The comparative effects of bone marrow mesenchymal stem cells and supernatant transplantation on demyelination and inflammation in cuprizone model.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with inflammation and immune dysfunction. OBJECTIVES: We compared the remyelination and immunomodulation properties of mesenchymal stem cells (MSCs) with their conditioned medium (CM) in the cuprizone model. METHODS: Twenty-four C57BL/ 6 mice were divided into four groups. After cuprizone demyelination, MSCs and their CM were injected into the right lateral ventricle of mice. The expression level of IL-1ß, TNF-α, and BDNF genes was evaluated using the qRT-PCR. APC antibody was used to assess the oligodendrocyte population using the immunofluorescent method. The remyelination and axonal repair were studied by specific staining of the LFB and electron microscopy techniques. RESULTS: Transplantation of MSCs and CM increased the expression of the BDNF gene and decreased the expression of IL-1ß and TNF-α genes compared to the cuprizone group, and these effects in the cell group were more than CM. Furthermore, cell transplantation resulted in a significant improvement in myelination and axonal repair, which was measured by luxol fast blue and transmission electron microscope images. The cell group had a higher number of oligodendrocytes than other groups. CONCLUSIONS: According to the findings, injecting MSCs intraventricularly versus cell-conditioned medium can be a more effective approach to improving chronic demyelination in degenerative diseases like MS.

Stem Cell-Derived Exosomal MicroRNAs as Novel Potential Approach for Multiple Sclerosis Treatment.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by inflammation and demyelination of CNS neurons. Up to now, there are many therapeutic strategies for MS but they are only being able to reduce progression of diseases and have not got any effect on repair and remyelination. Stem cell therapy is an appropriate method for regeneration but has limitations and problems. So recently, researches were used of exosomes that facilitate intercellular communication and transfer cell-to-cell biological information. MicroRNAs (miRNAs) are a class of short non-coding RNAs that we can used to their dysregulation in order to diseases diagnosis. The miRNAs of microvesicles obtained stem cells may change the fate of transplanted cells based on received signals of injured regions. The miRNAs existing in MSCs may be displayed the cell type and their biological activities. Current studies show also that the miRNAs create communication between stem cells and tissue-injured cells. In the present review, firstly we discuss the role of miRNAs dysregulation in MS patients and miRNAs expression by stem cells. Finally, in this study was confirmed the relationship of microRNAs involved in MS and miRNAs expressed by stem cells and interaction between them in order to find appropriate treatment methods in future for limit to disability progression.

MicroRNA targeting: A novel therapeutic intervention for ovarian cancer.

Ovarian cancer, a perilous form of cancer affecting the female reproductive system, exhibits intricate communication networks that contribute to its progression. This study aims to identify crucial molecular abnormalities linked to the disease to enhance diagnostic and therapeutic strategies. In particular, we investigate the role of microRNAs (miRNAs) as diagnostic biomarkers and explore their potential in treating ovarian cancer. By targeting miRNAs, which can influence multiple pathways and genes, substantial therapeutic benefits can be attained. In this review we want to shed light on the promising application of miRNA-based interventions and provide insights into the specific miRNAs implicated in ovarian cancer pathogenesis.

Mutant P53 in the formation and progression of the tumor microenvironment: Friend or foe.

TP53 is the most frequently mutated gene in human cancer. It encodes the tumor suppressor protein p53, which suppresses tumorigenesis by acting as a critical transcription factor that can induce the expression of many genes controlling a plethora of fundamental cellular processes, including cell cycle progression, survival, apoptosis, and DNA repair. Missense mutations are the most frequent type of mutations in the TP53 gene. While these can have variable effects, they typically impair p53 function in a dominant-negative manner, thereby altering intra-cellular signaling pathways and promoting cancer development. Additionally, it is becoming increasingly apparent that p53 mutations also have non-cell autonomous effects that influence the tumor microenvironment (TME). The TME is a complex and heterogeneous milieu composed of both malignant and non-malignant cells, including cancer-associated fibroblasts (CAFs), adipocytes, pericytes, different immune cell types, such as tumor-associated macrophages (TAMs) and T and B lymphocytes, as well as lymphatic and blood vessels and extracellular matrix (ECM). Recently, a large body of evidence has demonstrated that various types of p53 mutations directly affect TME. They fine-tune the inflammatory TME and cell fate reprogramming, which affect cancer progression. Notably, re-educating the p53 signaling pathway in the TME may be an effective therapeutic strategy in combating cancer. Therefore, it is timely to here review the recent advances in our understanding of how TP53 mutations impact the fate of cancer cells by reshaping the TME.

The combined therapy of miR-383-5p restoration and paclitaxel for treating MDA-MB-231 breast cancer.

The deregulation of microRNAs (miRs) has been identified in tumor development. Indeed, the restoration of tumor-suppressive miRs has been associated with inhibited tumor development in various cancers. Herein, we aimed to evaluate the impact of combined miR-383-5p restoration, as a tumor-suppressive miR, with taxol therapy in suppressing MDA-MB-231 breast cancer development. MDA-MB-231 cell line was restored with miR-383-5p and treated with paclitaxel both in combined and separate manners. The MTT experiment was carried out to measure the cytotoxicity of the therapeutic approaches on the tumoral cells. Besides, flow cytometry was conducted to assess apoptosis and cell cycle status following the treatments. Furthermore, the expression levels of critical factors contributed to tumor proliferation, migration, apoptosis were investigated via the qRT-PCR and western blotting techniques. The outcomes pointed out that the miR-383-5p might substantially enhance the chemosensitivity of MDA-MB-231 to taxol. Besides, miR-383-5p restoration and the combined therapy of miR-383-5p restoration with paclitaxel could remarkably increase apoptosis, decrease cell viability, arrest the cell cycle, inhibit clonogenicity, suppress tumor migration, suppress the PI3K/Akt signaling pathway, and down-regulate PD-L1 expression of BC cells. The restoration of miR-383-5p can enhance the chemosensitivity of MDA-MB-231 cells to taxol. Despite the anti-tumoral effects of miR-383-5p restoration on MDA-MB-231 breast cancer development, the combined therapy of miR-383-5p restoration with paclitaxel can be more effective in repressing MDA-MB-231 breast cancer development.

Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression.

Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance.

Crosstalk between miRNAs and signaling pathways involved in pancreatic cancer and pancreatic ductal adenocarcinoma.

Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide with 5-year survival rates below 8%. Most patients with PC and pancreatic ductal adenocarcinoma (PDAC) die after relapse and cancer progression as well as resistance to treatment. Pancreatic tumors contain a high desmoplastic stroma that forms a rigid mass and has a potential role in tumor growth and metastasis. PC initiates from intraepithelial neoplasia lesions leading to invasive cancer through various pathways. These lesions harbor particular changes in signaling pathways involved in the tumorigenesis process. These events affect both the epithelial cells, including the tumor and the surrounding stroma, and eventually lead to the formation of complex signaling networks. Genetic studies of PC have revealed common molecular features such as the presence of mutations in KRAS gene in more than 90% of patients, as well as the inactivation or deletion mutations of some tumor suppressor genes including TP53, CDKN2A, and SMAD4. In recent years, studies have also identified different roles of microRNAs in PC pathogenesis as well as their importance in PC diagnosis and treatment, and their involvement in various signaling pathways. In this study, we discussed the most common pathways involved in PC and PDAC as well as their role in tumorigenesis and progression. Furthermore, the miRNAs participating in the regulation of these signaling pathways in PC progression are summarized in this study. Therefore, understanding more about pathways involved in PC can help with the development of new and effective therapies in the future.

Increased levels of angiogenic factors in microvascular angina.

BACKGROUND: Recent studies have suggested that angiogenic factors may affect vascular endothelial integrity. On the other hand, endothelial dysfunction is the main pathological mechanism in microvascular angina (MVA) or cardiac syndrome X. Therefore, we aimed to determine the levels of angiogenic factors in MVA patients. In addition, we investigated the effects of metoprolol, as a beta blocker agent, on the serum levels of these factors. METHODS: Thirty patients with MVA (17 female/13 male; mean age: 55.53±9.18 years) and twenty healthy controls (14 female/6 male; mean age: 51.40±9.16 years) were enrolled.The serum amounts of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and tyrosine kinase-2 receptor (Tie-2) were measured in healthy controls, MVA patients at baseline and after metoprolol therapy (25 mg for one month) by enzyme-linked immunosorbent assay. RESULTS: The levels of Ang-2 and Tie-2 were significantly higher in MVA patients at baseline in comparison with controls (Ang-2: 277.02±186.08 vs.164.46±49.83 ng/l, P=0.011; Tie-2: 28.97±18.85 vs. 14.90±4.05 ng/ml, P=0.002; respectively). But this difference in the Ang-1 levels was not significant (P=0.829). Additionally, the levels of angiogenic factors in MVA patients after metoprolol therapy were not significantly changed in comparison with the baseline status (P>0.05). CONCLUSION: Our results considered a possible role for angiogenic factors in the pathophysiology of MVA, which need further investigation for elucidation. In addition, this study has not showed an effective role for metoprolol in changing the angiogenic factors levels as a therapeutic agent in MVA.