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1.
Korean Circulation Journal ; : 110-122, 2022.
Article in English | WPRIM | ID: wpr-917379

ABSTRACT

Pulmonary hypertension is a rare and progressive illness with a devastating prognosis. Promising research efforts have advanced the understanding and recognition of the pathobiology of pulmonary hypertension. Despite remarkable achievements in terms of improving the survival rate, reducing disease progression, and enhancing quality of life, pulmonary arterial hypertension (PAH) is not completely curable. Therefore, an effective treatment strategy is still needed. Recently, many studies of the underlying molecular mechanisms and technological developments have led to new approaches and paradigms for PAH treatment. Management based on stem cells and related paracrine effects, epigenetic drugs and gene therapies has yielded prospective results for PAH treatment in preclinical research. Further trials are ongoing to optimize these important insights into clinical circumstances.

2.
The Korean Journal of Physiology and Pharmacology ; : 27-38, 2021.
Article in English | WPRIM | ID: wpr-896235

ABSTRACT

Excessive salt intake induces hypertension, but several gamma-aminobutyric acid (GABA) supplements have been shown to reduce blood pressure. GABAsalt, a fermented salt by L. brevis BJ20 containing GABA was prepared through the post-fermentation with refined salt and the fermented GABA extract. We evaluated the effect of GABA-salt on hypertension in a high salt, high cholesterol diet induced mouse model. We analyzed type 1 macrophage (M1) polarization, the expression of M1 related cytokines, GABA receptor expression, endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation, and medial thicknesses in mice model. GABA-salt attenuated diet-induced blood pressure increases, M1 polarization, and TNF-α and inducible nitric oxide synthase (NOS) levels in mouse aortas, and in salt treated macrophages in vitro. Furthermore, GABA-salt induced higher GABAB receptor and endothelial NOS (eNOS) and eNOS phosphorylation levels than those observed in salt treated ECs. In addition, GABA-salt attenuated EC dysfunction by decreasing the levels of adhesion molecules (E-selectin, Intercellular Adhesion Molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) and of von Willebrand Factor and reduced EC death. GABA-salt also reduced diet-induced reductions in the levels of eNOS, phosphorylated eNOS, VSMC proliferation and medial thickening in mouse aortic tissues, and attenuated Endothelin-1 levels in salt treated VSMCs. In summary, GABA-salt reduced high salt, high cholesterol diet induced hypertension in our mouse model by reducing M1 polarization, EC dysfunction, and VSMC proliferation.

3.
The Korean Journal of Physiology and Pharmacology ; : 27-38, 2021.
Article in English | WPRIM | ID: wpr-903939

ABSTRACT

Excessive salt intake induces hypertension, but several gamma-aminobutyric acid (GABA) supplements have been shown to reduce blood pressure. GABAsalt, a fermented salt by L. brevis BJ20 containing GABA was prepared through the post-fermentation with refined salt and the fermented GABA extract. We evaluated the effect of GABA-salt on hypertension in a high salt, high cholesterol diet induced mouse model. We analyzed type 1 macrophage (M1) polarization, the expression of M1 related cytokines, GABA receptor expression, endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation, and medial thicknesses in mice model. GABA-salt attenuated diet-induced blood pressure increases, M1 polarization, and TNF-α and inducible nitric oxide synthase (NOS) levels in mouse aortas, and in salt treated macrophages in vitro. Furthermore, GABA-salt induced higher GABAB receptor and endothelial NOS (eNOS) and eNOS phosphorylation levels than those observed in salt treated ECs. In addition, GABA-salt attenuated EC dysfunction by decreasing the levels of adhesion molecules (E-selectin, Intercellular Adhesion Molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) and of von Willebrand Factor and reduced EC death. GABA-salt also reduced diet-induced reductions in the levels of eNOS, phosphorylated eNOS, VSMC proliferation and medial thickening in mouse aortic tissues, and attenuated Endothelin-1 levels in salt treated VSMCs. In summary, GABA-salt reduced high salt, high cholesterol diet induced hypertension in our mouse model by reducing M1 polarization, EC dysfunction, and VSMC proliferation.

4.
International Journal of Stem Cells ; : 114-124, 2019.
Article in English | WPRIM | ID: wpr-764055

ABSTRACT

BACKGROUND AND OBJECTIVES: Parkinson’s disease (PD) is a fatal and progressive degenerative disease of the nervous system. Until recently, its promising treatment and underlying mechanisms for neuronal death are poorly understood. This study was investigated to identify the molecular mechanism of neuronal death in the substantia nigra and corpus striatum of PD. METHODS: The soluble RAGE (sRAGE) secreting Umbilical Cord Blood—derived Mesenchymal Stem Cell (UCB-MSC) was generated by gene editing method using clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9). These cells were transplanted into Corpus Striatum of rotenone-induced PD animal models then behavioral test, morphological analysis, and immunohistochemical experiments were performed to determine the neuronal cell death and recovery of movement. RESULTS: The neuronal cell death in Corpus Striatum and Substantia Nigra was dramatically reduced and the movement was improved after sRAGE secreting UCB-MSC treatment in PD mice by inhibition of RAGE in neuronal cells. CONCLUSIONS: We suggest that sRAGE secreting UCB-MSC based therapeutic approach could be a potential treatment strategy for neurodegenerative disease including PD.


Subject(s)
Animals , Mice , Behavior Rating Scale , Cell Death , Corpus Striatum , Mesenchymal Stem Cells , Methods , Microglia , Models, Animal , Nervous System , Neurodegenerative Diseases , Neurons , Parkinson Disease , Rage , Substantia Nigra , Umbilical Cord
5.
The Korean Journal of Physiology and Pharmacology ; : 657-667, 2016.
Article in English | WPRIM | ID: wpr-728264

ABSTRACT

Critical limb ischemia (CLI) is one of the most severe forms of peripheral artery diseases, but current treatment strategies do not guarantee complete recovery of vascular blood flow or reduce the risk of mortality. Recently, human bone marrow derived mesenchymal stem cells (MSCs) have been reported to have a paracrine influence on angiogenesis in several ischemic diseases. However, little evidence is available regarding optimal cell doses and injection frequencies. Thus, the authors undertook this study to investigate the effects of cell dose and injection frequency on cell survival and paracrine effects. MSCs were injected at 10⁶ or 10⁵ per injection (high and low doses) either once (single injection) or once in two consecutive weeks (double injection) into ischemic legs. Mice were sacrificed 4 weeks after first injection. Angiogenic effects were confirmed in vitro and in vivo, and M2 macrophage infiltration into ischemic tissues and rates of limb salvage were documented. MSCs were found to induce angiogenesis through a paracrine effect in vitro, and were found to survive in ischemic muscle for up to 4 weeks dependent on cell dose and injection frequency. In addition, double high dose and low dose of MSC injections increased vessel formation, and decreased fibrosis volumes and apoptotic cell numbers, whereas a single high dose did not. Our results showed MSCs protect against ischemic injury in a paracrine manner, and suggest that increasing injection frequency is more important than MSC dosage for the treatment CLI.


Subject(s)
Animals , Humans , Mice , Bone Marrow , Cell Count , Cell Survival , Extremities , Fibrosis , In Vitro Techniques , Ischemia , Leg , Limb Salvage , Macrophages , Mesenchymal Stem Cells , Models, Animal , Mortality , Peripheral Arterial Disease
6.
Korean Journal of Physical Anthropology ; : 61-69, 2016.
Article in Korean | WPRIM | ID: wpr-107702

ABSTRACT

Critical limb ischemia (CLI) is the most severe peripheral artery disease and caused by thrombus formation in blood vessel. The current strategies for treating CLI does not protect limb amputation and reduction in the risk of mortality. Recently, human bone marrow derived mesenchymal stem cells (BD-MSC) were reported to have a paracrine effects on angiogenesis in several ischemic diseases. So, we validate to determine whether BD-MSC protect against ferric chloride treated CLI and induce angiogenesis. To characterized human bone marrow derived stem cell, BD-MSC differentiated to osteocytes and adipocytes and validated stemness using flow cytometry. Endothelial cell induced angiogenesis followed by mesenchymal stem cell cultured medium treatment in HUVEC in vitro. We also mimicked CLI patients condition using FeCl₃ treated CLI mouse and injected one hundred thousand of BD-MSC along the femoral artery to leg muscle. We validated stem cell survival, blood vessel formation, leg muscle condition and fibrosis compared by saline injected mice 28 days later. In this study, BD-MSC cultured medium treatment increased migration and tube formation of HUVEC and BD-MSC injection had an effective blood vessel formation in FeCl₃ treated CLI. As well as blood vessel formation, limb salvage rate also improved and fibrosis area statistically decreased in BD-MSC injected mice. In conclusion, bone marrow derived mesenchymal stem cell improved not only blood vessel formation but also reduction of fibrosis in FeCl₃ treated CLI mice and finally protected limb amputation.


Subject(s)
Animals , Humans , Mice , Adipocytes , Amputation, Surgical , Blood Vessels , Bone Marrow , Endothelial Cells , Extremities , Femoral Artery , Fibrosis , Flow Cytometry , In Vitro Techniques , Ischemia , Leg , Limb Salvage , Mesenchymal Stem Cells , Mortality , Osteocytes , Peripheral Arterial Disease , Stem Cells , Thrombosis
7.
Experimental Neurobiology ; : 55-70, 2015.
Article in English | WPRIM | ID: wpr-190710

ABSTRACT

Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins alphanubeta3, alpha4, beta1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1alpha to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.


Subject(s)
Animals , Humans , Rats , Angiogenesis Inducing Agents , Blood Vessels , Brain , Brain Injuries , Brain Ischemia , Capillaries , Cartilage Oligomeric Matrix Protein , Cell Membrane , Cell- and Tissue-Based Therapy , Fetal Blood , Human Umbilical Vein Endothelial Cells , Integrins , Ischemia , Morphogenesis , Salvage Therapy , Stem Cells , Wounds and Injuries
8.
Anatomy & Cell Biology ; : 47-52, 2012.
Article in English | WPRIM | ID: wpr-100674

ABSTRACT

A holy grail of curing neurodegenerative diseases is to identify the main causes and mechanisms underlying neuronal death. Many studies have sought to identify these targets in a wide variety of ways, but a more important task is to identify critical molecular targets and their origins. Potential molecular targets include advanced glycation end products (AGEs) that can promote neuronal cell death, thereby contributing to neurodegenerative disorders such as Alzheimer disease or Parkinson disease. In this study, we showed that AGE-albumin (glycated albumin) is synthesized in microglial cells and secreted in the human brain. Our results provide new insight into which microglial cells can promote the receptor for AGE-mediated neuronal cell death, eventually leading to neurodegenerative diseases.


Subject(s)
Humans , Alzheimer Disease , Brain , Cell Death , Microglia , Neurodegenerative Diseases , Neurons , Parkinson Disease
9.
Anatomy & Cell Biology ; : 245-255, 2011.
Article in English | WPRIM | ID: wpr-24644

ABSTRACT

Generation of induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine by providing researchers with a unique tool to derive disease-specific stem cells for study. iPSCs can self-renew and can differentiate into many cell types, offering a potentially unlimited source of cells for targeted differentiation into somatic effector cells. Hence, iPSCs are likely to be invaluable for therapeutic applications and disease-related research. In this review, we summarize the recent progress of iPSC generation that has been made with an emphasis on both basic and clinical applications including disease modeling, drug toxicity screening/drug discovery and cell replacement therapy.


Subject(s)
Humans , Drug Design , Genomics , Induced Pluripotent Stem Cells , Proteomics , Regenerative Medicine , Stem Cells
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