Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation

Xie, Zhongyu,Zhang, Di,Chung, Dongjun,Tang, Zhanyun,Huang, He,Dai, Lunzhi,Qi, Shankang,Li, Jingya,Colak, Gozde,Chen, Yue,Xia, Chunmei,Peng, Chao,Ruan, Haibin,Kirkey, Matt,Wang, Danli,Jensen, Lindy M. Elsevier 2016 Molecular cell Vol.62 No.2

<P><B>Summary</B></P> <P>Here we report the identification and verification of a β-hydroxybutyrate-derived protein modification, lysine β-hydroxybutyrylation (Kbhb), as a new type of histone mark. Histone Kbhb marks are dramatically induced in response to elevated β-hydroxybutyrate levels in cultured cells and in livers from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters and that the increased H3K9bhb levels that occur during starvation are associated with genes upregulated in starvation-responsive metabolic pathways. Histone β-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and diverse functions of β-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Lysine β-hydroxybutyrylation (Kbhb) is a new type of histone mark </LI> <LI> 44 non-redundant histone Kbhb sites are identified in human and mouse cells </LI> <LI> Histone Kbhb increases under starvation and STZ-induced ketoacidosis </LI> <LI> Starvation-induced H3K9bhb is associated with active gene expression </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Acute and repeated dose 26-week oral toxicity study of 20(S)-ginsenoside Rg3 in Kunming mice and Sprague-Dawley rats

Li, Chunmei,Wang, Zhezhe,Li, Guisheng,Wang, Zhenhua,Yang, Jianrong,Li, Yanshen,Wang, Hongtao,Jin, Haizhu,Qiao, Junhua,Wang, Hongbo,Tian, Jingwei,Lee, Albert W.,Gao, Yonglin The Korean Society of Ginseng 2020 Journal of Ginseng Research Vol.44 No.2

Background: 20(S)-ginsenoside-Rg3 (C₄₂H₇₂O₁₃), a natural triterpenoid saponin, is extracted from red ginseng. The increasing use of 20(S)-ginsenoside Rg3 has raised product safety concerns. Methods: In acute toxicity, 20(S)-ginsenoside Rg3 was singly and orally administrated to Kunming mice and Sprague-Dawley (SD) rats at the maximum doses of 1600 mg/kg and 800 mg/kg, respectively. In the 26-week toxicity study, we used repeated oral administration of 20(S)-ginsenoside Rg3 in SD rats over 26 weeks at doses of 0, 20, 60, or 180 mg/kg. Moreover, a 4-week recovery period was scheduled to observe the persistence, delayed occurrence, and reversibility of toxic effects. Results: The result of acute toxicity shows that oral administration of 20(S)-ginsenoside Rg3 to mice and rats did not induce mortality or toxicity up to 1600 and 800 mg/kg, respectively. During a 26-week administration period and a 4-week withdrawal period (recovery period), there were no significant differences in clinical signs, body weight, food consumption, urinalysis parameters, biochemical and hematological values, or histopathological findings. Conclusion: The mean oral lethal dose (LD₅₀) of 20(S)-ginsenoside Rg3, in acute toxicity, is above 1600 mg/kg and 800 mg/kg in mice and rats, respectively. In a repeated-dose 26-week oral toxicity study, the no-observed-adverse-effect level for female and male SD rats was 180 mg/kg.

Acute and repeated dose 26-week oral toxicity study of 20(S)-ginsenoside Rg3 in Kunming mice and Sprague – Dawley rats

Chunmei Li,ZhezheWang,Guisheng Li,ZhenhuaWang,Jianrong Yang,Yanshen Li,Hongtao Wang,Haizhu Jin,Junhua Qiao,Hongbo Wang,Jingwei Tian,Albert W. Lee,Yonglin Gao 고려인삼학회 2020 Journal of Ginseng Research Vol.44 No.2

Background: 20(S)-ginsenoside-Rg3 (C42H72O13), a natural triterpenoid saponin, is extracted from redginseng. The increasing use of 20(S)-ginsenoside Rg3 has raised product safety concerns. Methods: In acute toxicity, 20(S)-ginsenoside Rg3 was singly and orally administrated to Kunming miceand SpragueeDawley (SD) rats at the maximum doses of 1600 mg/kg and 800 mg/kg, respectively. In the26-week toxicity study, we used repeated oral administration of 20(S)-ginsenoside Rg3 in SD rats over 26weeks at doses of 0, 20, 60, or 180 mg/kg. Moreover, a 4-week recovery period was scheduled to observethe persistence, delayed occurrence, and reversibility of toxic effects. Results: The result of acute toxicity shows that oral administration of 20(S)-ginsenoside Rg3 to mice andrats did not induce mortality or toxicity up to 1600 and 800 mg/kg, respectively. During a 26-weekadministration period and a 4-week withdrawal period (recovery period), there were no significantdifferences in clinical signs, body weight, food consumption, urinalysis parameters, biochemical andhematological values, or histopathological findings. Conclusion: The mean oral lethal dose (LD50) of 20(S)-ginsenoside Rg3, in acute toxicity, is above 1600mg/kg and 800 mg/kg in mice and rats, respectively. In a repeated-dose 26-week oral toxicity study, theno-observed-adverse-effect level for female and male SD rats was 180 mg/kg.

Antioxidant Activity of Peach Blossom Extracts

Chunmei Li,왕명현 한국응용생명화학회 2011 Applied Biological Chemistry (Appl Biol Chem) Vol.54 No.1

Peach blossom, popularly consumed as tea, is believed to promote healthy, young-looking skin. The literature reporting pharmacological studies related to peach blossom is very limited. Thus, the antioxidant activities of the methanolic extract (ME) and the water extract (WE) from peach blossom were evaluated using various in vitro assays including total phenolic and flavonoid contents, total antioxidant activity, 2,2-Diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging activity, reducing power, metal chelating activity, lipid peroxidation inhibitory activity, and protective effects against DNA and protein damages. Results showed that ME demonstrated slightly higher antioxidant effects than WE, except for protection against protein damage. These results suggest that peach blossom has the potential for use as a source of natural antioxidants in the food and cosmetic industries.

Anti-inflammatory effect of the water fraction from hawthorn fruit on LPS-stimulated RAW 264.7 cells

Chunmei Li,Myeong-Hyeon Wang 한국영양학회 2011 Nutrition Research and Practice Vol.5 No.2

The hawthorn fruit (Crataegus pinnatifida Bunge var. typica Schneider) is used as a traditional medicine in Korea. The objective of this study was to understand the mechanisms of the anti-inflammatory effects of the water fractionated portion of hawthorn fruit on a lipopolysaccharide (LPS)-stimulated RAW 264.7 cellular model. The level of nitric oxide (NO) production in the water fraction and LPS-treated RAW 264.7 cells were determined with an ELISA. The cytotoxicity of the water fraction and LPS was measured with an MTT assay. Expression of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α, interleukin 6 (IL-6), and interleukin 1β (IL-1β) mRNA were analyzed with a reverse transcription polymerase chain reaction (RT-PCR). The water fraction of hawthorn fruit was determined to be safe and significantly inhibited NO production in LPS-stimulated RAW 264.7 cells and suppressed COX-2, TNF-α, IL-1β, and IL-6 expression. The observed anti-inflammatory effects of the water fraction of hawthorn fruit might be attributed to the down-regulation of COX-2, TNF-α, IL-1β, and IL-6 expression in LPS-stimulated RAW 264.7 cells.

Glycyrrhiza glabra L. Extract Inhibits LPS-Induced Inflammation in RAW 264.7 Mouse Macrophages

Chunmei Li,Hwayoung Noh,Hyein Kim,Inyong Kim,Taekil Eom,Sungryul Yu,Han Sub Kwak,Misook Kim,Youngseung Lee,Yoonhwa Jeong 한국식품영양과학회 2014 한국식품영양과학회 학술대회발표집 Vol.2014 No.10

Potential Biological Activities of Magnoflorine: A Compound from Aristolochia debilis Sieb. et Zucc

Li, Chunmei,Wang, Myeong-Hyeon The Plant Resources Society of Korea 2014 한국자원식물학회지 Vol.27 No.3

Magnoflorine, an important compound in Aristolochia, was usually used as an anxiolytic chemical. In this study, the magnoflorine was isolated from Aristolochia and the biological activities such as antioxidant, ${\alpha}$-tyrosinase inhibitory, anti-inflammatory, and anticancer activities were investigated. The magnoflorine showed significant antioxidant activity as a 2,2-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenger, $50{\mu}g/mL$ of the magnoflorine scavenged about 70.8% of all the free radicals. And it was good at ${\alpha}$-tyrosinase inhibiting, $100{\mu}g/mL$ of the magnoflorine inhibited 36.5% of the tyrosinase. High dosage of magnoflorine inhibited the inflammation production nitric oxide (NO), and the magnoflorine protected the murine macrophage cells (RAW 264.7) from LPS-induced apoptosis. The cell viability of human colon cancer calls (HT-29) was around 100% when treated with different dose of magnoflorine, it's suggesting that magnoflorine had no anticancer effect.

Antioxidant Activity of Peach Blossom Extracts

Li, Chunmei,Wang, Myeong-Hyeon The Korean Society for Applied Biological Chemistr 2011 Applied Biological Chemistry (Appl Biol Chem) Vol.54 No.1

Peach blossom, popularly consumed as tea, is believed to promote healthy, young-looking skin. The literature reporting pharmacological studies related to peach blossom is very limited. Thus, the antioxidant activities of the methanolic extract (ME) and the water extract (WE) from peach blossom were evaluated using various in vitro assays including total phenolic and flavonoid contents, total antioxidant activity, 2,2-Diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging activity, reducing power, metal chelating activity, lipid peroxidation inhibitory activity, and protective effects against DNA and protein damages. Results showed that ME demonstrated slightly higher antioxidant effects than WE, except for protection against protein damage. These results suggest that peach blossom has the potential for use as a source of natural antioxidants in the food and cosmetic industries.

Biological Activities of Water and Ethanolic Extracts from Allium victorialis L. Mature Leaves

Li, Chunmei,Lee, Young-Mee,Lee, Kyeong-Cheol,Han, Woong,Wang, Myeong-Hyeon,Han, Sang-Sup The Korean Society of Food Science and Nutrition 2011 Preventive Nutrition and Food Science Vol.16 No.3

Allium victorialis L. (A. victorialis) is a very popular vegetable in Korea. The most commonly used parts of this vegetable are the bulbs and young leaves. To determine if the mature leaves have any beneficial properties, we investigated antioxidant, anti-${\alpha}$-glucosidase, anti-inflammatory, and anticancer activities of water and ethanol extracts from A. victorialis. Antioxidant activity was evaluated by measuring total phenolic content, DPPH and superoxide radicals scavenging activities. The water extract from A. victorialis ($W{\cdot}A$. victorialis) exhibited higher antioxidant ability than the ethanol extract ($E{\cdot}A$. victorialis). Moreover, the water extract showed strong inhibitory effect on ${\alpha}$-glucosidase. On the other hand, the ethanol extract had greater anti-inflammatory activity on murine macrophage cells (RAW 264.7) and greater anticancer activities against human colon cancer cells (HT-29). These results suggest that mature leaves from E·A. victorialis may have health-enhancing effects.

Mammea longifolia Planch. and Triana Fruit Extract Induces Cell Death in the Human Colon Cancer Cell Line, SW480, via Mitochondria-Related Apoptosis and Activation of p53

Chunmei Li,정윤화,김미숙 한국식품영양과학회 2017 Journal of medicinal food Vol.20 No.5

The methanol extract of Mammea longifolia Planch. and Triana (M. longifolia) fruit was studied for anticancer and apoptotic effects in the SW480 colon cancer cell line. The apoptotic and necrotic effects of M. longifolia were detected by 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) and lactate dehydrogenase assays, respectively. One hundred lg/mL of the extract killed *82.4% of the cells; however, 2% of the death was related to necrosis. The morphological changes in M. longifolia-stimulated SW480 cells were observed directly by light microscopy. DNA fragmentation assay was employed to analyze the apoptosis induction. M. longifolia-treated SW480 cells promoted the expression of Bax, Bad, cleaved-poly-ADP-ribose polymerase (PARP), and p53 proteins and decreased the protein expression of procaspases Bcl-2 and Bcl-XL. The ratios of Bax/Bcl-2 and cleaved-PARP/PARP, predictive markers of apoptotic stimuli in cancer, increased and may play an important role in regulating the progression of apoptosis. The results suggested that M. longifolia induces cell death via mitochondrial-related apoptosis in SW480 cells.