The Intergenic Type LncRNA (LINC RNA) Faces in Cancer with In Silico Scope and a Directed Lens to LINC00511: A Step toward ncRNA Precision.

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.

Upregulation of necroptosis markers RIPK3/MLKL and their crosstalk with autophagy-related protein Beclin-1 in primary immune thrombocytopenia.

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.

Cytotoxic T Cell Expression of Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) in Viral Hepatitis C-Mediated Hepatocellular Carcinoma.

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.

Doxorubicin-induced hepatic toxicity in rats: Mechanistic protective role of Omega-3 fatty acids through Nrf2/HO-1 activation and PI3K/Akt/GSK-3ß axis modulation.

Doxorubicin (DOX), a common antibiotic used to treat a variety of tumors, has several substantial adverse effects that limit its clinical use. As a result, finding effective protective agents to combat DOX-induced organ damage is a necessity. The current study was set to delineate the hepatoprotective role of omega-3 fatty acids (ω-3FA) against DOX-mediated acute liver damage in rats and the underlined mechanism of GSK-3ß inhibition. Five groups of rats were orally received either saline (groups 1 & 2) or ω-3FA (25, 50 and 100 mg/kg/day; groups 3, 4 & 5, respectively) for 28 consecutive days. Single DOX intraperitoneal injection (20 mg/kg) was used to induce hepatic toxicity in all groups except group 1 (negative control). Blood samples and liver tissues were collected 48-hr after injection. Our results revealed that pre-administration of ω-3FA (25, 50 and 100 mg/kg) to DOX-induced hepatic injured rats showed a significant reduction in serum hepatic injury biomarkers (ALT, AST, total and direct bilirubin) as well as hepatic contents of MDA, GSH, Nrf2 and HO-1. Additionally, hepatic PI3K, pAkt and GSK-3ß have been restored significantly in a dose-dependent manner. Furthermore, all the hepatic histopathological features have been retained upon ω-3FA treatment together with the immunostaining intensity of tumor necrosis factor-α and caspase-3. These results suggest that ω-3FA have shown a marked activation of the Nrf2/HO-1 signaling pathway and modulation of the PI3K/pAkt/GSK-3ß axis against DOX-induced hepatotoxicity.

Anticancer Effects with Molecular Docking Confirmation of Newly Synthesized Isatin Sulfonamide Molecular Hybrid Derivatives against Hepatic Cancer Cell Lines.

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.

Competitive Endogenous Role of the LINC00511/miR-185-3p Axis and miR-301a-3p From Liquid Biopsy as Molecular Markers for Breast Cancer Diagnosis.

Breast cancer (BC) is the leading cause of female cancer-related mortalities. Evidence has illustrated the role of long non-coding RNAs (lncRNA) and microRNAs (miRNA) as promising pool of protein non-coding regulators, for tuning the aggressiveness of several malignancies. This research aims to unravel the expression pattern and the emphases of the diagnostic value of the long intergenic ncRNA00511 (LINC00511) and its downstream microRNA (miR-185-3p) and the pathogenic significance of the onco-miR-301a-3p in naïve BC patients. LINC00511 was chosen and validated, and its molecular binding was confirmed using bioinformatics. LINC00511 was measured in 25 controls and 70 patients using qPCR. The association between the investigated ncRNA's expression and the BC patients' clinicopathological features was assessed. Receiver operating characteristic (ROC) curve was blotted to weigh out their diagnostic efficacy over the classical tumor markers (TMs). Bioinformatics and Spearman correlation were used to predict the interaction between LINC00511, miR-185-3p, and miR-301a-3p altogether to patients' features. LINC00511 and miR-301a-3p, in BC patients' blood, were overexpressed, and their median levels increased significantly, while miR-185-3p was, in contrast, downregulated, being decreased fourfold. LINC00511 was elevated in BC early stages, when compared to late stages (p < 0.0003). LINC00511, miR-185-3p, and miR-301a-3p showed AUC superior to classical TMs, allowing us to conclude that the investigated ncRNAs, in BC patients' liquid biopsy, are novel diagnostic molecular biomarker signatures. Lymph node metastasis (LNM) and advanced tumor grade were directly correlated with LINC00511 significantly. Additionally, both LINC00511 and miR-301a-3p were positively correlated with the aggressiveness of BC, as manifested in patients with larger tumors (>2 cm) at (p < 0.001). Therefore, these findings aid our understanding of BC pathogenesis, in the clinical setting, being related in part to the LINC00511/miR axis, which could be a future potential therapeutic target.

MicroRNAs' role in the environment-related non-communicable diseases and link to multidrug resistance, regulation, or alteration.

The discovery of microRNAs (miRNAs) 20 years ago has advocated a new era of "small molecular genetics." About 2000 miRNAs are present that regulate one third of the genome. MiRNA dysregulated expression arising as a response to our environment insult or stress or changes may contribute to several diseases, namely non-communicable diseases, including tumor growth. Their presence in body fluids, reflecting level alteration in various cancers, merit circulating miRNAs as the "next-generation biomarkers" for early-stage tumor diagnosis and/or prognosis. Herein, we performed a comprehensive literature search focusing on the origin, biosynthesis, and role of miRNAs and summarized the foremost studies centering on miR value as non-invasive biomarkers in different environment-related non-communicable diseases, including various cancer types. Moreover, during chemotherapy, many miRNAs were linked to multidrug resistance, via modulating numerous, environment triggered or not, biological processes and/or pathways that will be highlighted as well.

Peripheral leucocytes and tissue gene expression of granzyme B/perforin system and serpinB9: Impact on inflammation and insulin resistance in coronary atherosclerosis.

AIM: The imbalance between proapoptotic granzyme B (GZB)/perforin (PRF) system and proteinase inhibitor-9 (PI-9; serpinB9); the only known inhibitor of human GZB, has been demonstrated in atherosclerosis. However, their role in atherosclerosis with the impact of type 2 diabetes mellitus (DM) as well as their contribution to hallmarks of atherosclerosis is not clear. SUBJECTS AND METHODS: ELISA for serum insulin, high sensitivity C-reactive protein (hsCRP) and GZB levels in atherosclerotic coronary artery diseases (CAD) patients were estimated in comparison to apparently healthy controls, while GZB, PRF and PI-9 mRNA expression levels were quantified by Taqman RT-PCR in both peripheral leucocytes and atherosclerotic tissues. RESULTS: Atherosclerotic patients showed significantly higher insulin, hsCRP and GZB levels than controls. There was a significant increase in GZB mRNA expression and significant reduction in PI-9 mRNA in both patient peripheral leucocytes and atherosclerotic lesions, while PRF mRNA increased significantly only in atherosclerotic tissues. PI-9 mRNA levels were significantly lower in patients with diabetes than patients without diabetes. In contrast to positive modulating effect of GZB, regression analysis revealed negative modulating effect of PI-9 on inflammation and insulin resistance. Circulating PI-9 mRNA was inversely contributed to CAD severity. CONCLUSIONS: GZB and PI-9 could be effective modulators for inflammation and insulin resistance in atherosclerosis.

hsCRP, sICAM-1 and TAFI in hemodialysis patients: linking inflammation and hypofibrinolysis to cardiovascular events.

BACKGROUND/AIMS: Growing evidence suggests that inflammation, oxidative stress and hypofibrinolysis may have a pivotal role in the high prevalence of cardiovascular disease (CVD) in chronic kidney disease (CKD) patients. This study aims to investigate the association of these processes with the incidence of CVD in hemodialysis (HD) patients and to examine the modulating effect of oral L-arginine in HD patients having CVD. METHODS: Blood malondialdehyde (MDA), highly sensitive C-reactive protein (hsCRP), soluble intracellular adhesion molecule-1 (sICAM-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) levels were measured in 12 healthy controls and in 62 CKD patients divided into 15 renal impairment, 21 HD, and 26 HD+CVD. Of the latter, 15 patients received oral L-arginine (15 g/day, 5 g t.i.d.) for 1 month. RESULTS: MDA, hsCRP, sICAM-1 and TAFI were significantly elevated in renal impairment patients. HD and HD+CVD experienced higher levels, but only MDA and TAFI were significantly higher in HD+CVD than HD patients. Only MDA was significantly reduced by 41% after L-arginine intake. CONCLUSION: This study demonstrates the association of inflammation and hypofibrinolysis with hemodialysis especially in patients with CVD. We found no added therapeutic value for L-arginine at the used dose and duration to ameliorate these cascades of events.