PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelialmesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers.Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.

Gastric cancer is the third leading cause of cancer death with 5-year survival rate of about 30-35%. Since early detection is associated with decreased mortality, identification of novel biomarkers for early diagnosis and proper management of patients with the best response to therapy is urgently needed. Long noncoding RNAs (lncRNAs) due to their high specificity, easy accessibility in a noninvasive manner, as well as their aberrant expression under different pathological and physiological conditions, have received a great attention as potential diagnostic, prognostic, or predictive biomarkers. They may also serve as targets for treating gastric cancer. In this review, we highlighted the role of lncRNAs as tumor suppressors or oncogenes that make them potential biomarkers for the diagnosis and prognosis of gastric cancer.Relatively, lncRNAs such as H19, HOTAIR, UCA1, PVT1, tissue differentiation-inducing nonprotein coding, and LINC00152 could be potential diagnostic and prognostic markers in patients with gastric cancer. Also, the impact of lncRNAs such as ecCEBPA, MLK7-AS1, TUG1, HOXA11-AS, GAPLINC, LEIGC, multidrug resistance-related and upregulated lncRNA, PVT1 on gastric cancer epigenetic and drug resistance as well as their potential as therapeutic targets for personalized medicine was discussed.

The evolutionarily conserved Hedgehog (Hh) signaling pathway have critical roles in development and homeostasis of tissues. Under physiological conditions, Hh is controlled at different levels via stem cell maintenance and tissue regeneration. Aberrant activation of this signaling pathway may occur in a wide range of human diseases including different types of cancer. In this review we present a concise overview on the key genes composing Hh signaling pathway and provide recent advances on the molecular mechanisms that regulate Hh signaling pathway from extracellular and receptors to the cytoplasmic and nuclear machinery with a highlight on the role of microRNAs. Furthermore, we focus on critical studies demonstrating dysregulation of the Hh pathway in human disease development, and potential therapeutic implications. Finally, we introduce recent therapeutic drugs acting as Shh signaling pathway inhibitors, including those in clinical trials and preclinical studies.

Breast cancer is the most prevalent cancer and one of the leading causes of death among women in the world. Plants and herbs may play an important role in complementary or alternative treatment. The aim of this study was to evaluate the antioxidant and anti-proliferative potential of Urtica dioica. The anti oxidant activity of an aqueous extract of Urtica dioica leaf was measured by MTT assay and the FRAP method while its anti-proliferative activity on the human breast cancer cell line (MCF-7) and fibroblasts isolated from foreskin tissue was evaluated using MTT assay. Mechanisms leading to apoptosis were also investigated at the molecular level by measuring the amount of anti and pro-apoptotic proteins and at the cellular level by studying DNA fragmentation and annexin V staining by flow cytometry. The aqueous extract of Urtica dioica showed antioxidant effects with a correlation coefficient of r 2 =0.997. Dose-dependent and anti-proliferative effects of the extract were observed only on MCF-7 cells after 72 hrs with an IC 50 value of 2 mg/ml. This anti proliferative activity was associated with an increase of apoptosis as demonstrated by DNA fragmentation, the appearance of apoptotic cells in flow cytometry analysis and an increase of the amount of calpain 1, calpastatin, caspase 3, caspase 9, Bax and Bcl-2, all proteins involved in the apoptotic pathway. This is the first time such in vitro antiproliferative effect of aqueous extract of Urtica dioica leaf has been described for a breast cancer cell line. Our findings warrant further research on Urtica dioica as a potential chemotherapeutic agent for breast cancer.

IntroductionCell‐based therapy is considered as promising strategy to cure stroke. However, employing appropriate type of stem cell to fulfill many therapeutic needs of cerebral ischemia is still challenging. In this regard, the current study was designed to elucidate therapeutic potential of epidermal neural crest stem cells (EPI‐NCSCs) compared to bone marrow mesenchymal stem cells (BM‐MSCs) in rat model of ischemic stroke.MethodsIschemic stroke was induced by middle cerebral artery occlusion (MCAO) for 45 minutes. Immediately after reperfusion, EPI‐NCSCs or BM‐MSCs were transplanted via intra‐arterial or intravenous route. A test for neurological function was performed before ischemia and 1, 3, and 7 days after MCAO. Also, infarct volume ratio and relative expression of 15 selected target genes were evaluated 7 days after transplantation.ResultsEPI‐NCSCs transplantation (both intra‐arterial and intravenous) and BM‐MSCs transplantation (only intra‐arterial) tended to result in a better functional outcome, compared to the MCAO group; however, this difference was not statistically significant. The infarct volume ratio significantly decreased in NCSC‐intra‐arterial, NCSC‐intravenous and MSC‐intra‐arterial groups compared to the control. EPI‐NCSCs interventions led to higher expression levels of Bdnf, nestin, Sox10, doublecortin, β‐III tubulin, Gfap, and interleukin‐6, whereas neurotrophin‐3 and interleukin‐10 were decreased. On the other hand, BM‐MSCs therapy resulted in upregulation of Gdnf, β‐III tubulin, and Gfap and down‐regulation of neurotrophin‐3, interleukin‐1, and interleukin‐10.ConclusionThese findings highlight the therapeutic effects of EPI‐NCSCs transplantation, probably through simultaneous induction of neuronal and glial formation, as well as Bdnf over‐expression in a rat model of ischemic stroke.

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Gastric cancer is a major health problem worldwide occupying most frequent causes of cancerrelated mortality. In addition to genetic modifications, epigenetic alterations catalyzed by DNA methyltransferases (DNMTs) is a well-characterized epigenetic hallmark in gastric cancer. The reversible nature of epigenetic alterations and central role of DNA methylation in diverse biological processes provides an opportunity for using DNA methyltransferase inhibitors to enhance the efficacy of chemotherapeutics. In this review, we discussed key factors or mechanisms such as SNPs, infections, and genetic modifications that trigger DNMTs level modification in gastric cancer, and their potential roles in cancer progression. Finally, we focused on how inhibitors of the DNMTs can most effectively be used for the treatment of gastric cancer with multidrug resistance.

Gastric cancer is a life-threatening disease; resulting from interaction among genetic, epigenetic, and environmental factors. Aberrant dysregulation and methylation changes in Wnt/β-catenin signaling downstream elements are a prevalent phenomenon encountered in gastric tumorigenesis. Also, viral infections play a role in gastric cancer development. CTNNBIP1 (β-catenin interacting protein 1) gene is an antagonist of Wnt signaling which binds to the β-catenin molecules. The CTNNBIP1 function as tumor suppressor gene or oncogene in different types of cancer is controversial. Moreover, its function and regulatory mechanisms in gastric cancer progression is unknown. In the present study, we examined CTNNBIP1 gene expression, the methylation status of the regulatory region of the gene, and their association with Epstein-Barr virus (EBV), and cytomegalovirus (CMV) and Helicobacter pylori infections in human gastric adenocarcinoma tissues in comparison with their adjacent nontumoral tissues. Our data revealed a significant downregulation of CTNNBIP1 in gastric tumors. Female patients showed lower level of CTNNBIP1 than males (p < 0.05). Also, decreased expression of CTNNBIP1 was markedly associated with well-differentiated tumor grades (p < 0.05). No methylation change was observed between tumoral and nontumoral tissues. Additionally, CTNNBIP1 down regulation was significantly associated with CMV infection (p < 0.05). In the absence of EBV infection, lower expression of CTNNBIP1 was observed. There was no association between H. pylori infection and CTNNBIP1 expression. Our findings revealed the tumor suppressor role for CTNNBIP1 in gastric adenocarcinoma. Interestingly, EBV and CMV infections modulate CTNNBIP1 expression.