In-Silico and In-Vitro Investigation of Key Long Non-coding RNAs Involved in 5-Fluorouracil Resistance in Colorectal Cancer Cells: Analyses Highlighting NEAT1 and MALAT1 as Contributors.

Background Acquired resistance to 5-fluorouracil (5-FU) frequently results in chemotherapy failure and disease recurrence in advanced colorectal cancer (CRC) patients. Research has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) mediates the development of chemotherapy resistance in cancerous cells. The present study aims to identify key lncRNAs associated with 5-FU resistance in CRC using bioinformatic and experimental validation approaches. Methods The Gene Expression Omnibus (GEO) dataset GSE119481, which contains miRNA expression profiles of the parental CRC HCT116 cell line (HCT116/P) and its in-vitro established 5-FU-resistant sub-cell line (HCT116/FUR), was downloaded. Firstly, differentially expressed microRNAs (DEmiRNAs) between the parental and 5-FU resistance cells were identified. LncRNAs and mRNAs were then predicted using online databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to uncover relevant biological mechanisms and pathways. Networks integrating lncRNAs, miRNAs, and mRNAs interactions were constructed, and topological analyses were used to identify key lncRNAs associated with 5-FU resistance. An in-vitro model of the HCT116/FUR sub-cell line was developed by exposing the HCT116/P cell line to increasing concentrations of 5-FU. Finally, real-time quantitative PCR (RT-qPCR) was performed on total RNA extracted from the HCT116/P cell line and the HCT116/FUR sub-cell line to validate the in-silico predictions of key lncRNAs. Results A total of 32 DEmiRNAs were identified. Enrichment analysis demonstrated that these DEmiRNAs were mainly enriched in several cancer hallmark pathways that regulate cell growth, cell cycle, cell survival, inflammation, immune response, and apoptosis. The predictive analysis identified 237 unique lncRNAs and 123 mRNAs interacting with these DEmiRNAs. The pathway analysis indicated that most of these predicted genes were enriched in the cellular response to starvation, protein polyubiquitination, chromatin remodeling, and negative regulation of gene expression. Topological analyses of the lncRNA-miRNA-mRNA network highlighted the nuclear enriched abundant transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and Opa interacting protein 5 antisense RNA 1 (OIP5-AS1) as central lncRNAs. Experimental analysis by RT-qPCR confirmed that the expression levels of NEAT1 and MALAT1 were significantly increased in HCT116/FUR cells compared to HCT116/P cells. However, no significant difference was observed in the OIP5-AS1 expression level between the two cells. Conclusion Our findings specifically highlight MALAT1 and NEAT1 as significant contributors to 5-FU resistance in CRC. These lncRNAs are promising biomarkers for diagnosing and predicting outcomes in CRC.

Cancer cells as a new source of induced pluripotent stem cells.

Over the last 2 decades, induced pluripotent stem cells (iPSCs) have had various potential applications in various medical research areas, from personalized medicine to disease treatment. Different cellular resources are accessible for iPSC generation, such as keratinocytes, skin fibroblasts, and blood or urine cells. However, all these sources are somatic cells, and we must make several changes in a somatic cell's transcriptome and chromatin state to become a pluripotent cell. It has recently been revealed that cancer cells can be a new source of iPSCs production. Cancer cells show similarities with iPSCs in self-renewal capacity, reprogramming potency, and signaling pathways. Although genetic abnormalities and potential tumor formation in cancer cells pose a severe risk, reprogrammed cancer-induced pluripotent stem cells (cancer-iPSCs) indicate that pluripotency can transiently overcome the cancer phenotype. This review discusses whether cancer cells can be a preferable source to generate iPSCs.

Bone marrow mesenchymal stromal cells for diabetes therapy: touch, fuse, and fix?

Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-inflammatory and pro-survival properties. Naturally, they do not express human leukocyte antigen class II surface antigens and have immunosuppressive capabilities. Together with their relatively easy accessibility and expansion, they are an attractive tool for organ support in transplantation and regenerative therapy. Autologous BM-MSC transplantation alone or together with transplanted islets improves ß-cell function, graft survival, and glycemic control in diabetes. Albeit MSCs' capacity to transdifferentiate into ß-cell is limited, their protective effects are mediated mainly by paracrine mechanisms through BM-MSCs circulating through the body. Direct cell-cell contact and spontaneous fusion of BM-MSCs with injured cells, although at a very low rate, are further mechanisms of their supportive effect and for tissue regeneration. Diabetes is a disease of long-term chronic inflammation and cell therapy requires stable, highly functional cells. Several tools and protocols have been developed by mimicking natural fusion events to induce and accelerate fusion in vitro to promote ß-cell-specific gene expression in fused cells. BM-MSC-islet fusion before transplantation may be a strategy for long-term islet survival and improved function. This review discusses the cell-protective and anti-inflammatory characteristics of BM-MSCs to boost highly functional insulin-producing cells in vitro and in vivo, and the efficacy of their fusion with ß-cells as a path to promote ß-cell regeneration.

Exosomes and Lung Cancer: Roles in Pathophysiology, Diagnosis and Therapeutic Applications.

Lung cancer is a malignancy with a high morbidity and mortality rate, and affected patients have low survival and poor prognosis. The therapeutic approaches for the treatment of this cancer, including radiotherapy and chemotherapy, are not particularly effective partly due to late diagnosis. Therefore, the search for new diagnostic and prognostic tools is a critical issue. Novel biomarkers, such as exosomes, could be considered as potential diagnostic tools for malignancies, particularly lung cancer. Exosomes are nanovesicles, which are associated with different physiological and pathological conditions. It has been shown that these particles are released from many cells, such as cancer cells, immune cells and to some degree normal cells. Exosomes could alter the behavior of target cells through intercellular transfer of their cargo (e.g. DNA, mRNA, long non-coding RNAs, microRNAs and proteins). Thus, these vehicles may play pivotal roles in various physiological and pathological conditions. The current insights into lung cancer pathogenesis suggest that exosomes are key players in the pathogenesis of this cancer. Hence, these nanovesicles and their cargos could be used as new diagnostic, prognostic and therapeutic biomarkers in the treatment of lung cancer. Besides the diagnostic roles of exosomes, their use as drug delivery systems and as cancer vaccines is under investigation. The present review summarizes the current information on the diagnostic and pathogenic functions of exosomes in lung cancer.

miRNAs derived from cancer-associated fibroblasts in colorectal cancer.

Currently, the incidence of colorectal cancer (CRC) is increasing across the world. The cancer stroma exerts an impact on the spread, invasion and chemoresistance of CRC. The tumor microenvironment involves a complex interaction between cancer cells and stromal cells, for example, cancer-associated fibroblasts (CAFs). CAFs can promote neoplastic angiogenesis and tumor development in CRC. Mounting evidence suggests that many miRNAs are overexpressed (miR-21, miR-329, miR-181a, miR-199a, miR-382 and miR-215) in CRC CAFs, and these miRNAs can influence the spread, invasiveness and chemoresistance in neighboring tumor cells via paracrine signaling. Herein, we summarize the pathogenic roles of miRNAs and CAFs in CRC. Moreover, for first time, we highlight the miRNAs derived from CRC-associated CAFs and their roles in CRC pathogenesis.

Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis?

Degenerative disorders of joints, especially osteoarthritis (OA), result in persistent pain and disability and high costs to society. Nevertheless, the molecular mechanisms of OA have not yet been fully explained. OA is characterized by destruction of cartilage and loss of extracellular matrix (ECM). It is generally agreed that there is an association between pro-inflammatory cytokines and the development of OA. There is increased expression of matrix metalloproteinase (MMP) and "a disintegrin and metalloproteinase with thrombospondin motifs" (ADAMTS). Mesenchymal stem cells (MSCs) have been explored as a new treatment for OA during the last decade. It has been suggested that paracrine secretion of trophic factors, in which exosomes have a crucial role, contributes to the mechanism of MSC-based treatment of OA. The paracrine secretion of exosomes may play a role in the repair of joint tissue as well as MSC-based treatments for other disorders. Exosomes isolated from various stem cells may contribute to tissue regeneration in the heart, limbs, skin, and other tissues. Recent studies have indicated that exosomes (or similar particles) derived from MSCs may suppress OA development. Herein, for first time, we summarize the recent findings of studies on various exosomes derived from MSCs and their effectiveness in the treatment of OA. Moreover, we highlight the likely mechanisms of actions of exosomes in OA.

Medicinal Plants As Natural Polarizers of Macrophages: Phytochemicals and Pharmacological Effects.

Macrophages are one of the crucial mediators of the immune response in different physiological and pathological conditions. These cells have critical functions in the inflammation mechanisms that are involved in the inhibition or progression of a wide range of diseases including cancer, autoimmune diseases, etc. It has been shown that macrophages are generally divided into two subtypes, M1 and M2, which are distinguished on the basis of their different gene expression patterns and phenotype. M1 macrophages are known as pro-inflammatory cells and are involved in inflammatory mechanisms, whereas M2 macrophages are known as anti-inflammatory cells that are involved in the inhibition of the inflammatory pathways. M2 macrophages help in tissue healing via producing anti-inflammatory cytokines. Increasing evidence indicated that the appearance of different macrophage subtypes is associated with the fate of diseases (progression versus suppression). Hence, polarization of macrophages can be introduced as an important venue in finding, designing and developing novel therapeutic approaches. Albeit, there are different pharmacological agents that are used for the treatment of various disorders, it has been shown that several natural compounds have the potential to regulate M1 to M2 macrophage polarization and vice versa. Herein, for the first time, we summarized new insights into the pharmacological effects of natural compounds on macrophage polarization.

Anti-cancer effects of cinnamon: Insights into its apoptosis effects.

Cancer is known as a leading cause of death worldwide. In the last two decades, the incidence of cancer has been dramatically increased mostly due to lifestyle changes. The importance of this issue has attracted further attention to discover novel therapies to prevent and treat cancers. According to previous studies, drugs used to treat cancer have shown significant limitations. Therefore, the role of herbal medicines alone or in combination with chemotherapy drugs has been extensively studied in cancer treatment. Cinnamon is a natural component showing a wide range of pharmacological functions including anti-oxidant, anti-microbial and anti-cancer activities. Impaired apoptosis plays critical roles in the initiation and progression of cancer. Increasing evidence indicates that cinnamon, as a therapeutic agent, has anti-cancer effects via affecting numerous apoptosis-related pathways in cancer cells. Here, we highlighted anticancer properties of cinnamon, particularly through targeting apoptosis-related mechanisms.

CFIm25 and alternative polyadenylation: Conflicting roles in cancer.

Alternative polyadenylation (APA) is now widely recognized to regulate gene expression. APA is an RNA-processing mechanism that generates distinct 3' termini on mRNAs, producing mRNA isoforms. Different factors influence the initiation and development of this process. CFIm25 (among others) is a cleavage and polyadenylation factor that plays a key role in the regulation of APA. Shortening of the 3'UTRs on mRNAs leads to enhanced cellular proliferation and tumorigenicity. One reason may be the up-regulation of growth promoting factors, such as Cyclin D1. Different studies have reported a dual role of CFIm25 in cancer (both oncogenic and tumor suppressor). microRNAs (miRNAs) may be involved in CFIm25 function as well as competing endogenous RNAs (ceRNAs). The present review focuses on the role of CFIm25 in cancer, cancer treatment, and possible involvement in other human diseases. We highlight the involvement of miRNAs and ceRNAs in the function of CFIm25 to affect gene expression. The lack of understanding of the mechanisms and regulation of CFIm25 and APA has underscored the need for further research regarding their role in cancer and other diseases.

The Prevalence of Resistance to Methicillin in Staphylococcus aureus Strains Isolated from Patients by PCR Method for Detec-tion of mecA and nuc Genes.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is the main cause of hospital infection emerged over the last decades. Rapid detection of MRSA is important for patient care and proper usage of infection control. Detection of mecA genes (encoding resistance to methicillin and other similar antibiotics) and nuc genes (encoding staphylococcal thermostable nuclease) by PCR method is now considered for rapid identification of MRSA strain. The aim of this study was to determine the prevalence of MRSA isolated from patients in Tehran, Iran by PCR method for detection of mecA and nuc genes. METHOD: Phenotypic method such as microscopic and colony morphology and catalase and coagulase tests were used for identification of S. aureus isolates. DNA was extracted from all isolates and the presence of nuc and mecA gene was detected by PCR method. For determination of MRSA by phenotypic methods, oxacillin disk diffusion test were used. Data were analyzed by SPSS software. RESULTS: Out of 126 clinical sample identified by phenotypic method, 101 isolates had nuc gene. In disk diffusion tests by oxacillin disk, 78.2% of isolates were considered to be MRSA, but in PCR method for mecA gene, 69% isolates were positive. CONCLUSIONS: The results showed a high prevalence of methicillin-resistance among S. aureus isolates. Identifying MRSA strains, isolating MRSA-positive patients and carrier's treatment in a hospital to prevent MRSA infection is important in limiting the spread of MRSA. The PCR method for detection of nuc and mecA genes has potential for rapid and accurate diagnosis of MRSA strains.