Long noncoding RNAs as regulators of epithelial mesenchymal transition in breast cancer: A recent review.

AIMS: Breast cancer (BC) is the most frequently occurring cancer in women worldwide. BC patients are often diagnosed at advanced stages which are characterized by low survival rates. Distant metastasis is considered a leading cause of mortalities among BC patients. Epithelial-to-mesenchymal transition (EMT) is a transdifferentiation program that is necessary for cancer cells to acquire metastatic potential. In the last decade, long noncoding RNAs (lncRNAs) proved their significant contribution to different hallmarks of cancer, including EMT and metastasis. The primary aim of our review is to analyze recent studies concerning the molecular mechanisms of lncRNAs implicated in EMT regulation in BC. MATERIALS AND METHODS: We adopted a comprehensive search on databases of PubMed, Web of Science, and Google Scholar using the following keywords: lncRNAs, EMT, breast cancer, and therapeutic targeting. KEY FINDINGS: The different roles of lncRNAs in the mechanisms and signaling pathways governing EMT in BC were summarized. LncRNAs could induce or inhibit EMT through WNT/ß-catenin, transforming growth factor-ß (TGF-ß), Notch, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways as well as via their interaction with histone modifying complexes and miRNAs. SIGNIFICANCE: LncRNAs are key regulators of EMT and BC metastasis, presenting potential targets for therapeutic interventions. Further research is necessary to investigate the practical application of lncRNAs in clinical therapeutics.

Unravelling the In Vitro and In Vivo Anti-Helicobacter pylori Effect of Delphinidin-3-O-Glucoside Rich Extract from Pomegranate Exocarp: Enhancing Autophagy and Downregulating TNF-α and COX2.

Fruits containing antioxidants, e.g., anthocyanins, exhibit antimicrobial activities. The emergence of drug resistance represents a major challenge in eradicating H. pylori. The current study aims to explore the effect of pomegranate exocarp anthocyanin methanol extract (PEAME) against H. pylori isolates recovered from antral gastric biopsies. The UPLC-PDA-MS/MS and 1H NMR analyses indicated delphinidin-3-O-glucoside as the major anthocyanin in the extract. The PEAME showed activity against all tested resistant isolates in vitro recording minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 128 and 256 µg/mL, respectively. In vivo investigation included evaluation of the rat gastric mucosa for malondialdehyde (MDA), catalase activity, COX2, TNF-α, and key autophagy gene expression. The combination of pomegranate with metronidazole markedly reduced the viable count of H. pylori and the level of COX2, with alleviation of H. pylori-induced inflammation and oxidative stress (reduction of MDA, p-value < 0.001; and increase in catalase activity, p-value < 0.001). Autophagy gene expression was significantly upregulated upon treatment, whereas TNF-α was downregulated. In conclusion, we comprehensively assessed the effect of PEAME against H. pylori isolates, suggesting its potential in combination with metronidazole for eradication of this pathogen. The beneficial effect of PEAME may be attributed to its ability to enhance autophagy.

Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors.

Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15a, 15b, and 15d showed IC50 from 17.39 to 47.10 µM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15d which came second with regard to antitumor assay with IC50 = 24.10, 40.90, and 33.40 µM against aforementioned cell lines, respectively. Furthermore, Compound 15d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15d showed IC50 of 253 and 381 nM against HER2 and FGFR, respectively.

Candesartan protects against d-galactose induced - Neurotoxicity and memory deficit via modulation of autophagy and oxidative stress.

PURPOSE: d-galactose induces neuroinflammation and memory deficit via oxidative stress. Candesartan is an angiotensin II-receptor blocker and has proved neuroprotective properties. This study aimed to investigate the neuroprotective effect of candesartan against d-galactose induced neuroinflammation and memory deficit via autophagy. METHODS: Twenty-eight male Wistar rats aged 3 months were divided into four equal groups: control (vehicle), d-gal (100 mg/kg d-galactose), cand (1 mg/kg candesartan), and cand+d-gal (100 mg/kg d-galactose & 1 mg/kg candesartan). All treatments were given orally and daily for 4 weeks. Assessment of memory was done using Morris water maze (MWM) test. Brain tissue was assessed for malondialdehyde (MDA), total thiol, catalase activity, glial fibrillary acidic protein (GFAP) and gene expression of TNF-α, GDNF-1 as well as autophagy genes (Beclin 1 and ATG 5). RESULTS: Prophylactic treatment of candesartan in d-galactose-treated rats significantly (p < 0.001) reduced oxidative stress via reduction of MDA as well as elevation of catalase activity and total thiol levels. Additionally, candesartan prophylactic treatment significantly increased gene expression of GDNF-1 and decreased gene expression of TNF-α. Furthermore, candesartan significantly increased the expression of autophagy related gene (Beclin 1 and ATG 5) in cand+d-gal treated rats. These results were supported by the histopathological findings which showed that candesartan prevented the neuronal injury in the cerebral cortex and hippocampus and decreased GFAP positive cells of the d-galactose-treated rats. Moreover, MWM test showed that candesartan significantly improved memory deficit in cand+d-gal treated rats. CONCLUSION: Candesartan prevents d-galactose-induced neurotoxicity and memory deficit via activating autophagy and decreasing oxidative stress. Therefore, candesartan was a good candidate for age-related neurodegenerative disorders and memory deficit.

The plausible mechanisms of tramadol for treatment of COVID-19.

Currently, no single medication has been approved for the management of coronavirus disease-2019 (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, drug repositioningby investigating the use of existing drugs for management of COVID-19 patients is considered a desperate need. Tramadol is a commonly prescribed analgesic drug for treatment of moderate to severe pain with less potential for dependence and respiratory depression. Multiple evidence support that tramadol is a promising drug for treatment of COVID-19 patients. Herein, we discuss the possible beneficial effects of using tramadol against SARS-CoV-2 infection and their underlying mechanism of action. The anti-inflammatory effect of tramadol may help to suppress the COVID-19 related cytokine storm through decreasing interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Besides, tramadol activates natural killer (NK) and T-cells and enhances IL-2 secretion, which produce immune-enhancing effect against SARS-CoV-2. Recent studies confirmed that COVID-19 patients with acute respiratory failure showed increased fibrin formation and polymerization that may lead to thrombosis. Tramadol owing to its hypocoagulable effect may protect against venous thromboembolism in these patients. Moreover, tramadol can exert a cardioprotective effect via decreasing lactate dehydrogenase (LDH) level which is elevated in most of patients with COVID-19. Furthermore, the severity and mortality of COVID-19 have been correlated with old age patients, which may be due to the lack of antioxidant mechanisms and increased oxidative damage. Tramadol could protect COVID-19 patient from disease complications by increases the antioxidant enzymes superoxide dismutase and glutathione peroxidase while diminished malondialdehyde. More interestingly, tramadol as an effective analgesic and antitussive may have a beneficial effect on COVID-19 patients suffering from cough, headache, ache, and pain. The tramadol anti-psychotic effect may also protect against psychiatric disorders associated with SARS-CoV-2 infection. Moreover, tramadol has bactericidal activity against a wide range of pathogens including Pseudomonas aeruginosa which is common in severe COVID-19 patients leading to pneumonia with worse clinical outcomes. Therefore, we hypothesize that tramadol might be a promising adjuvant therapeutic option against SARS-CoV-2 infection. Based on that, tramadol should be considered as adjuvant therapy for COVID-19 clinical trials.

Effect of modification of MTDH gene expression on colorectal cancer aggressiveness.

BACKGROUND: Metadherin (MTDH) is an oncogene that has been overexpressed in numerous types of malignancies including colorectal cancer (CRC). However, few investigations associated with the biological behavior of MTDH in CRC have been performed. The aim of the present study was to investigate the effect of modification of MTDH gene expression (knockdown and overexpression) on the biological behavior of CRC in vitro. METHODS: MTDH gene expression was analyzed in two CRC cell lines (Caco-2 and HCT116) by qPCR. MTDH was down-regulated via siRNA-mediated knockdown of human MTDH in HCT116 cells, which express high endogenous levels of MTDH gene. Also, MTDH gene was up-regulated via transfection of Caco-2 cells, which express low endogenous levels of MTDH gene, with a plasmid carrying human MTDH gene. RESULTS: Knockdown of MTDH gene expression significantly decreased the gene expression of multidrug resistance gene (MDR1), Snail and NF-κB p65, but increased the gene expression of E-cadherin. Furthermore, MTDH-knockdown significantly decreased anaerobic glycolysis (glucose consumption and lactate production), cell proliferation ability and transformation into cancer stem cell. Moreover, up-regulation of MTDH gene significantly increased the gene expression of MDR1, Snail and NF-κB p65, deceased the gene expression of E-cadherin, enhanced cell proliferation, and anaerobic glycolysis and activated transformation into cancer stem cells. CONCLUSIONS: MTDH has an important role in promoting CRC aggravation. Also, inhibition of MTDH expression may attenuate the carcinogenic behavior of CRC cells. Furthermore, MTDH-associated NF-κB p65 signaling pathways may be involved in mediating the biological behavior of CRC.

Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway.

Epithelial-mesenchymal transition (EMT) leads to tumor dissemination and metastasis. Metadherin (MTDH) is an oncogene that plays an important role in metastasis regulation. This study tries to investigate the effect of MTDH gene up-regulation on the activation of EMT in colorectal cancer (CRC) cells and identify the role of NF-κB p65. The CaCO2 cells were divided into three groups: one control group of cultured CaCO2 cells (C1), and two groups of CaCO2 cells co-transfected using human MTDH expression plasmid with either siRNA targeting human NF-κB p65 or its negative control (C2 and C3 respectively). The gene modification was confirmed by qPCR and the effect of gene modification on CRC aggravation was studied. MTDH up-regulation significantly promoted CRC cell proliferation, activated anaerobic respiration (glucose consumption and lactate production), and increased gene expression of multidrug resistance gene (MDR1), Snail transcription factor and NF-κB p65, but decreased the gene expression of E-cadherin. Moreover, MTDH up-regulation led to a significant increase in the acquisition of surface markers of CRC stem cells. Interference with NF-κB p65 gene expression reversed the action of MTDH gene up-regulation on MDR1 and E-cadherin gene expression and anaerobic respiration. Moreover, NF-κB p65 interference significantly decreased MTDH-induced cell proliferation and acquisition of surface markers of CRC stem cells but didn't affect the Snail transcription factor. MTDH-dependent EMT in CRC is activated via NF-κB p65 and is mediated by up-regulation of Snail. These results identify a pathway by which MTDH regulates NF-κB p65 induced EMT during CRC cell metastasis.