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.

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.

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.

First Report of Association Between Rare α-Thalassemia Mutation (HBA1: c.298A>T) and Hb Fontainebleau (HBA2: c.64G>C).

α-Thalassemia is one of the most common monogenic diseases worldwide. The combination of alpha-chain variants with thalassemia mutations may lead to clinical and hematological characteristics, which is of importance for genetic counseling. The present study describes for the first time a rare α1-globin nonsense mutation, codon 99 (HBA1: c.298A>T) associated with a α2-chain variant Hb Fontainebleau (HBA2: c.64G>C) in a family from northern Iran. The case is a 23-year-old man with hypochromic microcytic anemia that requested for prenatal diagnosis. The combination of α1-globin mutation and Hb Fontainebleau can cause clinical and hematologic features of thalassemia. This combination also highlights the important heterogeneity of alpha thalassemia in this part of the world.

Infection-associated epigenetic alterations in gastric cancer: New insight in cancer therapy.

Gastric cancer risk is higher for malignancies motivated by bacterial and viral infections. Epigenetic abnormalities including DNA methylation, histone modifications, and noncoding RNAs are important regulatory key players in gastric cancer development in infected patients. Epigenetic memory restoration is an extremely interesting phenomenon which should be considered in therapeutic approaches. In vitro and in vivo antiviral treatments in combination with epigenetic therapeutic strategies along with standard chemotherapy revealed promising outcomes in gastric cancer prevention and treatment. This review summarizes our current understanding of the gastric cancer infections and epigenetic alterations caused by these agents. We focus on studies highlighting recent advances in epigenetic restoration by target specific drugs and present also a comprehensive overview of effective antiviral drug treatments against gastric cancer.

Urtica dioica inhibits cell growth and induces apoptosis by targeting Ornithine decarboxylase and Adenosine deaminase as key regulatory enzymes in adenosine and polyamines homeostasis in human breast cancer cell lines.

Breast cancer is a heterogeneous and multifactorial disease with variable disease progression risk, and treatment response. Urtica dioica is a traditional herb used as an adjuvant therapeutic agent in cancer. In the present study, we have evaluated the effects of the aqueous extract of Urtica dioica on Adenosine deaminase (ADA) and Ornithine decarboxylase (ODC1) gene expression in MCF-7, MDA-MB-231, two breast cancer cell lines being estrogen receptor positive and estrogen receptor negative, respectively.  Cell lines were cultured in suitable media. After 24 h, different concentrations of the extract were added and after 72 h, ADA and ODC1 gene expression as well as BCL2 and BAX apoptotic genes were assessed by Taqman real time PCR assay. Cells viability was assessed by MTT assay, and apoptosis was also evaluated at cellular level. The intra and extracellular levels of ODC1 and ADA enzymes were evaluated by ELISA. Results showed differential expression of ADA and ODC1 genes in cancer cell lines. In MCF-7 cell line, the expression level of ADA was upregulated in a dose-dependent manner but its expression did not change in MDA-MB cell line. ODC1 expression was increased in both examined cell lines. Also, increased level of the apoptotic BAX/BCL-2 ratio was detected in MCF-7 cells. These results demonstrated that Urtica dioica induces apoptosis in breast cancer cells by influencing ODC1 and ADA genes expression, and estrogen receptors. The different responses observed with these cell lines could be due to the interaction of Urtica dioica as a phytoestrogen with the estrogen receptor.

CircZNF609 and circNFIX as possible regulators of glioblastoma pathogenesis via miR-145-5p/EGFR axis.

Glioblastoma is a rare and deadly malignancy with a low survival rate. Emerging evidence has shown that aberrantly expressed circular RNAs (circRNAs) play a critical role in the initiation and progression of GBM tumorigenesis. The oncogenic function of circZNF609 and circNFIX is involved in several types of cancer, but the role and underlying mechanism of these circRNAs in glioblastoma remain unclear. In this study, we hypothesized that circZNF609 and circNFIX may regulate EGFR through sponging miR-145-5p. Herein, we assessed the expression levels of circZNF609, circNFIX, miR-145-5p, and EGFR using quantitative polymerase chain reaction in glioblastoma patients and normal brain samples. The results showed that circZNF609, circNFIX, and EGFR expression levels were upregulated and miR145-5p was downregulated (p = 0.001, 0.06, 0.002, and 0.0065, respectively), while there was no significant association between clinicopathological features of the patients and the level of these genes expression. We also found a significant inverse correlation between miR145-5p and the expression of cZNF609, cNFIX and EGFR (p = 0.0003, 0.0006, and 0.009, respectively). These findings may open a new window for researchers to better understand the potential pathways involved in GBM pathogenesis. In conclusion, it may provide a new potential pathway for the development of effective drugs for the treatment of GBM patients.

MicroRNA biosensors for detection of glioblastoma.

Glioblastoma (GBM) is the most common type of malignant brain tumor.The discovery of microRNAs and their unique properties have made them suitable tools as biomarkers for cancer diagnosis, prognosis, and evaluation of therapeutic response using different types of nanomaterials as sensitive and specific biosensors. In this review, we discuss microRNA-based electrochemical biosensing systems and the use of nanoparticles in the evolving development of microRNA-based biosensors in glioblastoma.

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.

A specific haplotype in potential miRNAs binding sites of secreted frizzled-related protein 1 (SFRP1) is associated with BMD variation in osteoporosis.

PURPOSE: Osteoporosis is an important multifactorial disease which is largely influenced by Wnt signaling pathway. Considering regulatory single nucleotide polymorphisms in Wnt signaling pathway may pave the road of understanding the genetic basis of predisposition to osteoporosis. The aim of this study was to determine the possible association between variants of SFRP1 and WNT5b, and osteoporosis incidence risk. METHODS: The study population comprised 186 osteoporotic patients and 118 normal subjects from Amirkola Health and Ageing Project. rs1127379 (c.1406A>G) and rs3242 (c.3132C>T) variants in 3'UTR of SFRP1 gene, and rs3803164 (c.236C>T) in 3'UTR and rs735890 (c.622-536A>G) in intron 4 of WNT5b gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Regression analyses were used to calculate the association of genotype frequencies with bone mineral density (BMD) and bone mineral content (BMC) values of participants. Bioinformatics algorithms were used to detect the effect of each SNP on the secondary structure of mRNA, and predict putative 3'UTR microRNA target sites and splicing sites changes by related SNPs. RESULTS: WNT5b rs735890 was associated with lumbar spine BMD, BMC, and femoral neck BMC (P = 0.035, P = 0.007, and P = 0.038, respectively). WNT5b rs3803164, and SFRP1 rs3242 were significantly associated with lumbar spine BMD (P = 0.028 and P = 0.030, respectively). SFRP1 rs1127379 was associated with lumbar spine BMD in the male gender. Haplotype analysis showed a significant association of SFRP1 c.[1406A; 3132C] haplotype with lumbar spine BMD, and BMC (P = 0.019 and P = 0.030, respectively), and SFRP1 c.[1406G; 3132C] haplotype with lumbar spine BMC (P = 0.045). In silico analyses revealed that the G allele of SFRP1 rs1127379, and WNT5b rs3803164 appear as more possible target sites for many miRNAs. CONCLUSIONS: This study is the first evidence of the association of WNT5b rs735890, and c.[1406A; 3132C] and c.[1406G; 3132C] haplotypes of SFRP1 with BMD variation in osteoporosis, probably by altering microRNA target sites, in elderly persons.

Prevalence of multiple infections and the risk of gastric adenocarcinoma development at earlier age.

Helicobacter pylori and Epstein-Barr virus are well established infections for gastric cancer development. However, the role of cytomegalovirus alone or in combination with other infections is unclear. In this case-control study, the prevalence of different infections was evaluated, and their frequency was compared with clinicopathologic features among gastric cancer patients and normal volunteers from 2012 to 2017. Approximately two-thirds (61.9%) of the gastric cancer patients had at least 1 viral infection, while viral infection prevalence in normal volunteers was only 4.7% (P = 0.021). The higher infection frequency in gastric cancer patients was observed for EBV (49.2%). No CMV DNA was detected in normal volunteers. In contrast, one-fourth of the gastric cancer patients were infected with CMV. Furthermore, CMV frequency in tumoral tissues (68.75%) was significantly higher than in nontumoral tissues (12.5%) (P = 0.0311). Although H. pylori infection was significantly lower in tumoral tissues than in nontumoral tissues (P = 0.0136), all tumoral tissues had cagA, while only 61.5% of nontumoral tissues were cagA positive. CMV-infected patients were affected 14 years earlier than uninfected, and CMV-negative patients (mean age = 56 vs. 69 and 70 years; P= 7.6×10-3 and P = 2.7×10-4, respectively). Also, EBV viral load in earlier grades and stages was more than 100-fold higher than advanced grades and stages. Our results show a high level of infections in gastric cancer. The association of these infections especially with CMV contributes to gastric adenocarcinoma development at earlier age.