Caloric restriction maintains stem cells through niche and regulates stem cell aging.

The functional loss of adult stem cells is a major cause of aging and age-related diseases. Changes in the stem cell niche, increased energy metabolic rate, and accumulation of cell damage severely affect the function and regenerative capacity of stem cells. Reducing the cellular damage and maintaining a pristine stem cell niche by regulating the energy metabolic pathways could be ideal for the proper functioning of stem cells and tissue homeostasis.

Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat.

Memantine, a noncompetitive antagonist of the -methyl-D-aspartate (NMDA) receptor, suppresses the release of excessive levels of glutamate that may induce neuronal excitation. Here we investigated the effects of memantine on salicylate-induced tinnitus model. The expressions of the activity-regulated cytoskeleton-associated protein () and tumor necrosis factor-alpha () genes; as well as the () gene and protein, were examined in the SH-SY5Y cells and the animal model.

Autophagy: An evolutionarily conserved process in the maintenance of stem cells and aging.

Autophagy is an evolutionarily conserved process that degrades and recycles defective organelles, toxic proteins, and various other aggregates on the cytoplasmic surface by sequestering them into autophagosomes which, then, fuse with lysosomes which degrade them. If these aggregates are not cleared, they accumulate and damage the cell resulting in cellular senescence and aging. Stem cells, with their capacity to differentiate, are crucial for tissue homeostasis.

Reduced sirtuin 1/adenosine monophosphate-activated protein kinase in amyotrophic lateral sclerosis patient-derived mesenchymal stem cells can be restored by resveratrol.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neuron system. Our previous study has shown that bone marrow-mesenchymal stem cells (BM-MSCs) from ALS patients have functional limitations in releasing neurotrophic factors and exhibit the senescence phenotype. In this study, we examined sirtuin 1/adenosine monophosphate-activated protein kinase (SIRT1/AMPK) activities and identified significant decreases in the ALS-MSCs compared with normal healthy control originated BM-MSCs.

Metformin promotes neuronal differentiation and neurite outgrowth through AMPK activation in human bone marrow-mesenchymal stem cells.

Metformin is an AMP-activated kinase (AMPK) activator that plays a role in glucose energy metabolism and cell protection. It is widely used to treat several diseases, including type 2 diabetes, cardiovascular diseases, cancer, and metabolic diseases. In this study, we investigated whether AMPK activation upon treatment with metformin may promote neurite outgrowth during the progression of neuronal differentiation in human bone marrow-mesenchymal stem cells (hBM-MSCs).

Functional restoration of replicative senescent mesenchymal stem cells by the brown alga .

The brown alga , which is called Mi-Yoek in Korea, has been traditionally consumed as a health food in East Asian countries. Recent studies have reported that has beneficial effects on arteriosclerosis, inflammation, fat metabolism, and tumors In this study, we examined the anti-senescence effects of ethanol extracts of (UP-Ex) in human bone marrow mesenchymal stem cells (hBM-MSCs). UP-Ex protected hBM-MSCs against oxidative injury, as determined by MTT assays.

The tubulin deacetylase sirtuin-2 regulates neuronal differentiation through the ERK/CREB signaling pathway.

Modification of microtubule (MT) dynamics is important for diverse aspects of cellular function including differentiation, cargo trafficking, migration, and adhesion. MTs also play a crucial role in the progression of neuronal development. The MT deacetylase Sirtuin 2 (Sirt2) and histone deacetylase 6 (HDAC6) regulate MT dynamics by deacetylating alpha-tubulin (α-tubulin).

PDE4 Inhibition by Rolipram Promotes Neuronal Differentiation in Human Bone Marrow Mesenchymal Stem Cells.

Increased intracellular cyclic adenosine monophosphate (cAMP) can promote axonal elongation and facilitate neuronal repair, while decreased cAMP is associated with losses in neuronal regenerative capacity. Rolipram, which upregulates intracellular cAMP by blocking phosphodiesterase-4 (PDE4) enzyme activity, can mitigate diverse neurological disorders. In this study, we investigated whether rolipram induces neuronal differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs).

Accumulation of apoptosis-insensitive human bone marrow-mesenchymal stromal cells after long-term expansion.

Cells undergo replicative senescence during in vitro expansion, which is induced by the accumulation of cellular damage caused by excessive reactive oxygen species. In this study, we investigated whether long-term-cultured human bone marrow mesenchymal stromal cells (MSCs) are insensitive to apoptotic stimulation. To examine this, we established replicative senescent cells from long-term cultures of human bone marrow MSCs.

G9a inhibition promotes neuronal differentiation of human bone marrow mesenchymal stem cells through the transcriptional induction of RE-1 containing neuronal specific genes.

Recent studies have shown that epigenomic modifications are significantly associated with neuronal differentiation. Many neuronal specific genes contain the repressor element-1 (RE-1), which recruits epigenetic modulators, such as the histone methyltransferase G9a and interrupts the expression of neuronal genes in non-neuronal cells. This study investigated the functional role of G9a during neuronal differentiation of human bone marrow mesenchymal stem cells (BM-MSCs).

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase.

Alteration of DNA methylation is highly associated with aging and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Remedying these aberrant methylation patterns may serve to improve these diseases. Previously, we reported that human bone marrow mesenchymal stromal cells isolated from ALS patients (ALS-MSCs) have functionally decreased stem cell potency, and excessively express DNA methyltransferases (DNMTs).

Anti-senescence effects of DNA methyltransferase inhibitor RG108 in human bone marrow mesenchymal stromal cells.

Alteration of DNA methylation is highly associated with ageing and ageing-related diseases. Remedy of the altered methylation pattern may provide beneficial efficacy in these diseases. In this study, we used a DNA methyltransferase inhibitor, RG108, to investigate the senescence effects in human bone marrow mesenchymal stromal cells (hBM-MSCs).

Endogenous ROS levels are increased in replicative senescence in human bone marrow mesenchymal stromal cells.

Cellular senescence is characterized by functional decline induced by cumulative damage to DNA, proteins, lipids, and carbohydrates. Previous studies have reported that replicative senescence is caused by excessive amounts of reactive oxygen species (ROS) produced as a result of aerobic energy metabolism. In this study, we established human bone marrow mesenchymal stromal cells (hBM-MSCs) in replicative senescence after culture over a long term to investigate the relationship between ROS levels and stem cell potential and to determine whether differentiation potential can be restored by antioxidant treatment.

Trichostatin A modulates intracellular reactive oxygen species through SOD2 and FOXO1 in human bone marrow-mesenchymal stem cells.

Engraft cells are often exposed to oxidative stress and inflammation; therefore, any factor that can provide the stem cells resistance to these stresses may yield better efficacy in stem cell therapy. Studies indicate that histone deacetylase (HDACs) inhibitors alleviate damage induced by oxidative stress. In this study, we investigated whether regulation of reactive oxygen species (ROS) occurs through the HDAC inhibitor trichostatin A (TSA) in human bone marrow-mesenchymal stem cells (hBM-MSCs).

Resveratrol-induced SIRT1 activation promotes neuronal differentiation of human bone marrow mesenchymal stem cells.

Resveratrol-3,4',5-trihydroxy-trans-stillbene (resveratrol; RSV), a natural non-flavonoid polyphenol compound, provides protection against stress injury, excessive sunlight, ultraviolet radiation, infections, and invading fungi. There is increasing evidence that resveratrol, a sirtuin1 activator, plays a pivotal role in neuroprotection and neuronal differentiation. In this study, we investigated whether resveratrol induces neuronal differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs).

Proteomic analysis reveals KRIT1 as a modulator for the antioxidant effects of valproic acid in human bone-marrow mesenchymal stromal cells.

Valproic acid (VPA) protects human bone marrow-mesenchymal stromal cells (hBM-MSCs) against oxidative stress and improves their migratory ability through increasing the secretion of trophic factors. This suggests that VPA may be an excellent candidate for improving stem cell function. However, the molecular mechanisms of VPA in BM-MSCs are not known.

Valproic acid promotes neuronal differentiation by induction of neuroprogenitors in human bone-marrow mesenchymal stromal cells.

Recent studies have shown that the inhibition of histone deacetylases (HDACs) induces the differentiation of diverse cancer and stem cells, which suggests HDAC inhibitors may be good candidates for the induction of stem cell differentiation. In this study, we investigated the effects of a HDAC inhibitor, valproic acid (VPA), for the neuronal differentiation of human bone marrow-mesenchymal stromal cells (hBM-MSCs). VPA-treated MSCs had significant increases in their expression of the neuro-progenitor marker Nestin, Musashi, CD133, and GFAP, as measured by real-time PCR and immunoblot analysis.

Synthesis and evaluation of 8-amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives as glycogen synthase kinase-3 (GSK-3) inhibitors.

New potent glycogen synthase kinase-3 (GSK-3) inhibitors, 8-amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives, were designed by modeling, synthesized and evaluated in vitro. Compound 17c showed good potency in enzyme and cell-based assays (IC50=111 nM, EC50=1.78 μM).

Effects of valproic acid on the expression of trophic factors in human bone marrow mesenchymal stromal cells.

The potential of human bone marrow-mesenchymal stromal cells (hBM-MSCs) to differentiate into diverse cell types and secrete a variety of trophic factors makes them an excellent cell therapy tool for intractable diseases. However, their therapeutic efficacy has not yet been satisfied in preclinical and/or clinical trials with autologous or allogenic stem cells. To improve the efficacy of stem cell therapy, optimized conditions for stem cells need to be defined.

The functional deficiency of bone marrow mesenchymal stromal cells in ALS patients is proportional to disease progression rate.

Amyotrophic lateral sclerosis (ALS) is caused by motor neuron death. The relationship between the prognosis of ALS patients and the function of their bone marrow mesenchymal stromal cells (BM-MSCs) is unclear. We designed this study to assess the correlation between the progression rate of the ALS Functional Rating Scale-revised version (ΔFS), which is reported to predict prognosis, and the pluripotency and trophic factor secreting capacity of ALS patients' BM-MSCs.

β-PIX is critical for transplanted mesenchymal stromal cell migration.

Bone marrow-derived mesenchymal stromal cells (MSCs) have been used successfully as a source of stem cells for treating neurodegenerative diseases. However, for reasons that are not clear, autologous MSC transplants have not yielded successful results in human trials. To test one possible reason, we compared the migratory ability of MSCs from amyotrophic lateral sclerosis (ALS) patients with those of healthy controls.

Recombinant human erythropoietin reduces aggregation of mutant Cu/Zn-binding superoxide dismutase (SOD1) in NSC-34 cells.

Human erythropoietin (hEPO) has multiple actions in non-hematopoietic tissues, including neurotrophic, anti-oxidant, anti-apoptotic, and anti-inflammatory effects. To examine the effect of EPO in an vitro model of amyotrophic lateral sclerosis (ALS), we stably overexpressed wild SOD1 and a mutant form, SOD1/G93A, in NSC-34 motoneuron-like cells. Transformants harboring the wild and mutant forms of SOD1 were selected by G418 selection and immunoblot analysis.

Development of a cellular tau enzyme-linked immunosorbent assay method for screening GSK-3β inhibitors.

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase also known as tau protein kinase I, has been implicated in the pathogenic conditions of Alzheimer's disease. Many investigators have focused on GSK-3 inhibitor as a therapeutic drug. In this study, we established a cell-based assay for the screening of novel GSK-3β inhibitors.

Transduction of human EPO into human bone marrow mesenchymal stromal cells synergistically enhances cell-protective and migratory effects.

Human bone marrow mesenchymal stromal cells (hBM-MSCs) are a promising tools for cell therapy. However, the poor viability of the transplanted cells is a major limiting factor. Human erythropoietin (hEPO) has been extensively studied in non-hematopoietic tissues for its neurotrophic, anti-oxidant, anti-apoptotic, and antiinflammatory effects.

Inhibitory effects of cilostazol on proliferation of vascular smooth muscle cells (VSMCs) through suppression of the ERK1/2 pathway.

Aim: The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. During atherogenesis or in response to vessel injury, VSMC proliferation is induced by a number of peptide growth factors released from platelets and VSMCs. Cilostazol is a phosphodiesterase (PDE) 3 inhibitor that increases intracellular cAMP levels and decreases intracellular Ca(2+) levels, inhibiting platelet aggregation and inducing vasodilatation.