Melatonin as a Promising Anti-Inflammatory Agent in an In Vivo Animal Model of Sepsis-Induced Rat Liver Damage.

Melatonin (MLT), earlier described as an effective anti-inflammatory agent, could be a beneficial adjunctive drug for sepsis treatment. This study aimed to determine the effects of MLT application in lipopolysaccharide (LPS)-induced sepsis in Wistar rats by determining the levels of liver tissue pro-inflammatory cytokines (TNF-α, IL-6) and NF-κB as well as hematological parameters indicating the state of sepsis. Additionally, an immunohistological analysis of CD14 molecule expression was conducted. Our research demonstrated that treatment with MLT prevented an LPS-induced increase in pro-inflammatory cytokines TNF-α and IL-6 and NF-κB levels, and in the neutrophil to lymphocyte ratio (NLR). On the other hand, MLT prevented a decrease in the blood lymphocyte number induced by LPS administration. Also, treatment with MLT decreased the liver tissue expression of the CD14 molecule observed after sepsis induction. In summary, in rats with LPS-induced sepsis, MLT was shown to be a significant anti-inflammatory agent with the potential to change the liver's immunological marker expression, thus ameliorating liver function.

In silico approach for the development of novel antiviral compounds based on SARS-COV-2 protease inhibition.

The COVID-19 pandemic emerged in 2019, bringing with it the need for greater stores of effective antiviral drugs. This paper deals with the conformation-independent, QSAR model, developed by employing the Monte Carlo optimization method, as well as molecular graphs and the SMILES notation-based descriptors for the purpose of modeling the SARS-CoV-3CLpro enzyme inhibition. The main purpose was developing a reproducible model involving easy interpretation, utilized for a quick prediction of the inhibitory activity of SAR-CoV-3CLpro. The following statistical parameters were present in the best-developed QSAR model: (training set) R 2 = 0.9314, Q 2 = 0.9271; (test set) R 2 = 0.9243, Q 2 = 0.8986. Molecular fragments, defined as SMILES notation descriptors, that have a positive and negative impact on 3CLpro inhibition were identified on the basis of the results obtained for structural indicators, and were applied to the computer-aided design of five new compounds with (4-methoxyphenyl)[2-(methylsulfanyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl]methanone as a template molecule. Molecular docking studies were used to examine the potential inhibition effect of designed molecules on SARS-CoV-3CLpro enzyme inhibition and obtained results have high correlation with the QSAR modeling results. In addition, the interactions between the designed molecules and amino acids from the 3CLpro active site were determined, and the energies they yield were calculated. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02170-8.

Design and development of novel therapeutics for brucellosis treatment based on carbonic anhydrase inhibition.

Carbonic anhydrase is a metalloprotein, an enzyme with strong inhibition in antibacterial treatment. This study presents QSAR modeling for a series of 41 chemical compounds, 40 sulfonamides and one sulfamate, including 13 clinically tested drugs as carbonic anhydrase inhibitors based on the Monte Carlo optimization with molecular descriptors based on the SMILES notation and local invariants of the molecular graph, and field 3D based methods. Conformation independent QSAR models were developed for three random splits and a 3D QSAR model for one random split into the training and test sets. The statistical quality of the developed models, including robustness and predictability, was tested using various statistical approaches and the results that were obtained were very good. An excellent correlation between the results from the conformation independent and the 3D QSAR model was obtained. A novel statistical metric known as the index of ideality of correlation was used for the final assessment of the model, and the obtained results were good. Molecular fragments responsible for the increases and decreases of a studied activity were defined and further used for the computer-aided design of new compounds as potential carbonic anhydrase inhibitors. Molecular docking was applied for the final assessment of the developed QSAR model and designed inhibitors, and an excellent correlation between the results from QSAR modeling and molecular docking studies was obtained.Communicated by Ramaswamy H. Sarma.

Anthocyanins Protect Hepatocytes against CCl4-Induced Acute Liver Injury in Rats by Inhibiting Pro-inflammatory mediators, Polyamine Catabolism, Lipocalin-2, and Excessive Proliferation of Kupffer Cells.

: This study examined the hepatoprotective and anti-inflammatory effects of anthocyanins from Vaccinim myrtillus (bilberry) fruit extract on the acute liver failure caused by carbon tetrachloride-CCl4 (3 mL/kg, i.p.). The preventive treatment of the bilberry extract (200 mg anthocyanins/kg, orally, 7 days) prior to the exposure to the CCl4 resulted in an evident decrease in markers of liver damage (glutamate dehydrogenase, sorbitol dehydrogenase, malate dehydrogenase), and reduced pro-oxidative (conjugated dienes, lipid hydroperoxide, thiobarbituric acid reactive substances, advanced oxidation protein products, NADPH oxidase, hydrogen peroxide, oxidized glutathione), and pro-inflammatory markers (tumor necrosis factor-alpha, interleukin-6, nitrite, myeloperoxidase, inducible nitric oxide synthase, cyclooxygenase-2, CD68, lipocalin-2), and also caused a significant decrease in the dissipation of the liver antioxidative defence capacities (reduced glutathione, glutathione S-transferase, and quinone reductase) in comparison to the results detected in the animals treated with CCl4 exclusively. The administration of the anthocyanins prevented the arginine metabolism's diversion towards the citrulline, decreased the catabolism of polyamines (the activity of putrescine oxidase and spermine oxidase), and significantly reduced the excessive activation and hyperplasia of the Kupffer cells. There was also an absence of necrosis, in regard to the toxic effect of CCl4 alone. The hepatoprotective mechanisms of bilberry extract are based on the inhibition of pro-oxidative mediators, strong anti-inflammatory properties, inducing of hepatic phase II antioxidant enzymes (glutathione S-transferase, quinone reductase) and reduced glutathione, hypoplasia of Kupffer cells, and a decrease in the catabolism of polyamines.