Virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, despite successful treatment, hepatitis C virus (HCV) may progress to HCC from initiated liver cirrhosis. Cytotoxic T cells (Tcs) are known to be involved in HCV-related cirrhotic complications and HCC pathogenesis. The inhibitory checkpoint leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is expressed on Tcs. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression and to evaluate LAIR-1 expression as a noninvasive biomarker for HCC progression in the context of liver cirrhosis related to HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. A total of 64 patients with HCC and 37 patients with liver cirrhosis were enrolled in this case-controlled study, and their LAIR-1 expression on Tc related to the progression of liver cirrhosis was examined and compared to that of the apparently healthy control group (n = 20). LAIR-1 expression was analyzed using flow cytometry. Results: The HCC group had significantly higher LAIR-1 expression on Tc and percentage of Tc positive for LAIR-1 (LAIR-1+Tc%) than the HCV G4-related liver cirrhosis group. LAIR-1+Tc% was correlated with the HCC surrogate tumor marker AFP (r = 0.367, p = 0.001) and insulin resistance and inflammation prognostic ratios/indices. A receiver operating characteristic (ROC) curve revealed that adding LAIR-1+Tc% to AFP can distinguish HCC transformation in the Egyptian patients’ cohort. Upregulated LAIR-1 expression on Tc could be a potential screening noninvasive molecular marker for chronic inflammatory HCV G4 related liver cirrhosis. Moreover, LAIR-1 expression on Tc may be one of the players involved in the progression of liver cirrhosis to HCC.

The current study investigated the cytotoxic effect of ten sulfonamide-derived isatins, following molecular hybridization, based on the association principles, on hepatocellular carcinoma (HCC) HepG2 and Huh7 cell lines, compared for safety using human normal retina pigmented epithelial (RPE-1) cells. The ten compounds showed variable in vitro cytotoxicity on HepG2 and Huh7 cells, using the MTT assay. Four compounds (4/10) were highly cytotoxic to both HepG2 and HuH7. However, only 3 of these 4 were of the highest safety margin on RPE-1 cells in vitro and in the in vivo acute (14-day) oral toxicity study. These later, superior three compounds’ structures are 3-hydroxy-3-(2-oxo-2-(p-tolyl)ethyl)-5-(piperidin-1-ylsulfonyl)indolin-2-one (3a), N-(4-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4b), and N-(3-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4c). The half-maximal inhibitory concentration (IC50) of the tested compounds (3a, 4b, and 4c) on HepG2 cells were approximately 16.8, 44.7, and 39.7 μM, respectively. The 3a, 4b, and 4c compounds significantly decreased the angiogenic marker epithelial growth factor receptor (EGFR) level and that was further confirmed via molecular docking inside the EFGR active site (PDB: 1M17). The binding free energies ranged between −19.21 and −21.74 Kcal/mol compared to Erlotinib (−25.65 Kcal/mol). The most promising compounds, 3a, 4b, and 4c, showed variable anticancer potential on “hallmarks of cancer”, significant cytotoxicity, and apoptotic anti-angiogenic and anti-invasive effects, manifested as suppression of Bcl-2, urokinase plasminogen activation, and heparanase expression in HepG2-treated cells’ lysate, compared to non-treated HepG2 cells. In conclusion, compound “3a” is highly comparable to doxorubicin regarding cell cycle arrest at G2/M, the pre-G0 phases and early and late apoptosis induction and is comparable to Erlotinib regarding binding to EGFR active site. Therefore, the current study could suggest that compound “3a” is, hopefully, the most safe and active synthesized isatin sulfonamide derivative for HCC management.

Background: Long intergenic non-coding RNA, is one type of lncRNA, exerting various cellular activities, as does ncRNA, including the regulation of gene expression and chromatin remodeling. The abnormal expression of lincRNAs can induce or suppress carcinogenesis. Main body: LincRNAs can regulate cancer progression through different mechanisms and are considered as potential drug targets. Genetic variations such as single nucleotide polymorphisms (SNPs) in lincRNAs may affect gene expression and messenger ribonucleic acid (mRNA) stability. SNPs in lincRNAs have been found to be associated with different types of cancer, as well. Specifically, LINC00511 has been known to promote the progression of multiple malignancies such as breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, and others, making it a promising cancer prognostic molecular marker. Conclusion: LincRNAs have been proved to be associated with different cancer types through various pathways. Herein, we performed a comprehensive literature and in silico databases search listing lncRNAs, lincRNAs including LINC00511, lncRNAs’ SNPs, as well as LINC00511 SNPs in different cancer types, focusing on their role in various cancer types and mechanism(s) of action.

Possible protective mechanism of ω-3FA against DOX‐induced acute hepatic toxicity.

Necroptosis is a novel form of programmed necrotic cell death involved in various autoimmune diseases. The potential role of necroptosis in primary immune thrombocytopenia (ITP) and the possible interlink with autophagy have not been fully investigated. The gene expression of mixed lineage kinase-like domain (MLKL), receptor-interacting protein kinase 3 (RIPK3) and Beclin-1 were quantified in peripheral blood of 45 ITP patients and 20 healthy controls. Their associations with clinical, laboratory parameters and response to steroid therapy in ITP patients were evaluated. RIPK3, MLKL, and Beclin-1 were significantly upregulated in ITP patients than in healthy controls (P < 0.001). Beclin-1 mRNA levels were positively correlated with both RIPK3 and MLKL mRNA levels in ITP patients (P < 0.0001). In addition, MLKL, RIPK3, and Beclin-1 mRNA levels were inversely correlated with platelet count (r = −0.330, −0.527 and −0.608, respectively). On the hand, positive correlations between MLKL (P = 0.01), RIPK3 (P = 0.005), Beclin-1 (P = 0.002) mRNA levels and severity of bleeding in ITP patients were reported. Steroid responders (n = 18, 40%) had significantly lower MLKL, RIPK3, Beclin-1 mRNA expression levels than their levels in the non-responders (n = 27, 60%). Necroptosis may play a critical role in the pathogenesis of ITP and provide both novel therapeutic targets and promising biomarkers for the prediction of bleeding severity and treatment response in ITP patients. Additionally, this study highlighted the crosstalk between autophagy and necroptosis in ITP patients. Graphical abstract

Long intergenic non-coding RNA 00511 (LINC00511) has been involved in the development of several types of cancer including breast cancer (BC). Several single nucleotide polymorphisms (SNPs) can be found in the genomic regions of long non-coding RNAs (lncRNAs) and are associated with the tumorigenesis of many cancers. The objective of the current study is to assess whether LINC00511 SNPs (rs11657109, rs9906859, rs17780195, rs1558535, and rs4432291) could be related with BC incidence in the Egyptian population. Five SNPs of LINC00511 were analyzed in a case–control study of 267 BC cases and 150 controls. Logistic regression analysis was used to test the association between LINC00511 SNPs and BC incidence. We found that the TT genotype of rs11657109 significantly increased BC incidence (OR: 2.177, 95%CI: 1.260–3.763) and this SNP was associated with high incidence of luminal A BC specifically using different genetic models. Haplotype (A₀₉ A₉₁ A₃₅ G₉₅ T₅₉) was strongly associated with an increased BC incidence as it was totally absent in controls. These findings suggest that LINC00511 SNP rs11657109 is associated with BC susceptibility in the Egyptian population.