Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1–PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1–GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC50 5.46, 4.78 and 3.19 μM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC50 = 1.44 μM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells.

The present study assessed protein and gene expression levels of tissue inhibitor of metalloproteinase‐2 (TIMP‐2), matrix metalloproteinase‐2 (MMP‐2), and MMP‐9 in urine and blood samples of 50 patients with bladder carcinoma. The expression of TIMP‐2, MMP‐2, and MMP‐9 levels with tumor stage and grade was also assessed. Results showed that the expression levels of MMP‐2 and MMP‐9 in both blood and urine were significantly elevated in group 1 when compared with groups 2 and 3 healthy subjects. The discriminatory ability in the diagnosis of bladder carcinoma of MMP‐2 and MMP‐9 expression was confirmed by receiver operating characteristic curve analysis that revealed a sensitivity and specificity of 100%. MMP‐2 and MMP‐9 levels were not correlated with grade or stage of the tumor. With respect to TIMP‐2 blood and urine levels, results showed a significant decrease in gene expression levels in bladder carcinoma group, whereas, TIMP‐2 protein showed a significant increase in bladder carcinoma.

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS CoV-2) is currently an international pandemic causing coronavirus disease 19 (COVID-19). Viral entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2) for membrane fusion or through endosomal pathway. This Study aims to assess transcriptomic changes and differentially expressed genes (DFGs) in COVID-19. Methods Transcriptomic data of the publicly available dataset (GSE147507) was quantile normalized and analysed for DFGs, network analysis and pathway analysis. Results DFG sets showed that 8 genes (SAE1, AEBP2, ATP1A1, DKK3, MAFF, NUDC, TRAP1, and VAV1) were significantly dysregulated in all studied groups. Functional analysis revealed that negative regulation of glucocorticoid biosynthesis, protein SUMOylation (SAE1), blood coagulation (VAV1) and cellular response to stress were affected by SARS CoV-2 infection. Cell line transduction with ACE2 vector didn't show significant changes in the dysregulated pathways. Also, no significant change was observed in expression levels of ACE2 or TMPRSS2 in response to SARS CoV-2 infection. Further analysis showed dysregulation of several genes in the SUMOylation pathway and blood coagulation process in human and cell lines transcriptome. Also, several Cathepsins proteases were significantly dysregulated in case of SARS CoV-2 infection. Genes related to cellular response to stress such as TRAP-1 and NOX were dysregulated in cases of SARS CoV-2 infection. Conclusion Dysregulation in genes of protein SUMOylation, blood coagulation and response to oxidative stress pathways in SARS CoV-2 infection could be critical for disease progression. Drugs acting on SUMO pathway, VAV1, NOX genes could be studied for potential benefit to COVID-19 patients.

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