COVID-19-Induced Stroke and the Potential of Using Mesenchymal Stem Cells-Derived Extracellular Vesicles in the Regulation of Neuroinflammation.

Ischemic stroke (IS) is a known neurological complication of COVID-19 infection, which is associated with high mortality and disability. Following IS, secondary neuroinflammation that occurs can play both harmful and beneficial roles and lead to further injury or repair of damaged neuronal tissue, respectively. Since inflammation plays a pivotal role in the pathogenesis of COVID-19-induced stroke, targeting neuroinflammation could be an effective strategy for modulating the immune responses following ischemic events. Numerous investigations have indicated that the application of mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) improves functional recovery following stroke, mainly through reducing neuroinflammation as well as promoting neurogenesis and angiogenesis. Therefore, MSC-EVs can be applied for the regulation of SARS-CoV-2-mediated inflammation and the management of COVID-19- related ischemic events. In this study, we have first described the advantages and disadvantages of neuroinflammation in the pathological evolution after IS and summarized the characteristics of neuroinflammation in COVID-19-related stroke. Then, we have discussed the potential benefit of MSC-EVs in the regulation of inflammatory responses after COVID-19-induced ischemic events.

Therapeutic potential of mesenchymal stem cell-derived exosomes as a cell-free therapy approach for the treatment of skin, bone, and cartilage defects.

OBJECTIVE: The aim of this study was to collect the articles concerning mesenchymal stem cell (MSC)-derived exosomes for regeneration of bone, cartilage and skin defects. METHOD: Scopus, PubMed, EMBASE, and Web of Science were searched for keywords "Exosome, MSC, Skin, Bone and Cartilage defects, Regenerative medicine, and extracellular vesicles. RESULTS: MSC-derived exosomes can emulate the biological activity of MSCs by horizontal transfer of multiple functional molecules including mRNAs, miRNAs, proteins, and lipids to the local microenvironment and recipient cells, and subsequently mediate restoring homeostasis and tissue regeneration through various mechanisms. Compared to MSCs, MSC-derived exosomes reveal many advantages such as non-immunogenicity, easy access, easy preservation, and extreme stability under various conditions. CONCLUSION: Hence, exosomes could be considered as an alternative strategy for cell-based therapies in regenerative medicine. In this paper, after describing the characteristics of exosomes, we will review the recent literature on the therapeutic potentials of MSC-derived exosomes in skin, bone, and cartilage repair.

Validation strategies for identifying drug targets in dermal fibrotic disorders.

Fibrotic skin disorders, such as keloid disease (KD), are common clinically challenging disorders with unknown etiopathogenesis and ill-defined treatment strategies that affect millions of people worldwide. Thus, there is an urgent need to discover novel therapeutics. The validation of potential drug targets is an obligatory step in discovering and developing new therapeutic agents for the successful treatment of dermal fibrotic conditions, such as KD. The integration of multi-omics data with traditional and modern technological approaches, such as RNA interference (RNAi) and genome-editing tools, would provide unique opportunities to identify and validate novel targets in KD during early drug development. Thus, in this review, we summarize the current and emerging drug discovery process with a focus on validation strategies of potential drug targets identified in dermal fibrosis.

Early diagnosis of breast and ovarian cancers by body fluids circulating tumor-derived exosomes.

Exosomes (EXs) are small extracellular vesicles, a size range of 40-100 nm in diameter, actively secreted by most eukaryotic cells into surrounding body fluids like blood, saliva, urine, bile, breast milk and etc. These endosomal-derived vesicles mediate cell-cell communication between various cell populations through transmitting different signaling molecules such as lipids, proteins, and nucleic acids, and participate in a wide range of physiological and pathological body processes. Tumor-derived EXs (TDEs) are vehicles for intercellular communications by transferring bioactive molecules; they deliver oncogenic molecules and contain different molecular cargoes compared to EXs delivered from normal cells, therefore, they can be used as non-invasive invaluable biomarkers for early diagnosis and prognosis of most cancers, including breast and ovarian cancers. Their presence and stability in different types of body fluids highlight them as a suitable diagnostic biomarker for distinguishing various cancer stages. In addition, EXs can predict the therapeutic efficacy of chemotherapy agents and drug resistance in cancer cells, as well as determine the risk of metastasis in different disease stages. In this study, the recent literature on the potential role of TDEs in the diagnosis and prognosis of ovarian and breast cancers is summarized, and then exosome isolation techniques including traditional and new approaches are briefly discussed.

CRISPR/Cas9, a new approach to successful knockdown of ABCB1/P-glycoprotein and reversal of chemosensitivity in human epithelial ovarian cancer cell line.

OBJECTIVES: Multidrug resistance (MDR) is a major obstacle in the successful chemotherapy of ovarian cancer. Inhibition of P-glycoprotein (P-gp), a member of ATP-binding cassette (ABC) transporters, is a well-known strategy to overcome MDR in cancer. The aim of this study was to investigate the efficiency and ability of CRISPR/Cas9 genome editing technology to knockdown ABCB1 gene expression in adriamycin resistant (A2780/ADR) ovarian cancer cell line and evaluate the sensitivity changes to doxorubicin. MATERIALS AND METHODS: Three single-guide RNAs (sgRNAs) targeting the fourth and fifth exons of human ABCB1 gene were designed in this study. Expression level of ABCB1 was detected using quantitative real time PCR (qRT-PCR) after co-transfection of all three sgRNAs into A2780/ADR cell line and subsequent antibiotic selection. Drug sensitivity to doxorubicin was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The results showed that CRISPR/Cas9 system could significantly reduce the expression of P-gp. The dramatic decline in ABCB1 gene expression was associated with increased sensitivity of cells transfected with sgRNAs to doxorubicin. CONCLUSION: Based on the results of this study, it is concluded that the CRISPR-based systems, used in the present study, effectively down-regulated the target gene and acted as an ideal and cost-effective tool for gene editing of A2780/ADR cell line resulting in restoration of nonmalignant phenotype.

Molecular mechanisms of drug resistance in ovarian cancer.

Ovarian cancer is the most lethal malignancy among the gynecological cancers, with a 5-year survival rate, mainly due to being diagnosed at advanced stages, recurrence and resistance to the current chemotherapeutic agents. Drug resistance is a complex phenomenon and the number of known involved genes and cross-talks between signaling pathways in this process is growing rapidly. Thus, discovering and understanding the underlying molecular mechanisms involved in chemo-resistance are crucial for management of treatment and identifying novel and effective drug targets as well as drug discovery to improve therapeutic outcomes. In this review, the major and recently identified molecular mechanisms of drug resistance in ovarian cancer from relevant literature have been investigated. In the final section of the paper, new approaches for studying detailed mechanisms of chemo-resistance have been briefly discussed.