. For this purpose, we investigated the interaction of the GCK-TNKS complex with 13 compounds (TNKS inhibitors and their analogues) using the molecular docking approach as a first step, after which the compounds that generated the best affinity scores were evaluated for drug similarity and pharmacokinetic properties. Subsequently, we selected the six compounds that generated high affinity and that were in accordance with the parameters of the drug rules as well as pharmacokinetic properties to ensure a molecular dynamics study. The results allowed us to favor the two compounds (XAV939 and IWR-1), knowing that even the tested compounds (TNKS 22, (2215914) and (46824343)) produced good results that can also be exploited. These results are therefore interesting and encouraging, and they can be exploited experimentally to discover a treatment for diabetes, including gestational diabetes.Communicated by Ramaswamy H. Sarma.

MBL2 gene polymorphisms related to HIV-1 infection susceptibility and treatment response.

Human Mannose-binding lectin (MBL) is a protein encoded by MBL2 gene involved in the activation of the lectin-complement pathway. Several studies emphasized the role of MBL2 gene in several infectious diseases' susceptibility, including HIV-1 infection. We aim to investigate the impact of 10 MBL2 gene polymorphisms located in the promoter, 5'UTR and exon 1 regions on HIV-1 physiopathology. The polymorphisms genotyping of 400 individuals, which 200 were HIV-1 positive patients and 200 were controls, was performed by PCR-sequencing. Our results showed that rs503037 and rs1800451 polymorphisms are associated with a high risk of HIV-1 infection susceptibility while rs7096206 and rs11003123 showed a protective effect. A significant association between haplotype CGA and HIV-1 infection susceptibility was also found in the exon 1 region. Moreover, rs11003124, rs7084554, rs36014597 and rs11003123 polymorphisms revealed an association with treatment response outcome as measured by RNA viral load. This study highlights the importance of MBL2 polymorphisms in the modulation of HIV-1 infection susceptibility and the contribution to treatment response outcomes among Moroccan subjects.

Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 (TMPRSS2) and SARS-CoV-2.

The human transmembrane protease serine 2 (TMPRSS2) protein plays an important role in prostate cancer progression. It also facilitates viral entry into target cells by proteolytically cleaving and activating the S protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the current study, we used different available tools like SIFT, PolyPhen2.0, PROVEAN, SNAP2, PMut, MutPred2, I-Mutant Suite, MUpro, iStable, ConSurf, ModPred, SwissModel, PROCHECK, Verify3D, and TM-align to identify the most deleterious variants and to explore possible effects on the TMPRSS2 stability, structure, and function. The six missense variants tested were evaluated to have deleterious effects on the protein by SIFT, PolyPhen2.0, PROVEAN, SNAP2, and PMut. Additionally, V160M, G181R, R240C, P335L, G432A, and D435Y variants showed a decrease in stability by at least 2 servers; G181R, G432A, and D435Y are highly conserved and identified posttranslational modifications sites (PTMs) for proteolytic cleavage and ADP-ribosylation using ConSurf and ModPred servers. The 3D structure of TMPRSS2 native and mutants was generated using 7 meq as a template from the SwissModeller group, refined by ModRefiner, and validated using the Ramachandran plot. Hence, this paper can be advantageous to understand the association between these missense variants rs12329760, rs781089181, rs762108701, rs1185182900, rs570454392, and rs867186402 and susceptibility to SARS-CoV-2.

[Paraoxonase-1 (PON1) activity in patients with coronary artery diseases and in diabetic patients].

Cardiovascular diseases are the main cause of mortality in the world, diabetics and patients with coronary artery diseases in particular. In fact, the increase of cardiovascular risk was established in many epidemiological and clinical studies. The aim of this work is to study both the lipid profile and the enzymatic activity of PON1 in diabetics and coronary patients from Morocco (Casablanca region) along with the cardiovascular risk factors in this population. Three groups of Moroccan subjects were investigated: 36 patients with coronary artery diseases, 110 diabetic patients and 100 healthy subjects (control group). Total cholesterol (TC), triglycerides (TG) and high-density lipoprotein cholesterol (c-HDL) levels were evaluated using colorimetric methods. Low-density lipoprotein cholesterol (c-LDL) was calculated according to the Friedewald's formula. Serum activity of PON1 was measured by spectrophotometry. Compared to healthy subjects, we noted a significant decrease of PON1 activity in coronary artery disease (285 U/mL ±â€Š180 U/mL; P < 0.05) and in diabetic (167 U/mL ±â€Š71 U/mL; P < 0.05) patients. In addition, we found that diabetic patients recorded significantly elevated LDL, TG and TC levels. In parallel, coronary artery disease patients scored TG level. The present study revealed an abnormal lipoprotein profile associated with hypertriglyceridemia, low levels of c-HDL, high levels of c-LDL and significant decrease of PON1 activity. These findings confirm the high risk of cardiovascular diseases in diabetic and coronary artery disease patients.

Physiological and chronobiological changes during Ramadan intermittent fasting.

BACKGROUND AND AIMS: During the month of Ramadan, Moslems refrain from drinking and eating between sunrise and sunset. This review aimed to analyze the effects of Ramadan fasting on physiological and behavioral variables in healthy subjects. METHODS: Articles included in this paper were taken from Medline, three international congresses on health and Ramadan, and in several cases from local journals. RESULTS: Ramadan fasting did not dramatically affect the metabolism of lipids, carbohydrates and proteins, or the daily mean of hormonal serum levels. An increase in serum urea and uric acid was frequently reported and this could be attributed to dehydration during this month. Some changes, such as the increase of HDL and apoprotein A1, and the decrease in LDL, could be beneficial for the cardiovascular system. However, the chronobiological studies have shown that Ramadan fasting affects the circadian distribution of body temperature, cortisol, melatonin and glycemia. The amplitude of most of these rhythms decreased and the acrophase shifted. Nocturnal sleep, daytime alertness and psychomotor performance were decreased. CONCLUSION: The major changes during Ramadan fasting are chronobiological and behavioral. They could be responsible for the high incidence of road traffic accidents and the reduction of working hours during the month of Ramadan.