Cerebral ischemia is a major cause of morbidity and mortality in the aged population, as well as a tremendous burden on the healthcare system. Despite timely treatment with thrombolysis and percutaneous intravascular interventions, many patients are often left with irreversible neurological deficits. Bone marrow stromal cells (BMSCs), also referred to as mesenchymal stem cells (MSCs), are a type of nonhematopoietic stem cells which exists in bone marrow mesh, with the potential to self-renew. Unlike cells in the central nervous system, BMSCs differentiate not only into mesodermal cells, but also endodermal and ectodermal cells. Moreover, it has been reported that BMSCs develop into cells with neural and vascular markers and play a role in recovery from ischemic stroke. These findings have fuelled excitement in regenerative medicine for neurological diseases, especially for ischemic stroke. There is now preclinical evidence to suggest that BMSCs grafted into the brain of ischemic models abrogate neurological deficits. Based on the overwhelming evidence from animal studies as well as in clinical trials, BMSC transplantation is considered a promising strategy for treatment of ischemic stroke. The goal of this review is to present an integrated consideration of molecular mechanisms in a chronological fashion and discuss an optimal BMSC delivery route for ischemic stroke.
Glioma, like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect, which is a dominant phenotype of most tumor cells. Glioma tumors exhibit high glycolytic metabolism with increased lactate production. Data derived from the gene expression profiling interactive analysis (GEPIA) database show that pyruvate dehydrogenase kinase 1 (PDK1) is significantly highly expressed in glioma tissues compared with corresponding normal tissues. PDK1 is a key enzyme in the transition of glycolysis to tricarboxylic acid cycle, via inactivating PDH and converting oxidative phosphorylation to Warburg effect, resulting in increment of lactate production. Silencing of PDK1 expression resulted in reduced lactate and ATP, accumulation of ROS, mitochondrial damage, decreased cell growth, and increased cell apoptosis. Aberrant expression of miR‐128 has been observed in many human malignancies. Mechanistically, we discover that overexpressed miR‐128‐3p disturbs the Warburg effect in glioma cells via reducing PDK1. Our experiments confirmed that the miR‐128‐3p/PDK1 axis played a pivotal role in cancer cell metabolism and growth. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of PDK1, might act as a potential therapeutic target for glioma treatment.
Lymphocytes from patients with HLA class II-linked autoimmune diseases such as type I diabetes, systemic lupus erythematosus, rheumatoid arthritis, and Graves' have recently been shown to have a decrease in the expression of self-peptide-filled HLA class I antigens on the surface of peripheral lymphocytes. The human demyelinating diseases of multiple sclerosis in some cases are also associated with the presence of certain HLA class II genes, which may in turn be linked to genes in the class II region that control class I expression. Hence, we studied fresh peripheral blood mononuclear cells (PBMCs) and newly produced Epstein-Barr virus (EBV)-transformed cell lines from multiple sclerosis patients for the class I defect. Unseparated PBMCs, as well as T cells, B cells, and macrophages from multiple sclerosis patients had a decrease in the amount of conformationally correct peptide-filled HLA class I molecules on the cell surface compared with matched controls detectable by flow cytometry. To demonstrate the independence of this defect from exogenous serum factors, newly produced EBV-transformed cell lines from B cells of patients with multiple sclerosis maintained the defect. In addition, DR2 +/+, +/-, and -/- EBV-transformed B cells from these patients similarly demonstrated the self-antigen presentation defect. Analysis of a set of discordant multiple sclerosis twins revealed the class I defect was exclusively found on the affected twin lymphocytes, suggesting a role of this class I complex in disease expression. These data indicate that multiple sclerosis patients have abnormal presentation of self-antigens.(ABSTRACT TRUNCATED AT 250 WORDS)
Cerebral ischemia remains the most frequent cause of death and quality-of-life impairments due to neurological deficits, and accounts for the majority of total healthcare costs. However, treatments for cerebral ischemia are limited. Over the last decade, bone marrow stromal cell (BMSC) therapy has emerged as a particularly appealing option, as it is possible to help patients even when initiated days or even weeks after the ischemic insult. BMSCs are a class of multipotent, self-renewing cells that give rise to differentiated progeny when implanted into appropriate tissues. Therapeutic effects of BMSC treatment for ischemic stroke, including sensory and motor recovery, have been reported in pre-clinical studies and clinical trials. In this article, we review the recent progress in BMSC-based therapy for ischemic stroke, focusing on the route of delivery and pre-processing of BMSCs. Selecting an optimal delivery route is of particular importance. The ideal approach, as well as the least risky, for translational applications still requires further identification. Appropriate preprocessing of BMSCs or combination therapy has the benefi t of achieving the maximum possible restoration. Further pre-clinical studies are required to determine the time-window for transplantation and the appropriate dosage of cells.
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