Low SOD activity is associated with overproduction of peroxynitrite and nitric oxide in patients with acute coronary syndrome.

OBJECTIVE: The present study was undertaken to evaluate the variation of the oxidative/nitrosative stress status in a population of subjects; with acute coronary syndrome (ACS), and examine its possible implication in plaque rupture which is the main mechanism in the pathophysiology of ACS. PATIENTS AND METHODS: We made this study on 50 men with ACS and 50 age and sex matched healthy controls. Nitrosative/oxidative stress markers including; nitric oxide, superoxide anion levels, superoxide dismutase (SOD) activity and peroxynitrite levels were evaluated in blood samples of patients and controls. RESULTS: Compared with healthy subjects, coronary patients had significantly higher nitric oxide, peroxynitrite and superoxide anion concentrations in both plasma and erythrocytes associated to significant decrease of SOD activity. Erythrocytes peroxynitrite concentration was negatively correlated with the antioxidant enzyme activity (SOD). CONCLUSION: Our results show a significant accumulation of both intracellular and plasma pro-oxidants with a concomitant decrease in the SOD scavenging activity in ACS patients. Both seem to be associated with plaque rupture and ischemia observed in ACS.

Effects of subcutaneous vs. oral nanoparticle-mediated insulin delivery on hemostasis disorders in type 1 diabetes: A rat model study.

Complications associated with Type 1 diabetes (T1D) have complex origins that revolve around chronic hyperglycemia; these complications involve hemostasis disorders, coagulopathies, and vascular damage. Our study aims to develop innovative approaches to minimize these complications and to compare the outcomes of the new approach with those of traditional methods. To achieve our objective, we designed novel nanoparticles comprising covalent organic frameworks (nCOF) loaded with insulin, termed nCOF/Insulin, and compared it to subcutaneous insulin to elucidate the influence of insulin delivery methods on various parameters, including bleeding time, coagulation factors, platelet counts, cortisol plasma levels, lipid profiles, and oxidative stress parameters. Traditional subcutaneous insulin injections exacerbated hemostasis disorder and vascular injuries in streptozotocin (STZ)-induced diabetic rats through increasing plasma triglycerides and lipid peroxidation. Conversely, oral delivery of nCOF/Insulin ameliorated hemostatic disorders and restored the endothelial oxidant/antioxidant balance by reducing lipid peroxidation and enhancing the lipid profile. Our study pioneers the understanding of how STZ-induced diabetes disrupts bleeding time, induces a hypercoagulable state, and causes vascular damage through lipid peroxidation. Additionally, it provides the first evidence for the involvement of subcutaneous insulin treatment in exacerbating vascular and hemostasis disorders in type 1 diabetes (T1D). Introducing an innovative oral insulin delivery via the nCOF approach represents a potential paradigm shift in diabetes management and patient care and promises to improve treatment strategies for type 1 Diabetes.

Histological Injury to Rat Brain, Liver, and Kidneys by Gold Nanoparticles is Dose-Dependent.

Gold nanoparticles (GNPs) possess various interesting plasmonic properties that can provide a variety of diagnostic and therapeutic functionalities for biomedical applications. Compared to other inorganic metal nanoparticles (NPs), GNPs are less toxic and more biocompatible. However, the in vivo toxicity of gold nanoparticles on humans can be significant due to the size effect. This work aims to study the effect of multiple doses of small-size (≈20 nm) GNPs on the vital organs of Wistar rats. The study includes the oxidative stress in vital organs (liver, brain, and kidney) caused by GNPs and histopathology analysis. The rats were given a single caudal injection of NPs dispersed in PBS at 25, 50, 100, and 250 mg/kg of body weight. After sacrifice, both plasma and organs were collected for the determination of oxidant/antioxidant markers and histological studies. Our data show the high sensitivity of oxidative stress parameters to the GNPs in the brain, liver, and kidneys. However, the response to this stress is different between the organs and depends upon the antioxidant defense, where GSH levels control the MDA and PCO levels. Histological alterations are mild at 25, 50, and 100 mg/kg but significant at higher concentrations of 250 mg/kg. Therefore, histological impairments are shown to be dependent on the dose of GNPs. The results contribute to the understanding of oxidative stress and cellular interaction induced by nanoparticles.

In vivo oral insulin delivery via covalent organic frameworks.

With diabetes being the 7th leading cause of death worldwide, overcoming issues limiting the oral administration of insulin is of global significance. The development of imine-linked-covalent organic framework (nCOF) nanoparticles for oral insulin delivery to overcome these delivery barriers is herein reported. A gastro-resistant nCOF was prepared from layered nanosheets with insulin loaded between the nanosheet layers. The insulin-loaded nCOF exhibited insulin protection in digestive fluids in vitro as well as glucose-responsive release, and this hyperglycemia-induced release was confirmed in vivo in diabetic rats without noticeable toxic effects. This is strong evidence that nCOF-based oral insulin delivery systems could replace traditional subcutaneous injections easing insulin therapy.

Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: A molecular docking and simulation studies.

A novel coronavirus responsible of acute respiratory infection closely related to SARS-CoV has recently emerged. So far there is no consensus for drug treatment to stop the spread of the virus. Discovery of a drug that would limit the virus expansion is one of the biggest challenges faced by the humanity in the last decades. In this perspective, to test existing drugs as inhibitors of SARS-CoV-2 main protease is a good approach. Among natural phenolic compounds found in plants, fruit, and vegetables; flavonoids are the most abundant. Flavonoids, especially in their glycosylated forms, display a number of physiological activities, which makes them interesting to investigate as antiviral molecules. The flavonoids chemical structures were downloaded from PubChem and protease structure 6LU7 was from the Protein Data Bank site. Molecular docking study was performed using AutoDock Vina. Among the tested molecules Quercetin-3-O-rhamnoside showed the highest binding affinity (-9,7 kcal/mol). Docking studies showed that glycosylated flavonoids are good inhibitors for the SARS-CoV-2 protease and could be further investigated by in vitro and in vivo experiments for further validation. MD simulations were further performed to evaluate the dynamic behavior and stability of the protein in complex with the three best hits of docking experiments. Our results indicate that the rutin is a potential drug to inhibit the function of Chymotrypsin-like protease (3CL pro) of Coronavirus.

Biochemical characterization of a glycosyltransferase Gtf3 from Mycobacterium smegmatis: a case study of improved protein solubilization.

Glycosyltransferases (GTs) are widely present in several organisms. These enzymes specifically transfer sugar moieties to a range of substrates. The processes of bacterial glycosylation of the cell wall and their relations with host-pathogen interactions have been studied extensively, yet the majority of mycobacterial GTs involved in the cell wall synthesis remain poorly characterized. Glycopeptidolipids (GPLs) are major class of glycolipids present on the cell wall of various mycobacterial species. They play an important role in drug resistance and host-pathogen interaction virulence. Gtf3 enzyme performs a key step in the biosynthesis of triglycosylated GPLs. Here, we describe a general procedure to achieve expression, purification, and crystallization of recombinant protein Gtf3 from Mycobacterium smegmatis using an E. coli expression system. We reported also a combined bioinformatics and biochemical methods to predict aggregation propensity and improve protein solubilization of recombinant Gtf3. NVoy, a carbohydrate-based polymer reagent, was added to prevent protein aggregation by binding to hydrophobic protein surfaces of Gtf3. Using intrinsic tryptophan fluorescence quenching experiments, we also demonstrated that Gtf3-NVoy enzyme interacted with TDP and UDP nucleotide ligands. This case report proposes useful tools for the study of other glycosyltransferases which are rather difficult to characterize and crystallize.

In Vitro Antioxidant versus Metal Ion Chelating Properties of Flavonoids: A Structure-Activity Investigation.

Natural flavonoids such as quercetin, (+)catechin and rutin as well as four methoxylated derivatives of quercetin used as models were investigated to elucidate their impact on the oxidant and antioxidant status of human red blood cells (RBCs). The impact of these compounds against metal toxicity was studied as well as their antiradical activities with DPPH assay. Antihemolytic experiments were conducted on quercetin, (+)catechin and rutin with excess of Fe, Cu and Zn (400 µM), and the oxidant (malondialdehyde, carbonyl proteins) and antioxidant (reduced glutathione, catalase activity) markers were evaluated. The results showed that Fe and Zn have the highest prooxidant effect (37 and 33% of hemolysis, respectively). Quercetin, rutin and (+)catechin exhibited strong antioxidant properties toward Fe, but this effect was decreased with respect to Zn ions. However, the Cu showed a weak antioxidant effect at the highest flavonoid concentration (200 µM), while a prooxidant effect was observed at the lowest flavonoid concentration (100 µM). These results are in agreement with the physico-chemical and antiradical data which demonstrated that binding of the metal ions (for FeNTA: (+)Catechin, KLFeNTA = 1.6(1) × 106 M-1 > Rutin, KLFeNTA = 2.0(9) × 105 M-1 > Quercetin, KLFeNTA = 1.0(7) × 105 M-1 > Q35OH, KLFeNTA = 6.3(8.7) × 104 M-1 > Quercetin3'4'OH and Quercetin 3OH, KLFeNTA ~ 2 × 104 M-1) reflects the (anti)oxidant status of the RBCs. This study reveals that flavonoids have both prooxidant and antioxidant activity depending on the nature and concentration of the flavonoids and metal ions.