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Lee J.H.,Pusan National University | Lee J.H.,Johns Hopkins University | Jung H.K.,Jeollanamdo Development Institute of Traditional Korean Medicine | Han Y.-S.,Soonchunhyang University | And 5 more authors.
Molecular Medicine Reports | Year: 2016

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.


PubMed | Jeollanamdo Development Institute of Traditional Korean Medicine, Soonchunhyang University, Johns Hopkins University and Pusan National University
Type: Journal Article | Journal: Molecular medicine reports | Year: 2016

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 Cirsiumsetidens, a natural product, on oxidative stressinduced 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 apoptosisassociated proteins in MSCs. Treatment of MSCs with hydrogen peroxide (H2O2; 200M) significantly increased intracellular ROS levels and cell death; however, pretreatment with C.setidens (100g/ml) suppressed H2O2induced ROS generation and increased the survival of MSCs. H2O2induced ROS production increased the levels of phosphorylatedp38 mitogen activated protein kinase, cJun Nterminal kinase, ataxia telangiectasia mutated and p53; these increases were inhibited by pretreatment with C.setidens. In addition, C.setidens inhibited ROSinduced apoptosis of MSCs by increasing the expression levels of the antiapoptotic protein Bcell lymphoma2 (BCL2), and decreasing the expression levels of the proapoptotic protein BCL2associatedX protein. These findings indicated that pretreatment of MSCs with C.setidens may prevent ROSinduced oxidative injury by regulating the oxidative stressassociated signaling pathway, and suppressing the apoptosisassociated signal pathway. Therefore, C.setidens may be developed as a beneficial broadspectrum agent for enhancing the effectiveness of MSC transplantation in the treatment of ischemic diseases.


Kim M.-S.,Jeollanamdo Development Institute of Traditional Korean Medicine | Ham S.-H.,Jeollanamdo Development Institute of Traditional Korean Medicine | Kim J.-H.,Jeollanamdo Development Institute of Traditional Korean Medicine | Shin J.-E.,Jeollanamdo Development Institute of Traditional Korean Medicine | And 6 more authors.
Toxicological Research | Year: 2012

The aim of this study was to investigate the acute oral toxicity of fermented Scutellariae Radix (JKTMHGu- 100) in rats and dogs. JKTM-HGu-100 was orally administered at a dose of 2,000 mg/kg in Sprague-Dawley rats. An escalating single-dose oral toxicity test in beagle dogs was performed at doses of 500, 1000, and 2000 mg/kg with 4-day intervals. Clinical signs, changes in body weight, mortality, and necropsy findings were examined for 2 weeks following oral administration. No toxicological changes related to the test substance nor mortality was observed after administration of a single oral dose of JKTM-HGu-100 in rats or dogs. Therefore, the approximate lethal dose (LD) for oral administration of JKTMHGu-100 in rats was considered to be over 2,000 mg/kg, and the maximum tolerance doses (MTDs) in rats and dogs were also estimated to be over 2,000 mg/kg. These results indicate that JKTM-HGu-100 shows no toxicity in rodents or non-rodents at doses of 2,000 mg/kg or less.


Aryal P.,Wonkwang University | Kim K.,Wonkwang University | Park P.-H.,Yeungnam University | Ham S.,Jeollanamdo Development Institute of Traditional Korean Medicine | And 2 more authors.
FEBS Journal | Year: 2014

Baicalein, a flavonoid and aglycon hydrolyzed from baicalin, has anticancer properties in several human carcinomas, but its molecular mechanisms of action remain unclear. Here, we show that baicalein leads to human cancer cell death by inducing autophagy rather than apoptosis, because cell death induced by baicalein was completely reversed by suppressing the expression levels of key molecules in autophagy such as Beclin 1, vacuolar protein sorting 34 (Vps34), autophagy-related (Atg)5 and Atg7, but not by pan-caspase inhibitor. Our data revealed that baicalein significantly increased the number of green fluorescence protein-cytosol-associated protein light chain 3 (GFP- LC3)-containing puncta and LC3B-II expression levels, which were further enhanced by chloroquine treatment. Furthermore, a luciferase-based reporter assay showed that the ratio of RLuc-LC3wt/RLuc-LC3G120A was greatly reduced. The data suggested that baicalein induced not only autophagosome formation, but also autophagic flux. Experiments using short interfering RNAs and pharmacological inhibitors revealed that Beclin 1, Vps34, Atg5, Atg7 and UNC-51 (Caenorhabditis elegans)-like kinase 1 (ULK1) play pivotal roles in mediating baicalein-induced autophagy. Moreover, baicalein activated AMP-activated protein kinase (AMPK)a, leading to ULK1 activation through phosphorylation at Ser555, whereas both protein and mRNA levels of mammalian target of rapamycin (mTOR) and Raptor, upstream inhibitors of ULK1 and autophagy, were markedly downregulated by baicalein. Our data suggest that the anticancer effects of baicalein are mainly due to autophagic cell death through activation of the AMPK/ULK1 pathway and inhibition of mTOR/Raptor complex 1 expression. These results provide new mechanistic insights into the anticancer functions of autophagy inducers, such as baicalein, which may be used as potential therapeutics for cancer treatment.


PubMed | Jeollanamdo Development Institute of Traditional Korean Medicine
Type: Journal Article | Journal: Toxicological research | Year: 2013

The aim of this study was to investigate the acute oral toxicity of fermented Scutellariae Radix (JKTMHGu- 100) in rats and dogs. JKTM-HGu-100 was orally administered at a dose of 2,000 mg/kg in Sprague-Dawley rats. An escalating single-dose oral toxicity test in beagle dogs was performed at doses of 500, 1000, and 2000 mg/kg with 4-day intervals. Clinical signs, changes in body weight, mortality, and necropsy findings were examined for 2 weeks following oral administration. No toxicological changes related to the test substance nor mortality was observed after administration of a single oral dose of JKTM-HGu-100 in rats or dogs. Therefore, the approximate lethal dose (LD) for oral administration of JKTMHGu-100 in rats was considered to be over 2,000 mg/kg, and the maximum tolerance doses (MTDs) in rats and dogs were also estimated to be over 2,000 mg/kg. These results indicate that JKTM-HGu-100 shows no toxicity in rodents or non-rodents at doses of 2,000 mg/kg or less.

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