50 results on '"Yeo Min Yoon"'
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2. Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis
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Yeo Min Yoon, Gyeongyun Go, Sungtae Yoon, Ji Ho Lim, Gaeun Lee, Jun Hee Lee, and Sang Hun Lee
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chronic kidney disease ,melatonin ,miR-4516 ,mitophagy ,PINK1 ,renal fibrosis ,Cytology ,QH573-671 - Abstract
Dysregulation in mitophagy, in addition to contributing to imbalance in the mitochondrial dynamic, has been implicated in the development of renal fibrosis and progression of chronic kidney disease (CKD). However, the current understanding of the precise mechanisms behind the pathogenic loss of mitophagy remains unclear for developing cures for CKD. We found that miR-4516 is downregulated and its target SIAH3, an E3 ubiquitin protein ligase that reduces PINK1 accumulation to damaged mitochondria, is upregulated in the renal cortex of CKD mice. Here, we demonstrated that melatonin injection induces miR-4516 expression and suppresses SIAH3, and promotes PINK1/Parkin-mediated mitophagy. Furthermore, we demonstrated that melatonin injection attenuates the pathological features of CKD by improving mitochondrial homeostasis. Our data supports that mitochondrial autophagy regulation by activating miR-4516/SIAH3/PINK1 mitophagy signaling axis can be a viable new strategy for treating CKD.
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- 2021
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3. TUDCA-treated chronic kidney disease-derived hMSCs improve therapeutic efficacy in ischemic disease via PrPC
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Yeo Min Yoon, SangMin Kim, Yong-Seok Han, Chul Won Yun, Jun Hee Lee, Hyunjin Noh, and Sang Hun Lee
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Although autologous human mesenchymal stem cells (hMSCs) are a promising source for regenerative stem cell therapy in chronic kidney disease (CKD), the barriers associated with pathophysiological conditions limit therapeutic applicability to patients. We confirmed that level of cellular prion protein (PrPC) in serum was decreased and mitochondria function of CKD-derived hMSCs (CKD-hMSCs) was impaired in patients with CKD. We proved that treatment of CKD-hMSCs with tauroursodeoxycholic acid (TUDCA), a bile acid, enhanced the mitochondrial function of these cells through regulation of PINK1-PrPC-dependent pathway. In a murine hindlimb ischemia model with CKD, tail vein injection of TUDCA-treated CKD-hMSCs improved the functional recovery, including kidney recovery, limb salvage, blood perfusion ratio, and vessel formation along with restored expression of PrPC in the blood serum of the mice. These data suggest that TUDCA-treated CKD-hMSCs are a promising new autologous stem cell therapeutic intervention that dually treats cardiovascular problems and CKD in patients. Keywords: Chronic kidney disease, Mesenchymal stem cell, Tauroursodeoxycholic acid, Cellular prion protein, PINK1, Mitochondria, Mitophagy
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- 2019
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4. PrPC Aptamer Conjugated–Gold Nanoparticles for Targeted Delivery of Doxorubicin to Colorectal Cancer Cells
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Gyeongyun Go, Chang-Seuk Lee, Yeo Min Yoon, Ji Ho Lim, Tae Hyun Kim, and Sang Hun Lee
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PrPC ,PrPC aptamer ,colorectal cancer ,gold nanoparticle ,doxorubicin ,drug delivery ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Anticancer drugs, such as fluorouracil (5-FU), oxaliplatin, and doxorubicin (Dox) are commonly used to treat colorectal cancer (CRC); however, owing to their low response rate and adverse effects, the development of efficient drug delivery systems (DDSs) is required. The cellular prion protein PrPC, which is a cell surface glycoprotein, has been demonstrated to be overexpressed in CRC, however, there has been no research on the development of PrPC-targeting DDSs for targeted drug delivery to CRC. In this study, PrPC aptamer (Apt)-conjugated gold nanoparticles (AuNPs) were synthesized for targeted delivery of Dox to CRC. Thiol-terminated PrPC-Apt was conjugated to AuNPs, followed by hybridization of its complementary DNA for drug loading. Finally, Dox was loaded onto the AuNPs to synthesize PrPC-Apt-functionalized doxorubicin-oligomer-AuNPs (PrPC-Apt DOA). The PrPC-Apt DOA were spherical nanoparticles with an average diameter of 20 nm. Treatment of CRC cells with PrPC-Apt DOA induced reactive oxygen species generation by decreasing catalase and superoxide dismutase activities. In addition, treatment with PrPC-Apt DOA inhibited mitochondrial functions by decreasing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, complex 4 activity, and oxygen consumption rates. Compared to free Dox, PrPC-Apt DOA decreased proliferation and increased apoptosis of CRC cells to a greater degree. In this study, we demonstrated that PrPC-Apt DOA targeting could effectively deliver Dox to CRC cells. PrPC-Apt DOA can be used as a treatment for CRC, and have the potential to replace existing anticancer drugs, such as 5-FU, oxaliplatin, and Dox.
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- 2021
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5. Melatonin Suppresses Renal Cortical Fibrosis by Inhibiting Cytoskeleton Reorganization and Mitochondrial Dysfunction through Regulation of miR-4516
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Yeo Min Yoon, Gyeongyun Go, Chul Won Yun, Ji Ho Lim, Jun Hee Lee, and Sang Hun Lee
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melatonin ,miR-4516 ,renal cortical fibrosis ,TH1 cells ,cytoskeleton reorganization ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Renal fibrosis, a major risk factor for kidney failure, can lead to chronic kidney disease (CKD) and is caused by cytoskeleton reorganization and mitochondrial dysfunction. In this study, we investigated the potential of melatonin treatment to reduce renal fibrosis by recovering the cytoskeleton reorganization and mitochondrial dysfunction. We found that miR-4516 expression was downregulated in the renal cortex of CKD mice and P-cresol-treated TH1 cells. Decreased miR-4516 expression stimulated cytoskeleton reorganization and mitochondrial dysfunction, and induced renal fibrosis. Melatonin treatment suppressed fibrosis by inhibiting cytoskeleton reorganization and restoring mitochondrial function via increased miR-4516 expression. More specifically, melatonin treatment increased miR-4516 expression while decreasing ITGA9 expression, thereby inhibiting cytoskeleton reorganization. In addition, increased expression of miR-4516 by melatonin treatment reduced ROS formation and restored mitochondrial function. These findings suggest that melatonin may be a promising treatment for patients with CKD having renal fibrosis. Moreover, regulation of miR-4516 expression may be a novel strategy for the treatment of renal fibrosis.
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- 2020
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6. Melatonin Enhances Mitophagy by Upregulating Expression of Heat Shock 70 kDa Protein 1L in Human Mesenchymal Stem Cells under Oxidative Stress
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Yeo Min Yoon, Hyung Joo Kim, Jun Hee Lee, and Sang Hun Lee
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oxidative stress ,mesenchymal stem cells ,mitochondria ,melatonin ,mitophagy ,HSPA1L ,parkin ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Human mesenchymal stem cells (hMSCs) are a potent source of cell-based regenerative therapeutics used to treat patients with ischemic disease. However, disease-induced oxidative stress disrupts mitochondrial homeostasis in transplanted hMSCs, resulting in hMSC apoptosis and reducing their efficacy post-transplantation. To address this issue, we evaluated the effects of melatonin on cellular defense mechanisms and mitophagy in hMSCs subjected to oxidative stress. H2O2-induced oxidative stress increases the levels of reactive oxygen species and reduces membrane potential in hMSCs, leading to mitochondrial dysfunction and cell death. Oxidative stress also decreases the expression of 70-kDa heat shock protein 1L (HSPA1L), a molecular chaperone that assists in the recruitment of parkin to the autophagosomal mitochondrial membrane. Decreased expression of HSPA1L destabilizes parkin, thereby impairing mitophagy. Our results indicate that treating hMSCs with melatonin significantly inhibited mitochondrial dysfunction induced by oxidative stress, which decreased hMSCs apoptosis. In damaged hMSCs, treatment with melatonin increased the levels of HSPA1L, which bound to parkin. The interaction between HSPA1L and parkin increased membrane potential and levels of oxidative phosphorylation, resulting in enhanced mitophagy. Our results indicate that melatonin increased the expression of HSPA1L, thereby upregulating mitophagy and prolonging cell survival under conditions of oxidative stress. In this study, we have shown that melatonin, a readily available compound, can be used to improve hMSC-based therapies for patients with pathologic conditions involving oxidative stress.
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- 2019
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7. Pioglitazone Improves the Function of Human Mesenchymal Stem Cells in Chronic Kidney Disease Patients
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Yeo Min Yoon, Jun Hee Lee, Chul Won Yun, and Sang Hun Lee
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cellular prion protein ,chronic kidney disease ,endoplasmic reticulum stress ,mesenchymal stem cells ,mitochondria ,proliferator-activated receptor gamma coactivator 1-alpha ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mesenchymal stem cells (MSCs) are optimal sources of autologous stem cells for cell-based therapy in chronic kidney disease (CKD). However, CKD-associated pathophysiological conditions, such as endoplasmic reticulum (ER) stress and oxidative stress, decrease MSC function. In this work, we study the protective effect of pioglitazone on MSCs isolated from CKD patients (CKD-MSCs) against CKD-induced ER stress. In CKD-MSCs, ER stress is found to induce mitochondrial reactive oxygen species generation and mitochondrial dysfunction. Treatment with pioglitazone reduces the expression of ER stress markers and mitochondrial fusion proteins. Pioglitazone increases the expression of cellular prion protein (PrPC) in CKD-MSCs, which is dependent on the expression levels of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Treatment with pioglitazone is found to protect CKD-MSCs against reactive oxygen species generation, aberrant mitochondrial oxidative phosphorylation of complexes I and IV, and aberrant proliferation capacity through the PGC-1α-PrPC axis. These results indicate that pioglitazone protects the mitochondria of MSCs from CKD-induced ER stress. Pioglitazone treatment of CKD-MSCs may be a potential therapeutic strategy for CKD patients.
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- 2019
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8. TUDCA-Treated Mesenchymal Stem Cells Protect against ER Stress in the Hippocampus of a Murine Chronic Kidney Disease Model
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Jun Hee Lee, Yeo Min Yoon, and Sang Hun Lee
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chronic kidney disease ,mesenchymal stem cells ,endoplasmic reticulum stress ,tauroursodeoxycholic acid ,anti-oxidant ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD; however severe pathophysiological conditions can decrease their therapeutic potential. To address these issues, we established tauroursodeoxycholic acid (TUDCA)-treated MSCs using MSCs isolated from patients with CKD (CKD-hMSCs) and assessed the survival and ROS generation of neural cell line SH-SY5Y cells by co-culturing with TUDCA-treated CKD-hMSCs. In the presence of the uremic toxin P-cresol, the death of SH-SY5Y cells was induced by ROS-mediated ER stress. Co-culture with TUDCA-treated CKD-hMSCs increased anti-oxidant enzyme activities in SH-SY5Y cells through the upregulation of the cellular prion protein (PrPC) expression. Upregulated PrPC expression in SH-SY5Y cells protected against CKD-mediated ER stress and apoptosis. In an adenine-induced murine CKD model, injection with TUDCA-treated CKD-hMSCs suppressed ROS generation and ER stress in the hippocampus. These results indicate that TUDCA-treated CKD-hMSCs prevent the CKD-mediated cell death of SH-SY5Y cells by inhibiting ER stress. Our study suggests that treatment with TUDCA could be a powerful strategy for developing autologous MSC-based therapeutics for patients with CKD, and that PrPC might be a pivotal target for protecting neural cells from CKD-mediated ER stress.
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- 2019
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9. Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1
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Yeo Min Yoon, Yong-Seok Han, Chul Won Yun, Jun Hee Lee, Rang Kim, and Sang Hun Lee
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mesenchymal stem cell ,pioglitazone ,PTEN-induced putative kinase 1 ,cell proliferation ,chronic kidney disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mesenchymal stem cells (MSC) could be a candidate for cell-based therapy in chronic kidney disease (CKD); however, the uremic toxin in patients with CKD restricts the therapeutic efficacy of MSCs. To address this problem, we explored the effect of pioglitazone as a measure against exposure to the uremic toxin P-cresol (PC) in MSCs. Under PC exposure conditions, apoptosis of MSCs was induced, as well as PC-induced dysfunction of mitochondria by augmentation of mitofusion, reduction of mitophagy, and inactivation of mitochondrial complexes I and IV. Treatment of MSCs with pioglitazone significantly inhibited PC-induced apoptosis. Pioglitazone also prevented PC-induced mitofusion and increased mitophagy against PC exposure through up-regulation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK-1). Furthermore, pioglitazone protected against PC-induced mitochondrial dysfunction by increasing the cytochrome c oxidase subunit 4 (COX4) level and activating complexes I and IV, resulting in enhancement of proliferation. In particular, activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) regulated the pioglitazone-mediated up-regulation of PINK-1. These results indicate that pioglitazone protects MSCs against PC-induced accumulated mitochondrial dysfunction via the NF-κB–PINK-1 axis under P-cresol exposure conditions. Our study suggests that pioglitazone-treated MSCs could be a candidate for MSC-based therapy in patients with CKD.
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- 2018
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10. Tauroursodeoxycholic Acid Protects against the Effects of P-Cresol-Induced Reactive Oxygen Species via the Expression of Cellular Prion Protein
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Seung Pil Yun, Yeo Min Yoon, Jun Hee Lee, Minjee Kook, Yong-Seok Han, Seo Kyung Jung, and Sang Hun Lee
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mesenchymal stem cells ,P-cresol ,tauroursodeoxycholic acid ,cellular prion protein ,reactive oxygen species ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mesenchymal stem cells (MSCs) could be a promising solution in the treatment of various diseases including chronic kidney disease (CKD). However, endoplasmic reticulum (ER) stress induced by ischemia in the area of application limits the integration and survival of MSCs in patients. In our study, we generated ER stress-induced conditions in MSCs using P-cresol. As P-cresol is a toxic compound accumulated in the body of CKD patients and induces apoptosis and inflammation through reactive oxygen species (ROS), we observed ER stress-induced MSC apoptosis activated by oxidative stress, which in turn resulted from ROS generation. To overcome stress-induced apoptosis, we investigated the protective effects of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs. In ER stress, TUDCA treatment of MSCs reduced ER stress-associated protein activation, including GRP78, PERK, eIF2α, ATF4, IRE1α, and CHOP. Next, to explore the protective mechanism adopted by TUDCA, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. We confirmed that PrPC expression significantly increased ROS, which was eliminated by superoxide dismutase and catalase in MSCs. These findings suggest that TUDCA protects from inflammation and apoptosis in ER stress via PrPC expression. Our study demonstrates that TUDCA protects MSCs against inflammation and apoptosis in ER stress by PrPC expression in response to P-cresol exposure.
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- 2018
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11. Melatonin Protects Chronic Kidney Disease Mesenchymal Stem/Stromal Cells against Accumulation of Methylglyoxal via Modulation of Hexokinase-2 Expression
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Su-Yeon Han, Gyeongyun Go, Sang Hun Lee, Ji Ho Lim, Gaeun Lee, Sungtae Yoon, and Yeo Min Yoon
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Stromal cell ,urologic and male genital diseases ,Biochemistry ,Melatonin ,Cell therapy ,chemistry.chemical_compound ,Downregulation and upregulation ,Hexokinase ,Drug Discovery ,Methylglyoxal ,medicine ,Pharmacology ,Mesenchymal stem/stromal cells ,business.industry ,Mesenchymal stem cell ,medicine.disease ,female genital diseases and pregnancy complications ,Mitochondria ,chemistry ,Cancer research ,Molecular Medicine ,Original Article ,Kidney disorder ,business ,Glycolysis ,medicine.drug ,Kidney disease - Abstract
Treatment options for patients with chronic kidney disease (CKD) are currently limited; therefore, there has been significant interest in applying mesenchymal stem/stromal cell (MSC)-based therapy to treat CKD. However, MSCs harvested from CKD patients tend to show diminished viability and proliferation due to sustained exposure to uremic toxins in the CKD environment, which limits their utility for cell therapy. The application of melatonin has been demonstrated to improve the therapeutic efficacy of MSCs derived from and engrafted to tissues in patients suffering from CKD, although the underlying biological mechanism has not been elucidated. In this study, we observed overexpression of hexokinase-2 (HK2) in serum samples of CKD patients and MSCs harvested from an adenine-fed CKD mouse model (CKD-mMSCs). HK2 upregulation led to increased production levels of methylglyoxal (MG), a toxic metabolic intermediate of abnormal glycolytic processes. The overabundance of HK2 and MG was associated with impaired mitochondrial function and low cell proliferation in CKD-mMSCs. Melatonin treatment inhibited the increases in HK2 and MG levels, and further improved mitochondrial function, glycolytic metabolism, and cell proliferation. Our findings suggest that identifying and characterizing metabolic regulators such as HK2 in CKD may improve the efficacy of MSCs for treating CKD and other kidney disorders.
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- 2021
12. Role of PrPC in Cancer Stem Cell Characteristics and Drug Resistance in Colon Cancer Cells
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Chul Won Yun, Sang Hun Lee, Yeo Min Yoon, Gyeongyun Go, Jun Hee Lee, and Ji Ho Lim
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Cancer Research ,Gene knockdown ,Magnetic-activated cell sorting ,Colorectal cancer ,animal diseases ,Cell ,General Medicine ,Drug resistance ,Sphere formation ,Biology ,medicine.disease ,nervous system diseases ,Cancer treatment ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Cancer stem cell ,030220 oncology & carcinogenesis ,mental disorders ,Cancer research ,medicine - Abstract
Background/aim Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPC on cancer stem cell characteristics, migration, invasion, and drug resistance of 5FU-resistant CRC cells. Materials and methods PrPC negative and PrPC positive cells were isolated from 5FU-resistant CRC cells using magnetic activated cell sorting. Sphere formation, cancer stem cell marker expression, migration, invasion, and drug resistance were analyzed. Results PrPC positive cells showed increased sphere formation capacity and increased expression of cancer stem cell markers compared to PrPC negative cells. In addition, PrPC positive cells showed increased migration, invasion and drug resistance compared to PrPC negative cells. Furthermore, knockdown of PrPC abolished these effects. Conclusion PrPC expression is important in CRC cell behavior, such as sphere formation, migration, invasion, and drug resistance. PrPC is an important therapeutic target for the treatment of CRC.
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- 2020
13. Melatonin Protects Human Renal Proximal Tubule Epithelial Cells Against High Glucose-Mediated Fibrosis via the Cellular Prion Protein-TGF-β-Smad Signaling Axis
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Gyeongyun Go, Yeo Min Yoon, Sang Hun Lee, Yong-Seok Han, and Jun Hee Lee
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Radioimmunoprecipitation Assay ,Blotting, Western ,melatonin ,Collagen Type I ,Prion Proteins ,Extracellular matrix ,Melatonin ,Kidney Tubules, Proximal ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Transforming Growth Factor beta ,Renal fibrosis ,medicine ,Humans ,Phosphorylation ,Protein kinase B ,Cell Proliferation ,biology ,L-Lactate Dehydrogenase ,Chemistry ,Cell growth ,fibrosis ,General Medicine ,Th1 Cells ,medicine.disease ,renal proximal tubule epithelial cells ,Catalase ,Cell biology ,high glucose ,Fibronectins ,Fibronectin ,cellular prion protein ,Glucose ,biology.protein ,030211 gastroenterology & hepatology ,medicine.drug ,Research Paper ,Signal Transduction - Abstract
Diabetes-mediated hyperglycemia is a major risk factor for renal fibrosis, resulting in the development of chronic kidney diseases. To address this issue, the effect of melatonin, which has an antioxidative potential, on renal fibrosis in human renal proximal tubule epithelial cells under high glucose conditions was investigated. Under high glucose conditions, the generation of reactive oxygen species was drastically increased in human renal proximal tubule epithelial cells, which lead to the inhibition of cell proliferation, enlargement of cell size, reduction of cell survival, and suppression of antioxidant enzyme activities. High glucose also increased the expression of transforming growth factor-β, leading to an increase in Smad2 phosphorylation. These fibrotic phenotype changes increased the expression of fibrosis-mediated extracellular matrix proteins, such as fibronectin, collagen I, and α-smooth muscle actin. In addition, the level of cellular prion protein (PrPC), which is associated with several biological processes, was decreased by exposure to high glucose conditions. Melatonin recovered the expression levels of PrPC under high glucose conditions via phosphorylation of Akt, resulting in the prevention of high glucose-induced fibrosis. In particular, overexpression of PrPC blocked the high glucose-mediated fibrotic phenotype change. These findings indicate that melatonin could be a powerful agent for treating hyperglycemia-induced renal fibrosis.
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- 2020
14. Knockdown of CK2α reduces P-cresol-induced fibrosis in human renal proximal tubule epithelial cells via the downregulation of profilin-1
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Gyeongyun Go, Chul Won Yun, Ji Ho Lim, Yeo Min Yoon, and Sang Hun Lee
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Gene knockdown ,Chemistry ,General Medicine ,Cell cycle ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Profilin-1 ,Fibrosis ,Cancer research ,medicine ,Renal fibrosis ,030211 gastroenterology & hepatology ,Myofibroblast ,Kidney disease - Abstract
Renal fibrosis is one of the main causes of chronic kidney disease. Many studies have focused on fibroblasts and myofibroblasts involved in renal fibrogenesis. Recently, several studies have reported that renal proximal tubule epithelial cells are possible initiators of renal fibrosis. However, the mechanism through which cells induce renal fibrosis is poorly understood. In this study, we found that CK2α induces fibrosis in renal proximal tubule epithelial cells (TH1) by regulating the expression of profilin-1 (Pfn1). CKD mouse model and TH1 cells treated with P-cresol also showed an increased level of Pfn1. The knockdown of CK2α suppressed fibrosis in TH1 cells via the downregulation of Pfn1. In particular, CK2α knockdown inhibited the expression of stress fibers and fibrosis-related proteins in P-cresol-treated TH1 cells. Furthermore, the knockdown of CK2α inhibited mitochondrial dysfunction and restored cellular senescence and cell cycle in P-cresol-treated TH1 cells. These results indicate that CK2α induces renal fibrosis through Pfn1, which makes CK2α a key target molecule in the treatment of fibrosis related to chronic kidney disease.
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- 2020
15. Exosomes isolated from melatonin-stimulated mesenchymal stem cells improve kidney function by regulating inflammation and fibrosis in a chronic kidney disease mouse model
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Jun Hee Lee, Chul Won Yun, Ji-Hye Yea, Sang Hun Lee, and Yeo Min Yoon
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business.industry ,fibrosis ,Mesenchymal stem cell ,Biomedical Engineering ,Medicine (miscellaneous) ,Renal function ,Inflammation ,QD415-436 ,medicine.disease ,Biochemistry ,Microvesicles ,Biomaterials ,Melatonin ,inflammation ,Fibrosis ,Chronic kidney disease ,medicine ,Cancer research ,exosome ,Original Article ,medicine.symptom ,business ,mesenchymal stem cell ,medicine.drug ,Kidney disease - Abstract
Chronic kidney disease (CKD) is defined as structural and functional abnormalities of the kidney due to inflammation and fibrosis. We investigated the therapeutic effects of exosomes secreted by melatonin-stimulated mesenchymal stem cells (Exocue) on the functional recovery of the kidney in a CKD mouse model. Exocue upregulated gene expression of micro RNAs (miRNAs) associated with anti-inflammatory and anti-fibrotic effects. Exocue-treated groups exhibited low tumor necrosis factor-α and transforming growth factor-β levels in serum and fibrosis inhibition in kidney tissues mediated through regulation of cell apoptosis and proliferation of fibrosis-related cells. Exocue treatment decreased the gene expression of CKD progression-related miRNAs. Moreover, the CKD severity was alleviated in the Exocue group via upregulation of aquaporin 2 and 5 levels and reduction of blood urea nitrogen and creatinine, resulting in functional recovery of the kidney. In conclusion, Exocue could be a novel therapeutic agent for treating CKD by regulating inflammation and fibrosis.
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- 2021
16. Effective deep learning training method using blur and noise filter to detect defection in TFT-LCD PAD
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Jae-Gu Lee, Yeo Min Yoon, Seong baek Yoon, Seon Geol Kim, Hyo jin Lee, and Chang Woo Ha
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Pixel ,Computer science ,business.industry ,Noise reduction ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,Gaussian blur ,Filter (signal processing) ,Image segmentation ,Noise ,symbols.namesake ,Gaussian noise ,symbols ,Computer vision ,Data pre-processing ,Artificial intelligence ,business - Abstract
In this paper, we propose a preprocessing method of exploiting noise and blur for effective noise elimination in data. At present, there are many kinds of research to improve the performance of object classification, detection, and image segmentation based on deep learning. For instance, adding noise to data, multiple in-depth convolution layers, and data augmentation have been studied in many ways. An in-depth convolution network results in long processing time and data augmentation gives a burden to memory usage. However, adding noise and blur data preprocessing method gives less burden to hardware, which helps improve algorithm performance. The proposed method is applied to TFT-LCD (Thinfilm Transistor Liquid Crystal Display) PAD defect detection for improved performance. To verify the accuracy and repeatability, 691 actual defect images are used in experiments. These images are composed of complex patterns and defects in the images having barely 2 pixels with little intensity difference. To confirm which filters are better, Gaussian blur, Salt & Pepper noise, and Gaussian noise filters are used for comparison. According to the result, the experiments with Salt & Pepper and Gaussian noise detect all defects. However, the repeatability of the Gaussian noise filter seems better than that with Salt & pepper. Furthermore, applying noise and blur to train data shows more than twice higher detection accuracy than those without such applications. We verified that using Gaussian noise and blur indicates excellent accuracy and repeatability when inspecting the TFT-LCD PAD area in AOI machines.
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- 2021
17. Protective Role of Fucoidan on Cisplatin-mediated ER Stress in Renal Proximal Tubule Epithelial Cells
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Yeo Min Yoon, Sang Hun Lee, Jun Hee Lee, and Hyung Joo Kim
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Cancer Research ,DNA damage ,Apoptosis ,Protein Serine-Threonine Kinases ,Kidney ,Protective Agents ,Antioxidants ,Cell Line ,Kidney Tubules, Proximal ,eIF-2 Kinase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Polysaccharides ,medicine ,Humans ,Gene silencing ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Cisplatin ,chemistry.chemical_classification ,Reactive oxygen species ,Fucoidan ,Endoplasmic reticulum ,Epithelial Cells ,Cell Cycle Checkpoints ,General Medicine ,Th1 Cells ,Endoplasmic Reticulum Stress ,Up-Regulation ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Unfolded protein response ,Reactive Oxygen Species ,medicine.drug - Abstract
Background/aim Administration of cisplatin in cancer patients is limited by the kidney-related adverse effects; however, a protective strategy is absent. We hypothesized that fucoidan protects the proximal tubule epithelial (TH-1) cells against the effects of cisplatin. Materials and methods To assess the effect of fucoidan, its effect on reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress response, DNA damage response (DDR), apoptosis, and cell-cycle arrest in TH-1 cells was investigated. Results Cisplatin increased the accumulation of ROS, leading to excessive ER stress. In presence of cisplatin, treatment of TH-1 cells with fucoidan significantly reduced the ER stress by maintaining the complex of GRP78 with PERK and IRE1α. In particular, fucoidan enhanced the antioxidative capacity through up-regulation of PrPC Furthermore, fucoidan suppressed cisplatin-induced apoptosis and cell-cycle arrest, whereas silencing of PRNP blocked these effects of fucoidan. Conclusion Fucoidan may be a potential adjuvant therapy for cancer patients treated with cisplatin as it preserves renal functionality.
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- 2019
18. PrPC Aptamer Conjugated–Gold Nanoparticles for Targeted Delivery of Doxorubicin to Colorectal Cancer Cells
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Yeo Min Yoon, Gyeongyun Go, Ji Ho Lim, Chang-Seuk Lee, Sang Hun Lee, and Tae Hyun Kim
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animal diseases ,Cell ,Metal Nanoparticles ,Apoptosis ,02 engineering and technology ,lcsh:Chemistry ,Drug Delivery Systems ,0302 clinical medicine ,polycyclic compounds ,lcsh:QH301-705.5 ,Spectroscopy ,Membrane Potential, Mitochondrial ,Chemistry ,General Medicine ,Aptamers, Nucleotide ,Catalase ,021001 nanoscience & nanotechnology ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Mitochondria ,Computer Science Applications ,medicine.anatomical_structure ,Colloidal gold ,030220 oncology & carcinogenesis ,Drug delivery ,Colorectal Neoplasms ,0210 nano-technology ,medicine.drug ,Aptamer ,colorectal cancer ,PrPC aptamer ,doxorubicin ,Prion Proteins ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Cell Line, Tumor ,Spheroids, Cellular ,mental disorders ,medicine ,Humans ,Doxorubicin ,Physical and Theoretical Chemistry ,neoplasms ,Molecular Biology ,Cell Proliferation ,Superoxide Dismutase ,Organic Chemistry ,PrPC ,digestive system diseases ,Oxaliplatin ,nervous system diseases ,carbohydrates (lipids) ,lcsh:Biology (General) ,lcsh:QD1-999 ,Targeted drug delivery ,drug delivery ,Cancer research ,Gold ,Reactive Oxygen Species ,gold nanoparticle - Abstract
Anticancer drugs, such as fluorouracil (5-FU), oxaliplatin, and doxorubicin (Dox) are commonly used to treat colorectal cancer (CRC), however, owing to their low response rate and adverse effects, the development of efficient drug delivery systems (DDSs) is required. The cellular prion protein PrPC, which is a cell surface glycoprotein, has been demonstrated to be overexpressed in CRC, however, there has been no research on the development of PrPC-targeting DDSs for targeted drug delivery to CRC. In this study, PrPC aptamer (Apt)-conjugated gold nanoparticles (AuNPs) were synthesized for targeted delivery of Dox to CRC. Thiol-terminated PrPC-Apt was conjugated to AuNPs, followed by hybridization of its complementary DNA for drug loading. Finally, Dox was loaded onto the AuNPs to synthesize PrPC-Apt-functionalized doxorubicin-oligomer-AuNPs (PrPC-Apt DOA). The PrPC-Apt DOA were spherical nanoparticles with an average diameter of 20 nm. Treatment of CRC cells with PrPC-Apt DOA induced reactive oxygen species generation by decreasing catalase and superoxide dismutase activities. In addition, treatment with PrPC-Apt DOA inhibited mitochondrial functions by decreasing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, complex 4 activity, and oxygen consumption rates. Compared to free Dox, PrPC-Apt DOA decreased proliferation and increased apoptosis of CRC cells to a greater degree. In this study, we demonstrated that PrPC-Apt DOA targeting could effectively deliver Dox to CRC cells. PrPC-Apt DOA can be used as a treatment for CRC, and have the potential to replace existing anticancer drugs, such as 5-FU, oxaliplatin, and Dox.
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- 2021
19. Role of PrP
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Gyeongyun, Go, Chul Won, Yun, Yeo Min, Yoon, Ji Ho, Lim, Jun Hee, Lee, and Sang Hun, Lee
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Gene Expression Regulation, Neoplastic ,Cell Movement ,Colon ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Spheroids, Cellular ,Colonic Neoplasms ,Neoplastic Stem Cells ,Humans ,Neoplasm Invasiveness ,Fluorouracil ,Prion Proteins ,Cell Proliferation - Abstract
Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPPrPPrPPrP
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- 2020
20. Melatonin Suppresses Renal Cortical Fibrosis by Inhibiting Cytoskeleton Reorganization and Mitochondrial Dysfunction through Regulation of miR-4516
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Gyeongyun Go, Yeo Min Yoon, Jun Hee Lee, Ji Ho Lim, Chul Won Yun, and Sang Hun Lee
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Male ,medicine.medical_specialty ,ITGA9 ,cytoskeleton reorganization ,Kidney Cortex ,Renal cortex ,melatonin ,urologic and male genital diseases ,Catalysis ,Article ,TH1 cells ,Cell Line ,lcsh:Chemistry ,Inorganic Chemistry ,Melatonin ,Mice ,Fibrosis ,Internal medicine ,medicine ,Renal fibrosis ,Animals ,miR-4516 ,Physical and Theoretical Chemistry ,Renal Insufficiency, Chronic ,Cytoskeleton ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,Kidney ,Mice, Inbred BALB C ,renal cortical fibrosis ,business.industry ,Organic Chemistry ,General Medicine ,medicine.disease ,Computer Science Applications ,Mitochondria ,MicroRNAs ,medicine.anatomical_structure ,Endocrinology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Gene Expression Regulation ,business ,Reactive Oxygen Species ,medicine.drug ,Kidney disease - Abstract
Renal fibrosis, a major risk factor for kidney failure, can lead to chronic kidney disease (CKD) and is caused by cytoskeleton reorganization and mitochondrial dysfunction. In this study, we investigated the potential of melatonin treatment to reduce renal fibrosis by recovering the cytoskeleton reorganization and mitochondrial dysfunction. We found that miR-4516 expression was downregulated in the renal cortex of CKD mice and P-cresol-treated TH1 cells. Decreased miR-4516 expression stimulated cytoskeleton reorganization and mitochondrial dysfunction, and induced renal fibrosis. Melatonin treatment suppressed fibrosis by inhibiting cytoskeleton reorganization and restoring mitochondrial function via increased miR-4516 expression. More specifically, melatonin treatment increased miR-4516 expression while decreasing ITGA9 expression, thereby inhibiting cytoskeleton reorganization. In addition, increased expression of miR-4516 by melatonin treatment reduced ROS formation and restored mitochondrial function. These findings suggest that melatonin may be a promising treatment for patients with CKD having renal fibrosis. Moreover, regulation of miR-4516 expression may be a novel strategy for the treatment of renal fibrosis.
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- 2020
21. Knockdown of CK2α reduces
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Yeo Min, Yoon, Gyeongyun, Go, Chul Won, Yun, Ji Ho, Lim, and Sang Hun, Lee
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Male ,stress F-actin ,CK2α ,renal proximal tubule epithelial cell ,Adenine ,fibrosis ,Epithelial Cells ,Cell Line ,Kidney Tubules, Proximal ,Cresols ,Disease Models, Animal ,Profilins ,Gene Knockdown Techniques ,CKD ,Animals ,Humans ,Profilin-1 ,Renal Insufficiency, Chronic ,Casein Kinase II ,Cellular Senescence ,Research Paper - Abstract
Renal fibrosis is one of the main causes of chronic kidney disease. Many studies have focused on fibroblasts and myofibroblasts involved in renal fibrogenesis. Recently, several studies have reported that renal proximal tubule epithelial cells are possible initiators of renal fibrosis. However, the mechanism through which cells induce renal fibrosis is poorly understood. In this study, we found that CK2α induces fibrosis in renal proximal tubule epithelial cells (TH1) by regulating the expression of profilin-1 (Pfn1). CKD mouse model and TH1 cells treated with P-cresol also showed an increased level of Pfn1. The knockdown of CK2α suppressed fibrosis in TH1 cells via the downregulation of Pfn1. In particular, CK2α knockdown inhibited the expression of stress fibers and fibrosis-related proteins in P-cresol-treated TH1 cells. Furthermore, the knockdown of CK2α inhibited mitochondrial dysfunction and restored cellular senescence and cell cycle in P-cresol-treated TH1 cells. These results indicate that CK2α induces renal fibrosis through Pfn1, which makes CK2α a key target molecule in the treatment of fibrosis related to chronic kidney disease.
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- 2020
22. Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway
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Jun Hee Lee, Keon-Hyoung Song, Hyunjin Noh, Sang Hun Lee, and Yeo Min Yoon
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0301 basic medicine ,Senescence ,Male ,Aging ,Mice, Nude ,melatonin ,Biology ,Mitochondrion ,Protective Agents ,Melatonin ,03 medical and health sciences ,replicative senescence ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Ischemia ,Mitophagy ,medicine ,Animals ,Humans ,HSP70 Heat-Shock Proteins ,HSPA1L ,Cells, Cultured ,Cellular Senescence ,Membrane Potential, Mitochondrial ,Original Paper ,mesenchymal stem cells ,Mice, Inbred BALB C ,Mesenchymal stem cell ,Cell Biology ,Cell biology ,Mitochondria ,Disease Models, Animal ,030104 developmental biology ,Gene Knockdown Techniques ,Stem cell ,030217 neurology & neurosurgery ,medicine.drug ,Signal Transduction - Abstract
Mesenchymal stem cells (MSCs) are a popular cell source for stem cell‐based therapy. However, continuous ex vivo expansion to acquire large amounts of MSCs for clinical study induces replicative senescence, causing decreased therapeutic efficacy in MSCs. To address this issue, we investigated the effect of melatonin on replicative senescence in MSCs. In senescent MSCs (late passage), replicative senescence decreased mitophagy by inhibiting mitofission, resulting in the augmentation of mitochondrial dysfunction. Treatment with melatonin rescued replicative senescence by enhancing mitophagy and mitochondrial function through upregulation of heat shock 70 kDa protein 1L (HSPA1L). More specifically, we found that melatonin‐induced HSPA1L binds to cellular prion protein (PrPC), resulting in the recruitment of PrPC into the mitochondria. The HSPA1L‐PrPC complex then binds to COX4IA, which is a mitochondrial complex IV protein, leading to an increase in mitochondrial membrane potential and anti‐oxidant enzyme activity. These protective effects were blocked by knockdown of HSPA1L. In a murine hindlimb ischemia model, melatonin‐treated senescent MSCs enhanced functional recovery by increasing blood flow perfusion, limb salvage, and neovascularization. This study, for the first time, suggests that melatonin protects MSCs against replicative senescence during ex vivo expansion for clinical application via mitochondrial quality control., Replicative cellular senescence in MSCs increases mitofusion of damaged mitochondria, leading to suppression of mitophagy. Melatonin increases the expression of HSPA1L, leading to the recruitment of PrPC, which induces mitofission of damaged mitochondria, resulting in the increase in the mitochondrial activities. Melatonin‐treated senescent MSCs improve survival, proliferation, and neovascularization in ischemic disease.
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- 2020
23. Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases
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Gaeun Lee, Sang Hun Lee, Yeo Min Yoon, Gyeongyun Go, Sungtae Yoon, and Jiho Lim
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0301 basic medicine ,MAPK/ERK pathway ,kidney ,Cell signaling ,renal injury ,animal diseases ,renal cancer ,Cell ,Antineoplastic Agents ,Review ,SMAD ,Microbiology ,Biochemistry ,Prion Diseases ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Renal fibrosis ,Animals ,Humans ,Medicine ,PrPC Proteins ,Renal Insufficiency, Chronic ,Molecular Biology ,mesenchymal stem cell ,Kidney ,business.industry ,PrPC ,Extracellular vesicle ,Acute Kidney Injury ,medicine.disease ,renal fibrosis ,Fibrosis ,QR1-502 ,Kidney Neoplasms ,Mitochondria ,Neoplasm Proteins ,nervous system diseases ,cellular prion protein ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,PRNP ,business ,chronic kidney disease ,030217 neurology & neurosurgery ,Signal Transduction ,Kidney disease - Abstract
A cellular prion protein (PrPC) is a ubiquitous cell surface glycoprotein, and its physiological functions have been receiving increased attention. Endogenous PrPC is present in various kidney tissues and undergoes glomerular filtration. In prion diseases, abnormal prion proteins are found to accumulate in renal tissues and filtered into urine. Urinary prion protein could serve as a diagnostic biomarker. PrPC plays a role in cellular signaling pathways, reno-protective effects, and kidney iron uptake. PrPC signaling affects mitochondrial function via the ERK pathway and is affected by the regulatory influence of microRNAs, small molecules, and signaling proteins. Targeting PrPC in acute and chronic kidney disease could help improve iron homeostasis, ameliorate damage from ischemia/reperfusion injury, and enhance the efficacy of mesenchymal stem/stromal cell or extracellular vesicle-based therapeutic strategies. PrPC may also be under the influence of BMP/Smad signaling and affect the progression of TGF-β-related renal fibrosis. PrPC conveys TNF-α resistance in some renal cancers, and therefore, the coadministration of anti-PrPC antibodies improves chemotherapy. PrPC can be used to design antibody–drug conjugates, aptamer–drug conjugates, and customized tissue inhibitors of metalloproteinases to suppress cancer. With preclinical studies demonstrating promising results, further research on PrPC in the kidney may lead to innovative PrPC-based therapeutic strategies for renal disease.
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- 2021
24. Role of hypoxia-mediated cellular prion protein functional change in stem cells and potential application in angiogenesis
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Yong Seok Han, Chul Won Yun, Peter Rhee, Seung Pil Yun, Jun Hee Lee, Yeo Min Yoon, and Sang Hun Lee
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0301 basic medicine ,Cancer Research ,Angiogenesis ,medicine.medical_treatment ,Review ,tissue regeneration ,Biology ,Biochemistry ,Prion Proteins ,03 medical and health sciences ,angiogenesis ,Genetics ,medicine ,Humans ,Molecular Biology ,Protein kinase B ,Embryonic Stem Cells ,Neovascularization, Pathologic ,hypoxia ,anti-oxidant ,Stem-cell therapy ,Cell cycle ,Hypoxia-Inducible Factor 1, alpha Subunit ,Embryonic stem cell ,Cell Hypoxia ,Cell biology ,Oncogene Protein v-akt ,cellular prion protein ,030104 developmental biology ,Oncology ,Gene Expression Regulation ,STAT protein ,Cancer research ,Molecular Medicine ,Stem cell ,Signal transduction ,Signal Transduction - Abstract
Cellular prion protein (PrPC) can replace other pivotal molecules due to its interaction with several partners in performing a variety of important biological functions that may differ between embryonic and mature stem cells. Recent studies have revealed major advances in elucidating the putative role of PrPC in the regulation of stem cells and its application in stem cell therapy. What is special about PrPC is that its expression may be regulated by hypoxia‑inducible factor (HIF)‑1α, which is the transcriptional factor of cellular response to hypoxia. Hypoxic conditions have been known to drive cellular responses that can enhance cell survival, differentiation and angiogenesis through adaptive processes. Our group recently reported hypoxia‑enhanced vascular repair of endothelial colony‑forming cells on ischemic injury. Hypoxia‑induced AKT/signal transducer and activator of transcription 3 phosphorylation eventually increases neovasculogenesis. In stem cell biology, hypoxia promotes the expression of growth factors. According to other studies, aspects of tissue regeneration and cell function are influenced by hypoxia, which serves an essential role in stem cell HIF‑1α signaling. All these data suggest the possibility that hypoxia‑mediated PrPC serves an important role in angiogenesis. Therefore, the present review summarizes the characteristics of PrPC, which is produced by HIF‑1α in hypoxia, as it relates to angiogenesis.
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- 2017
25. Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis
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Chul Won Yun, Dongjun Jeong, Sang-Cheol Lee, Hyog Young Kwon, SangMin Kim, Jun Hee Lee, Moo-Jun Baek, Hyunjoo Lee, Ho Jae Han, Sei-Jung Lee, Yeo Min Yoon, Yong-Seok Han, and Seungpil Yun
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0301 basic medicine ,Proteasome Endopeptidase Complex ,Cancer Research ,Carcinogenesis ,animal diseases ,Cell Culture Techniques ,Biology ,Prion Proteins ,03 medical and health sciences ,Ubiquitin ,RNA interference ,mental disorders ,Genetics ,Humans ,HSP70 Heat-Shock Proteins ,Molecular Targeted Therapy ,HSPA1L ,RNA, Small Interfering ,Receptor ,Molecular Biology ,Gene knockdown ,Ubiquitination ,Flow Cytometry ,Hypoxia-Inducible Factor 1, alpha Subunit ,nervous system diseases ,Ubiquitin ligase ,Receptors, Autocrine Motility Factor ,030104 developmental biology ,Tumor progression ,Gene Knockdown Techniques ,Proteolysis ,Disease Progression ,biology.protein ,Cancer research ,RNA Interference ,Signal transduction ,Colorectal Neoplasms ,HT29 Cells ,Signal Transduction - Abstract
The cellular prion protein (PrPC) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrPC degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrPC accumulation and tumorigenicity in vivo. PrPC was degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrPC. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrPC, thereby increasing PrPC ubiquitination. Thus, GP78 was identified as the ubiquitinase for PrPC, thereby revealing an essential mechanism that controls PrPC levels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrPC accumulation during tumor progression.
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- 2017
26. Melatonin-stimulated exosomes enhance the regenerative potential of chronic kidney disease-derived mesenchymal stem/stromal cells via cellular prion proteins
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Jun Hee Lee, Yeo Min Yoon, Keon-Hyoung Song, Sang Hun Lee, and Hyunjin Noh
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0301 basic medicine ,Male ,Stromal cell ,urologic and male genital diseases ,Exosomes ,Mesenchymal Stem Cell Transplantation ,Exosome ,Prion Proteins ,Melatonin ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Endocrinology ,Downregulation and upregulation ,medicine ,Animals ,Humans ,Renal Insufficiency, Chronic ,Kidney ,Mice, Inbred BALB C ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,medicine.disease ,female genital diseases and pregnancy complications ,Microvesicles ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Female ,business ,030217 neurology & neurosurgery ,medicine.drug ,Kidney disease - Abstract
Chronic kidney disease (CKD) is caused by dysfunctional kidneys, which result in complications like cardiovascular diseases. Chronic kidney disease-induced pathophysiological conditions decrease efficacy of autologous mesenchymal stem/stromal cell (MSC)-based therapy by reducing MSC functionality. To enhance therapeutic potential in patients with CKD, we isolated exosomes derived from melatonin-treated healthy MSCs (MT exosomes) and assessed the biological functions of MT exosome-treated MSCs isolated from patients with CKD (CKD-MSCs). Treatment with melatonin increased the expression of cellular prion protein (PrPC ) in exosomes isolated from MSCs through the upregulation of miR-4516. Treatment with MT exosomes protected mitochondrial function, cellular senescence, and proliferative potential of CKD-MSCs. MT exosomes significantly increased the level of angiogenesis-associated proteins in CKD-MSCs. In a murine hindlimb ischemia model with CKD, MT exosome-treated CKD-MSCs improved functional recovery and vessel repair. These findings elucidate the regenerative potential of MT exosome-treated CKD-MSCs via the miR-4516-PrPC signaling axis. This study suggests that the treatment of CKD-MSCs with MT exosomes might be a powerful strategy for developing autologous MSC-based therapeutics for patients with CKD. Furthermore, miR-4516 and PrPC could be key molecules for enhancing the regenerative potential of MSCs in ischemic diseases.
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- 2019
27. TUDCA-Treated Mesenchymal Stem Cells Protect against ER Stress in the Hippocampus of a Murine Chronic Kidney Disease Model
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Sang Hun Lee, Jun Hee Lee, and Yeo Min Yoon
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Cell ,urologic and male genital diseases ,Hippocampus ,lcsh:Chemistry ,Cresols ,Mice ,chemistry.chemical_compound ,lcsh:QH301-705.5 ,Spectroscopy ,anti-oxidant ,General Medicine ,female genital diseases and pregnancy complications ,Up-Regulation ,Computer Science Applications ,medicine.anatomical_structure ,endoplasmic reticulum stress ,Signal Transduction ,Programmed cell death ,Cell Survival ,Mesenchymal Stem Cell Transplantation ,Article ,Catalysis ,Cell Line ,Taurochenodeoxycholic Acid ,Inorganic Chemistry ,Downregulation and upregulation ,medicine ,Animals ,Humans ,PrPC Proteins ,Renal Insufficiency, Chronic ,Physical and Theoretical Chemistry ,Molecular Biology ,mesenchymal stem cells ,tauroursodeoxycholic acid ,business.industry ,Adenine ,Endoplasmic reticulum ,Organic Chemistry ,Mesenchymal stem cell ,Tauroursodeoxycholic acid ,Coculture Techniques ,Disease Models, Animal ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Apoptosis ,Cancer research ,Unfolded protein response ,Reactive Oxygen Species ,business ,chronic kidney disease - Abstract
Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD, however severe pathophysiological conditions can decrease their therapeutic potential. To address these issues, we established tauroursodeoxycholic acid (TUDCA)-treated MSCs using MSCs isolated from patients with CKD (CKD-hMSCs) and assessed the survival and ROS generation of neural cell line SH-SY5Y cells by co-culturing with TUDCA-treated CKD-hMSCs. In the presence of the uremic toxin P-cresol, the death of SH-SY5Y cells was induced by ROS-mediated ER stress. Co-culture with TUDCA-treated CKD-hMSCs increased anti-oxidant enzyme activities in SH-SY5Y cells through the upregulation of the cellular prion protein (PrPC) expression. Upregulated PrPC expression in SH-SY5Y cells protected against CKD-mediated ER stress and apoptosis. In an adenine-induced murine CKD model, injection with TUDCA-treated CKD-hMSCs suppressed ROS generation and ER stress in the hippocampus. These results indicate that TUDCA-treated CKD-hMSCs prevent the CKD-mediated cell death of SH-SY5Y cells by inhibiting ER stress. Our study suggests that treatment with TUDCA could be a powerful strategy for developing autologous MSC-based therapeutics for patients with CKD, and that PrPC might be a pivotal target for protecting neural cells from CKD-mediated ER stress.
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- 2019
28. Pivotal Roles of Ginsenoside Rg3 in Tumor Apoptosis Through Regulation of Reactive Oxygen Species
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Jun Hee Lee, Yeo Min Yoon, Hwa Yeon Sun, Yong-Seok Han, Chul Won Yun, Jae Heon Kim, Sang Hun Lee, and Yun Seob Song
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0301 basic medicine ,Cancer Research ,Ginsenosides ,Cell Survival ,Cell ,Apoptosis ,Antioxidants ,Culture Media, Serum-Free ,Carcinoma, Lewis Lung ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Cell Proliferation ,chemistry.chemical_classification ,Reactive oxygen species ,Cell growth ,Kinase ,Cell Cycle ,Lewis lung carcinoma ,General Medicine ,Cell cycle ,Flow Cytometry ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Culture Media, Conditioned ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Apoptosis Regulatory Proteins ,Reactive Oxygen Species - Abstract
Background Elevated production of reactive oxygen species (ROS) is observed in various cancer types and pathophysiological conditions. In cancer cells, ROS induce cell proliferation, genetic instability, and a malignant phenotype. Ginsenoside Rg3 is the main pharmacologically active component in ginseng and has been reported to have an antioxidant effect. To overcome lung cancer by regulating the ROS level, we investigated the antitumor effect and mechanism of Rg3 and its antioxidative property on Lewis lung carcinoma (LLC) cells. Materials and methods Inhibition of ROS was suppressed in LLC cells by Rg3 treatment, and these cells were used to investigate the antioxidant, antiproliferative, and antitumor effects in LLC cells. Results ROS production was increased in cells grown in serum-containing media (conditioned media) compared to those grown in serum-free media. The high level of ROS induced LLC cell proliferation, but treatment with Rg3 (200 ng/ml) resulted in reduction of ROS, leading to inhibition of cell proliferation. Treatment with Rg3 significantly reduced cyclin and cyclin-dependent kinase expression in LLC cells. Additionally, Rg3 treatment significantly suppressed activation of mitogen-activated protein kinases and induced LLC cell apoptosis through activation of pro-apoptotic proteins and suppression of anti-apoptotic proteins. Conclusion Taken together, these findings demonstrate the role of Rg3 in reduction of the intracellular ROS level, attenuation of proliferation via augmentation of cell cycle- and cell proliferation-associated proteins, and activation of apoptosis through regulation of apoptosis-associated proteins in LLC. These findings suggest that Rg3 could be used as a therapeutic agent in lung cancer.
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- 2016
29. Antioxidant effects of Cirsium setidens extract on oxidative stress in human mesenchymal stem cells
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Chul Won Yun, Ho Kyung Jung, Sang Hun Lee, Jun Hee Lee, Yeo Min Yoon, Yong Seok Han, Hwa Yeon Sun, and Hyun Woo Cho
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0301 basic medicine ,Cancer Research ,Programmed cell death ,antioxidant ,food.ingredient ,Cirsium setidens ,Pharmacology ,Biology ,medicine.disease_cause ,Cirsium ,Biochemistry ,Antioxidants ,Cell Line ,03 medical and health sciences ,food ,Genetics ,medicine ,Humans ,Viability assay ,Molecular Biology ,chemistry.chemical_classification ,mesenchymal stem cells ,Reactive oxygen species ,Plant Extracts ,Mesenchymal stem cell ,apoptosis ,Hydrogen Peroxide ,Articles ,Transplantation ,Oxidative Stress ,030104 developmental biology ,Oncology ,chemistry ,Apoptosis ,Cancer research ,Molecular Medicine ,Apoptosis Regulatory Proteins ,Reactive Oxygen Species ,Oxidative stress - Abstract
Human mesenchymal stem cells (MSCs) may be used in cell-based therapy to promote neovascularization for the treatment of ischemic diseases. However, high levels of reactive oxygen species (ROS) derived from the pathophysiological ischemic environment induce senescence and apoptosis of MSCs, resulting in reduced functionality and defective neovascularization. Therefore, the present study aimed to determine the protective effects of Cirsium setidens, a natural product, on oxidative stress-induced apoptosis in MSCs. The present study investigated for the change of ROS levels in MSCs using ROS assays. In addition, cell viability determined by MTT and TUNEL assays. Western blot analysis was performed to investigate the change of apoptosis-associated proteins in MSCs. Treatment of MSCs with hydrogen peroxide (H2O2; 200 µM) significantly increased intracellular ROS levels and cell death; however, pretreatment with C. setidens (100 µg/ml) suppressed H2O2-induced ROS generation and increased the survival of MSCs. H2O2-induced ROS production increased the levels of phosphorylated-p38 mitogen activated protein kinase, c-Jun N-terminal kinase, ataxia telangiectasia mutated and p53; these increases were inhibited by pretreatment with C. setidens. In addition, C. setidens inhibited ROS-induced apoptosis of MSCs by increasing the expression levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL-2), and decreasing the expression levels of the proapoptotic protein BCL-2-associated X protein. These findings indicated that pretreatment of MSCs with C. setidens may prevent ROS-induced oxidative injury by regulating the oxidative stress-associated signaling pathway, and suppressing the apoptosis-associated signal pathway. Therefore, C. setidens may be developed as a beneficial broad-spectrum agent for enhancing the effectiveness of MSC transplantation in the treatment of ischemic diseases.
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- 2016
30. Pretreatment with Lycopene Attenuates Oxidative Stress-Induced Apoptosis in Human Mesenchymal Stem Cells
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Yong Seok Han, Sang Mo Kwon, Jai Sung Lee, Yeo Min Yoon, Jun Hee Lee, Sang Hun Lee, Inhyu Bae, and Ji Yong Kim
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MAPK/ERK pathway ,Apoptosis ,medicine.disease_cause ,Biochemistry ,MSC ,chemistry.chemical_compound ,Lycopene ,Drug Discovery ,medicine ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Kinase ,business.industry ,Anti-oxidant reagent ,Mesenchymal stem cell ,Transplantation ,chemistry ,Oxidative stress ,Cancer research ,Molecular Medicine ,Original Article ,business - Abstract
Human mesenchymal stem cells (MSCs) have been used in cell-based therapy to promote revascularization after peripheral or myocardial ischemia. High levels of reactive oxygen species (ROS) are involved in the senescence and apoptosis of MSCs, causing defective neovascularization. Here, we examined the effect of the natural antioxidant lycopene on oxidative stress-induced apoptosis in MSCs. Although H2O2 (200 μM) increased intracellular ROS levels in human MSCs, lycopene (10 μM) pretreatment suppressed H2O2-induced ROS generation and increased survival. H2O2-induced ROS increased the levels of phosphorylated p38 mitogen activated protein kinase (MAPK), Jun-N-terminal kinase (JNK), ataxia telangiectasia mutated (ATM), and p53, which were inhibited by lycopene pretreatment. Furthermore, lycopene pretreatment decreased the expression of cleaved poly (ADP ribose) polymerase-1 (PARP-1) and caspase-3 and increased the expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax), which were induced by H2O2 treatment. Moreover, lycopene significantly increased manganese superoxide dismutase (MnSOD) expression and decreased cellular ROS levels via the PI3K-Akt pathway. Our findings show that lycopene pretreatment prevents ischemic injury by suppressing apoptosis-associated signal pathway and enhancing anti-oxidant protein, suggesting that lycopene could be developed as a beneficial broad-spectrum agent for the successful MSC transplantation in ischemic diseases.
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- 2015
31. Protect TUDCA stimulated CKD-derived hMSCs against the CKD-Ischemic disease via upregulation of PrPC
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Hyunjin Noh, Sang Hun Lee, Yeo Min Yoon, Yong-Seok Han, Jun Hee Lee, SangMin Kim, and Chul Won Yun
- Subjects
Kidney ,Necrosis ,business.industry ,medicine.medical_treatment ,Mesenchymal stem cell ,PINK1 ,Stem-cell therapy ,medicine.anatomical_structure ,Blood serum ,mitochondrial fusion ,medicine ,Cancer research ,Stem cell ,medicine.symptom ,business - Abstract
Although autologous human mesenchymal stem cells (hMSCs) are a promising source for regenerative stem cell therapy, the barriers associated with pathophysiological conditions in this disease limit therapeutic applicability to patients. We proved treatment of CKD-hMSCs with TUDCA enhanced the mitochondrial function of these cells and increased complex I & IV enzymatic activity, increasing PINK1 expression and decreasing mitochondrial O2•− and mitochondrial fusion in a PrPC-dependent pathway. Moreover, TH-1 cells enhanced viability when co-cultured in vitro with TUDCA-treated CKD-hMSC. In vivo, tail vein injection of TUDCA-treated CKD-hMSCs into the mouse model of CKD associated with hindlimb ischemia enhanced kidney recovery, the blood perfusion ratio, vessel formation, and prevented limb loss, and foot necrosis along with restored expression of PrPC in the blood serum of the mice. These data suggest that TUDCA-treated CKD-hMSCs are a promising new autologous stem cell therapeutic intervention that dually treats cardiovascular problems and CKD in patients.
- Published
- 2018
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32. Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression
- Author
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Yong-Seok Han, Yeo Min Yoon, Seo Kyung Jung, Jun Hee Lee, and Sang Hun Lee
- Subjects
0301 basic medicine ,Male ,autophagy ,Mice, Nude ,melatonin ,Antioxidants ,Prion Proteins ,Melatonin ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Ischemia ,medicine ,Animals ,Viability assay ,Cells, Cultured ,mesenchymal stem cell ,Mice, Inbred BALB C ,Chemistry ,Endoplasmic reticulum ,Mesenchymal stem cell ,Autophagy ,Mesenchymal Stem Cells ,Cell Biology ,General Medicine ,Original Articles ,Endoplasmic Reticulum Stress ,Cell biology ,Hindlimb ,Oxidative Stress ,cellular prion protein ,030104 developmental biology ,Apoptosis ,030220 oncology & carcinogenesis ,Unfolded protein response ,Original Article ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Object The purpose of this study was to explore whether melatonin could protect mesenchymal stem cells (MSCs) against ischaemic injury, by inhibiting endoplasmic reticulum (ER) stress and autophagy both in vivo and in vitro. Materials and Methods To confirm the protective effect of melatonin against ER stress in MSCs, markers of cell viability, apoptosis and autophagy were analysed. To further investigate the regenerative effect of melatonin‐treated MSCs in ischaemic tissues, a murine hindlimb ischaemic model was established. Results Under oxidative stress conditions, treatment with melatonin suppressed the activation of ER stress–associated proteins and autophagy‐associated proteins acting through upregulation of cellular prion protein (PrPC) expression. Consequently, inhibition of apoptotic cell death occurred. Melatonin also promoted the activation of MnSOD and catalase activities in MSCs. In a murine hindlimb ischaemia model, melatonin‐treated MSCs also enhanced the functional limb recovery as well as neovascularization. These beneficial effects of melatonin were all blocked by knock‐down of PrPC expression. Conclusion Melatonin protects against ER stress/autophagy‐induced apoptotic cell death by augmenting PrPC expression. Thus, melatonin‐treated MSCs could be a potential cell‐based therapeutic agent for ER stress–induced ischaemic diseases, and melatonin‐induced PrPC might be a key molecule in ameliorating ER stress and autophagy.
- Published
- 2018
33. Administration of Cripto in <scp>GRP</scp> 78 overexpressed human <scp>MSC</scp> s enhances stem cell viability and angiogenesis during human <scp>MSC</scp> transplantation therapy
- Author
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Yeo Min Yoon, Sang-Cheol Lee, Yong-Seok Han, Jun Hee Lee, Jin Hur, and SangMin Kim
- Subjects
Male ,STAT3 Transcription Factor ,0301 basic medicine ,Cell Survival ,Angiogenesis ,Mice, Nude ,Biology ,GPI-Linked Proteins ,Mesenchymal Stem Cell Transplantation ,Cripto ,Cell Line ,Mice ,03 medical and health sciences ,Cell Movement ,Ischemia ,In vivo ,Animals ,Humans ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Cell Proliferation ,Mice, Inbred BALB C ,Wound Healing ,Migration Assay ,Neovascularization, Pathologic ,Stem Cells ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Original Articles ,Cell Biology ,General Medicine ,Janus Kinase 2 ,Cell Hypoxia ,Neoplasm Proteins ,Transplantation ,030104 developmental biology ,Lipofectamine ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Stem cell ,Signal Transduction - Abstract
OBJECTIVES: The purpose of this study was to explore the effectiveness of concurrent GRP78 overexpression combined with Cripto on hMSC proliferation and migration both in vitro and in vivo. Specifically, we explored whether the treatment enhances effectiveness of hMSC transplantation in ischaemic tissue. MATERIALS AND METHODS: Human MSCs obtained from human adipose tissue were cultured in α‐minimum essential medium (Hyclone, Logan, UT, USA) supplemented with 10% (v/v) foetal bovine serum (Hyclone), 100 U mL(−1) penicillin and 100 μg mL(−1) streptomycin. Murine hindlimb ischaemic model was generated with 8‐week‐old male nude BALB/c mice (Biogenomics, Seoul, Korea) maintained under a 12‐h light/dark cycle following the established protocol with minor modification. Cellular injection was performed no later than 3 hour after surgery. Lipofectamine transfection, single‐cell cultivation assay, transwell assay, scratch wound‐healing migration assay, immunohistochemistry and western blotting assays were performed. RESULTS: Overexpression of GRP78 along with Cripto enhanced hMSC proliferation, migration and invasion. It increased interaction of surface GRP78 receptor with Cripto via JAK2/STAT3 pathway. We confirmed our proposed mechanism by showing that treatment with GRP78 antibody blocks the enhancement in vitro. In vivo, we observed that Cripto induced by the hypoxic environment in hindlimb ischaemic model interacts with the overexpressed GRP78 and increases hMSC proliferation, migration and invasion potentials as well as angiogenesis around transplanted ischaemic site via cytokine secretions. CONCLUSIONS: These results demonstrate supporting evidences that GRP78‐Cripto combination technique offers novel strategy to enhance MSC proliferation, migration and invasion potentials as well as angiogenesis around ischaemic site, ultimately facilitating MSC‐based transplantation therapy in ischaemic conditions.
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- 2018
34. Melatonin Promotes Apoptosis of Oxaliplatin-resistant Colorectal Cancer Cells Through Inhibition of Cellular Prion Protein
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Chul Won Yun, Jun Hee Lee, Yong-Seok Han, Sang Hun Lee, and Yeo Min Yoon
- Subjects
0301 basic medicine ,Cancer Research ,Organoplatinum Compounds ,Colorectal cancer ,medicine.medical_treatment ,Apoptosis ,Melatonin ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,Superoxides ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,PrPC Proteins ,Chemotherapy ,biology ,Superoxide ,Endoplasmic reticulum ,General Medicine ,medicine.disease ,Endoplasmic Reticulum Stress ,Oxaliplatin ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,Colorectal Neoplasms ,medicine.drug - Abstract
Background/aim Drug resistance restricts the efficacy of chemotherapy in colorectal cancer. However, the detailed molecular mechanism of drug resistance in colorectal cancer cells remains unclear. Materials and methods The level of cellular prion protein (PrPC) in oxaliplatin-resistant colorectal cancer (SNU-C5/Oxal-R) cells was assessed. Results PrPC level in SNU-C5/Oxal-R cells was significantly increased compared to that in wild-type (SNU-C5) cells. Superoxide dismutase and catalase activities were higher in SNU-C5/Oxal-R cells than in SNU-C5 cells. Treatment of SNU-C5/Oxal-R cells with oxaliplatin and melatonin reduced PrPC expression, while suppressing antioxidant enzyme activity and increasing superoxide anion generation. In SNU-C5/Oxal-R cells, endoplasmic reticulum stress and apoptosis were significantly increased following co-treatment with oxaliplatin and melatonin compared to treatment with oxaliplatin alone. Conclusion Co-treatment with oxaliplatin and melatonin increased endoplasmic reticulum stress in and apoptosis of SNU-C5/Oxal-R cells through inhibition of PrPC, suggesting that PrPC could be a key molecule in oxaliplatin resistance of colorectal cancer cells.
- Published
- 2018
35. Tauroursodeoxycholic Acid Protects against the Effects of P-Cresol-Induced Reactive Oxygen Species via the Expression of Cellular Prion Protein
- Author
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Jun Hee Lee, Seo Kyung Jung, Seung Pil Yun, Yeo Min Yoon, Sang Hun Lee, Yong-Seok Han, and Minjee Kook
- Subjects
0301 basic medicine ,Apoptosis ,medicine.disease_cause ,P-cresol ,Antioxidants ,lcsh:Chemistry ,chemistry.chemical_compound ,Cresols ,0302 clinical medicine ,Endoplasmic Reticulum Chaperone BiP ,lcsh:QH301-705.5 ,Spectroscopy ,Cells, Cultured ,chemistry.chemical_classification ,reactive oxygen species ,biology ,General Medicine ,Endoplasmic Reticulum Stress ,Computer Science Applications ,Cell biology ,cellular prion protein ,Adipose Tissue ,030220 oncology & carcinogenesis ,medicine.symptom ,mesenchymal stem cells ,tauroursodeoxycholic acid ,Inflammation ,Catalysis ,Article ,Inorganic Chemistry ,Superoxide dismutase ,Taurochenodeoxycholic Acid ,03 medical and health sciences ,medicine ,Humans ,PrPC Proteins ,Physical and Theoretical Chemistry ,Molecular Biology ,Reactive oxygen species ,Endoplasmic reticulum ,Organic Chemistry ,Tauroursodeoxycholic acid ,Oxidative Stress ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Unfolded protein response ,biology.protein ,Oxidative stress - Abstract
Mesenchymal stem cells (MSCs) could be a promising solution in the treatment of various diseases including chronic kidney disease (CKD). However, endoplasmic reticulum (ER) stress induced by ischemia in the area of application limits the integration and survival of MSCs in patients. In our study, we generated ER stress-induced conditions in MSCs using P-cresol. As P-cresol is a toxic compound accumulated in the body of CKD patients and induces apoptosis and inflammation through reactive oxygen species (ROS), we observed ER stress-induced MSC apoptosis activated by oxidative stress, which in turn resulted from ROS generation. To overcome stress-induced apoptosis, we investigated the protective effects of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs. In ER stress, TUDCA treatment of MSCs reduced ER stress-associated protein activation, including GRP78, PERK, eIF2α, ATF4, IRE1α, and CHOP. Next, to explore the protective mechanism adopted by TUDCA, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. We confirmed that PrPC expression significantly increased ROS, which was eliminated by superoxide dismutase and catalase in MSCs. These findings suggest that TUDCA protects from inflammation and apoptosis in ER stress via PrPC expression. Our study demonstrates that TUDCA protects MSCs against inflammation and apoptosis in ER stress by PrPC expression in response to P-cresol exposure.
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- 2018
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36. GRP78 Regulates Apoptosis, Cell Survival and Proliferation in 5-Fluorouracil-resistant SNUC5 Colon Cancer Cells
- Author
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Jun Hee Lee, Sang Hun Lee, and Yeo Min Yoon
- Subjects
0301 basic medicine ,Cancer Research ,Antimetabolites, Antineoplastic ,Colorectal cancer ,Cell Survival ,medicine.medical_treatment ,Cell ,Apoptosis ,Drug resistance ,Biology ,03 medical and health sciences ,medicine ,Tumor Cells, Cultured ,Humans ,RNA, Small Interfering ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Cell Proliferation ,Gene knockdown ,Chemotherapy ,General Medicine ,medicine.disease ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Fluorouracil ,Drug Resistance, Neoplasm ,Colonic Neoplasms ,Signal transduction ,medicine.drug - Abstract
5-Fluorouracil (5-FU) is an effective anticancer drug. However, the development of drug resistance has limited its chemotherapeutic efficacy. To address this problem, we investigated the expression of glucose-regulated protein (GRP78, 78 kDa) in 5-FU-resistant colorectal cancer (CRC) cells (SNUC5/5FUR). GRP78 was highly expressed in the SNUC5/5FUR cells compared to wild-type SNUC5 cells. In the presence of 5-FU, GRP78 knockdown induced apoptosis via activation of caspase-3 and poly(ADP-ribose)-polymerase 1. GRP78 also inhibited the production of intracellular reactive oxygen species by regulating stress-associated signaling pathways. Furthermore, GRP78 enhanced cell survival and proliferation via activation of the phosphatidylinosito-3-kinase-AKT-mammalian target of rapamycin axis and cell cycle-associated proteins. These effects were blocked upon GRP78 knockdown, which indicates that GRP78 is involved in the development of 5-FU resistance in these CRC cells. Therefore, a combination of chemotherapy and GRP78-specific targeting may counteract 5-FU resistance in CRC cells.
- Published
- 2017
37. Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis
- Author
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Jun Hee Lee, Yeo Min Yoon, and Sang Hun Lee
- Subjects
0301 basic medicine ,Male ,Programmed cell death ,78-kDa glucose-regulated protein ,Cell Survival ,proliferation ,Ischemia ,mesenchymal stem cell ,hypoxia ,cell survival ,ischemic injury ,Mice, Nude ,Biology ,Hypoxic preconditioning ,Mesenchymal Stem Cell Transplantation ,Catalysis ,Article ,Cell Line ,Inorganic Chemistry ,03 medical and health sciences ,cellsurvival ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Protein kinase B ,Endoplasmic Reticulum Chaperone BiP ,Spectroscopy ,Heat-Shock Proteins ,Cell Proliferation ,Mice, Inbred BALB C ,Low oxygen ,Organic Chemistry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,General Medicine ,medicine.disease ,Hypoxia-Inducible Factor 1, alpha Subunit ,Cell Hypoxia ,Computer Science Applications ,Cell biology ,030104 developmental biology ,Immunology ,Cytokine secretion ,Stem cell ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Mesenchymal stem cells (MSC) are ideal materials for stem cell-based therapy. As MSCs reside in hypoxic microenvironments (low oxygen tension of 1% to 7%), several studies have focused on the beneficial effects of hypoxic preconditioning on MSC survival; however, the mechanisms underlying such effects remain unclear. This study aimed to uncover the potential mechanism involving 78-kDa glucose-regulated protein (GRP78) to explain the enhanced MSC bioactivity and survival in hindlimb ischemia. Under hypoxia (2% O2), the expression of GRP78 was significantly increased via hypoxia-inducible factor (HIF)-1α. Hypoxia-induced GRP78 promoted the proliferation and migration potential of MSCs through the HIF-1α-GRP78-Akt signal axis. In a murine hind-limb ischemia model, hypoxic preconditioning enhanced the survival and proliferation of transplanted MSCs through suppression of the cell death signal pathway and augmentation of angiogenic cytokine secretion. These effects were regulated by GRP78. Our findings indicate that hypoxic preconditioning promotes survival, proliferation, and angiogenic cytokine secretion of MSCs via the HIF-1α-GRP78-Akt signal pathway, suggesting that hypoxia-preconditioned MSCs might provide a therapeutic strategy for MSC-based therapies and that GRP78 represents a potential target for the development of functional MSCs.
- Published
- 2017
38. TUDCA-treated chronic kidney disease-derived hMSCs improve therapeutic efficacy in ischemic disease via PrPC
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Chul Won Yun, Hyunjin Noh, Sang Hun Lee, Yeo Min Yoon, SangMin Kim, Jun Hee Lee, and Yong-Seok Han
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmacology ,urologic and male genital diseases ,Biochemistry ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Blood serum ,Ischemia ,Chronic kidney disease ,lcsh:QH301-705.5 ,Mesenchymal stem cell ,Membrane Potential, Mitochondrial ,lcsh:R5-920 ,Kidney ,Bile acid ,Mitophagy ,Stem-cell therapy ,female genital diseases and pregnancy complications ,Mitochondria ,medicine.anatomical_structure ,Cytokines ,Inflammation Mediators ,Tauroursodeoxycholic acid ,Stem cell ,lcsh:Medicine (General) ,Research Paper ,endocrine system ,medicine.drug_class ,Cellular prion protein ,Mesenchymal Stem Cell Transplantation ,Taurochenodeoxycholic Acid ,03 medical and health sciences ,medicine ,Animals ,Humans ,PrPC Proteins ,Renal Insufficiency, Chronic ,Cell Proliferation ,business.industry ,PINK1 ,Organic Chemistry ,Mesenchymal Stem Cells ,equipment and supplies ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,lcsh:Biology (General) ,chemistry ,business ,Biomarkers ,030217 neurology & neurosurgery ,Kidney disease - Abstract
Although autologous human mesenchymal stem cells (hMSCs) are a promising source for regenerative stem cell therapy in chronic kidney disease (CKD), the barriers associated with pathophysiological conditions limit therapeutic applicability to patients. We confirmed that level of cellular prion protein (PrPC) in serum was decreased and mitochondria function of CKD-derived hMSCs (CKD-hMSCs) was impaired in patients with CKD. We proved that treatment of CKD-hMSCs with tauroursodeoxycholic acid (TUDCA), a bile acid, enhanced the mitochondrial function of these cells through regulation of PINK1-PrPC-dependent pathway. In a murine hindlimb ischemia model with CKD, tail vein injection of TUDCA-treated CKD-hMSCs improved the functional recovery, including kidney recovery, limb salvage, blood perfusion ratio, and vessel formation along with restored expression of PrPC in the blood serum of the mice. These data suggest that TUDCA-treated CKD-hMSCs are a promising new autologous stem cell therapeutic intervention that dually treats cardiovascular problems and CKD in patients., Graphical abstract Image 1
- Published
- 2019
39. Silencing Prion Protein in HT29 Human Colorectal Cancer Cells Enhances Anticancer Response to Fucoidan
- Author
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Yeo Min Yoon, Daniel An, Sang Hun Lee, Yong-Seok Han, Seungpil Yun, Chul Won Yun, and Jun Hee Lee
- Subjects
0301 basic medicine ,Male ,Vascular Endothelial Growth Factor A ,Cancer Research ,Colorectal cancer ,Angiogenesis ,animal diseases ,Antineoplastic Agents ,Apoptosis ,Biology ,Prion Proteins ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Cyclin-dependent kinase ,Cell Movement ,Polysaccharides ,Cell Line, Tumor ,Proliferating Cell Nuclear Antigen ,mental disorders ,medicine ,Gene silencing ,Animals ,Humans ,Gene Silencing ,RNA, Small Interfering ,Cell Proliferation ,Mice, Inbred BALB C ,Fucoidan ,Caspase 3 ,Cell Cycle ,Cancer ,General Medicine ,medicine.disease ,Molecular biology ,Immunohistochemistry ,nervous system diseases ,Platelet Endothelial Cell Adhesion Molecule-1 ,030104 developmental biology ,Oncology ,chemistry ,Colonic Neoplasms ,Cancer research ,biology.protein ,RNA Interference ,HT29 Cells - Abstract
Background: The putative functions of the cellular prion protein (PrPc) are believed to be associated with cell signaling, differentiation, survival, and cancer progression. With respect to cancer development and progression, elevations and mutations of PrPc expression have been shown to increase the risk for malignancy and metastasis in breast and colorectal cancer. Since both natural supplements and direct regulation of PrPc expression contribute to inhibition of cancer progression and growth, we hypothesized that knockdown of PrPc could lead to an enhanced synergic effect on the inhibition of cancer growth by fucoidan. Materials and Methods: PrPc expression was suppressed in HT29 human colon cancer cells by utilizing small-interfering RNA (si-PRNP), and cells were subsequently used to study the antiproliferative and anticancer effects of fucoidan treatment of HT29 human colon cancer cells. Results: Fucoidan treatment significantly inhibited growth and reduced cyclin and cyclin-dependent kinase (CDK) expression in HT29 colon cancer cells. Furthermore, silencing PrPc expression with si-PRNP amplified the fucoidan-induced changes in cell proliferation, apoptosis, and migration. Intraperitoneal injection of si-PRNP with fucoidan reduced proliferation and tumor volume in Balb/c nude mice. This enhanced antitumor efficacy was associated with decreased angiogenesis. Conclusion: Combination of fucoidan with silencing of PrPc has a synergic effect on the inhibition of HT29 colon cancer cell growth. Furthermore, we provide evidence for the therapeutic application of PrPc silencing with other anticancer drugs for cancer.
- Published
- 2016
40. Tauroursodeoxycholic acid reduces ER stress by regulating ofAkt-dependent cellular prion protein
- Author
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Jun Hee Lee, Chul Won Yun, Hyun Jik Lee, Seung Pil Yun, Sang Hun Lee, Ho Jae Han, Sei-Jung Lee, Yeo Min Yoon, Yong-Seok Han, and Hyunjin Noh
- Subjects
0301 basic medicine ,Male ,p38 mitogen-activated protein kinases ,Mice, Nude ,Biology ,Mesenchymal Stem Cell Transplantation ,Article ,Taurochenodeoxycholic Acid ,03 medical and health sciences ,chemistry.chemical_compound ,Downregulation and upregulation ,Animals ,Humans ,PrPC Proteins ,Protein kinase B ,Endoplasmic Reticulum Chaperone BiP ,Mice, Inbred BALB C ,Multidisciplinary ,Endoplasmic reticulum ,Mesenchymal stem cell ,Tauroursodeoxycholic acid ,Mesenchymal Stem Cells ,Endoplasmic Reticulum Stress ,Cell biology ,Transplantation ,030104 developmental biology ,Biochemistry ,chemistry ,ddc:000 ,Unfolded protein response ,Heterografts ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Scientific reports 6(1), 39838(2016). doi:10.1038/srep39838, Published by Nature Publishing Group, London
- Published
- 2016
41. Hypoxia-induced expression of cellular prion protein improves thetherapeutic potential of mesenchymal stem cells
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Hyunjin Noh, Yong-Seok Han, Chul Won Yun, Jun Hee Lee, Sang Hun Lee, and Yeo Min Yoon
- Subjects
0301 basic medicine ,STAT3 Transcription Factor ,Cancer Research ,Cell Survival ,Cellular differentiation ,Immunology ,Neovascularization, Physiologic ,Apoptosis ,Biology ,medicine.disease_cause ,Mesenchymal Stem Cell Transplantation ,Protective Agents ,Prion Proteins ,Neovascularization ,Superoxide dismutase ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,In vivo ,Ischemia ,medicine ,Animals ,Humans ,Cells, Cultured ,Cell Proliferation ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Recovery of Function ,Hypoxia (medical) ,Janus Kinase 2 ,Hypoxia-Inducible Factor 1, alpha Subunit ,Molecular biology ,Cell Hypoxia ,Cell biology ,Hindlimb ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Gene Knockdown Techniques ,biology.protein ,Original Article ,medicine.symptom ,Oxidative stress ,Signal Transduction - Abstract
Mesenchymal stem cells (MSCs) are ‘adult’ multipotent cells that promote regeneration of injured tissues in vivo. However, differences in oxygenation levels between normoxic culture conditions (21% oxygen) and both the MSC niche (2–8% oxygen) and ischemic injury-induced oxidative stress conditions in vivo have resulted in low efficacy of MSC therapies in both pre-clinical and clinical studies. To address this issue, we examined the effectiveness of hypoxia preconditioning (2% oxygen) for enhancing the bioactivity and tissue-regenerative potential of adipose-derived MSCs. Hypoxia preconditioning enhanced the proliferative potential of MSCs by promoting the expression of normal cellular prion protein (PrPC). In particular, hypoxia preconditioning-mediated MSC proliferation was regulated by PrPC-dependent JAK2 and STAT3 activation. In addition, hypoxia preconditioning-induced PrPC regulated superoxide dismutase and catalase activity, and inhibited oxidative stress-induced apoptosis via inactivation of cleaved caspase-3. In a murine hindlimb ischemia model, hypoxia preconditioning enhanced the survival and proliferation of transplanted MSCs, ultimately resulting in improved functional recovery of the ischemic tissue, including the ratio of blood flow perfusion, limb salvage, and neovascularization. These results suggest that Hypo-MSC offer a therapeutic strategy for accelerated neovasculogenesis in ischemic diseases, and that PrPC comprises a potential target for MSC-based therapies.
- Published
- 2016
42. Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1
- Author
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Yong-Seok Han, Chul Won Yun, Rang Kim, Yeo Min Yoon, Jun Hee Lee, and Sang Hun Lee
- Subjects
0301 basic medicine ,Pharmacology ,Mitochondrion ,urologic and male genital diseases ,Catalysis ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,Mitophagy ,medicine ,pioglitazone ,PTEN ,Tensin ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,mesenchymal stem cell ,Spectroscopy ,biology ,Chemistry ,Organic Chemistry ,Mesenchymal stem cell ,General Medicine ,NFKB1 ,female genital diseases and pregnancy complications ,PTEN-induced putative kinase 1 ,Computer Science Applications ,cell proliferation ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Apoptosis ,biology.protein ,Pioglitazone ,chronic kidney disease ,medicine.drug - Abstract
Mesenchymal stem cells (MSC) could be a candidate for cell-based therapy in chronic kidney disease (CKD), however, the uremic toxin in patients with CKD restricts the therapeutic efficacy of MSCs. To address this problem, we explored the effect of pioglitazone as a measure against exposure to the uremic toxin P-cresol (PC) in MSCs. Under PC exposure conditions, apoptosis of MSCs was induced, as well as PC-induced dysfunction of mitochondria by augmentation of mitofusion, reduction of mitophagy, and inactivation of mitochondrial complexes I and IV. Treatment of MSCs with pioglitazone significantly inhibited PC-induced apoptosis. Pioglitazone also prevented PC-induced mitofusion and increased mitophagy against PC exposure through up-regulation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK-1). Furthermore, pioglitazone protected against PC-induced mitochondrial dysfunction by increasing the cytochrome c oxidase subunit 4 (COX4) level and activating complexes I and IV, resulting in enhancement of proliferation. In particular, activation of nuclear factor &kappa, light-chain-enhancer of activated B cells (NF-&kappa, B) regulated the pioglitazone-mediated up-regulation of PINK-1. These results indicate that pioglitazone protects MSCs against PC-induced accumulated mitochondrial dysfunction via the NF-&kappa, B&ndash, PINK-1 axis under P-cresol exposure conditions. Our study suggests that pioglitazone-treated MSCs could be a candidate for MSC-based therapy in patients with CKD.
- Published
- 2018
43. Fucoidan protects mesenchymal stem cells against oxidative stress and enhances vascular regeneration in a murine hindlimb ischemia model
- Author
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Jin Sup Jung, Ho Jae Han, Yong-Seok Han, Moo Jun Baek, Sang Hun Lee, Jung Min Ryu, Yeo Min Yoon, Jun Hee Lee, and Hyunjin Noh
- Subjects
Programmed cell death ,Cell Survival ,Mice, Nude ,Neovascularization, Physiologic ,Inhibitor of apoptosis ,Mesenchymal Stem Cell Transplantation ,chemistry.chemical_compound ,Mice ,Ischemia ,Polysaccharides ,Medicine ,Animals ,Humans ,Protein kinase B ,PI3K/AKT/mTOR pathway ,chemistry.chemical_classification ,Reactive oxygen species ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Fucoidan ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Hindlimb ,Oxidative Stress ,chemistry ,Apoptosis ,Immunology ,Cancer research ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Mesenchymal stem cells (MSCs) have the potential to differentiate into multiple cell lineages. Given this potential for tissue regeneration, MSC-based therapeutic applications have been considered in recent years. However, ischemia-induced apoptosis has been reported to be one of the main causes of MSC death following transplantation. The primary objective of this study was to determine whether a natural antioxidant, fucoidan, could protect MSCs from ischemia-induced apoptosis in vitro and in vivo. Furthermore, we investigated the mechanism of action of fucoidan's anti-ischemic effect in MSCs. Methods and result Pre-treatment with fucoidan (10μg/mL) suppressed the increase in H 2 O 2 -induced reactive oxygen species (ROS) levels and drastically reduced apoptotic cell death in MSCs. Fucoidan inhibited the activation of the pro-apoptotic proteins p38-mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), and caspase-3, and augmented the expression of the anti-apoptosis protein cellular inhibitor of apoptosis (cIAP). Moreover, fucoidan significantly increased manganese superoxide dismutase (MnSOD) expression and decreased cellular ROS levels via the Akt pathway, resulting in enhanced cell survival. In a murine hindlimb ischemia model, transplanted fucoidan-treated MSCs showed significantly enhanced cell survival and proliferation in ischemic tissues. Functional recovery and limb salvage also remarkably improved in mice injected with fucoidan-stimulated MSCs compared with mice injected with non-stimulated MSCs. Conclusion Taken together, these results show that fucoidan protects MSCs from ischemia-induced cell death by modulation of apoptosis-associated proteins and cellular ROS levels through regulation of the MnSOD and Akt pathways, suggesting that fucoidan could be powerful therapeutic adjuvant for MSC-based therapy in ischemic diseases.
- Published
- 2014
44. Studies on The Plasma Analysis and Bioavailability of Phenytoin in Human
- Author
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Hae Jung Kang, Hae Ja Lee, Kweon Ho Nam, Yeo Min Yoon, Hee Kyeong Kang, and Eun Sook Yoo
- Abstract
A developed assay method to evaluate the pharmacokinetics of phenytoin in human plasma was investigated by reverse-phase HPLC-UV. We found the analytic condition that separate phenytoin from internal standard (triamcinolone acetonide) in human plasma sample at the wavelength of 225 nm. Proteins of the plasma samples were removed enough by using 0.1 N HC1. Mobile phase is consisted of buffer (pH3.0):CH3CN (65:35), and retention time of phenytoin is 8.2 min at a flow rate of 0.9 ml/min.. Tlie fundamental parameters such as linearity, accuracy, precision for this bioanalytical method validation were suitable to pharmacokinetic study and bioequvalence test. Eight volunteers in lasting were administered single dose of 100 mg of phenytoin (one tablet) orally together with 240 ml water for pharmacokinetic studies. The maximum concentration (0.82 ㎍/ml) of phenytoin was attained at 6.63 hour after dosing. T1/2 and AUC were 14.88 hr and 25.181 ㎍hr/ml respectively. According to our study, the accurate analysis for phenytoin achieved and the proposed guidance can be applied to pharmacokinetic study and bioequivalence test in human.
- Published
- 2003
45. Role of hypoxia‑mediated cellular prion protein functional change in stem cells and potential application in angiogenesis (Review).
- Author
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SEUNG PIL YUN, RHEE, PETER, YONG‑SEOK HAN, YEO MIN YOON, CHUL WON YUN, SANG HUN LEE, and JUN HEE LEE
- Subjects
HYPOXEMIA ,NEOVASCULARIZATION ,PRIONS ,STEM cells ,ANTIOXIDANTS ,TISSUES ,REGENERATION (Biology) - Abstract
Cellular prion protein (PrP
C ) can replace other pivotal molecules due to its interaction with several partners in performing a variety of important biological functions that may differ between embryonic and mature stem cells. Recent studies have revealed major advances in elucidating the putative role of PrPC in the regulation of stem cells and its application in stem cell therapy. What is special about PrPC is that its expression may be regulated by hypoxia‑inducible factor (HIF)‑1α, which is the transcriptional factor of cellular response to hypoxia. Hypoxic conditions have been known to drive cellular responses that can enhance cell survival, differentiation and angiogenesis through adaptive processes. Our group recently reported hypoxia‑enhanced vascular repair of endothelial colony‑forming cells on ischemic injury. Hypoxia‑induced AKT/signal transducer and activator of transcription 3 phosphorylation eventually increases neovasculogenesis. In stem cell biology, hypoxia promotes the expression of growth factors. According to other studies, aspects of tissue regeneration and cell function are influenced by hypoxia, which serves an essential role in stem cell HIF‑1α signaling. All these data suggest the possibility that hypoxia‑mediated PrPC serves an important role in angiogenesis. Therefore, the present review summarizes the characteristics of PrPC , which is produced by HIF‑1α in hypoxia, as it relates to angiogenesis. [ABSTRACT FROM AUTHOR]- Published
- 2017
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46. Genetic localization and in vivo characterization of a Monascus azaphilone pigment biosynthetic gene cluster
- Author
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Hyun-Ju Kim, Hyung-Jin Kwon, Bora Nam, Chien-Chi Chen, Bijinu Balakrishnan, Yeo-Min Yoon, Shih-Hau Chiu, Jae-Won Suh, and Suman Karki
- Subjects
Regulation of gene expression ,Genetics ,biology ,Mutant ,General Medicine ,Pigments, Biological ,biology.organism_classification ,Monascus ,Applied Microbiology and Biotechnology ,Mixed Function Oxygenases ,Fungal Proteins ,Polyketide ,Biochemistry ,Polyketide synthase ,Gene Expression Regulation, Fungal ,Multigene Family ,Gene cluster ,biology.protein ,Monascus purpureus ,Gene ,Polyketide Synthases ,Biotechnology - Abstract
Monascus spp. produce several well-known polyketides such as monacolin K, citrinin, and azaphilone pigments. In this study, the azaphilone pigment biosynthetic gene cluster was identified through T-DNA random mutagenesis in Monascus purpureus. The albino mutant W13 bears a T-DNA insertion upstream of a transcriptional regulator gene (mppR1). The transcription of mppR1 and the nearby polyketide synthase gene (MpPKS5) was significantly repressed in the W13 mutant. Targeted inactivation of MpPKS5 also gave rise to an albino mutant, confirming that mppR1 and MpPKS5 belong to an azaphilone pigment biosynthetic gene cluster. This M. purpureus sequence was used to identify the whole biosynthetic gene cluster in the Monascus pilosus genome. MpPKS5 contains SAT/KS/AT/PT/ACP/MT/R domains, and this domain organization is preserved in other azaphilone polyketide synthases. This biosynthetic gene cluster also encodes fatty acid synthase (FAS), which is predicted to assist the synthesis of 3-oxooactanoyl-CoA and 3-oxodecanoyl-CoA. These 3-oxoacyl compounds are proposed to be incorporated into the azaphilone backbone to complete the pigment biosynthesis. A monooxygenase gene (an azaH and tropB homolog) that is located far downstream of the FAS gene is proposed to be involved in pyrone ring formation. A homology search on other fungal genome sequences suggests that this azaphilone pigment gene cluster also exists in the Penicillium marneffei and Talaromyces stipitatus genomes.
- Published
- 2012
47. Antioxidant effects of Cirsium setidens extract on oxidative stress in human mesenchymal stem cells.
- Author
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JUN HEE LEE, HO KYUNG JUNG, YONG-SEOK HAN, YEO MIN YOON, CHUL WON YUN, HWA YEON SUN, HYUN WOO CHO, and SANG HUN LEE
- Subjects
CIRSIUM ,MESENCHYMAL stem cells ,CYTOPROTECTION ,OXIDATION-reduction reaction ,REACTIVE oxygen species - Abstract
Human mesenchymal stem cells (MSCs) may be used in cell-based therapy to promote neovascularization for the treatment of ischemic diseases. However, high levels of reactive oxygen species (ROS) derived from the pathophysiological ischemic environment induce senescence and apoptosis of MSCs, resulting in reduced functionality and defective neovascularization. Therefore, the present study aimed to determine the protective effects of Cirsium setidens, a natural product, on oxidative stress-induced apoptosis in MSCs. The present study investigated for the change of ROS levels in MSCs using ROS assays. In addition, cell viability determined by MTT and TUNEL assays. Western blot analysis was performed to investigate the change of apoptosis-associated proteins in MSCs. Treatment of MSCs with hydrogen peroxide (H
2 O2 ; 200 μM) significantly increased intracellular ROS levels and cell death; however, pretreatment with C. setidens (100 μg/ml) suppressed H2 O2 -induced ROS generation and increased the survival of MSCs. H2 O2 -induced ROS production increased the levels of phosphorylated-p38 mitogen activated protein kinase, c-Jun N-terminal kinase, ataxia telangiectasia mutated and p53; these increases were inhibited by pretreatment with C. setidens. In addition, C. setidens inhibited ROS-induced apoptosis of MSCs by increasing the expression levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL-2), and decreasing the expression levels of the proapoptotic protein BCL-2-associated X protein. These findings indicated that pretreatment of MSCs with C. setidens may prevent ROS-induced oxidative injury by regulating the oxidative stress-associated signaling pathway, and suppressing the apoptosis-associated signal pathway. Therefore, C. setidens may be developed as a beneficial broad-spectrum agent for enhancing the effectiveness of MSC transplantation in the treatment of ischemic diseases. [ABSTRACT FROM AUTHOR]- Published
- 2016
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48. Hypoxia accelerates vascular repair of endothelial colony-forming cells on ischemic injury via STAT3-BCL3 axis.
- Author
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Sang Hun Lee, Jun Hee Lee, Yong-Seok Han, Jung Min Ryu, Yeo Min Yoon, and Ho Jae Han
- Subjects
ISCHEMIA treatment ,HYPOXEMIA ,VASCULAR surgery ,TRANSPLANTATION of organs, tissues, etc. ,ENDOTHELIAL cells ,CARDIOVASCULAR system ,CELLULAR therapy ,ANATOMY - Abstract
Introduction: Endothelial colony-forming cells (ECFCs) significantly improve tissue repair by providing regeneration potential within injured cardiovascular tissue. However, ECFC transplantation into ischemic tissue exhibits limited therapeutic efficacy due to poor engraftment in vivo. We established an adequate ex vivo expansion protocol and identified novel modulators that enhance functional bioactivities of ECFCs. Methods: To augment the regenerative potential of ECFCs, functional bioactivities of hypoxia-preconditioned ECFCs (hypo-ECFCs) were examined. Results: Phosphorylations of the JAK2/STAT3 pathway and clonogenic proliferation were enhanced by short-term ECFC culturing under hypoxia, whereas siRNA-targeting of STAT3 significantly reduced these activities. Expression of BCL3, a target molecule of STAT3, was increased in hypo-ECFCs. Moreover, siRNA inhibition of BCL3 markedly reduced survival of ECFCs during hypoxic stress in vitro and ischemic stress in vivo. In a hindlimb ischemia model of ischemia, hypo-ECFC transplantation enhanced blood flow ratio, capillary density, transplanted cell proliferation and survival, and angiogenic cytokine secretion at ischemic sites. Conclusions: Hypoxia preconditioning facilitates functional bioactivities of ECFCs by mediating regulation of the STAT3-BCL3 axis. Thus, a hypoxic preconditioned ex vivo expansion protocol triggers expansion and functional bioactivities of ECFCs via modulation of the hypoxia-induced STAT3-BCL3 axis, suggesting that hypo-ECFCs offer a therapeutic strategy for accelerated neovasculogenesis in ischemic diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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49. Association between HaeIII polymorphism of scavenger receptor class B type I gene and plasma HDL-cholesterol concentration.
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Seung Ho Hong, Young-Ree Kim, Yeo Min Yoon, Won Ki Min, Sa Il Chun, and Kim, Jin Q.
- Subjects
GENETIC polymorphisms ,BLOOD plasma ,POLYMERASE chain reaction ,BLOOD lipids ,CHOLESTEROL ,ENDONUCLEASES - Abstract
Background: Evidence has recently been found for significant associations between genetic variation within the scavenger receptor class B type I gene (SR-BI), plasma lipids and anthropometric measurements in healthy Caucasians. The present case-control study was conducted to determine whether there is an association between three polymorphisms identified by the restriction endonucleases HaeIII, AluI and ApaI of SR-BI and coronary artery disease (CAD) in Korean subjects. Methods: DNA was extracted from 137 subjects with CAD and 124 age-matched controls; it was amplified using the polymerase chain reaction. Individual alleles at each of the three polymorphic sites were identified by digestion with the appropriate restriction enzyme. Results: Only a single allele was identified at the AluI and ApaI polymorphic sites. The frequency of the common (+) allele at the HaeIII polymorphic site was higher in CAD patients than in the controls (P = 0·001). The concentrations of plasma HDL-cholesterol and apolipoprotein AI also varied significantly among HaeIII genotypes in the CAD patients. The common (+) allele of the HaeIII polymorphism was associated with a lower body mass index in female controls. Conclusions: Allele frequencies of the AluI and ApaI polymorphisms in this study were different to those in a Caucasian population studied previously, suggesting a difference in the genetic background. Further comparative studies of SR-BI polymorphism in other racial or ethnic groups should therefore prove to be of value. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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50. Hypoxia accelerates vascular repair of endothelial colony-forming cells on ischemic injury via STAT3-BCL3 axis
- Author
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Yong-Seok Han, Jung Min Ryu, Sang Hun Lee, Yeo Min Yoon, Jun Hee Lee, and Ho Jae Han
- Subjects
Male ,STAT3 Transcription Factor ,Vascular Endothelial Growth Factor A ,Cell Survival ,Ischemia ,Medicine (miscellaneous) ,Mice, Nude ,Neovascularization, Physiologic ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Mice ,In vivo ,B-Cell Lymphoma 3 Protein ,Proto-Oncogene Proteins ,medicine ,Animals ,Regeneration ,Phosphorylation ,RNA, Small Interfering ,Clonogenic assay ,Cell Proliferation ,Mice, Inbred BALB C ,Research ,Endothelial Cells ,Cell Biology ,Hypoxia (medical) ,Janus Kinase 2 ,medicine.disease ,Molecular biology ,Immunohistochemistry ,Cell Hypoxia ,Hindlimb ,Up-Regulation ,Transplantation ,Vascular endothelial growth factor A ,Disease Models, Animal ,Cancer research ,Molecular Medicine ,Cytokines ,Cytokine secretion ,RNA Interference ,medicine.symptom ,Stem cell ,Signal Transduction ,Transcription Factors - Abstract
Introduction: Endothelial colony-forming cells (ECFCs) significantly improve tissue repair by providing regeneration potential within injured cardiovascular tissue. However, ECFC transplantation into ischemic tissue exhibits limited therapeutic efficacy due to poor engraftment in vivo. We established an adequate ex vivo expansion protocol and identified novel modulators that enhance functional bioactivities of ECFCs. Methods: To augment the regenerative potential of ECFCs, functional bioactivities of hypoxia-preconditioned ECFCs (hypo-ECFCs) were examined. Results: Phosphorylations of the JAK2/STAT3 pathway and clonogenic proliferation were enhanced by short-term ECFC culturing under hypoxia, whereas siRNA-targeting of STAT3 significantly reduced these activities. Expression of BCL3, a target molecule of STAT3, was increased in hypo-ECFCs. Moreover, siRNA inhibition of BCL3 markedly reduced survival of ECFCs during hypoxic stress in vitro and ischemic stress in vivo. In a hindlimb ischemia model of ischemia, hypo-ECFC transplantation enhanced blood flow ratio, capillary density, transplanted cell proliferation and survival, and angiogenic cytokine secretion at ischemic sites. Conclusions: Hypoxia preconditioning facilitates functional bioactivities of ECFCs by mediating regulation of the STAT3-BCL3 axis. Thus, a hypoxic preconditioned ex vivo expansion protocol triggers expansion and functional bioactivities of ECFCs via modulation of the hypoxia-induced STAT3-BCL3 axis, suggesting that hypo-ECFCs offer a therapeutic strategy for accelerated neovasculogenesis in ischemic diseases.
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