Standardized Kaempferia parviflora Extract Enhances Exercise Performance Through Activation of Mitochondrial Biogenesis

김미보,김태윤,김창희,황재관 한국식품영양과학회 2018 Journal of medicinal food Vol.21 No.1

Exercise enhances mitochondrial biogenesis in skeletal muscle. Increased mitochondrial function and content can contribute to the improvement in skeletal muscle function and the benefits of exercise by increasing the response to energy demands. The effect of standardized Kaempferia parviflora extract (KPE) on exercise performance was accessed in L6 myotubes and C57BL/6J mice. KPE significantly activated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased mitochondrial density in L6 myotubes. KPE also upregulated the expression of transcription factors for mitochondrial biogenesis (estrogen-related receptor-α [ERRα], nuclear respiratory factor-1 [NRF-1], and mitochondrial transcription factor A [Tfam]) through activation of PGC-1α in L6 myotubes. In vivo models including normal diet mice and high-fat diet obese mice showed that KPE effectively enhanced running endurance and increased the skeletal muscle weight/body weight ratio. Furthermore, these observations were associated with a significant upregulation of mitochondrial biogenesis regulatory genes in skeletal muscle tissue. KPE enhanced the protein expression of the sirtuin 1 (SIRT1)/adenosine monophosphate (AMP)-activated protein kinase (AMPK)/PGC-1α/peroxisome proliferator-activated receptor-δ (PPARδ) signaling pathway components in vitro and in vivo, acting as an exercise metabolism regulator. These results suggest that KPE has the potential to enhance exercise performance through mitochondrial biogenesis and the SIRT1/AMPK/PGC-1α/PPARδ signaling pathways.

Standardized Siegesbeckia orientalis L. Extract Increases Exercise Endurance Through Stimulation of Mitochondrial Biogenesis

김미보,김창희,황재관 한국식품영양과학회 2019 Journal of medicinal food Vol.22 No.11

Siegesbeckia orientalis has been reported to exhibit anti-allergic, anti-infertility, anti-inflammatory, anti-rheumatic, and immunosuppressive activities. However, there are very few studies describing its stimulatory effects on exercise capacity. This study elucidated whether S. orientalis extract (SOE) standardized to kirenol content can enhance exercise endurance by increasing mitochondrial biogenesis. SOE significantly improved the running distance and time in mice fed normal diet (ND) and high-fat diet (HFD). SOE also enhanced mitochondrial biogenesis by stimulating the mitochondrial regulatory genes including peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM) in the skeletal muscles of ND and HFD mice. Furthermore, SOE upregulated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/PGC-1α/peroxisome proliferator-activated receptor delta (PPARδ) signaling pathway in the skeletal muscles of ND and HFD mice. Kirenol markedly increased adenosine triphosphate production and mitochondrial activity by stimulating the expression of markers of mitochondrial biogenesis and upregulating the AMPK/SIRT1/PGC-1α/PPARδ signaling pathway in L6 myotubes. These results show that SOE has the potential to be used to develop an exercise supplement capable of stimulating mitochondrial biogenesis through the AMPK/SIRT1/PGC-1α/PPARδ signaling pathway.

Emodin inhibits TNF‐α‐induced human aortic smooth‐muscle cell proliferation via caspase‐ and mitochondrial‐dependent apoptosis

Heo, Sook‐,Kyoung,Yun, Hyun‐,Jeong,Park, Won‐,Hwan,Park, Sun‐,Dong Wiley Subscription Services, Inc., A Wiley Company 2008 Journal of cellular biochemistry Vol.105 No.1

<P><B>Abstract</B></P><P>Vascular smooth‐muscle cell (VSMC) proliferation plays a vital role in hypertension, atherosclerosis and restenosis. It has been reported that emodin, an active component extracted from rhubarb, can stop the growth of cancer cells; however, it is not known if emodin exerts similar anti‐atherogenic effects in TNF‐α treated human aortic smooth‐muscle cells (HASMC). In this study, emodin treatment showed potent inhibitory effects in TNF‐α‐induced HASMC proliferation that were associated with induced apoptosis, including the cleavage of poly ADP‐ribose polymerase (PARP). Moreover, inhibitors of caspase‐3, ‐8 and ‐9 (Ac‐DEVD‐CHO, Z‐IETD‐FMK and Z‐LEHD‐FMK) efficiently blocked emodin‐induced apoptosis in TNF‐α treated HASMC. Therefore, emodin‐induced cell death occurred via caspase‐dependent apoptosis. Emodin treatment resulted in the release of cytochrome <I>c</I> into cytosol and a loss of mitochondrial membrane potential (ΔΨ<SUB>m</SUB>), as well as a decrease in the expression of an anti‐apoptotic protein (Bcl‐2) and an increase in the expression of an a pro‐apoptotic protein (Bax). Emodin‐mediated apoptosis was also blocked by a mitochondrial membrane depolarization inhibitor, which indicates that emodin‐induced apoptosis occurred via a mitochondrial pathway. Taken together, the results of this study showed that emodin inhibits TNF‐α‐induced HASMC proliferation via caspase‐ and a mitochondrial‐dependent apoptotic pathway. In addition, these results indicate that emodin has potential as an anti‐atherosclerosis agent. J. Cell. Biochem. 105: 70–80, 2008. © 2008 Wiley‐Liss, Inc.</P>

Induction of Intrinsic and Extrinsic Apoptosis Pathways in the Human Leukemic MOLT-4 Cell Line by Terpinen-4-ol

Khaw-On, Patompong,Banjerdpongchai, Ratana Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.7

Terpinen-4-ol is a terpene found in the rhizome of Plai (Zingiber montanum (Koenig) Link ex Dietr.). In this study apoptogenic activity and mechanisms of cell death induced by terpinen-4-ol were investigated in the human leukemic MOLT-4 cell line. Terpinen-4-ol exhibited cytotoxicity in MOLT-4 cells, with characteristic morphological features of apoptosis by Wright's staining. The mode of cell death was confirmed to be apoptosis by flow cytometric analysis after staining with annexin V-FITC and propidium iodide. A sub-G1 peak in DNA histograms of cell cycle assays was observed. Terpinen-4-ol induced-MOLT-4 cell apoptosis mediated through an intrinsic pathway involving the loss of mitochondrial transmembrane potential (MTP) and release of cytochrome c into the cytosol. In addition, terpinen-4-ol also induced apoptosis via an extrinsic pathway by caspase-8 activation resulting in the cleavage of cytosolic Bid. Truncated-Bid (tBid) translocated to mitochondria and activated the mitochondrial pathway in conjunction with down-regulation of Bcl-2 protein expression. Caspase-3 activity also increased. In conclusion, terpinen-4-ol can induce human leukemic MOLT-4 cell apoptosis via both intrinsic and extrinsic pathways.

Stigmalactam from Orophea Enterocarpa Induces Human Cancer Cell Apoptosis Via a Mitochondrial Pathway

Banjerdpongchai, Ratana,Wudtiwai, Benjawan,Pompimon, Wilart Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.23

Stigmalactam, an aristolactam-type alkaloid extracted from Orophea enterocarpa, exerts cytotoxicity against several human and murine cancer cell lines, but the molecular mechanisms remain elusive. The aims of this study were to identify the mode and mechanisms of human cancer cell death induced by stigmalactam employing human hepatocellular carcinoma HepG2 and human invasive breast cancer MDA-MB-231 cells as models, compared to normal murine fibroblasts. It was found that stigmalactam was toxic to HepG2 and MDA-MB-231 cells with $IC_{50}$ levels of $23.0{\pm}2.67{\mu}M$ and $33.2{\pm}4.54{\mu}M$, respectively, using MTT assays. At the same time the $IC_{50}$ level towards murine normal fibroblast NIH3T3 cells was $24.4{\pm}6.75{\mu}M$. Reactive oxygen species (ROS) production was reduced in stigmalactam-treated cells dose dependently after 4 h of incubation, indicating antioxidant activity, measured by using 2',7',-dichlorohydrofluorescein diacetate and flow cytometry. Caspase-3 and caspase-9 activities were increased in a dose response manner, while stigmalactam decreased the mitochondrial transmembrane potential dose-dependently in HepG2 cells, using 3,3'-dihexyloxacarbocyanine iodide and flow cytometry, indicating mitochondrial pathway-mediated apoptosis. In conclusion, stigmalactam from O. enterocarpa was toxic to both HepG2 and MDA-MB-231 cells and induced human cancer HepG2 cells to undergo apoptosis via the intrinsic (mitochondrial) pathway.

Bufalin Induces Mitochondrial Pathway-Mediated Apoptosis in Lung Adenocarcinoma Cells

Ding, Da-Wei,Zhang, Yong-Hong,Huang, Xin-En,An, Qing,Zhang, Xun Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.23

Background: To evaluate the effects of bufalin in A549 human lung adenocarcinoma epithelial cells in vitro and assess the underlying mechanisms. Materials and Methods: Human A549 non-small cell lung cancer (NSCLC) cells were treated with various concentrations of bufalin. Cell proliferation was measured by CCK-8 assay, apoptotic cell percentage was calculated by flow cytometry and morphological change was observed by inverted phase contrast microscopy/transmission electron microscopy. In addition, the membrane potential of mitochondria was detected by JC-1 fluorescence microscopy assay, and the related protein expression of cytochrome C and caspase-3 was analyzed by Western blotting. Results: Bufalin could inhibit the proliferation of A549 cells via induction of apoptosis, with the evidence of characteristic morphological changes in the nucleus and mitochondria. Furthermore, bufalin decreased the mitochondrial membrane potential with up-regulation of cytochrome C in the cytosol, and activation of caspase-3. Conclusions: Bufalin inhibits the proliferation of A549 cells and triggers mitochondria-dependent apoptosis, pointing to therapeutic application for NSCLC.

Assessment of the Cytotoxic and Apoptotic Effects of Chaetominine in a Human Leukemia Cell Line

Jing-Yun Yao,Ruihua Jiao,Changqing Liu,Yupeng Zhang,Wan-Guo Yu,Yan-Hua Lu,Renxiang Tan 한국응용약물학회 2016 Biomolecules & Therapeutics(구 응용약물학회지) Vol.24 No.2

Chaetominine is a quinazoline alkaloid originating from the endophytic fungus Aspergillus fumigatus CY018. In this study, we showed evidence that chaetominine has cytotoxic and apoptotic effects on human leukemia K562 cells and investigated the pathway involved in chaetominine-induced apoptosis in detail. Chaetominine inhibited K562 cell growth, with an IC50 value of 35 nM, but showed little inhibitory effect on the growth of human peripheral blood mononuclear cells. The high apoptosis rates, morphological apoptotic features, and DNA fragmentation caused by chaetominine indicated that the cytotoxicity was partially caused by its pro-apoptotic effect. Under chaetominine treatment, the Bax/Bcl-2 ratio was upregulated (from 0.3 to 8), which was followed by a decrease in mitochondrial membrane potential, release of cytochrome c from mitochondria into the cytosol, and stimulation of Apaf-1. Furthermore, activation of caspase-9 and caspase-3, which are the main executers of the apoptotic process, was observed. These results demonstrated that chaetominine induced cell apoptosis via the mitochondrial pathway. Chaetominine inhibited K562 cell growth and induced apoptotic cell death through the intrinsic pathway, which suggests that chaetominine might be a promising therapeutic for leukemia.

Assessment of the Cytotoxic and Apoptotic Effects of Chaetominine in a Human Leukemia Cell Line

Yao, Jingyun,Jiao, Ruihua,Liu, Changqing,Zhang, Yupeng,Yu, Wanguo,Lu, Yanhua,Tan, Renxiang The Korean Society of Applied Pharmacology 2016 Biomolecules & Therapeutics(구 응용약물학회지) Vol.24 No.2

Chaetominine is a quinazoline alkaloid originating from the endophytic fungus Aspergillus fumigatus CY018. In this study, we showed evidence that chaetominine has cytotoxic and apoptotic effects on human leukemia K562 cells and investigated the pathway involved in chaetominine-induced apoptosis in detail. Chaetominine inhibited K562 cell growth, with an $IC_{50}$ value of 35 nM, but showed little inhibitory effect on the growth of human peripheral blood mononuclear cells. The high apoptosis rates, morphological apoptotic features, and DNA fragmentation caused by chaetominine indicated that the cytotoxicity was partially caused by its pro-apoptotic effect. Under chaetominine treatment, the Bax/Bcl-2 ratio was upregulated (from 0.3 to 8), which was followed by a decrease in mitochondrial membrane potential, release of cytochrome c from mitochondria into the cytosol, and stimulation of Apaf-1. Furthermore, activation of caspase-9 and caspase-3, which are the main executers of the apoptotic process, was observed. These results demonstrated that chaetominine induced cell apoptosis via the mitochondrial pathway. Chaetominine inhibited K562 cell growth and induced apoptotic cell death through the intrinsic pathway, which suggests that chaetominine might be a promising therapeutic for leukemia.

Assessment of the Cytotoxic and Apoptotic Effects of Chaetominine in a Human Leukemia Cell Line

( Jing Yun Yao ),( Rui Hua Jiao ),( Chang Qing Liu ),( Yu Peng Zhang ),( Wan Guo Yu ),( Yan Hua Lu ),( Ren Xiang Tan ) 한국응용약물학회 2016 Biomolecules & Therapeutics(구 응용약물학회지) Vol.24 No.2

Chaetominine is a quinazoline alkaloid originating from the endophytic fungus Aspergillus fumigatus CY018. In this study, we showed evidence that chaetominine has cytotoxic and apoptotic effects on human leukemia K562 cells and investigated the pathway involved in chaetominine-induced apoptosis in detail. Chaetominine inhibited K562 cell growth, with an IC50 value of 35 nM, but showed little inhibitory effect on the growth of human peripheral blood mononuclear cells. The high apoptosis rates, morphological apoptotic features, and DNA fragmentation caused by chaetominine indicated that the cytotoxicity was partially caused by its pro-apoptotic effect. Under chaetominine treatment, the Bax/Bcl-2 ratio was upregulated (from 0.3 to 8), which was followed by a decrease in mitochondrial membrane potential, release of cytochrome c from mitochondria into the cytosol, and stimulation of Apaf-1. Furthermore, activation of caspase-9 and caspase-3, which are the main executers of the apoptotic process, was observed. These results demonstrated that chaetominine induced cell apoptosis via the mitochondrial pathway. Chaetominine inhibited K562 cell growth and induced apoptotic cell death through the intrinsic pathway, which suggests that chaetominine might be a promising therapeutic for leukemia.

Gossypol acetic acid induces apoptosis in RAW264.7 cells via a caspase-dependent mitochondrial signaling pathway

Sijun Deng,Hui Yuan,Jine Yi,Yin Lu,Qiang Wei,Chengzhi Guo,Jing Wu,Zuping He,Li-yun Yuan 대한수의학회 2013 Journal of Veterinary Science Vol.14 No.3

To investigate the effects of gossypol acetic acid (GA) on proliferation and apoptosis of the macrophage cell line RAW264.7 and further understand the possible underlying mechanism responsible for GA-induced cell apoptosis,RAW264.7 cells were treated with GA (25∼35 μmol/L) for 24h and the cytotoxicity was determined by MTT assay, while apoptotic cells were identified by TUNEL assay, acridine orange/ethidium bromide staining and flow cytometry. Moreover, mitochondrial membrane potential (ΔΨ m) with Rhodamine 123 and reactive oxygen species (ROS) with DCFH-DA were analyzed by fluorescence spectrofluorometry. In addition, the expression of caspase-3 and caspase-9 was assessed by Western Blot assay. Finally, the GA-induced cell apoptosis was evaluated by flow cytometry in the present of caspase inhibitors Z-VAD-FMK and Ac-LEHD-FMK,respectively. GA significantly inhibited the proliferation of RAW264.7 cells in a dose-dependent manner, and caused obvious cell apoptosis and a loss of ΔΨ m in RAW264.7 cells. Moreover, the ROS production in cells was elevated, and the levels of activated caspase-3 and caspase-9 were up-regulated in a dose-dependent manner. Notably, GA-induced cell apoptosis was markedly inhibited by caspase inhibitors. These results suggest that GA-induced RAW264.7 cell apoptosis may be mediated via a caspase-dependent mitochondrial signaling pathway.