Publications by authors named "Young-Sool Hah"

73 Publications

Draft genome of Semisulcospira libertina, a species of freshwater snail.

Genomics Inform 2021 Sep 30;19(3):e32. Epub 2021 Sep 30.

Department of Orthopaedic Surgery, Gyeongsang National University Hospital, Jinju 52727, Korea.

Semisulcospira libertina, a species of freshwater snail, is widespread in East Asia. It is important as a food source. Additionally, it is a vector of clonorchiasis, paragonimiasis, metagonimiasis, and other parasites. Although S. libertina has ecological, commercial, and clinical importance, its whole-genome has not been reported yet. Here, we revealed the genome of S. libertina through de novo assembly. We assembled the whole-genome of S. libertina and determined its transcriptome for the first time using Illumina NovaSeq 6000 platform. According to the k-mer analysis, the genome size of S. libertina was estimated to be 3.04 Gb. Using RepeatMasker, a total of 53.68% of repeats were identified in the genome assembly. Genome data of S. libertina reported in this study will be useful for identification and conservation of S. libertina in East Asia.
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http://dx.doi.org/10.5808/gi.21039DOI Listing
September 2021

Two Types of Mouse Models for Sarcopenia Research: Senescence Acceleration and Genetic Modification Models.

J Bone Metab 2021 Aug 31;28(3):179-191. Epub 2021 Aug 31.

Department of Orthopaedic Surgery, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, Korea.

Sarcopenia leads to loss of skeletal muscle mass, quality, and strength due to aging; it was recently given a disease code (International Classification of Diseases, Tenth Revision, Clinical Modification, M62.84). As a result, in recent years, sarcopenia-related research has increased. In addition, various studies seeking to prevent and treat sarcopenia by identifying the various mechanisms related to the reduction of skeletal muscle properties have been conducted. Previous studies have identified muscle synthesis and breakdown; investigating them has generated evidence for preventing and treating sarcopenia. Mouse models are still the most useful ones for determining mechanisms underlying sarcopenia through correlations and interventions involving specific genes and their phenotypes. Mouse models used to study sarcopenia often induce muscle atrophy by hindlimb unloading, denervation, or immobilization. Though it is less frequently used, the senescence-accelerated mouse can also be useful for sarcopenia research. Herein, we discuss cases where senescence-accelerated and genetically engineered mouse models were used in sarcopenia research and different perspectives to use them.
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http://dx.doi.org/10.11005/jbm.2021.28.3.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441530PMC
August 2021

The Role of Nuclear Factor of Activated T Cells 5 in Hyperosmotic Stress-Exposed Human Lens Epithelial Cells.

Int J Mol Sci 2021 Jun 11;22(12). Epub 2021 Jun 11.

Department of Ophthalmology, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Gyeongsang National University Hospital, Jinju 52727, Korea.

We investigated the role of nuclear factor of activated T cells 5 (NFAT5) under hyperosmotic conditions in human lens epithelial cells (HLECs). Hyperosmotic stress decreased the viability of human lens epithelial B-3 cells and significantly increased NFAT5 expression. Hyperosmotic stress-induced cell death occurred to a greater extent in NFAT5-knockout (KO) cells than in NFAT5 wild-type (NFAT5 WT) cells. Bcl-2 and Bcl-xl expression was down-regulated in NFAT5 WT cells and NFAT5 KO cells under hyperosmotic stress. Pre-treatment with a necroptosis inhibitor (necrostatin-1) significantly blocked hyperosmotic stress-induced death of NFAT5 KO cells, but not of NFAT5 WT cells. The phosphorylation levels of receptor-interacting protein kinase 1 (RIP1) and RIP3, which indicate the occurrence of necroptosis, were up-regulated in NFAT5 KO cells, suggesting that death of these cells is predominantly related to the necroptosis pathway. This finding is the first to report that necroptosis occurs when lens epithelial cells are exposed to hyperosmolar conditions, and that NFAT5 is involved in this process.
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http://dx.doi.org/10.3390/ijms22126296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230750PMC
June 2021

Serum hepatocyte growth factor as a predictor of disease severity and future exacerbations in patients with non-cystic fibrosis bronchiectasis.

Respir Med 2021 Aug-Sep;185:106505. Epub 2021 Jun 9.

Division of Pulmonology and Allergy, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, South Korea. Electronic address:

Background: Serum biomarkers associated with the severity of non-cystic fibrosis (CF) bronchiectasis are insufficient. This study determined the association of serum hepatocyte growth factor (HGF), osteopontin, and pentraxin-3 levels with disease severity and exacerbation in patients with non-CF bronchiectasis.

Methods: Serum levels of HGF, osteopontin, and pentraxin-3 were measured in patients with clinically stable non-CF bronchiectasis (n = 61). The correlation between the biomarkers and bronchiectasis severity index (BSI) and FACED score was assessed using univariate and multivariate linear regression analyses. Predictive variables associated with exacerbation were analyzed using a Cox proportional hazards model and the time to first exacerbation in high and low HGF groups during the observation period was compared using Kaplan-Meier survival curves.

Results: The BSI showed significant correlation with HGF (r = 0.423; p = 0.001) and pentraxin-3 (r = 0.316; p = 0.013). The FACED score was significantly correlated with HGF (r = 0.406; p = 0.001). Univariate and multivariate linear regression analysis revealed that serum level of HGF was independently associated with both scoring systems. The high HGF group showed a significantly shorter time to first exacerbation (Log-rank test, p = 0.014). Multivariate Cox proportional hazards regression analysis revealed that high serum HGF level and colonization with non-pseudomonas organisms were independent predictors of future exacerbations (HR 2.364; p = 0.024 and HR 2.438; p = 0.020, respectively).

Conclusion: Serum level of HGF is a potential biomarker that is closely associated with disease severity and future risk of exacerbations in patients with non-CF bronchiectasis.
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http://dx.doi.org/10.1016/j.rmed.2021.106505DOI Listing
June 2021

MDM2-dependent Sirt1 degradation is a prerequisite for Sirt6-mediated cell death in head and neck cancers.

Exp Mol Med 2021 Mar 16;53(3):422-431. Epub 2021 Mar 16.

Department of Otolaryngology & Department of Biochemistry and Molecular Biology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.

Sirt6 is involved in multiple biological processes, including aging, metabolism, and tumor suppression. Sirt1, another member of the sirtuin family, functionally overlaps with Sirt6, but its role in tumorigenesis is controversial. In this study, we focused on cell death in association with Sirt6/Sirt1 and reactive oxygen species (ROS) in head and neck squamous cell carcinomas (HNSCCs). Sirt6 induced cell death, as widely reported, but Sirt1 contributed to cell death only when it was suppressed by Sirt6 via regulation of MDM2. Sirt6 and Sirt6-mediated suppression of Sirt1 upregulated ROS, which further led to HNSCC cell death. These results provide insight into the molecular roles of Sirt6 and Sirt1 in tumorigenesis and could therefore contribute to the development of novel strategies to treat HNSCC.
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http://dx.doi.org/10.1038/s12276-021-00578-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080835PMC
March 2021

Upregulation of TRESK Channels Contributes to Motor and Sensory Recovery after Spinal Cord Injury.

Int J Mol Sci 2020 Nov 26;21(23). Epub 2020 Nov 26.

Department of Physiology and Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Korea.

TWIK (tandem-pore domain weak inward rectifying K)-related spinal cord K channel (TRESK), a member of the two-pore domain K channel family, is abundantly expressed in dorsal root ganglion (DRG) neurons. It is well documented that TRESK expression is changed in several models of peripheral nerve injury, resulting in a shift in sensory neuron excitability. However, the role of TRESK in the model of spinal cord injury (SCI) has not been fully understood. This study investigates the role of TRESK in a thoracic spinal cord contusion model, and in transgenic mice overexpressed with the TRESK gene (TG). Immunostaining analysis showed that TRESK was expressed in the dorsal and ventral neurons of the spinal cord. The TRESK expression was increased by SCI in both dorsal and ventral neurons. TRESK mRNA expression was upregulated in the spinal cord and DRG isolated from the ninth thoracic (T9) spinal cord contusion rats. The expression was significantly upregulated in the spinal cord below the injury site at acute time points (6, 24, and 48 h) after SCI ( < 0.05). In addition, TRESK expression was markedly increased in DRGs below and adjacent to the injury site. TRESK was expressed in inflammatory cells. In addition, the number and fluorescence intensity of TRESK-positive neurons increased in the dorsal and ventral horns of the spinal cord after SCI. TG SCI mice showed faster paralysis recovery and higher mechanical threshold compared to wild-type (WT)-SCI mice. TG mice showed lower TNF-α concentrations in the blood than WT mice. In addition, IL-1β concentration and apoptotic signals in the caudal spinal cord and DRG were significantly decreased in TG SCI mice compared to WT-SCI mice ( < 0.05). These results indicate that TRESK upregulated following SCI contributes to the recovery of paralysis and mechanical pain threshold by suppressing the excitability of motor and sensory neurons and inflammatory and apoptotic processes.
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http://dx.doi.org/10.3390/ijms21238997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731147PMC
November 2020

Rodent Model of Muscular Atrophy for Sarcopenia Study.

J Bone Metab 2020 May 31;27(2):97-110. Epub 2020 May 31.

Department of Orthopaedic Surgery, Gyoengsang National University Hospital, Gyeongsang National University, Jinju, Korea.

The hallmark symptom of sarcopenia is the loss of muscle mass and strength without the loss of overall body weight. Sarcopenia patients are likely to have worse clinical outcomes and higher mortality than do healthy individuals. The sarcopenia population shows an annual increase of ~0.8% in the population after age 50, and the prevalence rate is rapidly increasing with the recent worldwide aging trend. Based on International Classification of Diseases, Tenth Revision, a global classification of disease published by the World Health Organization, issued the disease code (M62.84) given to sarcopenia in 2016. Therefore, it is expected that the study of sarcopenia will be further activated based on the classification of disease codes in the aging society. Several epidemiological studies and meta-analyses have looked at the correlation between the prevalence of sarcopenia and several environmental factors. In addition, studies using cell lines and rodents have been done to understand the biological mechanism of sarcopenia. Laboratory rodent models are widely applicable in sarcopenia studies because of the advantages of time savings, cost saving, and various analytical applications that could not be used for human subjects. The rodent models that can be applied to the sarcopenia research are diverse, but a simple and fast method that can cause atrophy or aging is preferred. Therefore, we will introduce various methods of inducing muscular atrophy in rodent models to be applied to the study of sarcopenia.
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http://dx.doi.org/10.11005/jbm.2020.27.2.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297619PMC
May 2020

Periostin Plays a Key Role in Radioresistance of Head and Neck Cancer Cells Epithelial-to-Mesenchymal Transition.

Anticancer Res 2020 May;40(5):2627-2635

Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea

Background/aim: Head and neck squamous cell carcinoma (HNSCC) is an aggressive head and neck malignancy. The aim of this study was to elucidate the role of periostin (POSTN) in the epithelial-to-mesenchymal transition (EMT) process mediating the acquisition of radioresistance in HNSCC.

Materials And Methods: The expression levels of EMT hallmark genes including POSTN and Erk/Akt signaling pathways were compared between radiosensitive and radioresistant HNSCC cells.

Results: POSTN mRNA expression was higher in radioresistant HNSCC cells, and silencing POSTN significantly impaired their invasiveness under the effect of EMT process represented by up-regulation of mesenchymal markers and down-regulation of an epithelial marker. Expression levels of Erk and Akt were higher in radioresistant cells.

Conclusion: POSTN in association with the Erk and Akt signaling pathways was up-regulated during the EMT process, leading to the conversion of radiosensitive to radioresistant HNSCC cells. POSTN may be a key marker for predicting the radioresistance and therapeutic target of HNSCC.
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http://dx.doi.org/10.21873/anticanres.14233DOI Listing
May 2020

In vitro effects of alendronate on fibroblasts of the human rotator cuff tendon.

BMC Musculoskelet Disord 2020 Jan 11;21(1):19. Epub 2020 Jan 11.

Department of Orthopaedic Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea, 51472.

Background: Bone mineral density of the humeral head is an independent determining factor for postoperative rotator cuff tendon healing. Bisphosphonates, which are commonly used to treat osteoporosis, have raised concerns regarding their relationships to osteonecrosis of the jaw and to atypical fracture of the femur. In view of the prevalence of rotator cuff tear in osteoporotic elderly people, it is important to determine whether bisphosphonates affect rotator cuff tendon healing. However, no studies have investigated bisphosphonates' cytotoxicity to human rotator cuff tendon fibroblasts (HRFs) or bisphosphonates' effects on rotator cuff tendon healing. The purpose of this study was to evaluate the cytotoxicity of alendronate (Ald), a bisphosphonate, and its effects on HRF wound healing.

Methods: HRFs were obtained from human supraspinatus tendons, using primary cell cultures. The experimental groups were control, 0.1 μM Ald, 1 μM Ald, 10 μM Ald, and 100 μM Ald. Alendronate exposure was for 48 h, except during a cell viability analysis with durations from 1 day to 6 days. The experimental groups were evaluated for cell viability, cell cycle and cell proliferation, type of cell death, caspase activity, and wound-healing ability.

Results: The following findings regarding the 100 μM Ald group contrasted with those for all the other experimental groups: a significantly lower rate of live cells (p < 0.01), a higher rate of subG1 population, a lower rate of Ki-67 positive cells, higher rates of apoptosis and necrosis, a higher number of cells with DNA fragmentation, higher caspase-3/7 activity (p < 0.001), and a higher number of caspase-3 positive staining cells. In scratch-wound healing analyses of all the experimental groups, all the wounds healed within 48 h, except in the 100 μM Ald group (p < 0.001).

Conclusions: Low concentrations of alendronate appear to have little effect on HRF viability, proliferation, migration, and wound healing. However, high concentrations are significantly cytotoxic, impairing cellular proliferation, cellular migration, and wound healing in vitro.
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http://dx.doi.org/10.1186/s12891-019-3014-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955091PMC
January 2020

Involvement of mitochondrial biogenesis during the differentiation of human periosteum-derived mesenchymal stem cells into adipocytes, chondrocytes and osteocytes.

Arch Pharm Res 2019 Dec 4;42(12):1052-1062. Epub 2019 Dec 4.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea.

Due to a rapidly expanding aging population, the incidence of age-related or degenerative diseases has increased, and efforts to handle the issue with regenerative medicine via adult stem cells have become more important. And it is now clear that the mitochondrial energy metabolism is important for stem cell differentiation. When stem cells commit to differentiate, glycolytic metabolism is being shifted to mitochondrial oxidative phosphorylation (OXPHOS) to meet an increased cellular energy demand required for differentiated cells. However, the nature of cellular metabolisms during the differentiation process of periosteum-derived mesenchymal stem cells (POMSC) is still unclear. In the present study, we investigated mitochondrial biogenesis during the adipogenic, chondrogenic, and osteogenic differentiation of POMSCs. Both mitochondrial DNA (mtDNA) contents and mitochondrial proteins (VDAC and mitochondrial OXPHOS complex subunits) were increased during all of these mesenchymal lineage differentiations of POMSCs. Interestingly, glycolytic metabolism is reduced as POMSCs undergo osteogenic differentiation. Furthermore, reducing mtDNA contents by ethidium bromide treatments prevents osteogenic differentiation of POMSCs. In conclusion, these results indicate that mitochondrial biogenesis and OXPHOS metabolism play important roles in the differentiation of POMCS and suggest that pharmaceutical modulation of mitochondrial biogenesis and/or function can be a novel regulation for POMSC differentiation and regenerative medicine.
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http://dx.doi.org/10.1007/s12272-019-01198-xDOI Listing
December 2019

Reduced NGF Level Promotes Epithelial-Mesenchymal Transition in Human Lens Epithelial Cells Exposed to High Dexamethasone Concentrations.

Curr Eye Res 2020 06 6;45(6):686-695. Epub 2019 Dec 6.

Department of Ophthalmology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Korea.

: To investigate the protective effects of nerve growth factor (NGF) against steroid-induced cataract formation in dexamethasone (Dex)-treated human lens epithelial B-3 (HLE-B3) cells and the possible molecular mechanisms underlying this protection.: HLE-B3 cells were treated with Dex, and cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. The levels of expression of NGF, fibronectin, α-smooth muscle actin (α-SMA), and E-cadherin mRNAs were measured by real-time quantitative polymerase chain reaction (qPCR), and the levels of NGF, fibronectin, α-SMA, E-cadherin, tropomyosin receptor kinase A (TrkA), and Akt proteins were measured by Western blot analysis. Gene expression profiles of growth factors in Dex-treated HLE-B3 cells were determined by PCR arrays. In addition, anterior capsule tissue was obtained during cataract surgery, and the specimens were also examined expressions of NGF.: NGF was expressed in HLE-B3 cells and also in lens epithelial cells of anterior lens capsules. Dex treatment of HLE-B3 cells increased their expression of epithelial-mesenchymal transition (EMT) markers and migration activity, while markedly downregulating the expression of NGF. NGF treatment significantly reduced the expression of α-SMA and fibronectin, as well as cell proliferation. The decreased phosphorylation of p38 MAPK and Akt induced by Dex treatment was significantly reversed by treatment with NGF.: NGF/TrkA may repress EMT by targeting the p38 MAPK and pAkt pathways in Dex-treated HLE-B3 cells. NGF may be a novel therapeutic target for patients with steroid-induced cataract.
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http://dx.doi.org/10.1080/02713683.2019.1695844DOI Listing
June 2020

Nicotinamide N‑methyltransferase induces the proliferation and invasion of squamous cell carcinoma cells.

Oncol Rep 2019 Nov 16;42(5):1805-1814. Epub 2019 Sep 16.

Department of Dermatology and Institute of Health Sciences, School of Medicine, Gyeongsang National University and Hospital, Jinju 52727, Republic of Korea.

Cutaneous squamous cell carcinoma (cSCC) is a common malignancy initiated by keratinocytes of the epidermis, which are able to invade the dermis and its periphery. Although most patients with cSCC present with curable localized tumors, recurrence, metastasis and mortality occasionally occur. In the present study, nicotinamide N‑methyltransferase (NNMT) was identified as an upregulated protein in the SCC12 cell line, which has high invasive potential compared with the SCC13 cell line. The effects of NNMT knockdown on proliferation, migration and invasion were investigated using SCC cells. shRNA‑mediated downregulation of NNMT expression levels inhibited the proliferation and density‑dependent growth of SCC12 cells. In addition, the results of a cell motility assay showed that the migration and invasion of SCC cells were markedly decreased in NNMT‑knockdown cells. The assessment of epithelial‑mesenchymal transition (EMT)‑associated gene expression using PCR array analysis revealed that high NNMT expression levels were accompanied by high expression levels of EMT‑associated genes, and that NNMT knockdown effectively suppressed the expression of matrix metalloproteinase 9, osteopontin, versican core protein and zinc finger protein SNAI2 in SCC12 cells. These results revealed that the upregulation of NNMT induced cellular invasion via EMT‑related gene expression in SCC cells.
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http://dx.doi.org/10.3892/or.2019.7315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787961PMC
November 2019

p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3β-βTrCP-Induced Snail Degradation.

Cancer Res 2019 08 17;79(16):4135-4148. Epub 2019 Jun 17.

Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea.

Snail is a key regulator of epithelial-mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial posttranslational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3β-dependent Snail phosphorylation and βTrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38-Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38-Snail axis in ovarian cancer. SIGNIFICANCE: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0049DOI Listing
August 2019

N-acetylcysteine reduces glutamate-induced cytotoxicity to fibroblasts of rat supraspinatus tendons.

Connect Tissue Res 2019 09 8;60(5):431-443. Epub 2019 May 8.

d Department of Orthopaedic Surgery , School of Medicine and Gyeongsang National University Changwon Hospital , Changwon , Republic of Korea.

: Neuronal theory regarding rotator cuff degeneration has developed from the findings that glutamate, an amino acid and an excitatory neurotransmitter, is present in increased concentrations in tendon tissues with tendinopathy and that glutamate induces cell death in fibroblasts of origin in rat supraspinatus tendon. The purpose of the current study was to determine whether N-acetylcysteine (NAC) has cytoprotective effects against glutamate-induced fibroblast death. : Primary cultured fibroblasts were obtained from rat supraspinatus tendons. Varying concentrations of glutamate (0.5, 1, 5, and 10 mM) and of NAC (0.5, 1, 2, and 5 mM) were used for evaluation of cytotoxicity. Cell viability, cell cycles, types of cell death, intracellular ROS production, expressions of caspase-3/7, and Ca influx were evaluated. : Glutamate significantly induced cell death, apoptosis, and Ca influx and significantly increased caspase-3/7 activity and intracellular ROS production ( < 0.001). NAC significantly reduced the glutamate-induced cell death, apoptosis, Ca influx, caspase-3/7 activity, and intracellular ROS production ( < 0.001). : The glutamate-induced cytotoxic effects can be reduced by NAC, an antioxidant, through the reduction of intracellular oxidative stress and/or Ca influx.
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http://dx.doi.org/10.1080/03008207.2019.1580702DOI Listing
September 2019

Relationship between endothelial function and skeletal muscle strength in community dwelling elderly women.

J Cachexia Sarcopenia Muscle 2018 12 6;9(6):1034-1041. Epub 2018 Aug 6.

Department of Preventive Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, South Korea.

Background: The aim of this study is to determine whether there is correlation between endothelial function and skeletal muscle function measured by hand grip strength in elderly women.

Methods: This cross-sectional study used data of NAMGARAM-2 cohort. The NAMGARAM-2 cohort consisted of a group of people living in three rural communities. They were enrolled for studies on activity limitation due to age-related musculoskeletal disorders including knee osteoarthritis, osteoporosis, and sarcopenia. They were residents aged 40 years or older. They agreed to participate in this cohort from March 2016 to May 2017. Peripheral endothelial function was assessed by reactive hyperaemia-peripheral arterial tonometry using EndoPAT2000 system. Hand grip strength was measured using a digital hand dynamometer.

Results: Endothelial function index assessed by EndoPAT was worse in the low grip strength group than that in the normal group of elderly women (1.54 ± 0.51 in the low grip strength group vs. 1.77 ± 0.67 in the normal group, P = 0.003). There was a positive correlation between hand grip strength and endothelial function (r = 0.176, P = 0.007). On stepwise multivariate analysis, endothelial dysfunction (reactive hyperaemia-peripheral arterial tonometry index < 1.67) significantly increased the risk of low hand grip strength (odds ratio = 2.019; 95% confidence interval = 1.107-3.682; P = 0.022).

Conclusions: Endothelial function and skeletal muscle strength had a significant correlation in elderly women, providing additional support for the relevant role of vascular system in sarcopenia.
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http://dx.doi.org/10.1002/jcsm.12340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240755PMC
December 2018

Overexpression of Neuron-Specific Enolase as a Prognostic Factor in Patients with Gastric Cancer.

J Gastric Cancer 2017 Sep 25;17(3):228-236. Epub 2017 Aug 25.

Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.

Purpose: Enolase is a cytoplasmic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in the glycolytic pathway. The aim of this study was to investigate whether the overexpression of neuron-specific enolase (NSE) can serve as a prognostic factor in patients with gastric cancer (GC).

Materials And Methods: To assess its prognostic value in GC, NSE expression was measured by immunohistochemistry in a clinically annotated tissue microarray comprising of 327 human GC specimens. Cytoplasmic NSE expression was scored from 0 to 4, reflecting the percentage of NSE-positive cells.

Results: In terms of histology as per the World Health Organization criteria (P=0.340), there were no differences between the NSE overexpression (NSE-OE) and NSE underexpression (NSE-UE) groups. The NSE-OE group showed a significantly lower rate of advanced GC (P<0.010), lymph node metastasis (P=0.010), advanced stage group (P<0.010), cancer-related death (P<0.010), and cancer recurrence (P<0.010). Additionally, a Kaplan-Meier survival analysis revealed that the NSE-OE group had longer cumulative survival times than the NSE-UE group (log-rank test, P<0.010). However, there were no significant differences in the serum levels of NSE expression in patients with GC and healthy volunteers (P=0.280).

Conclusions: Patients with NSE overexpressing GC tissues showed better prognostic results, implying that NSE could be a candidate biomarker of GC.
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http://dx.doi.org/10.5230/jgc.2017.17.e28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620092PMC
September 2017

Suppressive Effects of TSAHC in an Experimental Mouse Model and Fibroblast-Like Synoviocytes of Rheumatoid Arthritis.

Inflammation 2017 Dec;40(6):1825-1835

Department of Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, 79 Gangnam-ro, JinJu, 660-702, Gyeongnam, Republic of Korea.

The purpose of this study is to investigate the effect of TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] in K/BxN serum transfer arthritis model and fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS). In in vivo experiments, TSAHC attenuated the incidence and severity of arthritis in comparison with the vehicle group. Histological findings showed that TSAHC decreased the inflammation, bone erosion, cartilage damage, and osteoclasts activity in the ankle. Furthermore, we confirmed by biochemical analysis that the observations were associated with the decreased expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and RANKL in serum and ankle. In in vitro experiments, TSAHC induced apoptosis, while it significantly suppressed tumor necrosis factor-α (TNF-α)-induced cell proliferation in RA-FLS. Moreover, TSAHC inhibited mRNA expression of TNF-α-induced interleukin (IL)-6, MMP-1, MMP-3, and MMP-13. Evaluation of signaling events showed that TSAHC inhibited the translocation and transcriptional activity of nuclear factor-kappa B (NF-κB) by regulating phosphorylated-IκB-α (p-IκB-α) and IκB-α in TNF-α-induced RA-FLS. Our results suggest that TSAHC inhibits experimental arthritis in mice and suppresses TNF-α-induced RA-FLS activities via NF-κB pathway. Therefore, TSAHC may have therapeutic potential for the treatment of RA.
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http://dx.doi.org/10.1007/s10753-017-0621-6DOI Listing
December 2017

Procyanidins from seeds induce apoptotic and autophagic cell death via generation of reactive oxygen species in squamous cell carcinoma cells.

Oncol Lett 2017 Aug 19;14(2):1925-1932. Epub 2017 Jun 19.

Department of Dermatology, Gyeongsang National University Hospital, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongsangnam-do 52727, Republic of Korea.

Procyanidins can inhibit cell proliferation and tumorigenesis and induce apoptosis in human skin, breast and prostate carcinoma cell lines. Squamous cell carcinoma (SCC) of the skin is a common form of keratinocytic or non-melanoma skin cancer and is a deadly disease with a poor prognosis due to the ineffectiveness of therapy. The present study aimed to determine whether grape seed proanthocyanidin (GSP) may regulate different modes of cell death in the human SCC12 cell line. The present study found that the treatment of SCC12 cells with GSP inhibited proliferation in a dose-dependent manner and reduced the motility and invasiveness of SCC12 cells through suppression of matrix metalloproteinase-2/9 expression. GSP treatment also resulted in induction of apoptosis and autophagy via generation of reactive oxygen species. The inhibition of autophagy by 3-methyladenine decreased GSP-induced cell death, which suggested that GSP-induced autophagy can promote cell death. The results of the present study suggested that autophagy functions as a death mechanism in SCC and provided a rationale for the use of GSP in combination with autophagy activators for treating cancers such as SCC.
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http://dx.doi.org/10.3892/ol.2017.6422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530194PMC
August 2017

Ascorbic acid concentrations in aqueous humor after systemic vitamin C supplementation in patients with cataract: pilot study.

BMC Ophthalmol 2017 Jul 11;17(1):121. Epub 2017 Jul 11.

Department of Ophthalmology, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, South Korea.

Background: To measure ascorbic acid concentration in aqueous humor of patients with cataract after oral or intravenous vitamin C supplementation.

Methods: Forty-two eyes of 42 patients with senile cataract who underwent uncomplicated cataract surgery were enrolled. Patients (n = 14 each) were administered oral vitamin C (2 g), intravenous vitamin C (20 g) or no treatment (control group) on the day before surgery. Samples of aqueous humor (0.1 cm) were obtained by anterior chamber aspiration at the beginning of surgery and stored at -80 °C. Ascorbic acid concentration in aqueous humor was measured by high-pressure liquid chromatography.

Results: The mean age at surgery was 62.5 years, with no difference among the three groups. The mean ± standard deviation concentrations of ascorbic acid in aqueous humor in the control and oral and intravenous vitamin C groups were 1347 ± 331 μmol/L, 1859 ± 408 μmol/L and 2387 ± 445 μmol/L, respectively. Ascorbic acid concentration was significantly lower in the control than in the oral (P < 0.01) and intravenous (P < 0.001) vitamin C groups and was significantly higher in the intravenous than in the oral vitamin C group (P < 0.05).

Conclusions: Ascorbic acid concentration in aqueous humor is increased by systemic vitamin C supplementation, with intravenous administration being more effective than oral administration.
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http://dx.doi.org/10.1186/s12886-017-0515-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504646PMC
July 2017

Ultraviolet B Radiation Stimulates the Interaction between Nuclear Factor of Activated T Cells 5 (NFAT5) and Nuclear Factor-Kappa B (NF-κB) in Human Lens Epithelial Cells.

Curr Eye Res 2017 07 26;42(7):987-994. Epub 2017 Feb 26.

a Department of Ophthalmology, Institute of Health Sciences , Gyeongsang National University School of Medicine, Gyeongsang National University Hospital , Jinju , Korea.

Purpose: Nuclear factor-kappa B (NF-κB) has been proposed as a therapeutic target for the treatment of cataracts. The authors investigated the relationship between nuclear factor of activated T cells 5 (NFAT5) and NF-κB in ultraviolet B (UVB)-irradiated human lens epithelial (HLE) cells.

Methods: Human lens epithelial B-3 (HLE-B3) cells were exposed to UVB light at a dose of 10 mJ/cm and then incubated for 24 h. Cell viability was assessed by using the Cell Counting Kit-8 (CCK-8) assay. Gene expression level of NFAT5 was determined using real-time quantitative polymerase chain reaction (qPCR). Protein expression levels of NFAT5, NF-κB p65, and α-smooth muscle actin (α-SMA) and the association of NFAT5 with the NF-κB p65 subunit were measured by Western blot analysis and a co-immunoprecipitation assay, respectively. The cellular distribution of NFAT5 and NF-κB p65 was examined by triple immunofluorescence staining.

Results: At 24 h after UVB exposure, cell viability significantly decreased in a dose-dependent manner, and UVB light (15 and 20 mJ/cm) significantly increased the ROS generation. UVB irradiation increased NFAT5 mRNA and protein levels and increased phosphorylation of NF-κB in HLE-B3 cells. α-SMA protein levels were increased in the irradiated cells. In addition, NFAT5 and NF-κB translocated from the cytoplasm to the nucleus, and binding between the p65 subunit and NFAT5 was increased.

Conclusions: Exposure to UVB radiation induces nuclear translocation and stimulates binding between NFAT5 and NF-κB proteins in HLE-B3 cells. These interactions may form part of the biochemical mechanism of cataractogenesis in UVB-irradiated HLECs.
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http://dx.doi.org/10.1080/02713683.2016.1270327DOI Listing
July 2017

PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3.

Autophagy 2016 11 19;12(11):2183-2196. Epub 2016 Aug 19.

a Department of Biochemistry and Convergence Medical Sciences , Institute of Health Sciences, Gyeongsang National University School of Medicine , JinJu , Korea.

Autophagy plays a critical role in maintaining cell homeostasis in response to various stressors through protein conjugation and activation of lysosome-dependent degradation. MAP1LC3B/LC3B (microtubule- associated protein 1 light chain 3 β) is conjugated with phosphatidylethanolamine (PE) in the membranes and regulates initiation of autophagy through interaction with many autophagy-related proteins possessing an LC3-interacting region (LIR) motif, which is composed of 2 hydrophobic amino acids (tryptophan and leucine) separated by 2 non-conserved amino acids (WXXL). In this study, we identified a new putative LIR motif in PEBP1/RKIP (phosphatidylethanolamine binding protein 1) that was originally isolated as a PE-binding protein and also a cellular inhibitor of MAPK/ERK signaling. PEBP1 was specifically bound to PE-unconjugated LC3 in cells, and mutation (WXXL mutated to AXXA) of this LIR motif disrupted its interaction with LC3 proteins. Interestingly, overexpression of PEBP1 significantly inhibited starvation-induced autophagy by activating the AKT and MTORC1 (mechanistic target of rapamycin [serine/threonine kinase] complex 1) signaling pathway and consequently suppressing the ULK1 (unc-51 like autophagy activating kinase 1) activity. In contrast, ablation of PEBP1 expression dramatically promoted the autophagic process under starvation conditions. Furthermore, PEBP1 lacking the LIR motif highly stimulated starvation-induced autophagy through the AKT-MTORC1-dependent pathway. PEBP1 phosphorylation at Ser153 caused dissociation of LC3 from the PEBP1-LC3 complex for autophagy induction. PEBP1-dependent suppression of autophagy was not associated with the MAPK pathway. These findings suggest that PEBP1 can act as a negative mediator in autophagy through stimulation of the AKT-MTORC1 pathway and direct interaction with LC3.
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http://dx.doi.org/10.1080/15548627.2016.1219013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103343PMC
November 2016

Autophagy Has a Beneficial Role in Relieving Cigarette Smoke-Induced Apoptotic Death in Human Gingival Fibroblasts.

Int J Med Sci 2016 27;13(5):357-64. Epub 2016 Apr 27.

1. Department of Oral and Maxillofacial Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Institute of Health Sciences, Gyeongsang National University, Chilam-dong, Jinju, 660-702, Republic of Korea.

The deleterious role of cigarette smoke has long been documented in various human diseases including periodontal complications. In this report, we examined this adverse effect of cigarette smoke on human gingival fibroblasts (HGFs) which are critical not only in maintaining gingival tissue architecture but also in mediating immune responses. As well documented in other cell types, we also observed that cigarette smoke promoted cellular reactive oxygen species in HGFs. And we found that this cigarette smoke-induced oxidative stress reduced HGF viability through inducing apoptosis. Our results indicated that an increased Bax/Bcl-xL ratio and resulting caspase activation underlie the apoptotic death in HGFs exposed to cigarette smoke. Furthermore, we detected that cigarette smoke also triggered autophagy, an integrated cellular stress response. Interesting, a pharmacological suppression of the cigarette smoke-induced autophagy led to a further reduction in HGF viability while a pharmacological promotion of autophagy increased the viability of HGFs with cigarette smoke exposures. These findings suggest a protective role for autophagy in HGFs stressed with cigarette smoke, highlighting that modulation of autophagy can be a novel therapeutic target in periodontal complications with cigarette smoke.
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http://dx.doi.org/10.7150/ijms.14592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879768PMC
April 2017

Cytoprotective Mechanism of Cyanidin and Delphinidin against Oxidative Stress-Induced Tenofibroblast Death.

Biomol Ther (Seoul) 2016 Jul 25;24(4):426-32. Epub 2016 Apr 25.

School of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea.

Age-related rotator cuff tendon degeneration is related to tenofibroblast apoptosis. Anthocyanins reduce oxidative stress-induced apoptotic cell death in tenofibroblasts. The current study investigated the presence of cell protective effects in cyanidin and delphinidin, the most common aglycon forms of anthocyanins. We determined whether these anthocyanidins have antiapoptotic and antinecrotic effects in tenofibroblasts exposed to H2O2, and evaluated their biomolecular mechanisms. Both cyanidin and delphinidin inhibited H2O2-induced apoptosis in a dose-dependent manner. However, at concentrations of 100 μg/ml or greater, delphinidin showed cytotoxicity against tenofibroblasts and a decreased antinecrotic effect. Cyanidin and delphinidin both showed inhibitory effects on the H2O2-induced increase in intracellular ROS formation and the activation of ERK1/2 and JNK. In conclusion, both cyanidin and delphinidin have cytoprotective effects on cultured tenofibroblasts exposed to H2O2. These results suggest that cyanidin and delphinidin are both beneficial for the treatment of oxidative stress-mediated tenofibroblast cell death, but their working concentrations are different.
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http://dx.doi.org/10.4062/biomolther.2015.169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930287PMC
July 2016

N-acetyl cysteine protects cells from chondrocyte death induced by local anesthetics.

J Orthop Res 2017 02 18;35(2):297-303. Epub 2016 Apr 18.

Department of Orthopaedic Surgery and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Korea.

Local anesthetics (LA) are among the drugs most frequently used for musculoskeletal problems, in procedures ranging from diagnosis to postoperative pain control. Chondrocyte toxicity induced by LA is an emerging area of concern. The purpose of this study was to determine whether N-acetyl cysteine (NAC), an antioxidant, will exert cytoprotective effects against chondrocyte death induced by LA. Primary cultured human chondrocytes were used for this study. This study used control, NAC, LA, and NAC-LA groups. Cytotoxicity was induced in the LA subgroups and their paired NAC-LA subgroups through exposure to ropivacaine (0.075%), bupivacaine (0.05%), or lidocaine (0.2%) for 24 h. The NAC-LA subgroups were exposed to 10 mM NAC for 1 h, before LA exposure. These study groups were evaluated for rates of cell viability, apoptosis, necrosis, intracellular ROS production, and caspase-3/7 activity. Cell viability in all LA subgroups was significantly lower than in the control group (p < 0.001). Cell viability in the NAC-LA subgroups was significantly higher than in their paired LA subgroups (p < 0.001). In the LA subgroups, rates of apoptosis and necrosis, intracellular ROS production, and caspase-3/7 activity were significantly higher than in the control group (p ≤ 0.029). In the NAC-LA subgroups, rates of apoptosis and necrosis, intracellular ROS production, and caspase-3/7 activity were significantly lower than in their paired LA subgroups (p ≤ 0.023). These results indicate that N-acetyl cysteine, an antioxidant, has cytoprotective effects against LA-induced toxicity to chondrocytes in vitro. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:297-303, 2017.
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http://dx.doi.org/10.1002/jor.23254DOI Listing
February 2017

Myeloid deletion of SIRT1 suppresses collagen-induced arthritis in mice by modulating dendritic cell maturation.

Exp Mol Med 2016 Mar 18;48:e221. Epub 2016 Mar 18.

Department of Internal Medicine and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.

The type III histone deacetylase silent information regulator 1 (SIRT1) is an enzyme that is critical for the modulation of immune and inflammatory responses. However, the data on its role in rheumatoid arthritis (RA) are limited and controversial. To better understand how SIRT1 regulates adaptive immune responses in RA, we evaluated collagen-induced arthritis (CIA) in myeloid cell-specific SIRT1 knockout (mSIRT1 KO) and wild-type (WT) mice. Arthritis severity was gauged on the basis of clinical, radiographic and pathologic scores. Compared with their WT counterparts, the mSIRT1 KO mice exhibited less severe arthritis, which was less destructive to the joints. The expression levels of inflammatory cytokines, matrix metalloproteinases and ROR-γT were also reduced in the mSIRT1 KO mice compared with the WT mice and were paralleled by reductions in the numbers of Th1 and Th17 cells and CD80- or CD86-positive dendritic cells (DCs). In addition, impaired DC maturation and decreases in the Th1/Th17 immune response were observed in the mSIRT1 KO mice. T-cell proliferation was also investigated in co-cultures with antigen-pulsed DCs. In the co-cultures, the DCs from the mSIRT1 KO mice showed decreases in T-cell proliferation and the Th1/Th17 immune response. In this study, myeloid cell-specific deletion of SIRT1 appeared to suppress CIA by modulating DC maturation. Thus, a careful investigation of DC-specific SIRT1 downregulation is needed to gauge the therapeutic utility of agents targeting SIRT1 in RA.
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http://dx.doi.org/10.1038/emm.2015.124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892877PMC
March 2016

Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity.

Oncotarget 2016 Jan;7(4):4632-46

Department of Biochemistry and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea.

Raf kinase inhibitory protein (RKIP), an endogenous inhibitor of the extracellular signal-regulated kinase (ERK) pathway, has been implicated as a suppressor of metastasis and a prognostic marker in cancers. However, how RKIP acts as a suppressor during metastasis is not fully understood. Here, we show that RKIP activity in cervical and stomach cancer is inversely correlated with endogenous levels of the Notch1 intracellular domain (NICD), which stimulates the epithelial to mesenchymal transition (EMT) and metastasis. The levels of RKIP were significantly decreased in tumor tissues compared to normal tissues, whereas NICD levels were increased. Overexpression of RKIP in several cell lines resulted in a dramatic decrease of NICD and subsequent inhibition of several mesenchymal markers, such as vimentin, N-cadherin, and Snail. In contrast, knockdown of RKIP exhibited opposite results both in vitro and in vivo using mouse models. Nevertheless, knockdown of Notch1 in cancer cells had no effect on the expression of RKIP, suggesting that RKIP is likely an upstream regulator of the Notch1 pathway. We also found that RKIP directly interacts with Notch1 but has no influence on the intracellular level of the γ-secretase complex that is necessary for Notch1 activation. These data suggest that RKIP plays a distinct role in activation of Notch1 during EMT and metastasis, providing a new target for cancer treatment.
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http://dx.doi.org/10.18632/oncotarget.6728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826232PMC
January 2016

FOXO1 Is Involved in the Effects of Cigarette Smoke Extract on Osteoblastic Differentiation of Cultured Human Periosteum-derived Cells.

Int J Med Sci 2015 21;12(11):881-90. Epub 2015 Oct 21.

3. Department of Oral and Maxillofacial Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea.

Cigarette smoke is associated with delayed fracture healing, alterations in mineral content, and osteoporosis, however, its effects on osteoblastic differentiation of osteoprogenitor cells are not fully understood. In the present study, we examined the effects of cigarette smoke extract (CSE) on osteoblastic differentiation of cultured human periosteum-derived cells. We found that CSE inhibited alkaline phosphatase (ALP) activity, mineralization and Runx2 transactivation of the periosteum-derived cells. Nucleofection of RUNX2 into the periosteum-derived cells increased expression of endogenous osteocalcin (OC) and ALP genes in osteogenic induction medium and increased OC expression in non-osteogenic medium. Treatment of the periosteum-derived cells with CSE resulted in decreased phosphorylation of AKT and forkhead box protein O1 (FOXO1). The AKT phosphorylation-resistant mutant, FOXO1-A3, inhibited transcriptional activity of RUNX2 in the periosteum-derived cells. The current study suggests one mechanism by which CSE exposure leads to inhibition of osteoblastic differentiation of cultured human periosteum-derived cells.
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http://dx.doi.org/10.7150/ijms.13172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643079PMC
September 2016

Cell source-dependent in vivo immunosuppressive properties of mesenchymal stem cells derived from the bone marrow and synovial fluid of minipigs.

Exp Cell Res 2015 May 27;333(2):273-288. Epub 2015 Mar 27.

College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Gyeongnam, Republic of Korea; Research Institute of Life Sciences, Gyeongsang National University, Jinju 660-701, Gyeongnam, Republic of Korea. Electronic address:

The in vitro differentiation and immunosuppressive capacity of mesenchymal stem cells (MSCs) derived from synovial fluid (SF-MSCs) and bone marrow extract (BM-MSCs) in an isogenic background of minipigs were comparatively analyzed in a collagen-induced arthritis (CIA) mouse model of rheumatoid arthritis (RA). The proliferation capacity and expression of pluripotent transcription factors (Oct3/4 and Sox2) were significantly (P<0.05) higher in SF-MSCs than in BM-MSCs. The differentiation capacity of SF-MSCs into adipocytes, osteocytes and neurocytes was significantly (P<0.05) lower than that of BM-MSCs, and the differentiation capacity of SF-MSCs into chondrocytes was significantly (P<0.05) higher than that of BM-MSCs. Systemic injection of BM- and SF-MSCs significantly (P<0.05) ameliorated the clinical symptoms of CIA mice, with SF-MSCs having significantly (P<0.05) higher clinical and histopathological recovery scores than BM-MSCs. Furthermore, the immunosuppressive properties of SF-MSCs in CIA mice were associated with increased levels of the anti-inflammatory cytokine interleukin (IL)-10, and decreased levels of the pro-inflammatory cytokine IL-1β and osteoclast-related sRANKL. In conclusion, SF-MSCs exhibited eminent pluripotency and differentiation capacity into chondrocytes, addition to substantial in vivo immunosuppressive capacity by elevating IL-10 and reducing IL-1β levels in CIA mice.
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http://dx.doi.org/10.1016/j.yexcr.2015.03.015DOI Listing
May 2015

Antioxidant's cytoprotective effects on rotator cuff tenofibroblasts exposed to aminoamide local anesthetics.

J Orthop Res 2015 Jul 14;33(7):1001-7. Epub 2015 Apr 14.

Department of Orthopaedic Surgery and Institute of Health Sciences, School of Medicine and Hospital, Gyeongsang National University, Jinju, Korea.

Local anesthetics (LA) are among the drugs most frequently used for musculoskeletal problems, in procedures ranging from diagnosis to postoperative pain control. The cytotoxicity of LA is an emerging area of concern. The purpose of this study was to determine whether cyanidin, an antioxidant, exerts cytoprotective effects against tenofibroblast death induced by LA. Primary cultured human rotator cuff tenofibroblasts were used to evaluate the cytotoxicity of these LA: Ropivacaine (0.075%), Bupivacaine (0.05%), and Lidocaine (0.2%). The effects of cyanidin (100 μg/ml) on the cytotoxicity induced by these LA were investigated. Cell viability, ROS production, caspase-3/7 activity, and expressions of phospho-extracellular signal-regulated kinases (ERK), phospho-p38, phospho-c-Jun N-terminal kinase (JNK), and cleaved PARP-1 were evaluated. Exposure to LA significantly induced cell death (p < 0.001), ROS production (p ≤ 0.04), the activation of caspase-3/7 (p < 0.001), and the increased expressions of phospho-ERK, phospho-p38, phospho-JNK, and cleaved PARP-1. These LA-induced cytotoxic effects were reduced by cyanidin. These data indicate that cyanidin, an antioxidant, has cytoprotective effects against LA-induced cytotoxicity to rotator cuff tenofibroblasts.
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http://dx.doi.org/10.1002/jor.22814DOI Listing
July 2015

Cytotoxic effects of ropivacaine, bupivacaine, and lidocaine on rotator cuff tenofibroblasts.

Am J Sports Med 2014 Dec 8;42(12):2888-96. Epub 2014 Oct 8.

Department of Orthopaedic Surgery, School of Medicine, Gyeongsang National University, Jinju, Korea

Background: Concern has recently arisen over the safety of local anesthetics used on human tissues.

Hypothesis: Aminoamide local anesthetics have cytotoxic effects on human rotator cuff tenofibroblasts.

Study Design: Controlled laboratory study.

Methods: Cultured human rotator cuff tenofibroblasts were divided into control, phosphate buffered saline (PBS), and local anesthetic study groups; the PBS study group was further subdivided by pH level (pH 7.4, 6.0, and 4.4). The 6 local anesthetic subgroups (0.2% and 0.75% ropivacaine, 0.25% and 0.5% bupivacaine, and 1% and 2% lidocaine) were also studied at 10% dilutions of their original concentrations. Exposure times were 5, 10, 20, 40, or 60 minutes for the higher concentrations and 2, 6, 12, 24, 48, or 72 hours for the lower concentrations. Cell viability was evaluated through live, apoptotic, and necrotic cell rates using the annexin V-propidium iodide double-staining method. Intracellular reactive oxygen species (ROS) and the activity of mitogen-activated protein kinases (MAPKs) and caspase-3/7 were investigated.

Results: The control and PBS groups showed no significant differences in cell viability (P > .999). In the local anesthetic study groups, cell viability decreased significantly with increases in anesthetic concentrations (P < .001) and exposure times (P < .001), with the exception of the lidocaine subgroups, where this effect was masked by the very high cytotoxicity of even low concentrations. Among the studied local anesthetic subgroups, 0.2% ropivacaine was the least toxic. The levels of intracellular ROS of each local anesthetic subgroup also increased significantly (P < .05). The studied local anesthetics showed increases in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 as well as in levels of caspase-3/7 activity (P < .001).

Conclusion: The cytotoxicity of the anesthetics studied to tenofibroblasts is dependent on exposure time and concentration. Of the evaluated anesthetics, ropivacaine is the least toxic in the clinically used concentration. The studied anesthetics induce tenofibroblast cell death, mediated by the increased production of ROS, by the increased activation of ERK1/2, JNK, and p38 and by the activation of caspase-3/7.

Clinical Relevance: This study identified the cytotoxic mechanisms of aminoamide local anesthetics acting on rotator cuff tenofibroblasts. The greatest margin of safety was found in lower anesthetic concentrations in general and more specifically in the use of ropivacaine.
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http://dx.doi.org/10.1177/0363546514550991DOI Listing
December 2014
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