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Triterpenoids from aerial parts of Glochidion eriocarpum.
Thu, Vu Kim,Kiem, Phan Van,Yen, Pham Hai,Nhiem, Nguyen Xuan,Tung, Nguyen Huu,Cuong, Nguyen Xuan,Minh, Chau Van,Huong, Hoang Thanh,Lau, Trinh Van,Thuan, Ngo Thi,Kim, Young Ho Natural Product Communications 2010 Natural product communications Vol.5 No.3
<P>From the aerial parts of Glochidion eriocarpum, a new triterpene, glochieriol (1), three new triterpenoid saponins, glochieriosides C - E (2 - 4), together with four known triterpenes (glochidonol, glochidiol, lupeol, and 3-epi-lupeol) were isolated by using combined chromatographic separations. The structures of the new compounds were elucidated on the basis of spectroscopic data, including FTICR-MS, 1D and 2D NMR.</P>
NecroX-5 prevents hypoxia/reoxygenation injury by inhibiting the mitochondrial calcium uniporter.
Thu, Vu Thi,Kim, Hyoung-Kyu,Long, Le Thanh,Lee, Sung-Ryul,Hanh, Tran My,Ko, Tae Hee,Heo, Hye-Jin,Kim, Nari,Kim, Soon Ha,Ko, Kyung Soo,Rhee, Byoung Doo,Han, Jin British Medical Association 2012 Cardiovascular research Vol.94 No.2
<P>Preservation of mitochondrial function is essential to limit myocardial damage in ischaemic heart disease. We examined the protective effects and mechanism of a new compound, NecroX-5, on rat heart mitochondria in a hypoxia/reoxygenation (HR) model.</P>
Thu, Vu Thi,Cuong, Dang Van,Kim, Na-Ri,Youm, Jae-Boum,Warda, Mohamad,Park, Won-Sun,Ko, Jae-Hong,Kim, Eui-Yong,Han, Jin The Korean Society of Pharmacology 2007 The Korean Journal of Physiology & Pharmacology Vol.11 No.2
Ischemic preconditioning (IPC) is known to protect the heart against ischemia/reperfusion (IR)-induced injuries, and regional differences in the mitochondrial antioxidant state during IR or IPC may promote the death or survival of viable and infarcted cardiac tissues under oxidative stress. To date, however, the interplay between the mitochondrial antioxidant enzyme system and the level of reactive oxygen species (ROS) in the body has not yet been resolved. In the present study, we examined the effects of IR- and IPC-induced oxidative stresses on mitochondrial function in viable and infarcted cardiac tissues. Our results showed that the mitochondria from viable areas in the IR-induced group were swollen and fused, whereas those in the infarcted area were heavily damaged. IPC protected the mitochondria, thus reducing cardiac injury. We also found that the activity of the mitochondrial antioxidant enzyme system, which includes manganese superoxide dismutase (Mn-SOD), was enhanced in the viable areas compared to the infarcted areas in proportion with decreasing levels of ROS and mitochondrial DNA (mtDNA) damage. These changes were also present between the IPC and IR groups. Regional differences in Mn-SOD expression were shown to be related to a reduction in mtDNA damage as well as to the release of mitochondrial cytochrome c (Cyt c). To the best of our knowledge, this might be the first study to explore the regional mitochondrial changes during IPC. The present findings are expected to help elucidate the molecular mechanism involved in IPC and helpful in the development of new clinical strategies against ischemic heart disease.
Thu, Vu Thi,Kim, Hyoung Kyu,Long, Le Thanh,Thuy, To Thanh,Huy, Nguyen Quang,Kim, Soon Ha,Kim, Nari,Ko, Kyung Soo,Rhee, Byoung Doo,Han, Jin The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.3
Inflammatory and fibrotic responses are accelerated during the reperfusion period, and excessive fibrosis and inflammation contribute to cardiac malfunction. NecroX compounds have been shown to protect the liver and heart from ischemia-reperfusion injury. The aim of this study was to further define the role and mechanism of action of NecroX-5 in regulating inflammation and fibrosis responses in a model of hypoxia/reoxygenation (HR). We utilized HR-treated rat hearts and lipopolysaccharide (LPS)-treated H9C2 culture cells in the presence or absence of NecroX-5 ($10{\mu}mol/L$) treatment as experimental models. Addition of NecroX-5 significantly increased decorin (Dcn) expression levels in HR-treated hearts. In contrast, expression of transforming growth factor beta 1 ($TGF{\beta}1$) and Smad2 phosphorylation (pSmad2) was strongly attenuated in NecroX-5-treated hearts. In addition, significantly increased production of tumor necrosis factor alpha ($TNF{\alpha}$), $TGF{\beta}1$, and pSmad2, and markedly decreased Dcn expression levels, were observed in LPS-stimulated H9C2 cells. Interestingly, NecroX-5 supplementation effectively attenuated the increased expression levels of $TNF{\alpha}$, $TGF{\beta}1$, and pSmad2, as well as the decreased expression of Dcn. Thus, our data demonstrate potential antiinflammatory and anti-fibrotic effects of NecroX-5 against cardiac HR injuries via modulation of the $TNF{\alpha}/Dcn/TGF{\beta}1/Smad2$ pathway.
Vu, Thi Thu,Kim, Hyoung Kyu,Le, Thanh Long,Nyamaa, Bayalagmaa,Song, In-Sung,To, Thanh Thuy,Nguyen, Quang Huy,Marquez, Jubert,Kim, Soon Ha,Kim, Nari,Ko, Kyung Soo,Rhee, Byoung Doo,Han, Jin The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.2
Although the antioxidant and cardioprotective effects of NecroX-5 on various in vitro and in vivo models have been demonstrated, the action of this compound on the mitochondrial oxidative phosphorylation system remains unclear. Here we verify the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity during hypoxia-reoxygenation (HR). Necrox-5 treatment ($10{\mu}M$) and non-treatment were employed on isolated rat hearts during hypoxia/reoxygenation treatment using an ex vivo Langendorff system. Proteomic analysis was performed using liquid chromatography-mass spectrometry (LC-MS) and non-labeling peptide count protein quantification. Real-time PCR, western blot, citrate synthases and mitochondrial complex activity assays were then performed to assess heart function. Treatment with NecroX-5 during hypoxia significantly preserved electron transport chain proteins involved in oxidative phosphorylation and metabolic functions. NecroX-5 also improved mitochondrial complex I, II, and V function. Additionally, markedly higher peroxisome proliferator-activated receptor-gamma coactivator-$1{\alpha}$ ($PGC1{\alpha}$) expression levels were observed in NecroX-5-treated rat hearts. These novel results provide convincing evidence for the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity and in preserving $PGC1{\alpha}$ during cardiac HR injuries.
Kim, Hyoung Kyu,Song, In-Sung,Lee, Sun Young,Jeong, Seung Hun,Lee, Sung Ryul,Heo, Hye Jin,Thu, Vu Thi,Kim, Nari,Ko, Kyung Soo,Rhee, Byoung Doo,Jeong, Dae Hun,Kim, Young Nam,Han, Jin Springer-Verlag 2014 Pfl ugers Arch Vol.466 No.12
<P>B7-H4 is a B7 family coregulatory protein that inhibits T cell-mediated immunity. B7-H4 is overexpressed in various cancers; however, the functional role of B7-H4 in cancer metabolism is poorly understood. Because mitochondria play pivotal roles in development, proliferation, and death of cancer cells, we investigated molecular and functional alterations of mitochondria in B7-H4-depleted HeLa cells. In a human study, overexpression of B7-H4 was confirmed in the cervices of adenocarcinoma patients (n = 3) compared to noncancer patients (n = 3). In the cell line model, B7-H4 depletion was performed by transfection with small interfering RNA (siRNA). B7-H4 depletion suppressed oxygen consumption rate, ATP production, and mitochondrial membrane potential and mass and increased reactive oxygen species production. In particular, electron transport complex III activity was significantly impaired in siB7-H4-treated cells. Coincidently, depletion of B7-H4 suppressed major mitochondrial regulators (peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC1-관] and mitochondrial transcription factor A), a component of oxidative phosphorylation (ubiquinol-cytochrome c reductase core protein 1), and an antiapoptosis protein (Bcl-XL). Mitochondrial dysfunction in siRNA-treated cells significantly augmented oxidative stress, which strongly activated the JNK/P38/caspase axis in the presence of doxorubicin, resulting in increased apoptotic cell death. Investigating the mechanism of B7-H4-mediated mitochondrial modulation, we found that B7-H4 depletion significantly downregulated the cAMP/cAMP response element-binding protein/PGC1-관 signaling pathway. Based on these findings, we conclude that B7-H4 has a role in the regulation of mitochondrial function, which is closely related to cancer cell physiology and drug sensitivity.</P>
Kim, Hyoung Kyu,Jeon, Jouhyun,Song, In-Sung,Heo, Hae Jin,Jeong, Seung Hun,Long, Le Thanh,Thu, Vu Thi,Ko, Tae Hee,Kim, Min,Kim, Nari,Lee, Sung Ryul,Yang, Jae-Seong,Kang, Mi Seon,Ahn, Jung-Mo,Cho, Je-Yo Elsevier 2019 Biochimica et biophysica acta Vol.1865 No.11
<P><B>Abstract</B></P> <P>Tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous target in cardiovascular diseases. Although it is involved in cardiovascular metabolism and mitochondrial biology, its mechanisms of action are unclear. We investigated how BH4 regulates cardiovascular metabolism using an unbiased multiple proteomics approach with a sepiapterin reductase knock-out (<I>Spr</I> <SUP>−/−</SUP>) mouse as a model of BH4 deficiency. <I>Spr</I> <SUP>−/−</SUP> mice exhibited a shortened life span, cardiac contractile dysfunction, and morphological changes. Multiple proteomics and systems-based data-integrative analyses showed that BH4 deficiency altered cardiac mitochondrial oxidative phosphorylation. Along with decreased transcription of major mitochondrial biogenesis regulatory genes, including <I>Ppargc1a</I>, <I>Ppara</I>, <I>Esrra</I>, and <I>Tfam</I>, <I>Spr</I> <SUP>−/−</SUP> mice exhibited lower mitochondrial mass and severe oxidative phosphorylation defects. Exogenous BH4 supplementation, but not nitric oxide supplementation or inhibition, rescued these cardiac and mitochondrial defects. BH4 supplementation also recovered mRNA and protein levels of PGC1α and its target proteins involved in mitochondrial biogenesis (mtTFA and ERRα), antioxidation (Prx3 and SOD2), and fatty acid utilization (CD36 and CPTI-M) in <I>Spr</I> <SUP>−/−</SUP> hearts. These results indicate that BH4-activated transcription of PGC1α regulates cardiac energy metabolism independently of nitric oxide and suggests that BH4 has therapeutic potential for cardiovascular diseases involving mitochondrial dysfunction.</P> <P><B>Highlights</B></P> <P> <UL> <LI> BH4 deficiency impairs mitochondrial and cardiac function. </LI> <LI> BH4 regulates PGC1α, ERRα, and mtTFA transcription. </LI> <LI> BH4 regulates proteins related to mitochondrial antioxidation and fatty acid utilization. </LI> <LI> BH4 is essential for mitochondrial biogenesis and oxidative phosphorylation. </LI> <LI> BH4 has therapeutic potential for cardiovascular diseases involving mitochondrial dysfunction. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>