The epigenetics orchestra of Notch signaling: a symphony for cancer therapy.

The aberrant regulation of the Notch signaling pathway, which is a fundamental developmental pathway, has been implicated in a wide range of human cancers. The Notch pathway can be activated by both canonical and noncanonical Notch ligands, and its role can switch between acting as an oncogene or a tumor suppressor depending on the context. Epigenetic modifications have the potential to modulate Notch and its ligands, thereby influencing Notch signal transduction. Consequently, the utilization of epigenetic regulatory mechanisms may present novel therapeutic opportunities for both single and combined therapeutics targeted at the Notch signaling pathway. This review offers insights into the mechanisms governing the regulation of Notch signaling and explores their therapeutic potential.

Ninety-six-hour starved peripheral blood mononuclear cell supernatant inhibited LA7 breast cancer stem cells induced tumor via reduction in angiogenesis and alternations in Gch1 and Spr expressions.

Introduction: The microenvironment of solid tumors such as breast cancer is heterogeneous and complex, containing different types of cell, namely, cancer stem cells and immune cells. We previously reported the immunoregulatory behavior of the human immune cell in a solid tumor microenvironment-like culture under serum starvation stress for 96 h. Here, we examined the effect of this culture-derived solution on breast cancer development in rats. Method: Ninety-six-hour starved PBMCs supernatant (96 h-SPS) was collected after culturing human PBMCs for 96 h under serum starvation condition. Breast cancer stem cells, LA7 cell line, was used for in vitro study by analyzing gene expression status and performing cytotoxicity, proliferation, scratch wound healing assays, followed by in vivo tumor induction in three groups of mature female Sprague Dawley rats. Animals were treated with 96 h-SPS or RPMI and normal saline as control, n = 6 for each group. After biochemical analysis of iron, lactate, and pH levels in the dissected tumors, Ki67 antigen expression, angiogenesis, and necrosis evaluation were carried out. Metabolic-related gene expression was assessed using RT-qPCR. Moreover, 96 h-SPS composition was discovered by Nano-LC-ESI-MS/MS. Results: 96 h-SPS solution reduced the LA7 cell viability, proliferation, and migration and Gch1 and Spr genes expression in vitro (p< 0.05), whereas stemness gene Oct4 was upregulated (p< 0.01). The intracellular lactate was significantly decreased in the 96 h-SPS treated group (p = 0.007). In this group, Gch1 and Spr were significantly downregulated (p< 0.05), whereas the Sox2 and Oct4 expression was not changed significantly. The number of vessels and mitosis (Ki67+ cells) in the 96 h-SPS-treated group was significantly reduced (p = 0.024). The increased rate of necrosis in this group was statistically significant (p = 0.04). Last, proteomics analysis revealed candidate effectors' components of 96 h-SPS solution. Conclusion: 96 h-SPS solution may help to prevent cancer stem cell mediated tumor development. This phenomenon could be mediated through direct cytotoxic effects, inhibition of cell proliferation and migration in association with reduction in Gch1 and Spr genes expression, angiogenesis and mitosis rate, and necrosis augmentation. The preliminary data obtained from the present study need to be investigated on a larger scale and can be used as a pilot for further studies on the biology of cancer development.

Downregulation of Stemness Genes and Induction of Necrosis in Rat LA7 Cancer Stem Cells Induced Tumors Treated with Starved Fibroblasts Culture Supernatant.

BACKGROUND: Stem cell differentiation therapy is a promising strategy in cancer treatment. we show that protein cocktail prepared from serum starved fibroblasts has therapeutic potential based on this strategy. METHODS: The condition medium was prepared from foreskin isolated fibroblasts and analyzed by Liquid chromatography electrospray ionization mass spectrometry-mass spectrometry (LC-ESI-MS/MS). LA7 mammary gland cancer stem cells originated tumors were induced in Sprague Dawley rats. The rats treated subcutaneously with DMEM (group A), condition medium (group B), or normal saline (group C) once daily for 7 days. Then the tumors were removed and divided into the two parts, one part was used to quantify gene expression by stem-loop RT-qPCR assay and the other part was used for Hematoxylin & Eosin (H & E), Giemsa, and immunohistochemistry (IHC) staining. RESULTS: All induced tumors appeared as sarcomatoid carcinoma (SC). Immunohistochemistry staining confirmed this conclusion by recognizing the tumor as Ki67+, cytokeratin+, vimentine+, and estrogen receptor negative SC. RT-qPCR analysis revealed that Oct4-, Sox-2, Nanog- gene expression was much reduced in the condition medium treated tumors versus proper controls (p< 0.05). Tissue necrosis was more prevalent in this group while tumors volume was diminished almost by 40%. The LC-ESI-MS/MS analysis unrevealed the stemness reducing and the cell death inducing proteins such as, pigment epithelium-derived factor (PEDF), insulin like growth factor binding protein-5 (IGFBP-5) and -7 (IGFBP-7) in the condition medium. CONCLUSION: This study showed that the substances released from starved human fibroblasts were able to down-regulate the stemness-related genes and induce necrosis in LA7 derived tumors.

LINC02688 and PP7080 as novel biomarkers in early diagnosis of gastric cancer.

Despite considerable progress in gastric cancer screening, prevention, and treatment, it remains a major cause of morbidity and mortality worldwide. Due to late diagnosis of the disease, early potential diagnostic biomarkers are needed. Accumulating evidence indicates that non-coding RNAs have potential applications as diagnostic and prognostic biomarkers in gastric cancer. Herein, we investigated the expression levels of two novel non-coding RNAs, long intergenic non-protein coding RNA 2688 (LINC02688) and LOC25845 (PP7080) by real-time PCR for the first time in 47 gastric cancer patients. We found significant downregulation of LINC02688 and LOC25845 (PP7080) with 3.44 and 2.2-fold decrease, respectively in tumoral tissues in comparison with their adjacent non-tumoral counterparts (P < 0.0001). Our data also indicates that more than 96% and 88% of patients showed unchanged or decreased expression of LINC02688 and LOC25845 (PP7080), respectively. As most gastric cancer patients showed lower expression of these two lncRNAs, no significant association between clinicopathological features of the patients and the level of LINC02688 and LOC25845 (PP7080) expression could be detected. Furthermore, ROC curve analysis indicated that LINC02688 and PP7080 can serve as good predictive biomarkers for distinguishing tumoral tissues from their adjacent non-tumoral counterparts. Taken together, our findings suggested that these two novel tumor suppressor non-coding RNAs may act as novel diagnostic biomarkers for diagnosis of carcinogenesis event even at earlier stages of gastric adenocarcinoma.

RNA Sequencing of Early-Stage Gastric Adenocarcinoma Reveals Multiple Activated Pathways and Novel Long Non-Coding RNAs in Patient Tissue Samples.

BACKGROUND: Gastric cancer is among the most common cancers worldwide that currently lacks effective diagnostic biomarkers and therapeutic targets. Next-generation RNA sequencing is a powerful tool that allows rapid and accurate transcriptome-wide profiling to detect differentially expressed transcripts involved in normal biological and pathological processes. Given the function of this technique, it has the potential to identify new molecular targets for the early diagnosis of disease, particularly in gastric adenocarcinoma. METHODS: In this study, whole-transcriptome analysis was performed with RNA sequencing on tumoral and non-tumoral tissue samples from patients with early-stage gastric cancer. Gene ontology and pathway enrichment analysis were used to determine the main function of the specific genes and pathways present in tissue samples. RESULTS: Analysis of the differentially expressed genes revealed 5 upregulated and 234 downregulated genes in gastric cancer tissues. Pathway enrichment analysis revealed significantly dysregulated signalling pathways, including those involved in gastric acid secretion, drug metabolism and transporters, molecular toxicology, O-linked glycosylation of mucins, immunotoxicity, metabolism of xenobiotics by cytochrome P450, and glycosylation. We also found novel downregulated non-coding RNAs present in gastric cancer tissues, including GATA6 antisense RNA 1, antisense to LYZ, antisense P4HB, overlapping ACER2, long intergenic non-protein coding RNA 2688 (LINC02688) and uncharacterized LOC25845 (PP7080). CONCLUSION: The transcriptomic data found in this study illustrates the power of RNA-sequencing in discovering novel genes and tumorigenic pathways involved in human carcinogenesis. The anomalies present in these genes may serve as promising tools for the development of accurate diagnostic biomarkers for the detection of early-stage gastric cancer.

Association of sonic hedgehog signaling pathway genes IHH, BOC, RAB23a and MIR195-5p, MIR509-3-5p, MIR6738-3p with gastric cancer stage.

Gastric cancer is the leading cause of cancer-related mortality worldwide. Given the importance of gastric cancer in public health, identifying biomarkers associated with disease onset is an important part of precision medicine. The hedgehog signaling pathway is considered as one of the most significant widespread pathways of intracellular signaling in the early events of embryonic development. This pathway contributes also to the maintenance of pluripotency of cancer stem cells pluripotency. In this study, we analyzed the expression levels of sonic hedgehog (Shh) signaling pathway genes IHH, BOC, RAB23a and their regulatory miRNAs including MIR-195-5p, MIR-509-3-5p, MIR-6738-3p in gastric cancer patients. In addition, the impact of infection status on the expression level of those genes and their regulatory miRNAs was investigated. One hundred samples taken from 50 gastric cancer patients (50 tumoral tissues and their adjacent non-tumoral counterparts) were included in this study. There was a significant difference in all studied genes and miRNAs in tumoral tissues in comparison with their adjacent non-tumoral counterparts. The lower expression of IHH, BOC, RAB23, miR-195-5p, and miR-6738-3p was significantly associated with more advanced cancer stage. Additionally, IHH upregulation was significantly associated with CMV infection (P < 0.001). Also, receiver operating characteristic (ROC) curve analysis indicated that mir-195 was significantly related to several clinicopathological features including tumor stage, grade, age, gender, and infection status of gastric cancer and can be considered as a potential diagnostic biomarker for gastric cancer. This study confirms the important role of Shh signaling pathway genes in gastric cancer tumorigenesis and their potential as novel molecular biomarkers and therapeutic targets.

Insights into the Links between MYC and 3D Chromatin Structure and Epigenetics Regulation: Implications for Cancer Therapy.

MYC is embedded in the transcriptional oasis of the 8q24 gene desert. A plethora of genomic elements has roles in MYC aberrant expression in cancer development by interacting with transcription factors and epigenetics regulators as well as altering the structure of chromatin at the MYC locus and tissue-specific long-range enhancer-promoter contacts. Furthermore, MYC is a master regulator of several human cancers by modulating the transcription of numerous cancer-related genes through epigenetic mechanisms. This review provides a comprehensive overview of the three-dimensional genomic organization around MYC and the role of epigenetic machinery in transcription and function of MYC as well as discusses various epigenetic-targeted therapeutic strategies in MYC-driven cancers.

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations.

Current SARS-CoV-2 pandemy mortality created the hypothesis that some populations may be more susceptible to SARS-CoV-2. TMPRSS2 encodes a transmembrane serine protease which plays a crucial role in SARS-CoV-2 cell entry. Single nucleotide polymorphisms (SNPs) in TMPRSS2 might influence SARS-CoV2 entry into the cell. This study aimed to investigate the impact of SNPs on TMPRSS2 function and structure. In silico tools such as Ensembl, Gtex, ExPASY 2, GEPIA, CCLE, KEGG and GO were engaged to characterize TMPRSS2 and its expression profile. The functional effects of SNPs were analyzed by PolyPhen-2, PROVEN, SNAP2, SIFT and HSF. Also, Phyre2, GOR IV and PSIPRED were used to predict the secondary structure of TMPRSS2. Moreover, post-translational modification (PTM) and secretory properties were analyzed through Modpredand Phobius, respectively. Finally, miRNA profiles were investigated by PolymiRTS and miRSNPs. Out of 11,184 retrieved SNPs from dbSNP, 92 showed a different frequency between Asians and other populations. Only 21 SNPs affected the function and structure of TMPRSS2 by influencing the protein folding, PTM, splicing and miRNA function. Particularly, rs12329760 may create a de novo pocket protein. rs875393 can create a donor site, silencer and broken enhancer motifs. rs12627374 affects a wide spectrum of miRNAs profile. This study highlighted the role of TMPRSS2 SNPs and epigenetic mechanisms especially non-coding RNAs in appearance of different susceptibility to SARS-CoV-2 among different populations. Also, this study could pave the way to potential therapeutic implication of TMPRSS2 in designing antiviral drugs.Communicated by Ramaswamy H. Sarma.

PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond.

PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelial-mesenchymal 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.

Emerging role of IL-6 and NLRP3 inflammasome as potential therapeutic targets to combat COVID-19: Role of lncRNAs in cytokine storm modulation.

The world has witnessed a high morbidity and mortality caused by SARS-CoV-2, and global death toll is still rising. Exaggerated inflammatory responses are thought to be more responsible for infiltrated immune cells accumulation, organ damage especially lung, dyspnea, and respiratory failure rather than direct effect of viral replication. IL-6 and NLRP3 inflammasome are the major immune components in immune responses stimulation upon pathogen infection. It's noteworthy that the function and expression of these components are remarkably influenced by non-coding RNAs including long non-coding RNAs. Given the potential role of these components in organ damage and pathological manifestations of patients infected with COVID-19, their blockage might be a hopeful and promising treatment strategy. Notably, more study on long non-coding RNAs involved in inflammatory responses could elevate the efficacy of anti-inflammatory therapy. In this review we discuss the potential impact of IL-6 and NLRP3 inflammasome blocker drugs on inflammatory responses, viral clearance, and pathological and clinical manifestations. Collectively, anti-inflammatory strategy might pave the way to diminish clinical and pathological manifestations and thereby discharging patients infected with COVID-19 from hospital.

Systemic effects of starved fibroblast culture supernatant on immunosuppressed rats treated with cancer stem cells (LA7).

BACKGROUND: The present study aimed to investigate and compare the effect of starved fibroblast culture supernatant (SFS), DMEM and normal saline alone or along with LA7 on dexamethasone-treated immunosuppressed Wistar rats. METHODS: After the isolation of fibroblasts from the fresh foreskin of children, it was cultured in serum-free DMEM, and the supernatant collected after 16 hours (16h-SFS). This solution and the other treatments were injected subcutaneously into the rats from each group once daily for 14 days. The liver, intestine and lung histology along with blood cellular and biochemical characteristics were studied. RESULTS: The results showed that dexamethasone as immunosuppressant reduced the body weight. The histological change in the liver was mild fibrosis induced by LA7+16h-SFS. Also, among the different blood cellular and biochemical indices measured, the eosinophil percentage in the 16h-SFS treated rats , glucose levels in the 16h-SFS+LA7 group and triglyceride concentrations in the 16h-SFS group were changed (p<0.05). CONCLUSION: This study showed that the secretions of starved fibroblasts especially that combined with LA7 cancer stem cells could induce some minor histological and biochemical changes in immunosuppressed rats, and also it opened a new window for subsequent investigations on unknown mechanisms related to this work.

Urtica dioica Extract Inhibits Cell Proliferation and Induces Apoptosis in HepG2 and HTC116 as Gastrointestinal Cancer Cell Lines.

BACKGROUND: Nowadays the use of plant-derived products has been extensively examined in the treatment of many types of gastrointestinal cancers such as hepatocarcinoma and colon cancer. Urtica dioica is a traditional herb that has many pharmacological effects and wildly used as a therapeutic agent in cancer. Herein, we have evaluated the effects of the different concentrations of Methanolic Extract of Urtica dioica (MEUD) on viability, death pattern, and expression of the apoptosis-related gene in normal Human Dermal Fibroblast (HDF), hepatocarcinoma cell lines (HepG2) and colon-cancer cell line (HCT116). METHODS: A high-performance liquid chromatography method was developed to simultaneously separate 3 phenolic acids in MEUD. HepG2 and HCT116 cell lines as well as HDF normal cell line were cultured in suitable media. After 24 and 48h, in the cultured cell with different concentrations of MEUD, cells viability was assessed by MTT assay, and apoptosis was also evaluated at the cellular level by Annexin V/PI flow cytometry analyzing and AO/EB staining. BCL2 and BAX gene expressions were assessed by TaqMan real-time PCR assay. RESULTS: MEUD showed antiproliferative effects on HepG2 and HTC116 cells after 48h with an IC50 value of about 410 and 420µg/ml, respectively (P < 0.001). Apoptotic cells were observed in HepG2 and HTC116 cells but not in HDF. Furthermore, the increased level of BAX/BCL-2 ratio was observed in HepG2 and HTC116 cells under the treatment of different concentrations of MEUD. CONCLUSION: The MEUD may influence hepatocarcinoma and colon-cancer cell lines at specific doses and change their proliferation rate by changing the expression of BAX and BCL2.

Targeting LA7 breast cancer stem cells of rat through repressing the genes of stemness-related transcription factors using three different biological fluids.

Down-regulation of stemness genes expression is important in differentiation therapy against cancer stem cells (CSCs). The aim of this study was to evaluate the Oct4 , Sox2, Nanog, and C-myc expression in rat breast cancer stem cells (LA7) which treated with human ovarian follicular fluid (FF), replicative senescent fibroblast culture supernatant (P14), and 16 h serum starved fibroblast supernatant (16 h-SFS). The cells were exposed to these biological fluids for 24 h, 72 h, and 7 days. Stem-loop RT-qPCR assay was used to quantify the expression of above mentioned genes. Results showed that FF had the least cytotoxic effect on the LA7 cells. Except for Nanog gene, exposure of LA7 cell line to 16 h-SFS and P14 decreased significantly expression of the three other genes after 24 h (P < 0.05). Nanog and Sox2 genes expression was also decreased in LA7 cells which have been already treated with FF for 24 h. Moreover, compared to the control solution, the expression of Oct4 increased significantly after 7 days exposure to FF (P < 0.05). Annexin V-PE /7-AAD-, acridine orange/ethidium bromide staining and doubling time assays revealed apoptosis and necrosis induction by these biological fluids in LA7 cells. Moreover, in an in vitro model of metastasis assay, i.e., scratch test, these fluids exhibited anti-LA7 migration activity which culminated in 16 h-SFS treated cells. Generally, this study showed that FF, 16 h-SFS, and P14 have positive effects on down-regulation of Nanog, Oct4, Sox2 and C-myc expression, and consequently can increase the differentiation of breast cancer stem cells. For the first time, this study provided some evidence indicating that some biological fluids have potential to differentiate the CSCs, show anti- survival, growth-, and cell migration activity.

LncRNAs as potential diagnostic and prognostic biomarkers in gastric cancer: A novel approach to personalized medicine.

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.

CDX1/2 and KLF5 Expression and Epigenetic Modulation of Sonic Hedgehog Signaling in Gastric Adenocarcinoma.

Gastric cancer is among the commonplace causes of cancer death worldwide. Sonic hedgehog (Shh) signaling is an important pathway which may be dysregulated in many cancers.CDX1/2, and KLF5are key transcription factors involved in Shh pathway and cancer stem cells. The aim of this study was to investigate the expression and epigenetic alterations of these genes in gastric cancer patients. DNA methylation's modifications of CDX1, KLF5 and CDX2 genes alongside with the expressions of these genes in gastric cancer tissues and their non-tumoral counterparts (margin tissues) were analyzed using methylation specific sequencing, and Real time PCR Taq man assays, respectively. The expression of CDX1 (P = 0.002) and KLF5 (P = 0.010) were decreased significantly, but it was considerably increased for CDX2 (P = 0.001). Relatively, the results for the regulatory region methylation status of each CpG site had shown a notable fluctuation in these genes with no significant difference in most places. The creation of metastatic lymph nodes in patients was significantly associated with increased expression of CDX2 gene. The modifications of these genes expression can be considered as a cancer biomarker in future studies. Methylation of the investigated genes is not the main mechanism of gastric cancer development.

CTNNBIP1 downregulation is associated with tumor grade and viral infections in gastric adenocarcinoma.

Gastric cancer is a life-threatening disease; resulting from interaction among genetic, epigenetic, and environmental factors. Aberrant dysregulation and methylation changes in Wnt/ß-catenin signaling downstream elements are a prevalent phenomenon encountered in gastric tumorigenesis. Also, viral infections play a role in gastric cancer development. CTNNBIP1 (ß-catenin interacting protein 1) gene is an antagonist of Wnt signaling which binds to the ß-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.

Epigenetic alterations of CYLD promoter modulate its expression in gastric adenocarcinoma: A footprint of infections.

Gastric cancer (GC) is one of the most common causes of cancer-related death in the world, with multiple genetic and epigenetic alterations involved in disease development. CYLD tumor suppressor gene encodes a multifunctional deubiquitinase which negatively regulates various signaling pathways. Deregulation of this gene has been found in different types of cancer. This study aimed to evaluate for the first time the CpG island methylation pattern of CYLD gene promoter, and its expression level in gastric adenocarcinoma. CYLD messenger RNA expression and promoter methylation in 53 tumoral and their non-neoplastic counterpart tissues were assessed using quantitative polymerase chain reaction and bisulfite sequencing. Also, we investigated the impacts of the infectious agents including Helicobacter pylori (H. pylori), EBV, and CMV on CYLD expression and promoter methylation in GC. Results showed that the expression level of CYLD was downregulated in GC, and was significantly associated with gender (female), patient's age (<60), high grade, and no lymph-node metastasis (p = 0.001, 0.002, 0.03, and 0.003, respectively). Among the 31 analyzed CpG sites located in about 600 bp region within the promoter, two CpG sites were hypermethylated in GC tissues. We also found a significant inverse association between DNA promoter methylation and CYLD expression (p = 0.02). Furthermore, a direct association between H. pylori, EBV, and CMV infections with hypermethylation and reduced CYLD expression was observed (p = 0.04, 0.03, and 0.03, respectively). Our findings indicate that CYLD is downregulated in GC. Infectious agents may influence CYLD expression.

PI3k/AKT signaling pathway: Erythropoiesis and beyond.

Erythropoiesis is a multi-step process that involves the differentiation of hematopoietic stem cells into mature red blood cells (RBCs). This process is regulated by several signaling pathways, transcription factors and microRNAs (miRNAs). Many studies have shown that dysregulation of this process can lead to hematologic disorders. PI3K/AKT is one of the most important pathways that control many cellular processes including, cell division, autophagy, survival, and differentiation. In this review, we focus on the role of PI3K/AKT pathway in erythropoiesis and discuss the function of some of the most important genes, transcription factors, and miRNAs that regulate different stages of erythropoiesis which play roles in differentiation and maturation of RBCs, prevention of apoptosis, and autophagy induction. Understanding the role of the PI3K pathway in erythropoiesis may provide new insights into diagnosing erythrocyte disorders.

Informative combination of CLU rs11136000, serum HDL levels, diabetes, and age as a new piece of puzzle-picture of predictive medicine for cognitive disorders.

Clusterin (CLU) is the third most important associated risk gene in cognitive disorders. Regarding the controversy about the association of CLU rs11136000 with mild cognitive impairment (MCI), the aim of this study was to investigate a putative association of CLU rs11136000 with MCI as well as the serum biological factors with a special attention to the age as a main dimension of a multifactorial elderly disease in an Iranian elderly cohort in which the mentioned association was not previously investigated. The study also checked the association between diabetes and MCI in this population. A population of 418 individuals containing 236 MCI and 192 control subjects was recruited from the Amirkola health and aging population cohort. Serum biological indexes were assessed by biochemical and enzyme-linked immunosorbent assay, and rs11136000 genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. Bioinformatics analyses were used to identify the putative effect of rs11136000 on the secondary structure of RNA and chromatin location in different cell lines and tissues. Type 2 diabetes was present with a higher proportion in the MCI group in comparison with the control group (P = 0.041). The frequency of the C allele of CLU rs11136000 was significantly different between cases and controls and was associated with MCI risk (OR 1.79, P = 0.019). Under a dominant genetic model, the CC genotype showed a predisposing effect in individuals aged ≥ 75 years (OR 3.33, P = 0.0004). Interestingly, under an over-dominant model, the CT genotype had a protective effect in this population (OR 4.52, P = < 0.0001). We also found a significant association between the genotypes and high-density lipoprotein (HDL) levels in MCI patients (P = 0.0004). Bioinformatics analysis showed that rs11136000 is located in the transcribed region without any regulatory features such as being enhancer or insulator. Also, the T>C transition of CLU rs11136000 could not cause significant mRNA folding (P = 0.950). Contrary to other studies on Asian populations, this study demonstrated an association between rs11136000 and MCI in an elderly Iranian population. This study also suggests that an age-dependent approach to the previous studies may be performed in order to revise the previous belief in this geographical area. The rs11136000 genotypes in combination with HDL levels and knowledge about diabetes background may be used as a predictive medicine tool for cognitive disorders.