Novel tetrazole and cyanamide derivatives as inhibitors of cyclooxygenase-2 enzyme: design,synthesis, anti-inflammatory evaluation,ulcerogenic liability and docking study

Nineteen new compounds containing tetrazole and/or cyanamide moiety have been designed and synthesised. Their structures were confirmed using spectroscopic methods and elemental analyses. Anti-inflammatory activity for all the synthesised compounds was evaluated in vivo. The most active compounds 4c, 5a, 5d–f, 8a and b and 9a and b were further investigated for their ulcerogenic liability and analgesic activity. Pyrazoline derivatives 9b and 8b bearing trimethoxyphenyl part and SO₂NH₂ or SO₂Me pharmacophore showed equal or nearly the same ulcerogenic liability (UI: 0.5, 0.75, respectively), to celecoxib (UI: 0.50). Most of tested compounds showed potent central and/or peripheral analgesic activities. Histopathological investigations were done to evaluate test compounds effect on rat's gastric tissue. The obtained results were in consistent with the in vitro data on COX evaluation. Docking study was also done for all the target compounds inside COX-2-active site.     

Mesenchymal stem cells and COVID-19: What they do and what they can do

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) pandemic has exhausted the health systems in many countries with thousands cases diagnosed daily. The currently used treatment guideline is to manage the common symptoms like fever and cough, but doesn’t target the virus itself or halts serious complications arising from this viral infection. Currently, SARS-CoV-2 exhibits many genetic modulations which have been associated with the appearance of highly contagious strains. The number of critical cases of COVID-19 increases markedly, and many of the infected people die as a result of respiratory failure and multiple organ dysfunction. The regenerative potential of mesenchymal stem cells (MSCs) has been extensively studied and confirmed. The impressive immunomodulation and anti-inflammatory activity of MSCs have been recognized as a golden opportunity for the treatment of COVID-19 and its associated complications. Moreover, MSCs regenerative and repairing abilities have been corroborated by many studies with positive outcomes and high recovery rates. Based on that, MSCs infusion could be an effective mechanism in managing and stemming the serious complications and multiple organ failure associated with COVID-19. In the present review, we discuss the commonly reported complications of COVID-19 viral infection and the established and anticipated role of MSCs in managing these complications.     

Immunological microenvironment gene expression in patients with diffuse large B cell non Hodgkin lymphoma

BackgroundNon Hodgkin lymphoma (NHL) is one of the immune system cancers. The occurrence and progression of malignant lymphomas depends on cellular pathways deregulation. Understanding the relationship between the immune system at the genetic level and malignant transformation is critical to reach its etiology.ObjectiveThe aim of this work is to evaluate the expression of five immune related genes (PD-1, FOXP3, GrA, GrB and CD11c) in patients with diffuse large B cell non Hodgkin lymphoma (DLBCL).Materials and methodsThis study was conducted on fifty patients with DLBCL and fifty sex and age matched apparently healthy subjects. The participants were subjected to these laboratory investigations: complete blood count, serum lactate dehydrogenase and β2microglobulin (β₂M) levels and determination of PD-1, FOXP3, GrA, GrB and CD11c gene expressions.ResultsThe results of this study revealed that PD-1, FOXP3, GrA, GrB and CD11c gene expressions were significantly increased in DLBCL patients.ConclusionPatients with DLBCL have variablePD-1, FOXP3,GrA, GrB and CD11cgene expressions levels, which are correlated with the overall survival (OS) indicating that they can be good predictors of outcome in these patients.     

The role of LncRNA MALAT-1 and MiRNA-9 in Psoriasis

BackgroundPsoriasis is a chronic skin disorder manifested by recurrent episodes of scaly, red, itchy skin patches that occur within apparently normal skin.ObjectivesThis study was performed to detect the expression of serum and tissue (lesion and non-lesion) LncRNA MALAT-1 and MiRNA-9 that might be used as biomarkers for psoriasis.MethodsBlood samples were obtained from 60 psoriasis patients and 40 controls, as well as 4 mm punch biopsy from lesional and non lesional skin of psoriatic patient and normal skin of healthy controls. Expression of LncRNA MALAT-1 and miRNNA-9 in serum and tissues was detected by real time qRT-PCR.Resultsa statistically significant increase in the expression of MALAT-1 in lesional and non-lesional skin and serum of psoriatic patients in comparison to controls were detected. Moreover, there was statistically significant increase in serum MiRNA-9 in patients in comparison to controls, while its tissue level was significantly lower in patients.ConclusionThis study highlights the dysregulation of LncRNA MALAT-1 and miRNA-9 in psoriasis. Elevated expression of MALAT-1 in lesional skin of psoriatic patients compared to non-lesional skin may possibly contribute to the development of psoriatic plaques.     

Converting the Yeast Arginine Can1 Permease to a Lysine Permease

Amino acid uptake in yeast cells is mediated by about 16 plasma membrane permeases, most of which belong to the amino acid-polyamine-organocation (APC) transporter family. These proteins display various substrate specificity ranges. For instance, the general amino acid permease Gap1 transports all amino acids, whereas Can1 and Lyp1 catalyze specific uptake of arginine and lysine, respectively. Although Can1 and Lyp1 have different narrow substrate specificities, they are close homologs. Here we investigated the molecular rules determining the substrate specificity of the H⁺-driven arginine-specific permease Can1. Using a Can1-Lyp1 sequence alignment as a guideline and a three-dimensional Can1 structural model based on the crystal structure of the bacterial APC family arginine/agmatine antiporter, we introduced amino acid substitutions liable to alter Can1 substrate specificity. We show that the single substitution T456S results in a Can1 variant transporting lysine in addition to arginine and that the combined substitutions T456S and S176N convert Can1 to a Lyp1-like permease. Replacement of a highly conserved glutamate in the Can1 binding site leads to variants (E184Q and E184A) incapable of any amino acid transport, pointing to a potential role for this glutamate in H⁺ coupling. Measurements of the kinetic parameters of arginine and lysine uptake by the wild-type and mutant Can1 permeases, together with docking calculations for each amino acid in their binding site, suggest a model in which residues at positions 176 and 456 confer substrate selectivity at the ligand-binding stage and/or in the course of conformational changes required for transport.     

Evaluation of mRNA expression level of the ATP synthase membrane subunit c locus 1 (ATP5G1) gene in patients with schizophrenia

BackgroundSchizophrenia is a serious, complex mental disorder. The impairment of oxidative phosphorylation has a detrimental consequence on CNS function. Different ATP synthase subunits have been involved in the pathological process of various neurodegenerative disorders. Our goal was to evaluate the mRNA expression level of the ATP synthase membrane subunit c locus 1 (ATP5G1, also named ATP5MC1) gene in patients with schizophrenia.MethodsDetermination of the expression levels of ATP5G1 in plasma and peripheral blood mononuclear cells (PBMCs) were performed by real-time PCR in 90 controls and 90 patients with schizophrenia.ResultsPatients had significantly decreased ATP5G1 mRNA expression levels in both plasma and PBMCs compared to controls. The receiver operating characteristic curve was applied to detect a cut-off value of ATP5G1 expression in plasma and PBMCs. The ATP5G1 relative expression in PBMCs had better performance with a cut-off value ≤ 21 (AUC = 0.892, P < 0.001), sensitivity of 94.44%, and specificity of 72.22% in discriminating between schizophrenic patients. ATP5G1 expression in PBMCs was an independent predictor in schizophrenia.ConclusionThis study revealed a down-regulation of ATP5G1 expression in schizophrenia, precisely expression in PBMCs. That might give insight into the role of ATP5G1 gene in the pathogenesis of schizophrenia.