Publications by authors named "Il Je Cho"

90 Publications

Hemistepsin A inhibits T0901317-induced lipogenesis in the liver.

BMB Rep 2021 Feb;54(2):106-111

College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Korea.

Hemistepsin A (HsA) is a guaianolide sesquiterpene lactone that inhibits hepatitis and liver fibrosis. We evaluated the effects of HsA on liver X receptor (LXR)-mediated hepatic lipogenesis in vitro and in vivo. Up to 10 μM, HsA did not affect the viability of HepG2 and Huh7 cells. Pretreatment with 5-10 μM HsA significantly decreased the luciferase activity of the LXR response element, which was transactivated by T0901317, GW 3965, and LXRα/retinoid X receptor α overexpression. In addition, it significantly inhibited the mRNA expression of LXRα in HepG2 and Huh7 cells. It also suppressed the expression of sterol regulatory element-binding protein-1c and lipogenic genes and reduced the triglyceride accumulation triggered by T0901317. Intraperitoneal injection of HsA (5 and 10 mg/kg) in mice significantly alleviated the T0901317-mediated increases in hepatocyte diameter and the percentage of regions in hepatic parenchyma occupied by lipid droplets. Furthermore, HsA significantly attenuated hepatic triglyceride accumulation by restoring the impaired expression of LXRα-dependent lipogenic genes caused by T0901317. Therefore, based on its inhibition of the LXRα-dependent signaling pathway, HsA has prophylactic potential for steatosis. [BMB Reports 2021; 54(2): 106-111].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907741PMC
February 2021

Hepatoprotective Effect of Extract Is Mediated via Antagonism of Oxidative Stress.

Evid Based Complement Alternat Med 2020 9;2020:6761842. Epub 2020 Jul 9.

Department of Psychopharmacology, Qiqihar Medical University, Qiqihar 161006, China.

has been extensively used in traditional Oriental medicine to treat gastric disorders and has anti-inflammatory and antioxidative activities. Therefore, the present study examined a possible hepatoprotective effect of a extract (PZE) and investigated the underlying molecular mechanisms. We employed an model of arachidonic acid (AA) + iron-induced hepatocyte damage and an model of CCl-induced liver injury to assess the effects of PZE and evaluated the relevant molecular targets using biochemical assays, flow cytometry analysis, Western blot, and histopathological analysis. The PZE inhibited AA + iron-induced hepatotoxicity in HepG2 cells, improved mitochondrial dysfunction, and reversed an increase in the cellular HO production and a decrease in the reduced GSH levels induced by AA + iron. Treatment with either 30 or 100 g/ml PZE significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, and the latter dose also increased the antioxidant response element- (ARE-) driven luciferase activity and enhanced the protein expressions of glutamate-cysteine ligase catalytic subunit and NAD(P)H:quinone oxidoreductase 1. In addition, treatment with 100 g/ml PZE for 3 or 6 h increased the phosphorylation rates of Nrf2 and the extracellular signal-regulated kinase. In the experiment, oral treatment with both 100 and 300 mg/kg PZE inhibited the plasma aspartate aminotransferase activity, and the latter also inhibited the plasma alanine aminotransferase activity. In addition, both doses of PZE ameliorated the parenchymal degeneration and necrosis in the liver induced by CCl administration, which was associated with reduced expressions of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase, nitrotyrosine, and 4-hydroxynonenal by PZE. These findings suggest that PZE has protective effects against hepatotoxicity both and , which are mainly mediated via its antioxidant activity.
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http://dx.doi.org/10.1155/2020/6761842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368226PMC
July 2020

Lemon balm and dandelion leaf extract synergistically alleviate ethanol-induced hepatotoxicity by enhancing antioxidant and anti-inflammatory activity.

J Food Biochem 2020 08 4;44(8):e13232. Epub 2020 Jun 4.

Department of Foodscience and Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.

We investigated the effect of a 2:1 (w/w) mixture of lemon balm and dandelion extracts (LD) on ethanol (EtOH)-mediated liver injury and explored the underlying mechanisms. Administration of LD synergistically reduced relative liver weight and decreased the levels of serum biomarkers of hepatic injury. Histopathological and biochemical analyses indicated that LD synergistically attenuated hepatic accumulation of triacylglycerides (TGs) and restored the levels of mRNAs related to fatty acid metabolism. In addition, LD significantly reduced EtOH-induced hepatic oxidative stress by attenuating the reduction in levels of nuclear factor E2-related factor 2 (Nrf2) mRNA and enhancing antioxidant activity. Moreover, LD decreased the EtOH-mediated increase in levels of hepatic tumor necrosis factor-α (TNF-α) mRNA. In vitro, LD significantly scavenged free radicals, increased cell viability against tert-butylhydroperoxide (tBHP), and transactivated Nrf2 target genes in HepG2 cells. Furthermore, LD decreased levels of pro-inflammatory mediators in lipopolysaccharide-stimulated Raw264.7 cells. Therefore, LD shows promise for preventing EtOH-mediated liver injury. PRACTICAL APPLICATIONS: There were no approved therapeutic agents for preventing and/or treating alcoholic liver diseases. In this study, a 2:1 (w/w) mixture of lemon balm and dandelion leaf extract (DL) synergistically ameliorated EtOH-induced hepatic injury by inhibiting lipid accumulation, oxidative stress, and inflammation. Our findings will enable the development of a novel food supplement for the prevention or treatment of alcohol-mediated liver injury.
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http://dx.doi.org/10.1111/jfbc.13232DOI Listing
August 2020

Luteolin prevents liver from tunicamycin-induced endoplasmic reticulum stress via nuclear factor erythroid 2-related factor 2-dependent sestrin 2 induction.

Toxicol Appl Pharmacol 2020 07 11;399:115036. Epub 2020 May 11.

College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea. Electronic address:

Endoplasmic reticulum (ER) stress designates a cellular response to the accumulation of misfolded proteins, which is related to disease progression in the liver. Luteolin (3',4',5,7-tetrahydroxyflavone) is a phytochemical found frequently in medicinal herbs. Although luteolin has been reported to possess the therapeutic potential to prevent diverse stage of liver diseases, its role in hepatic ER stress has not been established. Thus, the present study aimed to determine the role of luteolin in tunicamycin (Tm)-induced ER stress, and to identify the relevant mechanisms involved in its hepatoprotective effects. In hepatocyte-derived cells and primary hepatocytes, luteolin significantly decreased Tm- or thapsigargin-mediated C/EBP homologous protein (CHOP) expression. In addition, luteolin reduced the activation of three canonical signaling pathways related to the unfolded protein response, and decreased mRNA levels of glucose-regulated protein 78, ER DNA J domain-containing protein 4, and asparagine synthetase. Luteolin also significantly upregulated sestrin 2 (SESN2), and luteolin-mediated CHOP inhibition was blocked in SESN2 (+/-) cells. Moreover, luteolin resulted in phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as increased nuclear Nrf2 expression. Deletion of the antioxidant response element in the human SESN2 promoter inhibited increased luciferase activation by luteolin, suggesting that Nrf2 is a critical transcription factor for luteolin-dependent SESN2 expression. In a Tm-mediated liver injury model, luteolin decreased serum alanine aminotransferase and aspartate aminotransferase activities, prevented degenerative changes and apoptosis of hepatocytes, and inhibited CHOP and glucose-regulated protein 78 expression in hepatic tissues. Therefore, luteolin may be an effective phytochemical to manage ER stress-related liver injury.
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http://dx.doi.org/10.1016/j.taap.2020.115036DOI Listing
July 2020

Effects of and Coptis Rhizoma 2 : 1 Mixed Formula (PS + CR) on Ovalbumin-Induced Asthma in Mice.

Evid Based Complement Alternat Med 2020 28;2020:9135637. Epub 2020 Feb 28.

College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.

(PS) is traditionally used to treat respiratory and gastrointestinal infections, dysmenorrhea, and hepatic disorders in South Africa. Coptis Rhizoma (CR) is used to treat gastroenteric disorders, cardiovascular diseases, and cancer in East Asia. In the present study, we intended to observe the possible beneficial antiasthma effects of PS and CR on the ovalbumin- (OVA-) induced asthma C57BL/6J mice. Asthma in mice was induced by OVA sensitization and subsequent boosting. PS + CR (300 and 1,000 mg/kg; PO) or dexamethasone (IP) was administered once a day for 16 days. The changes in the body weight and gains, lung weights and gross inspections, total and differential cell counts of leukocytes in bronchoalveolar lavage fluid (BALF), serum OVA-specific immunoglobulin E (OVA-sIgE) levels, interleukin-4 (IL-4) and IL-5 levels in BALF and lung tissue homogenate, and IL-4 and IL-5 mRNA levels in lung tissue homogenates were analyzed with lung histopathology: mean alveolar surface area (ASA), alveolar septal thickness, numbers of inflammatory cells, mast cells, and eosinophils infiltrated in the alveolar regions, respectively. Significant increases in lung weights, total and differential cell counts of leukocytes in BALF, serum OVA-sIgE levels, and IL-4 and IL-5 levels in BALF and lung tissue homogenate were observed in OVA control as compared to those of intact control. In addition, OVA control showed a significant decrease in mean ASA and increases in alveolar septal thickness, numbers of inflammatory cells, mast cells, and eosinophils infiltrated in alveolar regions. However, these allergic and inflammatory asthmatic changes were significantly inhibited by PS + CR in a dose-dependent manner. In this study, PS + CR showed dose-dependent beneficial effects on OVA-induced asthma in mice through anti-inflammatory and antiallergic activities. Therefore, it is expected that PS + CR have enough potential as a new therapeutic agent or as an ingredient of a medicinal agent for various allergic and inflammatory respiratory diseases including asthma.
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http://dx.doi.org/10.1155/2020/9135637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066403PMC
February 2020

Involvement of ER stress and reactive oxygen species generation in anti-cancer effect of CKD-516 for lung cancer.

Cancer Chemother Pharmacol 2020 04 11;85(4):685-697. Epub 2020 Mar 11.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.

Purpose: CKD-516 (Valecobulin), a vascular-disrupting agent, inhibits microtubule elongation. We evaluated the effect of CKD-516 on lung cancer cells and the underlying molecular mechanisms.

Methods: The effects of S516, an active metabolite of CKD-516, were evaluated in HUVECs and three lung cancer cell lines and by a microtubule polymerization assay. Tubulin cross-linking was used to identify the binding site of S516 on tubulin, and Western blotting was performed to identify the intracellular pathways leading to cell death. Subcutaneous lung cancer xenograft models were used to assess the in vivo effect of CKD-516 on tumor growth.

Results: S516 targeted the colchicine binding site on β-tubulin. In lung cancer cells, S516 increased endoplasmic reticulum (ER) stress and induced reactive oxygen species (ROS) generation by mitochondria and the ER. In addition, CKD-516 monotherapy strongly inhibited the growth of lung cancer xenograft tumors and exerted a synergistic effect with carboplatin.

Conclusion: The findings suggest that CKD-516 exerts an anticancer effect in company with inducing ER stress and ROS production via microtubule disruption in lung cancer cells. CKD-516 may thus have therapeutic potential for lung cancer.
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http://dx.doi.org/10.1007/s00280-020-04043-xDOI Listing
April 2020

Hepatoprotective Effect of Neoagarooligosaccharide via Activation of Nrf2 and Enhanced Antioxidant Efficacy.

Biol Pharm Bull 2020 Apr 31;43(4):619-628. Epub 2020 Jan 31.

College of Pharmacy, Chosun University.

Neoagarooligosaccharides (NAOS) are generated by β-agarases, which cleave the β-1,4 linkage in agarose. Previously, we reported that NAOS inhibited fat accumulation in the liver and decreased serum cholesterol levels. However, the hepatoprotective effect of NAOS on acute liver injury has not yet been investigated. Thus, we examined whether NAOS could activate nuclear factor (NF)-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) and upregulates its target gene, and has hepatoprotective effect in vivo. In hepatocytes, phosphorylation and subsequent nuclear translocation of Nrf2 are increased by treatment with NAOS, in a manner dependent on p38 and c-Jun N-terminal kinase (JNK). Consistently, NAOS augmented ARE reporter gene activity and the antioxidant protein levels, resulting in increased intracellular glutathione levels. NAOS antagonized tert-butylhydroperoxide-induced reactive oxygen species (ROS) generation. Moreover, NAOS inhibited acetaminophen (APAP)-induced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and significantly decreased hepatocyte degeneration and inflammatory cell infiltration. Moreover, ROS production and glutathione depletion by APAP were reversed by NAOS. APAP-mediated apoptotic signaling pathways were also inhibited in NAOS-treated mice. Upregulalted hepatic expression of genes related to inflammation by APAP were consistently diminished by NAOS. Collectively, our results demonstrate that NAOS exhibited a hepatoprotective effect against APAP-mediated acute liver damage through its antioxidant capacity.
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http://dx.doi.org/10.1248/bpb.b19-00697DOI Listing
April 2020

Hemistepsin A alleviates liver fibrosis by inducing apoptosis of activated hepatic stellate cells via inhibition of nuclear factor-κB and Akt.

Food Chem Toxicol 2020 Jan 9;135:111044. Epub 2019 Dec 9.

College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea. Electronic address:

Hemistepsin A (HsA), isolated from Hemistepta lyrata (Bunge) Bunge, has the ability to ameliorate hepatitis in mice. However, the effects of H. lyrata and HsA on other types of liver disease have not been explored. In this report, we investigated the effects of H. lyrata and HsA on liver fibrosis and the underlying molecular mechanisms in activated hepatic stellate cells (HSCs). Based on cell viability-guided isolation, we found HsA was the major natural product responsible for H. lyrata-mediated cytotoxicity in LX-2 cells. HsA significantly decreased the viability of LX-2 cells and primary activated HSCs, increased the binding of Annexin V, and altered the expression of apoptosis-related proteins, suggesting that HsA induces apoptosis in activated HSCs. HsA reduced the phosphorylation of IKKε and the transactivation of nuclear factor-κB (NF-κB). Moreover, HsA decreased the phosphorylation of Akt and its downstream signaling molecules. Transfection experiments suggested that inhibition of NF-κB or Akt is essential for HsA-induced apoptosis of HSCs. In a CCl-induced liver fibrosis model, HsA administration significantly decreased ALT and AST activities. Furthermore, HsA attenuated CCl-mediated collagen deposits and profibrogenic genes expression in hepatic tissue. Thus, HsA may serve as a natural product for managing liver fibrosis through inhibition of NF-κB/Akt-dependent signaling.
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http://dx.doi.org/10.1016/j.fct.2019.111044DOI Listing
January 2020

Ginseng berry aqueous extract prevents scopolamine-induced memory impairment in mice.

Exp Ther Med 2019 Dec 8;18(6):4388-4396. Epub 2019 Oct 8.

Research Center for Herbal Convergence on Liver Disease, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.

Ginseng berry exhibits a diverse range of pharmacological activities. The present study aimed to examine the neuroprotective effects of ginseng berry aqueous extract (GBE) against oxidative stress and to assess the impact of GBE on memory impairment in mice. In HT-22 cells, GBE pretreatment significantly inhibited glutamate- and hydrogen peroxide-mediated cytotoxicity in a concentration-dependent manner, while treatment with up to 100 µg/ml GBE alone did not change cell viability. In a murine model of scopolamine (SCP)-induced memory impairment, results from the passive avoidance test and the Morris water maze test indicated that GBE administration for 4 weeks prolonged step-through latency time and shortened escape latency time, suggesting that GBE can attenuate deficits in long-term memory induced by SCP. Additionally, GBE prevented SCP-induced reductions in acetylcholine by decreasing acetylcholinesterase activity and upregulating choline acetyltransferase mRNA levels in the hippocampus. GBE mitigated SCP-mediated mRNA decreases in brain-derived neurotrophic factor levels and its associated signaling molecules. Furthermore, GBE administration significantly suppressed malondialdehyde production and increased glutathione levels, catalase activity and superoxide dismutase activity in SCP-induced memory impaired mice. Therefore, the results of the current study indicated that ginseng berry may be a potential candidate for treating or preventing memory deficits that are associated with neurodegenerative disorders.
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http://dx.doi.org/10.3892/etm.2019.8090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862129PMC
December 2019

Overproduction of inter-α-trypsin inhibitor heavy chain 1 after loss of Gα in liver exacerbates systemic insulin resistance in mice.

Sci Transl Med 2019 10;11(513)

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.

The impact of liver disease on whole-body glucose homeostasis is largely attributed to dysregulated release of secretory proteins in response to metabolic stress. The molecular cues linking liver to whole-body glucose metabolism remain elusive. We found that expression of G protein α-13 (Gα) was decreased in the liver of mice and humans with diabetes. Liver-specific deletion of the gene in mice resulted in systemic glucose intolerance. Comparative secretome analysis identified inter-α-trypsin inhibitor heavy chain 1 (ITIH1) as a protein secreted by liver that was responsible for systemic insulin resistance in deficient mice. Liver expression of ITIH1 positively correlated with surrogate markers for diabetes in patients with impaired glucose tolerance or overt diabetes. Mechanistically, a decrease in hepatic Gα caused ITIH1 oversecretion by liver through induction of -GlcNAc transferase expression, facilitating ITIH1 deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle. Neutralization of secreted ITIH1 ameliorated glucose intolerance in obese mice. Our findings demonstrate systemic insulin resistance in mice resulting from liver-secreted ITIH1 downstream of Gα and its reversal by ITIH1 neutralization.
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http://dx.doi.org/10.1126/scitranslmed.aan4735DOI Listing
October 2019

Secretome profiling of PC3/nKR cells, a novel highly migrating prostate cancer subline derived from PC3 cells.

PLoS One 2019 12;14(8):e0220807. Epub 2019 Aug 12.

BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.

Prostate cancer (PCa) is the most common cancer among men worldwide. Most PCa cases are not fatal; however, the outlook is poor when PCa spreads to another organ. Bone is the target organ in about 80% of patients who experience metastasis from a primary PCa tumor. In the present study, we characterized the secretome of PC3/nKR cells, which are a new subline of PC3 cells that were originally isolated from nude mice that were implanted with PC3 cells without anti-natural killer (NK) cell treatment. Wound healing and Transwell assays revealed that PC3/nKR cells had increased migratory and invasive activities in addition to a higher resistance to NK cells-induced cytotoxicity as compared to PC3 cells. We quantitatively profiled the secreted proteins of PC3/nKR and PC3 cells by liquid chromatography-tandem mass spectrometry analysis coupled with 2-plex tandem mass tag labeling. In total, 598 secretory proteins were identified, and 561 proteins were quantified, among which 45 proteins were secreted more and 40 proteins were secreted less by PC3/nKR cells than by PC3 cells. For validation, the adapter molecule crk, serpin B3, and cystatin-M were analyzed by western blotting. PC3/nKR cells showed the selective secretion of NKG2D ligand 2, HLA-A, and IL-6, which may contribute to their NK cell-mediated cytotoxicity resistance, and had a high secretion of crk protein, which may contribute to their high migration and invasion properties. Based on our secretome analysis, we propose that PC3/nKR cells represent a new cell system for studying the metastasis and progression of PCa.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220807PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690527PMC
March 2020

Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury.

Toxicol Appl Pharmacol 2019 09 16;379:114665. Epub 2019 Jul 16.

College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea. Electronic address:

Ferroptosis is the non-apoptotic form of cell death caused by small molecules or conditions that inhibit glutathione biosynthesis or resulting in iron-dependent accumulation of lipid peroxidation by lipid reactive oxygen species (ROS). Sestrin2 (Sesn2), a conserved antioxidant protein, is responsive to various stresses including genotoxic, metabolic, and oxidative stresses and acts to restore homeostatic balance. Sesn2 expression was reported to be regulated via stress-responsive transcription factors including p53, Nrf2, and HIF-1α. However, the role of Sesn2 in regulating ferroptosis is not known. In the current study, we investigated whether ferroptosis inducing compounds including erastin, sorafenib, and buthionine sulfoximine affect Sesn2 expression and the role of Sesn2 in cytoprotection against ferroptosis-mediated cell death. Our data demonstrate that ferroptosis inducers significantly increased Sesn2 in hepatocytes in a dose- and time-dependent manner. Treatment with erastin upregulated Sesn2 mRNA levels and luciferase reporter gene activity, and erastin-mediated Sesn2 induction was transcriptionally regulated by NF-E2-related factor 2 (Nrf2). Furthermore, deletion of the antioxidant response element (ARE) in the Sesn2 promoter or Nrf2 knockout or knockdown abolished erastin-induced Sesn2 expression. In cells expressing Sesn2, erastin-induced cell death, ROS formation, and glutathione depletion were almost completely inhibited compared to that in control cells. Treatment with phenylhydrazine in mice, well-reported iron overload liver injury model, increased ALT and AST levels and altered histological features, which were almost completely inhibited by adenoviral Sesn2 infection. Collectively, our results suggest that ferroptosis-mediated Sesn2 induction is dependent on Nrf2 and plays a protective role against iron overload and ferroptosis-induced liver injury.
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http://dx.doi.org/10.1016/j.taap.2019.114665DOI Listing
September 2019

Extract and Its Major Constituents Inhibit Oxidative Stress-Induced Liver Injury.

J Med Food 2019 Jun 2;22(6):602-613. Epub 2019 May 2.

1 College of Pharmacy, Chosun University, Gwangju, Korea.

The fruits, leaves, and roots of have been reported to contain large amounts of vitamin B, vitamin C, and flavonoids. They exhibit various physiological activities such as antitumor and anti-inflammatory effects. However, the hepatoprotective effects of extracts against oxidative stress-mediated liver injury have not yet been investigated. We thus examined whether leaf extracts (CTEs) protect against oxidative stress-mediated liver injury and and elucidated the underlying mechanism. The cytoprotective effects of CTE through the NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) activation were presented and measured by biochemical analysis in HepG2 cells. To assess the protective effects of CTE , mice were administered with CTE (250 and 500 mg/kg; 5 days; p.o.) before a single dose of acetaminophen (APAP) (300 mg/kg; 24 h; i.p.). CTE increased ARE luciferase activity when compared with extracts of other parts of CTE upregulated nuclear translocation of Nrf2 and its target gene expression. In addition, CTE inhibited the generation of reactive oxygen species (ROS) and cell death induced by arachidonic acid (AA) and iron (Fe) treatment in primary hepatocytes or HepG2 cells. The cytoprotective effects of CTE against oxidative stress might be due to kaempferol, the major flavonoid present in CTE. Kaempferol pretreatment blocked AA+Fe-induced ROS production and reversed glutathione depletion, which in turn led to decreased cell death. Furthermore, the protective effects of CTE against liver injury induced by excess APAP in mice or primary hepatocytes were observed. CTE could be a promising therapeutic candidate against oxidative stress-induced liver injury.
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http://dx.doi.org/10.1089/jmf.2018.4322DOI Listing
June 2019

Inhibitory Effect of Sestrin 2 on Hepatic Stellate Cell Activation and Liver Fibrosis.

Antioxid Redox Signal 2019 07 24;31(3):243-259. Epub 2019 Apr 24.

1 College of Pharmacy, Chosun University, Gwangju, Republic of Korea.

Hepatic fibrosis results from chronic liver injury and inflammatory responses. Sestrin 2 (Sesn2), an evolutionarily conserved antioxidant enzyme, reduces the severities of acute hepatitis and metabolic liver diseases. However, the role of Sesn2 in the pathogenesis of liver fibrosis remains obscure. Here, we used cultured hepatic stellate cells (HSCs) and chronic carbon tetrachloride (CCl) and bile duct ligation (BDL) murine models to investigate the effects of Sesn2 on fibrogenesis. Sesn2 protein and mRNA levels were upregulated in activated primary HSCs, and by increasing transcription, transforming growth factor-β (TGF-β) also increased Sesn2 expression in HSCs. Furthermore, Smad activation was primarily initiated by TGF-β signaling, and Smad3 activation increased Sesn2 luciferase activity. analysis of the 5' upstream region of the gene revealed a putative Smad-binding element (SBE), and its deletion demonstrated that the SBE between -964 and -956 bp within human promoter was critically required for TGF-β-mediated response. Moreover, ectopic expression of Sesn2 reduced gene expressions associated with HSC activation, and this was accompanied by marked decreases in SBE luciferase activity and Smad phosphorylation. Infection of recombinant adenovirus Sesn2 reduced hepatic injury severity, as evidenced by reductions in CCl- or BDL-induced alanine aminotransferase and aspartate aminotransferase, and inhibited collagen accumulation. Furthermore, HSC-specific lentiviral delivery of Sesn2 prevented CCl-induced liver fibrosis. Finally, Sesn2 expression was downregulated in the livers of patients with liver cirrhosis and in mouse models of hepatic fibrosis. Our findings suggest that Sesn2 has the potential to inhibit HSC activation and hepatic fibrosis.
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http://dx.doi.org/10.1089/ars.2018.7559DOI Listing
July 2019

Hepatoprotective effects of blue honeysuckle on CCl-induced acute liver damaged mice.

Food Sci Nutr 2019 Jan 27;7(1):322-338. Epub 2018 Nov 27.

Department of Food and Nutrition College of BioNano Technology Gachon University Seongnam-si Gyeonggi-do Korea.

The objective of this study was to evaluate the hepatoprotective effects of blue honeysuckle (BH) on carbon tetrachloride (CCl)-induced acute hepatic damage in mice. The experiment used a total of 60 ICR mice, which were divided into six groups. Except for the intact control groups, all groups received a single intraperitoneal injection of CCl after a 7 day pre-treatment period with distilled water, BH extracts, or silymarin. Twenty-four hours after the CCl injection, the following observations, representative of classical oxidative stress-mediated centrolobular necrotic acute liver injuries, were observed: decreased body weight; small nodule formation and enlargement on the gross inspections with related liver weight increase; elevation of serum AST and ALT, increases in hepatic lipid peroxidation and related depletion of endogenous antioxidants and antioxidative enzymes; centrolobular necrosis; increases in apoptotic markers, lipid peroxidation markers, and oxidative stress markers. However, liver damage was significantly inhibited by the pre-treatment with BH extracts. The present study demonstrated that oral administration of BH extracts prior to exposure to CCl conferred favorable hepatoprotective effects. These results demonstrated that BHe possessed suitable properties for use as a potent hepatoprotective medicinal food.
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http://dx.doi.org/10.1002/fsn3.893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341158PMC
January 2019

Bamboo Stems ( variety henosis) Containing Polyphenol Mixtures Activate Nrf2 and Attenuate Phenylhydrazine-Induced Oxidative Stress and Liver Injury.

Nutrients 2019 Jan 8;11(1). Epub 2019 Jan 8.

Laboratory of Toxicology, College of Pharmacy, Chosun University, Gwangju 61452, Korea.

This study was designed to investigate the hepatoprotective effect of bamboo stems using in vitro and in vivo experimental liver damage models. Ethyl acetate fraction of 80% ethanol extract of stem (PN3) containing polyphenols had a higher reporter gene activity as monitored by the activity of the NF-E2-related factor (Nrf2) antioxidant pathway in cells in comparison to extracts from other species and under other conditions. The Nrf2 was translocated from the cytosol to the nucleus in response to PN3, followed by induction of the Nrf2 target gene expression, including , , and in HepG2 cells. Phosphorylation of Nrf2 in HepG2 cells was enhanced in PN3, which was mediated by PKCδ, ERK, and p38 MAPK. Consequently, PN3 inhibited arachidonic acid (AA) + iron-induced reactive oxygen species generation and glutathione depletion, and, thus, highlighted their role in cytotoxicity. Treatment with major polyphenols of PN3, including catechin, chlorogenic acid, caffeic acid, and -coumaric acid, also improved AA + iron-mediated oxidative stress and, thus, improved cell viability. Treatment with phenylhydrazine in mice, i.e., the iron overload liver injury model, increased plasma alanine aminotransferase and aspartate aminotransferase levels and changed histological features in mice-a response that was almost completely blocked by PN3 administration. Moreover, PN3 extract mitigated phenylhydrazine-induced oxidative stress and inflammatory responses. Conclusively, PN3 can exert a hepatoprotective effect against iron overload-induced acute liver damage due to its antioxidant properties.
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http://dx.doi.org/10.3390/nu11010114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357197PMC
January 2019

Alleviates Oxidative Stress-Mediated Liver Injury through Activation of the CaMKK2-AMPK Signaling Pathway.

Evid Based Complement Alternat Med 2018 6;2018:8609285. Epub 2018 Nov 6.

Department of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.

(SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4-hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury.
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http://dx.doi.org/10.1155/2018/8609285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247439PMC
November 2018

Evaluation of in vitro anti-oxidant and anti-inflammatory activities of Korean and Chinese .

Nutr Res Pract 2018 Dec 16;12(6):486-493. Epub 2018 Nov 16.

Department of Food and Nutrition, College of BioNano Technology, Gachon University, 1342, Seongnam-daero, Sujeong-gu, Seongnam, Gyeonggi 13120, Korea.

Background/objectives: The honeysuckle berry (HB) contains ascorbic acid and phenolic components, especially anthocyanins, flavonoids, and low-molecular-weight phenolic acids. In order to examine the potential of HB as a hepatoprotective medicinal food, we evaluated the anti-oxidant and anti-inflammatory activities of Korean HB (HBK) and Chinese HB (HBC).

Materials/methods: Antioxidant and anti-inflammatory effects of the extracts were examined in HepG2 and RAW 264.7 cells, respectively. The anti-oxidant capacity was determined by DPPH, SOD, CAT, and ARE luciferase activities. The production of nitric oxide (NO) as an inflammatory marker was also evaluated. The -mediated mRNA levels of heme oxygenase-1 (), NAD(P)H dehydrogenase [quinone] 1 (), and glutamate-cysteine ligase catalytic subunit () were measured. The concentrations of HB extracts used were 3, 10, 30, 100, and 300 µg/mL.

Results: The radical scavenging activity of all HB extracts increased in a concentration-dependent manner ( < 0.01 or < 0.05). SOD ( < 0.05) and CAT ( < 0.01) activities were increased by treatment with 300 µg/mL of each HB extract, when compared to those in the control. NO production was observed in cells pretreated with 100 or 300 µg/mL of HBC and HBK ( < 0.01). Treatment with 300 µg/mL of HBC significantly increased ( < 0.01) and ( < 0.05) mRNA levels compared to those in the control. Treatment with 300 µg/mL of HBK ( < 0.05) and HBC ( < 0.01) also significantly increased the mRNA level compared to that in the control.

Conclusions: Thus, the Korean and Chinese HBs were found to possess favorable anti-oxidant and anti-inflammatory activities. and its related anti-oxidant genes were associated with both anti-oxidant and anti-inflammatory activities in HB-treated cells. Further studies are needed to confirm these effects.
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http://dx.doi.org/10.4162/nrp.2018.12.6.486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277309PMC
December 2018

Anti-obesity and fatty liver-preventing activities of Lonicera caerulea in high-fat diet-fed mice.

Int J Mol Med 2018 Dec 14;42(6):3047-3064. Epub 2018 Sep 14.

Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam, Gyeonggi 13120, Republic of Korea.

Blue honeysuckle (BH, Lonicera caerulea) is used as a traditional medicine in Russia, Japan and China, but is not commonly considered as an edible berry in Europe, USA or Korea. BH has been revealed to decrease serum cholesterol and triacylglycerol (triglyceride or TG) levels through the activation of AMP‑activated protein kinase (AMPK), thus it is expected to be a health functional food and pharmaceutical agent for the prevention of non‑alcoholic liver damage, in addition to effects as a suppressor of hyperlipidemia and as an anti‑obesity agent. In the present study, the pharmacological activity of BH extract (BHe) was observed in high‑fat diet (HFD)‑fed mice. Significant increases in fat pad weight, body weight, fat accumulation (body and abdominal fat density, and thickness of the periovarian and abdominal wall) and serum biochemical levels (aspartate transaminase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, γ‑glutamyltransferase, total cholesterol, low‑density lipoprotein and TG, with the exception of high‑density lipoprotein) were observed in HFD‑fed mice. In addition, increases in adipocyte hypertrophy, the area of steatohepatitis and hepatocyte hypertrophy were observed, whereas decreased zymogen content was identified upon histopathological observation. Increased deterioration of the endogenous antioxidant defense system (liver catalase, glutathione and superoxide dismutase) and hepatic lipid peroxidation was observed. In addition, there were decreases in hepatic glucokinase activity, AMPKα1 and AMPKα2 mRNA expression, adipose tissue uncoupling protein 2 expression, and adiponectin mRNA expression, increases in phosphoenolpyruvate carboxykinase and glucose‑6‑phosphatase activity, hepatic acetyl‑CoA carboxylase 1 mRNA expression, and the expression of leptin, CCAAT/enhancer‑binding protein (C/EBP) α, C/EBPβ and sterol‑regulatory‑element‑binding protein 1c mRNA in the periovarian tissue. Furthermore, non‑alcoholic fatty liver disease (NAFLD) and obesity were significantly inhibited by the continuous administration of BHe for 84 days. These results revealed that BHe may be a promising novel drug or functional food candidate for the treatment of obesity and NAFLD.
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http://dx.doi.org/10.3892/ijmm.2018.3879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202101PMC
December 2018

Induction of REDD1 via AP-1 prevents oxidative stress-mediated injury in hepatocytes.

Free Radic Biol Med 2018 08 14;124:221-231. Epub 2018 Jun 14.

College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea. Electronic address:

Regulated in development and DNA damage responses 1 (REDD1) is an inducible gene in response to various stresses, which functions as a negative regulator of the mammalian target of rapamycin protein kinase in complex 1. In the present study, we identified the role of REDD1 under the oxidative stress-mediated hepatocyte injury and its regulatory mechanism. REDD1 protein was increased in HO or tert-butylhydroperoxide (t-BHP)-treated hepatocytes HO also elevated REDD1 mRNA levels. This event was inhibited by antioxidants such as diphenyleneiodonium chloride, N-acetyl-L-cysteine, or butylated hydroxy anisole. Interestingly, we found that HO-mediated REDD1 induction was transcriptionally regulated by activator protein-1 (AP-1), and that overexpression of c-Jun increased REDD1 protein levels and REDD1 promoter-driven luciferase activity. Deletion of the putative AP-1 binding site in proximal region of the human REDD1 promoter significantly abolished REDD1 transactivation by c-Jun. A NF-E2-related factor 2 activator, tert-butylhydroquinone treatment also elevated REDD1 levels, but it was independent on NF-E2-related factor 2 activation. Furthermore, we observed that REDD1 overexpression attenuated HO or t-BHP-derived reactive oxygen species formation as well as cytotoxicity. Conversely, siRNA against REDD1 aggravated t-BHP-induced reactive oxygen species generation and cell death. In addition, we showed that REDD1 was induced by in vitro or in vivo ischemia/reperfusion model. Our results demonstrate that REDD1 induction by oxidative stress is mainly transcriptionally regulated by AP-1, and protects oxidative stress-mediated hepatocyte injury. These findings suggest REDD1 as a novel molecule that reduced susceptibility to oxidant-induced liver injury.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.06.014DOI Listing
August 2018

Amelioration of inflammatory responses by Socheongryong-Tang, a traditional herbal medicine, in RAW 264.7 cells and rats.

Int J Mol Med 2018 May 6;41(5):2771-2783. Epub 2018 Feb 6.

Medical Research Center-Globalization of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.

Socheongryong-Tang (SCRT) is a natural medicine prescription that has been mainly used in East Asia for the treatment of inflammatory disorders, including asthma and allergic rhinitis. The present study evaluated the anti-inflammatory effects of SCRT on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and in a rat model of carrageenan (CA)-induced paw edema. Levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and prostaglandin E2 (PGE2) in the culture supernatant were quantified and nitric oxide (NO) production was monitored. In addition, the effect of SCRT on the protein expression of nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) was assessed by western blot analysis. Furthermore, the effects of SCRT on acute inflammation in vivo and changes in the histomorphometry and histopathology of paw skin were observed using CA-treated rats. SCRT (1 mg/ml) inhibited the LPS-induced changes in the protein expression of NF-κB, JNK, ERK1/2, iNOS and COX-2, as well as the production of NO, PGE2 and cytokines. In the rat paw edema assay, administration of 1 g/kg of lyophilized powder obtained from the aqueous extracts of SCRT for 3 consecutive days inhibited the CA-induced increases in skin thickness, mast cell degranulation, and infiltration of inflammatory cells in the ventral and dorsal pedis skin within 4 h. These results demonstrated that SCRT exerts its anti-inflammatory activities in LPS-stimulated RAW 264.7 cells through decreasing the production of inflammatory mediators, including PGE2, NO and cytokines, via suppression of the NF-κB and JNK and ERK1/2 signaling pathways. In addition, the data of the CA-induced paw edema indicated an anti-edema effect of SCRT. SCRT (1 g/kg) reduced acute edematous inflammation through inhibition of mast cell degranulation and infiltration of inflammatory cells. Therefore, the present study provided scientific evidence for the anti-inflammatory activities of SCRT as well as the underlying mechanisms.
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http://dx.doi.org/10.3892/ijmm.2018.3465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846657PMC
May 2018

Epimedium koreanum Ameliorates Oxidative Stress-Mediated Liver Injury by Activating Nuclear Factor Erythroid 2-Related Factor 2.

Am J Chin Med 2018 12;46(2):469-488. Epub 2018 Feb 12.

* College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.

Oxidative stress induced by reactive oxygen species is the main cause of various liver diseases. This study investigated the hepatoprotective effect of Epimedium koreanum Nakai water extract (EKE) against arachidonic acid (AA)[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells and carbon tetrachloride (CCl-)-mediated acute liver injury in mice. Pretreatment with EKE (30 and 100[Formula: see text][Formula: see text]g/mL) significantly inhibited AA[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells by preventing changes in the expression of cleaved caspase-3 and poly(ADP-ribose) polymerase. EKE attenuated hydrogen peroxide production, glutathione depletion, and mitochondrial membrane dysfunction. EKE also increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), transactivated anti-oxidant response element harboring luciferase activity, and induced the expression of anti-oxidant genes. Furthermore, the cytoprotective effect of EKE against AA[Formula: see text][Formula: see text][Formula: see text]iron was blocked in Nrf2 knockout cells. Ultra-performance liquid chromatography analysis showed that EKE contained icariin, icaritin, and quercetin; icaritin and quercetin were both found to protect HepG2 cells from AA[Formula: see text][Formula: see text][Formula: see text]iron via Nrf2 activation. In a CCl-induced mouse model of liver injury, pretreatment with EKE (300[Formula: see text]mg/kg) for four consecutive days ameliorated CCl-mediated increases in serum aspartate aminotransferase activity, histological activity index, hepatic parenchyma degeneration, and inflammatory cell infiltration. EKE also decreased the number of nitrotyrosine-, 4-hydroxynonenal-, cleaved caspase-3-, and cleaved poly(ADP-ribose) polymerase-positive cells in hepatic tissues. These results suggest EKE is a promising candidate for the prevention or treatment of oxidative stress-related liver diseases via Nrf2 activation.
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http://dx.doi.org/10.1142/S0192415X18500246DOI Listing
August 2018

Combination of Pelargonium sidoides and Coptis chinensis root inhibits nuclear factor kappa B-mediated inflammatory response in vitro and in vivo.

BMC Complement Altern Med 2018 Jan 19;18(1):20. Epub 2018 Jan 19.

College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Republic of Korea.

Background: Pelargonium sidoides (PS) and Coptis chinensis root (CR) have traditionally been used to treat various diseases, including respiratory and gastrointestinal infections, dysmenorrhea, and hepatic disorders. The present study was conducted to evaluate the anti-inflammatory effects of a combination of PS and CR in vitro and in vivo.

Methods: The in vitro effects of PS + CR on the induction of inflammation-related proteins were evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The levels of nitric oxide (NO) and of inflammatory cytokines and prostaglandin E (PGE) were measured using the Griess reagent and enzyme-linked immunosorbent assay (ELISA) methods, respectively. The expression of inflammation-related proteins was confirmed by Western blot. Additionally, the effects of PS + CR on paw edema volume, skin thickness, and numbers of infiltrated inflammatory cells, mast cells, COX-2-, iNOS-, and TNF-α-immunoreactive cells in dorsum and ventrum pedis skin were evaluated in a rat model of carrageenan (CA)-induced paw edema.

Results: PS + CR significantly reduced production of NO, PGE and three pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6) and also decreased levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Treatment with PS + CR significantly reduced the protein expression levels of LPS-stimulated nuclear factor kappa B (NF-κB) and phosphorylated inhibitor of NF-κB (p-I-κBα). Additionally, PS + CR significantly inhibited the increases in paw swelling, skin thickness, infiltrated inflammatory cells, mast cell degranulation, COX-2-, iNOS-, and TNF-α-immunoreactive cells in the rat model of CA-induced acute edematous paw.

Conclusions: These results demonstrate that PS + CR exhibits anti-inflammatory properties through decreasing the production of pro-inflammatory mediators (NO, PGE, TNF-α, IL-1β, and IL-6), suppressing NF-κB signaling in LPS-induced RAW 264.7 cells. Additionally, the results of the CA-induced rat paw edema assay revealed an anti-edema effect of PS + CR. Furthermore, it is suggested that PS + CR also inhibits acute edematous inflammation by suppressing mast cell degranulation and inflammatory mediators (COX-2, iNOS, and TNF-α). Thus, PS + CR may be a potential candidate for the treatment of various inflammatory diseases, and it may also contribute to a better understanding of the molecular mechanisms underlying inflammatory response regulation.
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http://dx.doi.org/10.1186/s12906-018-2088-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775528PMC
January 2018

Blockade of nicotine sensitization by methanol extracts of Glycyrrhizae radix mediated via antagonism of accumbal oxidative stress.

BMC Complement Altern Med 2017 Nov 16;17(1):493. Epub 2017 Nov 16.

School of Mental Health, Qiqihar Medical University, 333 Bukuibei Street, Jianhua District, Qiqihar, 161006, China.

Background: We previously reported that a methanol extract of Glycyrrhizae radix (MEGR) blocked methamphetamine-induced locomotor sensitization and conditioned place preference in rats. In the present study, the effects of MEGR on repeated nicotine-induced locomotor sensitization and enhanced extracellular dopamine (DA) release in the nucleus accumbens (Nacc) were evaluated.

Methods: Male Sprague-Dawley rats received repeated administrations of nicotine (0.4 mg/kg, subcutaneous) or saline twice a day for 7 d and were challenged with nicotine 4 d after the last daily dosing. During the 4-d withdrawal period, the rats were treated once a day with MEGR (60 or 180 mg/kg/d). Extracellular DA levels were measured by in vivo microdialysis, the malondialdehyde levels and the activities of superoxide dismutase and catalase in the Nacc were biochemically evaluated, and the expression of antioxidant proteins was confirmed by Western blot assays. All data were assessed with analysis of variance tests followed by post-hoc comparison tests and p values <0.05 were considered statistically significant.

Results: The expression of repeated nicotine-induced locomotor sensitization was dose-dependently attenuated by MEGR, and 180 mg/kg/d MEGR significantly inhibited augmented accumbal DA release induced by a direct local challenge of nicotine. Moreover, 180 mg/kg/d MEGR reversed increases in malondialdehyde production, decreases in superoxide dismutase and catalase activities, and the reduced expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1 in the nicotine-sensitized Nacc.

Conclusions: These results suggest that MEGR inhibited nicotine-induced locomotion and dopaminergic sensitization via antioxidant action.
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http://dx.doi.org/10.1186/s12906-017-1999-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691594PMC
November 2017

Hemistepsin A ameliorates acute inflammation in macrophages via inhibition of nuclear factor-κB and activation of nuclear factor erythroid 2-related factor 2.

Food Chem Toxicol 2018 Jan 9;111:176-188. Epub 2017 Nov 9.

College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea. Electronic address:

Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata (Bunge) Bunge. We investigated the anti-inflammatory effects of HsA and sought to determine its mechanisms of action in macrophages. HsA pretreatment inhibited nitric oxide production, and reduced the expression of iNOS and COX-2 in Toll-like receptor ligand-stimulated RAW 264.7 cells. Additionally, HsA decreased the secretion of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated Kupffer cells as well as in RAW 264.7 cells. HsA inhibited phosphorylation of IKKα/β and degradation of IκBα, resulting in decreased nuclear translocation of nuclear factor-κB (NF-κB) and its transcriptional activity. Moreover, HsA phosphorylated nuclear factor erythroid 2-related factor 2 (Nrf2), increased expression levels of antioxidant genes, and attenuated LPS-stimulated HO production. Phosphorylation of p38 and c-Jun N-terminal kinase was required for HsA-mediated Nrf2 phosphorylation. In a D-galactosamine/LPS-induced liver injury model, HsA ameliorated D-galactosamine/LPS-induced hepatocyte degeneration and inflammatory cells infiltration. Moreover, immunohistochemical analyses using nitrotyrosine, 4-hydroxynonenal, and cleaved poly (ADP-ribose) polymerase antibodies revealed that HsA protected the liver from oxidative stress. Furthermore, HsA reduced the numbers of proinflammatory cytokine-positive cells in hepatic tissues. Thus, these results suggest HsA may be a promising natural product to manage inflammation-mediated tissue injuries through inhibition of NF-κB and activation of Nrf2.
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http://dx.doi.org/10.1016/j.fct.2017.11.014DOI Listing
January 2018

Manual Acupuncture at PC6 Ameliorates Acute Restraint Stress-Induced Anxiety in Rats by Normalizing Amygdaloid Noradrenergic Response.

Evid Based Complement Alternat Med 2017 16;2017:4351723. Epub 2017 Aug 16.

Department of Pharmacology, Mudanjiang Medical University, Mudanjiang 157011, China.

Acupuncture improves ethanol withdrawal-induced anxiety in rats in an acupoint-dependent manner. Thus, the present study investigated the effects of acupuncture on acute restraint stress- (ARS-) induced anxiety. Male rats were exposed to ARS for 3 h followed by acupuncture at either PC6 (Neiguan), HT7 (Shenmen), or a nonacupoint (tail) once a day for three consecutive days. Five minutes after the third acupuncture treatment, anxiety-like behavior was evaluated in an elevated plus maze (EPM). Additionally, plasma corticosterone (CORT) levels were measured by radioimmunoassay and the concentrations of norepinephrine (NE) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the central nucleus of the amygdala (CeA) were determined using high-performance liquid chromatography. Acupuncture at PC6, but not HT7 or a nonacupoint, attenuated anxiety-like behavior, but this attenuation was abolished by a postacupunctural intra-CeA infusion of NE. Acupuncture at PC6 also reduced the oversecretion of plasma CORT and inhibited increases in amygdaloid NE and MHPG induced by ARS. Further, Western blot analyses and real-time polymerase chain reaction assays revealed that acupuncture at PC6 prevented ARS-induced enhancements in the protein and mRNA expressions of tyrosine hydroxylase in the CeA. These results suggest that acupuncture performed specifically at acupoint PC6 reduces ARS-induced anxiety-like behavior by dampening amygdaloid noradrenergic responses.
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http://dx.doi.org/10.1155/2017/4351723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576413PMC
August 2017

Tryptanthrin prevents oxidative stress-mediated apoptosis through AMP-activated protein kinase-dependent p38 mitogen-activated protein kinase activation.

Arch Pharm Res 2017 Sep 21;40(9):1071-1086. Epub 2017 Aug 21.

College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea.

Tryptanthrin (6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline) has been reported to have a variety of pharmacological activities. Present study investigated the cytoprotective effects of tryptanthrin on arachidonic acid (AA) + iron-mediated oxidative stress and the molecular mechanisms responsible. In HepG2 cells, pretreatment with tryptanthrin inhibited the cytotoxic effect of AA + iron in a concentration-dependent manner. In addition, tryptanthrin prevented the changes in the levels of apoptosis-related proteins, and attenuated reactive oxygen species production, glutathione depletion, and mitochondrial membrane impairment induced by AA + iron. Mechanistic investigations showed that tryptanthrin increased the phosphorylations of AMP-activated protein kinase (AMPK) and of p38 mitogen-activated protein kinase (p38). Furthermore, inhibition of AMPK or p38 reduced the ability of tryptanthrin to prevent AA + iron-induced cell death and mitochondrial dysfunction. Transfection experiments using AMPK mutants indicated that p38 phosphorylation by tryptanthrin was dependent on AMPK activation. In a phenylhydrazine-induced acute liver injury model, tryptanthrin decreased serum levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin in mice. Additionally, tryptanthrin reduced numbers of degenerating hepatocytes, infiltrating inflammatory cells, 4-hydroxynonenal-, and nitrotyrosine-positive cells in hepatic tissues. Thus, these results suggest tryptanthrin has therapeutic potential to protect cells from oxidative injury via AMPK-dependent p38 activation.
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http://dx.doi.org/10.1007/s12272-017-0947-5DOI Listing
September 2017

Anticancer effects of an extract from the scallop on MCF-7 human breast carcinoma cells.

Oncol Lett 2017 Aug 20;14(2):2207-2217. Epub 2017 Jun 20.

Institute of Marine Biotechnology, Pusan National University, Busan 609-735, Republic of Korea.

, is a species of scallop and a marine bivalve mollusk. In traditional East Asian medicine, scallop meat is used as a drug for the treatment of diabetes, pollakisuria, and indigestion. The present study was conducted in order to examine the potential anticancer effects of scallop flesh extract (SE) on MCF-7 human breast cancer cells. An MTT assay was used to evaluate cell viability and flow cytometry was used for the assessment of cell cycle distribution and apoptosis. The alteration in protein expression level was determined by western blot analysis, and the amounts of docosahexaenoic acid and eicosapentaenoic acid in the SE were measured by gas chromatography. SE inhibited the growth of MCF-7 human breast cancer cells in a dose-dependent manner by inducing G0/G1 phase arrest. The cell cycle arrest was associated with the upregulation of p53 and p21, and downregulation of G1 phase-associated cyclin D1/cyclin-dependent kinase (Cdk) 4 and cyclin E1/Cdk 2. In addition, SE-mediated cell cycle arrest was associated with the promotion of apoptosis, as indicated by the expression of apoptosis-associated proteins and changes in nuclear morphology. SE appeared to induce the mitochondrial apoptotic cascade, as indicated by a decreased expression of Bcl-2, activation of Bcl-2 associated X protein, release of cytochrome c, decrease in procaspase-3, and an increase in cleaved-poly (ADP-ribose) polymerase (PARP). Furthermore, the expression levels of Fas-associated via death domain and cleaved caspase-8 were increased in a SE dose-dependent manner. Taken together, these results suggest that the intrinsic and extrinsic pathways of apoptosis are associated with the anticancer effects of SE on MCF-7 cells. Thus, SE may be a suitable candidate for the treatment and prevention of human breast cancer.
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http://dx.doi.org/10.3892/ol.2017.6424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530092PMC
August 2017

20-Protopanaxadiol, an aglycosylated ginsenoside metabolite, induces hepatic stellate cell apoptosis through liver kinase B1-AMP-activated protein kinase activation.

J Ginseng Res 2017 Jul 25;41(3):392-402. Epub 2017 Jan 25.

MRC-GHF, Department of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan, Republic of Korea.

Background: Previously, we reported that Korean Red Ginseng inhibited liver fibrosis in mice and reduced the expressions of fibrogenic genes in hepatic stellate cells (HSCs). The present study was undertaken to identify the major ginsenoside responsible for reducing the numbers of HSCs and the underlying mechanism involved.

Methods: Using LX-2 cells (a human immortalized HSC line) and primary activated HSCs, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assays were conducted to examine the cytotoxic effects of ginsenosides. HO productions, glutathione contents, lactate dehydrogenase activities, mitochondrial membrane permeabilities, apoptotic cell subpopulations, caspase-3/-7 activities, transferase dUTP nick end labeling (TUNEL) staining, and immunoblot analysis were performed to elucidate the molecular mechanism responsible for ginsenoside-mediated cytotoxicity. Involvement of the AMP-activated protein kinase (AMPK)-related signaling pathway was examined using a chemical inhibitor and small interfering RNA (siRNA) transfection.

Results And Conclusion: Of the 11 ginsenosides tested, 20-protopanaxadiol (PPD) showed the most potent cytotoxic activity in both LX-2 cells and primary activated HSCs. Oxidative stress-mediated apoptosis induced by 20-PPD was blocked by -acetyl-l-cysteine pretreatment. In addition, 20-PPD concentration-dependently increased the phosphorylation of AMPK, and compound C prevented 20-PPD-induced cytotoxicity and mitochondrial dysfunction. Moreover, 20-PPD increased the phosphorylation of liver kinase B1 (LKB1), an upstream kinase of AMPK. Likewise, transfection of LX-2 cells with LKB1 siRNA reduced the cytotoxic effect of 20-PPD. Thus, 20-PPD appears to induce HSC apoptosis by activating LKB1-AMPK and to be a therapeutic candidate for the prevention or treatment of liver fibrosis.
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http://dx.doi.org/10.1016/j.jgr.2017.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489770PMC
July 2017