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Shin MR, Lee JH, Lee JA, Kim MJ, Park HJ, Park BW, Seo SB, Roh SS. Immunomodulatory and anti-inflammatory effects of Phellinus linteus mycelium. BMC Complement Med Ther 2021; 21:269. [PMID: 34702240 PMCID: PMC8547106 DOI: 10.1186/s12906-021-03441-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 10/08/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The present study extensively aimed to evaluate the underlying mechanism of the immunomodulatory and anti-inflammatory effects of Phellinus linteus mycelium (PLM). METHODS To assess whether PLM influences the production of markers related to inflammation, Lipopolysaccharide (LPS)-stimulated RAW264.7 cells were treated with PLM (50, 100, 200, and 500 μg/mL). Splenocyte, thymus, peritoneal exudate cells (PEC), and peripheral blood mononuclear cells (PBMC) were isolated from the Balb/c mice treated with Korean red ginseng or PLM once a day for 5 weeks. Moreover, all mice except normal mice were stimulated with 10% proteose peptone (PP) treated 3 days before the sacrifice and 2% starch treated 2 days before the sacrifice. Subsequently, the cytotropic substance was evaluated by using flow cytometry analysis and ELISA assay. RESULTS PLM200 treatment significantly suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and inhibited the release of proinflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α dose-dependently in the LPS-stimulated RAW264.7 cells. PLM200 supplementation showed a significant increase in IL-2, IL-12, and interferon (IFN)-γ production and upregulated the ratio of IFN-γ (T-helper type 1, Th1) to IL-4 (T-helper type 2, Th2) in splenocytes. After PLM200 treatment, the significant elevation of CD4+CD25+, CD4+&CD8+, and CD4+CD69+ treatment were detected in thymus. Moreover, CD4+ and CD4+CD69+ in PBMC and CD69+ in PEC were also shown in a significant increase. CONCLUSIONS Taken together, these results showed an immunomodulatory effect of PLM about an elevated INF-γ/IL4 ratio, as an index of Th1/Th2, as well as the anti-inflammatory effect in the LPS-stimulated RAW264.7 cells. Therefore, our findings demonstrate that PLM possesses immunostimulatory and anti-inflammatory effects.
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Affiliation(s)
- Mi-Rae Shin
- Department of Herbology, College of Korean Medicine, Daegu Haany University, 136, Shinchendong–ro, Suseong-gu, Deagu, 42158 Republic of Korea
| | - Ji Hye Lee
- College of Korean Medicine, Semyung University, 65, Semyung-Ro, Jecheon, Chungbuk 27136 Republic of Korea
| | - Jin A Lee
- Department of Herbology, College of Korean Medicine, Daegu Haany University, 136, Shinchendong–ro, Suseong-gu, Deagu, 42158 Republic of Korea
| | - Min Ju Kim
- Department of Herbology, College of Korean Medicine, Daegu Haany University, 136, Shinchendong–ro, Suseong-gu, Deagu, 42158 Republic of Korea
| | - Hae-Jin Park
- DHU Bio Convergence Testing Center, 1, Hanuidae-ro, Gyeongsan-si, Gyeongsangbuk-do 38610 Republic of Korea
| | - Byeong Wook Park
- Hankook Shinyak Pharm. Co. Ltd, 39-83 Zhongshan-gil, Yangchon-myeon, Nonsan-si, Chungcheongnam-do 33023 Republic of Korea
| | - Seung Bo Seo
- Hankook Shinyak Pharm. Co. Ltd, 39-83 Zhongshan-gil, Yangchon-myeon, Nonsan-si, Chungcheongnam-do 33023 Republic of Korea
| | - Seong-Soo Roh
- Department of Herbology, College of Korean Medicine, Daegu Haany University, 136, Shinchendong–ro, Suseong-gu, Deagu, 42158 Republic of Korea
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Duan J, Chen H, Li Y, Xu D, Li X, Zhang Z, Cheng J, Yang L, Li Q. 17β-Estradiol Enhances Porcine Meiosis Resumption from Autophagy-Induced Gap Junction Intercellular Communications and Connexin 43 Phosphorylation via the MEK/ERK Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:11847-11855. [PMID: 34609142 DOI: 10.1021/acs.jafc.1c04212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Estrogen and its analogues are ubiquitous in agricultural environments, with large biological functions of oocyte development. Gap junction intercellular communications (GJICs) are the structural basis in cumulus-oocyte complexes (COCs) and regulate oocyte maturation and developmental material transport through a number of pathways. This study mainly determines the effect and potential mechanism of estrogen (17β-estradiol) in regulating GJICs in porcine COCs. In our study, 17β-estradiol increased porcine nuclear maturation in a time-dependent manner. The analysis revealed that 17β-estradiol upregulated the autophagy in COCs during in vitro maturation. In contrast with the control, 17β-estradiol decreased GJICs in a time-dependent manner between cumulus cells and oocytes, while it was consistent with the control group at 24 h. Carbenoxolone (CBX) blocks GJICs as a negative control group used in our system. Autophagy inhibitor autophinib decreased oocyte maturation, and the reduced nuclear maturation treated with autophinib was abolished by 17β-estradiol. Besides, the upregulation effect of autophinib on GJICs and transzonal projections (TZPs) was decreased by 17β-estradiol. 17β-Estradiol could reduce serine 368 phosphorylation of connexin 43 (Cx43) protein by autophinib in porcine COCs. These results were dependent upon the MEK/ERK signaling pathway. Furthermore, 17β-estradiol-induced GJICs and Cx43 phosphorylation were inhibited by autophinib or the MEK/ERK pathway inhibitors (Trametinib and FR 180204), indicating that 17β-estradiol regulated GJICs through the MEK/ERK signaling pathway. In conclusion, 17β-estradiol improves the autophagy-mediated nuclear maturation with downregulating GJICs and TZPs in porcine COCs. Such an effect occurs by phosphorylation of Cx43, which was regulated via the MEK/ERK signaling pathway.
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Affiliation(s)
- Jiaxin Duan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, Shaanxi 712100, People's Republic of China
| | - Huali Chen
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, Sichuan 621000, People's Republic of China
| | - Yuan Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, Shaanxi 712100, People's Republic of China
| | - Dejun Xu
- College of Animal Science and Technology, Southwest University, Chongqing, Sichuan 400000, People's Republic of China
| | - Xiaoya Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, Shaanxi 712100, People's Republic of China
| | - Zelin Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, Shaanxi 712100, People's Republic of China
| | - Jianyong Cheng
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, Shaanxi 712100, People's Republic of China
| | - Li Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, Shaanxi 712100, People's Republic of China
| | - Qingwang Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, Shaanxi 712100, People's Republic of China
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Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing. Int J Mol Sci 2021; 22:ijms22168977. [PMID: 34445682 PMCID: PMC8396440 DOI: 10.3390/ijms22168977] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/30/2021] [Accepted: 07/31/2021] [Indexed: 12/27/2022] Open
Abstract
Dysregulation of gap junction intercellular communication (GJIC) is recognized as one of the key hallmarks for identifying non-genotoxic carcinogens (NGTxC). Currently, there is a demand for in vitro assays addressing the gap junction hallmark, which would have the potential to eventually become an integral part of an integrated approach to the testing and assessment (IATA) of NGTxC. The scrape loading-dye transfer (SL-DT) technique is a simple assay for the functional evaluation of GJIC in various in vitro cultured mammalian cells and represents an interesting candidate assay. Out of the various techniques for evaluating GJIC, the SL-DT assay has been used frequently to assess the effects of various chemicals on GJIC in toxicological and tumor promotion research. In this review, we systematically searched the existing literature to gather papers assessing GJIC using the SL-DT assay in a rat liver epithelial cell line, WB-F344, after treating with chemicals, especially environmental and food toxicants, drugs, reproductive-, cardio- and neuro-toxicants and chemical tumor promoters. We discuss findings derived from the SL-DT assay with the known knowledge about the tumor-promoting activity and carcinogenicity of the assessed chemicals to evaluate the predictive capacity of the SL-DT assay in terms of its sensitivity, specificity and accuracy for identifying carcinogens. These data represent important information with respect to the applicability of the SL-DT assay for the testing of NGTxC within the IATA framework.
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Dietary calcium deficiency suppresses follicle selection in laying ducks through mechanism involving cyclic adenosine monophosphate-mediated signaling pathway. Animal 2020; 14:2100-2108. [PMID: 32367795 DOI: 10.1017/s1751731120000907] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Ovarian follicle selection is a natural biological process in the pre-ovulatory hierarchy in birds that drives growing follicles to be selected within the ovulatory cycle. Follicle selection in birds is strictly regulated, involving signaling pathways mediated by dietary nutrients, gonadotrophic hormones and paracrine factors. This study aimed to test the hypothesis that dietary Ca may participate in regulating follicle selection in laying ducks through activating the signaling pathway of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/extracellular signal-regulated kinase (ERK), possibly mediated by gonadotrophic hormones. Female ducks at 22 weeks of age were initially fed one of two Ca-deficient diets (containing 1.8% or 0.38% Ca) or a Ca-adequate control diet (containing 3.6% Ca) for 67 days (depletion period), then all birds were fed the Ca-adequate diet for an additional 67 days (repletion period). Compared with the Ca-adequate control, ducks fed 0.38% Ca during the depletion period had significantly decreased (P < 0.05) numbers of hierarchical follicles and total ovarian weight, which were accompanied by reduced egg production. Plasma concentration of FSH was decreased by the diet containing 1.8% Ca but not by that containing 0.38%. The ovarian content of cAMP was increased with the two Ca-deficient diets, and phosphorylation of PKA and ERK1/2 was increased with 0.38% dietary Ca. Transcripts of ovarian estradiol receptor 2 and luteinizing hormone receptor (LHR) were reduced in the ducks fed the two Ca-deficient diets (P < 0.05), while those of the ovarian follicle stimulating hormone receptor (FSHR) were decreased in the ducks fed 0.38% Ca. The transcript abundance of ovary gap junction proteins, A1 and A4, was reduced with the Ca-deficient diets (P < 0.05). The down-regulation of gene expression of gap junction proteins and hormone receptors, the increased cAMP content and the suppressed hierarchical follicle numbers were reversed by repletion of dietary Ca. These results indicate that dietary Ca deficiency negatively affects follicle selection of laying ducks, independent of FSH, but probably by activating cAMP/PKA/ERK1/2 signaling pathway.
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Xu D, He H, Liu D, Geng G, Li Q. A novel role of SIRT2 in regulating gap junction communications via connexin-43 in bovine cumulus-oocyte complexes. J Cell Physiol 2020; 235:7332-7343. [PMID: 32039484 DOI: 10.1002/jcp.29634] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 01/30/2020] [Indexed: 01/04/2023]
Abstract
SIRT2, the predominantly cytosolic sirtuin, plays important role in multiple biological processes, including metabolism, stress response, and aging. However, the function of SIRT2 in gap junction intercellular communications (GJICs) of cumulus-oocyte complexes (COCs) is not yet known. The purpose of the present study was to evaluate the effect and underlining mechanism of SIRT2 on GJICs in COCs. Here, we found that treatment with SIRT2 inhibitors (SirReal2 or TM) inhibited bovine oocyte nuclear maturation. Further analysis revealed that SIRT2 inactivation disturbed the GJICs of COCs during in vitro maturation. Correspondingly, both the Cx43 phosphorylation levels and MEK/MER signaling pathways were induced by SIRT2 inhibition. Importantly, SIRT2-mediated Cx43 phosphorylation was completely abolished by treatment with MEK1/2 inhibitor (Trametinib). Furthermore, treatment with SIRT2 inhibitors resulted in the high levels of MEK1/2 acetylation. Functionally, downregulating the MER/ERK pathways with inhibitors (Trametinib or SCH772984) could attenuate the closure of GJICs caused by SIRT2 inactivation in partly. In addition, inhibition of SIRT2 activity significantly decreased the membrane and zona pellucida localization of Cx43 by upregulating the levels of Cx43 acetylation. Taken together, these results demonstrated a novel role that SIRT2 regulates GJICs via modulating the phosphorylation and deacetylation of Cx43 in COCs.
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Affiliation(s)
- Dejun Xu
- Department of Zoology and Animal Reproduction, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Huanshan He
- Department of Zoology and Animal Reproduction, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Dingbang Liu
- Department of Zoology and Animal Reproduction, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Guoxia Geng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Qingwang Li
- Department of Zoology and Animal Reproduction, College of Animal Science and Technology, Northwest A&F University, Yangling, China
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Lin XF, Luo JW, Liu G, Zhu YB, Jin Z, Lin X. Genetic mutation of familial dilated cardiomyopathy based on next‑generation semiconductor sequencing. Mol Med Rep 2018; 18:4271-4280. [PMID: 30221713 PMCID: PMC6172371 DOI: 10.3892/mmr.2018.9455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 08/02/2018] [Indexed: 01/10/2023] Open
Abstract
Dilated cardiomyopathy (DCM) is a complex myocardial disease of multifactorial etiologies, including enlarged cardiac chambers and contractile dysfunction. It has been suggested that the inheritance of DCM‑associated mutations predominates its onset. Therefore, the present study investigated the pathogenesis of DCM via pedigree analysis and genetic diagnosis by massive whole‑exome screening, and targeted exon capture. To study the familial gene‑phenotype association, the exon and splice sites of 325 hereditary disease‑associated genes in the proband with familial dilated cardiomyopathy (FDC), including 61 cardiac disease‑associated genes, such as the lamins A/C (LMNA), were analyzed by ultra‑high multiplex polymerase chain reaction and the Ion AmpliSeq™ Inherited Disease Panel. The present study also conducted Sanger DNA Sequencing for family members with global minor allele frequencies <1% to verify potential pathogenic mutation sites. A total of three rare missense mutations were detected, including heterozygous c.244G>A in LMNA, c.546C>G in potassium voltage‑gated channel subfamily KQT (KCNQ4) and c.1276G>A in EYA transcriptional coactivator and phosphatase 1 (EYA1), indicating a glutamic acid to lysine substitution at amino acid 82 (p.E82K) in LMNA, a p.F182L in KCNQ4 (a mutation associated with pathogenic deafness) and p.G426S in EYA1 (associated with Branchiootorenal syndrome 1 and Branchiootic syndrome 1 pathogenesis). In the present study, a carrier with slight hearing impairment was detected in the family analyzed; however, no patients with deafness or branchiootorenal syndrome were observed. LMNA p.E82K revealed SIFT and PolyPhen‑2 scores of 0 and 1, respectively. In the second generation, 3 patients with DCM underwent permanent pacemaker implantation due to sick sinus syndrome, atrioventricular block and unstable cardiac electrophysiology. The present study suggested that LMNA p.E82K may contribute to the pathogenesis of FDC and concomitant atrioventricular block. At present, only three families with DCM resulting from similar mutations have been reported. The present study demonstrated the strong pathogenic effects of LMNA p.E82K on DCM.
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Affiliation(s)
- Xin-Fu Lin
- Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Jie-Wei Luo
- Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Gui Liu
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Yao-Bin Zhu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Zhao Jin
- Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Xing Lin
- Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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Yu T, Ganapathy S, Shen L, Peng B, Kim SH, Makriyannis A, Chen C. A lethal synergy induced by phellinus linteus and camptothecin11 in colon cancer cells. Oncotarget 2018; 9:6308-6319. [PMID: 29464074 PMCID: PMC5814214 DOI: 10.18632/oncotarget.23918] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 12/11/2017] [Indexed: 12/20/2022] Open
Abstract
Side effects of anti-cancer drugs are always challenging for effective cancer treatments. The polysaccharides extracted from Phellinus linteus (PLGL) have been widely used in treating cancers. However, the mechanism by which PLGL antagonizes cancerous growth has not been fully investigated. The current study demonstrated that human colon cancer HCT116 and HT29 cells became highly susceptible to cell death when being co-treated with PLGL and low dose of camptothecin11 (CPT11, a topoisomerase inhibitor-based drug), the efficacy of which was comparable as that generated by the high dose of CPT11. However, the co-treatment, unlike high doses of CPT11, was not cytotoxic to the control immortalized colon Caco-2 cells. The co-treatment caused high percentages of the colon cancer cells to accumulate in S phase of the cell cycle, which was also seen in the same cells received the high dose of CPT11 treatment. Chk1 was phosphorylated, and then rapidly degraded in the cancer cells treated with the high dose of CPT11 or co-treatment, but not in the cells treated with PLGL alone or low doses of CPT11. PLGL appeared enhancing CPT11 inhibitory effect on topoisomerase, and Chk1 degradatopm in the cancer cells. Furthermore, cyclin E (clnE) became unstable at the transcription level in co-treated or PLGL-treated colon cancer cells. The data suggested that PLGL functions in two ways to achieve its lethal synergy with CPT11 in colon cancer cells. Our findings are of potential significance as PLGL represents a promising medicine for overcoming the side effects of CPT11 and perhaps also for improving other CPTs-based regimens.
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Affiliation(s)
- Tianqi Yu
- The Center for Drug Discovery, Northeastern University, Boston, MA, USA
| | | | - Ling Shen
- The Center for Drug Discovery, Northeastern University, Boston, MA, USA
| | - Bo Peng
- The Center for Drug Discovery, Northeastern University, Boston, MA, USA
| | - Sung-Hoon Kim
- Cancer Molecular Targeted Herbal Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | | | - Changyan Chen
- The Center for Drug Discovery, Northeastern University, Boston, MA, USA
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Anti-Inflammatory Phenolic Metabolites from the Edible Fungus Phellinus baumii in LPS-Stimulated RAW264.7 Cells. Molecules 2017; 22:molecules22101583. [PMID: 28934155 PMCID: PMC6151649 DOI: 10.3390/molecules22101583] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 09/20/2017] [Accepted: 09/20/2017] [Indexed: 11/17/2022] Open
Abstract
The edible fungus Phellinus baumii Pilat (Hymenochaetaceae) has been used in Korean traditional medicines for strengthening health and prolonging life. An extract of the fruiting bodies of P. baumii was subjected to bioassay-guided fractionation based on its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The resulting fractions were chemically investigated, leading to isolation of three phenolic compounds (1-3), a sesquiterpene (4), two steroids (5-6), a fatty acid (7), and a cerebroside (8). Spectroscopic analyses including 1D and 2D NMR spectroscopy and LC/MS were used to determine their chemical structures. Compounds 2, 4, 5, 7 and 8 were identified in P. baumii for the first time. Since all compounds were isolated from active fractions with anti-inflammatory activity, their ability to inhibit LPS-stimulated nitric oxide (NO) production in RAW264.7 cells were evaluated in vitro. Compounds 1, 2, 3, 5 and 7 inhibited LPS-stimulated NO production, and compounds 1-3 had IC50 values <10 μM. Treatment of LPS-stimulated RAW264.7 cells with compounds 1-3 inhibited phosphorylation of IKKα and IκBα. In addition, treatment of compounds 1-3 reduced LPS-induced increases of nuclear factor-kappa B (NF-κB) p65, iNOS and COX-2 protein expressions. Collectively, compounds 1-3 inhibited NF-κB-dependent inflammation in RAW264.7 cells. Thus, P. baumii is a potential source of natural anti-inflammatory agents, and active compounds 1-3 could be promising lead compounds for the development of novel anti-inflammatory agents.
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Prevention of TGF-β-induced early liver fibrosis by a maleic acid derivative anti-oxidant through suppression of ROS, inflammation and hepatic stellate cells activation. PLoS One 2017; 12:e0174008. [PMID: 28384213 PMCID: PMC5383026 DOI: 10.1371/journal.pone.0174008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 03/01/2017] [Indexed: 11/19/2022] Open
Abstract
Current anti-fibrotic effect of antioxidants in vivo is disappointing due probably to the fact that once liver fibrogenesis is established it is too advanced to be reversed by anti-oxidation mechanism. We consider antioxidant may only act on the early phase of fibrogenesis. Thus, we had previously established an early liver fibrosis animal model using an inducible expression vector (pPK9a), which contains TGF-β gene and was hydro-dynamically transferred into mice to induce a transient liver fibrosis. TGF-β1 has been well documented to up-regulate the expression of α2(1) collagen (Col 1A2) gene in the liver via the reactive oxygen species (ROS); the process triggers inflammation, leading to hepatic stellate cells (HSC) activation and liver fibrogenesis. Using our animal model and ROS, cyclooxygenase-2 (Cox-2) and Col 1A2 promoter assays as screening targets, we report here that a maleic acid derivative isolated from the Antrodia camphorata mycelium strongly decreases ROS production, promoter activity of Cox-2 and Col 1A2, intracellular calcium, expression of alpha-smooth muscle actin (α-SMA), Smad4-p-Smad2/3 co-localization in cell nucleus and the DNA binding activity of Sp1. Our results suggest that the maleic acid derivative prevents liver fibrosis at an early phase both in vitro and in vivo through the inhibition of ROS, inflammation and the activation of HSC.
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Chen H, Tian T, Miao H, Zhao YY. Traditional uses, fermentation, phytochemistry and pharmacology of Phellinus linteus: A review. Fitoterapia 2016; 113:6-26. [PMID: 27343366 DOI: 10.1016/j.fitote.2016.06.009] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 06/18/2016] [Accepted: 06/20/2016] [Indexed: 02/02/2023]
Abstract
Medicinal mushroom Phellinus linteus ("Sanghuang" in Chinese, ) is a famous fungus which is widely used in China, Korea, and other Asian countries. As a traditional Chinese medicine with a 2000-year long history, medicinal applications of Phellinus linteus mainly include treating hemorrhage, hemostasis and diseases related to female menstruation according to Chinese clinical empirical practice. A number of studies reported Phellinus linteus possessed good therapeutic effects on various ailments including tumor, diabetes, inflammation, obesity, etc. The present paper comprehensively reviewed the traditional uses, fermentation, constituent and pharmacology of Phellinus linteus based on scientific literature as well as critical analysis of the research. This review aimed to provide latest information and new foundations and directions for further investigations on Phellinus linteus. All available information about Phellinus linteus was supplied by library database and electronic search (CNKI, Google Scholar, ScienceDirect, Web of Science, PubMed, etc.). Some local and ancient books as well as brilliant scholars were also important information resources. Improvement of fermentation techniques promoted the production of Phellinus linteus. Studies of constituents showed the main chemical composition of Phellinus linteus included polysaccharides, flavones, triterpenes, aromatic acids, amino acids, etc. and polysaccharides were found to account for the largest proportion. Pharmacological researches revealed Phellinus linteus possessed a variety of biological activities including anti-cancer, immuno-regulation, anti-diabetes, anti-oxidation and anti-inflammation. Based on these summarized information, this review was presented to provide helpful references and beneficial directions for future studies of Phellinus linteus.
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Affiliation(s)
- Hua Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China
| | - Ting Tian
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China
| | - Hua Miao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China
| | - Ying-Yong Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.
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Steuer A, Schmidt A, Labohá P, Babica P, Kolb JF. Transient suppression of gap junctional intercellular communication after exposure to 100-nanosecond pulsed electric fields. Bioelectrochemistry 2016; 112:33-46. [PMID: 27439151 DOI: 10.1016/j.bioelechem.2016.07.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 07/07/2016] [Accepted: 07/08/2016] [Indexed: 12/18/2022]
Abstract
Gap junctional intercellular communication (GJIC) is an important mechanism that is involved and affected in many diseases and injuries. So far, the effect of nanosecond pulsed electric fields (nsPEFs) on the communication between cells was not investigated. An in vitro approach is presented with rat liver epithelial WB-F344 cells grown and exposed in a monolayer. In order to observe sub-lethal effects, cells were exposed to pulsed electric fields with a duration of 100ns and amplitudes between 10 and 20kV/cm. GJIC strongly decreased within 15min after treatment but recovered within 24h. Gene expression of Cx43 was significantly decreased and associated with a reduced total amount of Cx43 protein. In addition, MAP kinases p38 and Erk1/2, involved in Cx43 phosphorylation, were activated and Cx43 became hyperphosphorylated. Immunofluorescent staining of Cx43 displayed the disassembly of gap junctions. Further, a reorganization of the actin cytoskeleton was observed whereas tight junction protein ZO-1 was not significantly affected. All effects were field- and time-dependent and most pronounced within 30 to 60min after treatment. A better understanding of a possible manipulation of GJIC by nsPEFs might eventually offer a possibility to develop and improve treatments.
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Affiliation(s)
- Anna Steuer
- Leibniz Institute for Plasma Science and Technology, Greifswald, Germany
| | - Anke Schmidt
- Leibniz Institute for Plasma Science and Technology, Greifswald, Germany
| | - Petra Labohá
- Leibniz Institute for Plasma Science and Technology, Greifswald, Germany; Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Pavel Babica
- Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Juergen F Kolb
- Leibniz Institute for Plasma Science and Technology, Greifswald, Germany.
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Liu MM, Zeng P, Li XT, Shi LG. Antitumor and immunomodulation activities of polysaccharide from Phellinus baumii. Int J Biol Macromol 2016; 91:1199-205. [PMID: 27370747 DOI: 10.1016/j.ijbiomac.2016.06.086] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 06/24/2016] [Accepted: 06/27/2016] [Indexed: 11/26/2022]
Abstract
A homogeneous polysaccharide (PPB) was purified from fruiting bodies of Phellinus baumii. And in vitro antitumor and immunomodulation activities were investigated on HeLa, SGC-7901 and RAW264.7 cell lines. PPB inhibited the proliferation of HeLa and SGC-7901 cells significantly, and flow cytometric studies revealed that PPB could mediate the cell cycle in the G0/G1 and S phases. Furthermore, PPB could promote the growth and phagocytosis of RAW264.7 cells, activate the secretion of cytokines such as TNF-α and IL-6, which indicated that PPB had low toxicity. The results make PPB as a candidate adjuvant in cancer therapy.
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Affiliation(s)
- Ming-Ming Liu
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Peng Zeng
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiao-Tong Li
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lian-Gen Shi
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.
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Kim JS, Lee WM, Rhee HC, Kim S. Red paprika (Capsicum annuum L.) and its main carotenoids, capsanthin and β-carotene, prevent hydrogen peroxide-induced inhibition of gap-junction intercellular communication. Chem Biol Interact 2016; 254:146-55. [PMID: 27154496 DOI: 10.1016/j.cbi.2016.05.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 04/20/2016] [Accepted: 05/02/2016] [Indexed: 11/23/2022]
Abstract
This study was conducted to investigate the protective effect of red paprika extract (RPE) and its main carotenoids, namely, capsanthin (CST) and β-carotene (BCT), on the H2O2-induced inhibition of gap-junction intercellular communication (GJIC) in WB-F344 rat liver epithelial cells (WB cells). We found that pre-treatment with RPE, CST and BCT protected WB cells from H2O2-induced inhibition of GJIC. RPE, CST and BCT not only recovered connexin 43 (Cx43) mRNA expression but also prevented phosphorylation of Cx43 protein by H2O2 treatment. RPE attenuated the phosphorylation of ERK, p38 and JNK, whereas pre-treatment with CST and BCT only attenuated the phosphorylation of ERK and p38 and did not affect JNK in H2O2-treated WB cells. RPE, CST and BCT significantly suppressed the formation of reactive oxygen species (ROS) in H2O2-treated cells compared to untreated WB cells. These results suggest that dietary intake of red paprika might be helpful for lowering the risk of diseases caused by oxidative stress.
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Affiliation(s)
- Ji-Sun Kim
- Department of Food and Nutrition in Human Ecology, College of Natural Sciences, Korea National Open University, 86, Daehak-ro, Jongno-gu, Seoul, 03078, Republic of Korea
| | - Woo-Moon Lee
- Vegetable Research Division, National Institute of Horticultural & Herbal Science, RDA, Wanju, 55365, Republic of Korea
| | - Han Cheol Rhee
- Protected Horticulture Research Institute, National Institute of Horticultural & Herbal Science, RDA, Haman, 52054, Republic of Korea
| | - Suna Kim
- Department of Food and Nutrition in Human Ecology, College of Natural Sciences, Korea National Open University, 86, Daehak-ro, Jongno-gu, Seoul, 03078, Republic of Korea.
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Species identity of Phellinus linteus (sanghuang) extensively used as a medicinal mushroom in Korea. J Microbiol 2016; 54:290-5. [PMID: 27033204 DOI: 10.1007/s12275-016-5520-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 02/23/2016] [Accepted: 03/03/2016] [Indexed: 10/22/2022]
Abstract
Sanghuang is a medicinal mushroom that has gained particular attention in Korea. It has been extensively studied for the past few decades as a natural immune booster and cancer suppressor. Although the scientific name, Phellinus linteus, has been commonly used to refer to the sanghuang mushroom, the species identity of sanghuang has been called into question due to the ambiguity of its circumscription and the inadequacy of morphological distinctions within allied species. Because the species concept of sanghuang has been elucidated by recent molecular phylogenetic studies, it has become necessary to clarify the taxonomic positions of sanghuang strains extensively utilized in Korea. We conducted a phylogenetic analysis of 74 strains belonging to the P. linteus-baumii complex based on ITS nrDNA sequences. Parental stains of sanghuang varieties formally registered in the Korea Seed & Variety Service, including ASI 26046 (Corea sanghuang), 26114 (Boolro), and 26115 (HK 1-ho) were grouped with Sanghuangporus sanghuang instead of P. linteus in the inferred phylogeny.
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Kabátková M, Svobodová J, Pěnčíková K, Mohatad DS, Šmerdová L, Kozubík A, Machala M, Vondráček J. Interactive effects of inflammatory cytokine and abundant low-molecular-weight PAHs on inhibition of gap junctional intercellular communication, disruption of cell proliferation control, and the AhR-dependent transcription. Toxicol Lett 2015; 232:113-21. [DOI: 10.1016/j.toxlet.2014.09.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 09/23/2014] [Accepted: 09/26/2014] [Indexed: 12/11/2022]
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Kim YJ, Kim J, Tian C, Lim HJ, Kim YS, Chung JH, Choung YH. Prevention of cisplatin-induced ototoxicity by the inhibition of gap junctional intercellular communication in auditory cells. Cell Mol Life Sci 2014; 71:3859-71. [PMID: 24623558 PMCID: PMC11113131 DOI: 10.1007/s00018-014-1594-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 02/02/2014] [Accepted: 02/21/2014] [Indexed: 12/14/2022]
Abstract
Cis-diamminedichloroplatinum (cisplatin) is an effective chemotherapeutic drug for cancer therapy. However, most patients treated with cisplatin are at a high risk of ototoxicity, which causes severe hearing loss. Inspired by the "Good Samaritan effect" or "bystander effect" from gap junction coupling, we investigated the role of gap junctions in cisplatin-induced ototoxicity as a potential therapeutic method. We showed that connexin 43 (Cx43) was highly expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, mediating cell-cell communication. The viability of HEI-OC1 cells was greatly decreased by cisplatin treatment, and cisplatin-treated HEI-OC1 cells showed lower Cx43 expression compared to that of untreated HEI-OC1 cells. In particular, high accumulation of Cx43 was observed around the nucleus of cisplatin-treated cells, whereas scattered punctuate expression of Cx43 was observed in the cytoplasm and membrane in normal cells, suggesting that cisplatin may interrupt the normal gap junction communication by inhibiting the trafficking of Cx43 to cell membranes in HEI-OC1 cells. Interestingly, we found that the inhibition of gap junction activity reduced cisplatin-induced apoptosis of auditory hair cells. Cx43 siRNA- or 18α-GA-treated HEI-OC1 cells showed higher cell viability compared to control HEI-OC1 cells during cisplatin treatment; this was also supported by fluorescence recovery after photobleaching studies. Inhibition of gap junction activity reduced recovery of calcein acetoxymethyl ester fluorescence compared to control cells. Additionally, analysis of the mechanisms involved demonstrated that highly activate extracellular signal-regulated kinase and protein kinase B, combined with inhibition of gap junctions may promote cell viability during cisplatin treatment.
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Affiliation(s)
- Yeon Ju Kim
- Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon, 443-721 Republic of Korea
| | - Jangho Kim
- Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul, 151-742 Republic of Korea
| | - Chunjie Tian
- Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon, 443-721 Republic of Korea
| | - Hye Jin Lim
- Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon, 443-721 Republic of Korea
| | - Young Sun Kim
- Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon, 443-721 Republic of Korea
| | - Jong Hoon Chung
- Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul, 151-742 Republic of Korea
| | - Yun-Hoon Choung
- Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon, 443-721 Republic of Korea
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Chen J, Sun S, Zha D, Wu J, Mao L, Deng H, Chu X, Luo H, Zha L. Soyasaponins prevent H₂O₂-induced inhibition of gap junctional intercellular communication by scavenging reactive oxygen species in rat liver cells. Nutr Cancer 2014; 66:1342-51. [PMID: 25268883 DOI: 10.1080/01635581.2014.956245] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
It appears to be more practical and effective to prevent carcinogenesis by targeting the tumor promotion stage. Gap junctional intercellular communication (GJIC) is strongly involved in carcinogenesis, especially the tumor promotion stage. Considerable interest has been focused on the chemoprevention activities of soyasaponin (SS), which are major phytochemicals found in soybeans and soy products. However, less is known about the preventive effects of SS (especially SS with different chemical structures) against tumor promoter-induced inhibition of GJIC. We investigated the protective effects of SS-A1, SS-A2, and SS-I against hydrogen peroxide (H2O2)-induced GJIC inhibition and reactive oxygen species (ROS) production in Buffalo rat liver (BRL) cells. The present results clearly show for the first time that SS-A1, SS-A2, and SS-I prevent the H2O2-induced GJIC inhibition by scavenging ROS in BRL cells in a dose-dependent manner at the concentration range of from 25 to 100 μg/mL. Soyasaponins attenuated the H2O2-induced ROS through potentiating the activities of superoxide dismutase and glutathione peroxidase. This may be an important mechanism by which SS protects against tumor promotion. In addition, various chemical structures of SS appear to exhibit different protective abilities against GJIC inhibition. This may partly attribute to their differences in ROS-scavenging activities.
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Affiliation(s)
- Jiading Chen
- a Department of Nutrition and Food Hygiene, School of Public Health and Tropical Medicine , Southern Medical University , Guangzhou , P.R. China
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Gong G, Yuan L, Cai L, Ran M, Zhang Y, Gong H, Dai X, Wu W, Dong H. Tetramethylpyrazine suppresses transient oxygen-glucose deprivation-induced connexin32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathway in cultured hippocampal neurons. PLoS One 2014; 9:e105944. [PMID: 25237906 PMCID: PMC4169508 DOI: 10.1371/journal.pone.0105944] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 07/29/2014] [Indexed: 11/19/2022] Open
Abstract
Tetramethylpyrazine (TMP) has been widely used in China as a drug for the treatment of various diseases. Recent studies have suggested that TMP has a protective effect on ischemic neuronal damage. However, the exact mechanism is still unclear. This study aims to investigate the mechanism of TMP mediated ischemic hippocampal neurons injury induced by oxygen-glucose deprivation (OGD). The effect of TMP on hippocampal neurons viability was detected by MTT assay, LDH release assay and apoptosis rate was measured by flow cytometry. TMP significantly suppressed neuron apoptosis in a concentration-dependent manner. TMP could significantly reduce the elevated levels of connexin32 (Cx32) induced by OGD. Knockdown of Cx32 by siRNA attenuated OGD injury. Moreover, our study showed that viability was increased in siRNA-Cx32-treated-neurons, and neuron apoptosis was suppressed by activating Bcl-2 expression and inhibiting Bax expression. Over expression of Cx32 could decrease neurons viability and increase LDH release. Furthermore, OGD increased phosphorylation of ERK1/2 and p38, whose inhibitors relieved the neuron injury and Cx32 up-regulation. Taken together, TMP can reverse the OGD-induced Cx32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathways.
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Affiliation(s)
- Gu Gong
- Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu, Sichuan, China
| | - Libang Yuan
- Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu, Sichuan, China
| | - Lin Cai
- Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu, Sichuan, China
| | - Maorong Ran
- Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu, Sichuan, China
| | - Yulan Zhang
- Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu, Sichuan, China
| | - Huaqu Gong
- Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu, Sichuan, China
| | - Xuemei Dai
- Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu, Sichuan, China
| | - Wei Wu
- Department of Anesthesia, General Hospital of Chengdu Military Area Command, Chengdu, Sichuan, China
| | - Hailong Dong
- Department of Anesthesia, the Fourth Military Medical University Xijing Hospital, Xi’an, Shaanxi, China
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Inhibition of Connexin 26/43 and Extracellular-Regulated Kinase Protein Plays a Critical Role in Melatonin Facilitated Gap Junctional Intercellular Communication in Hydrogen Peroxide-Treated HaCaT Keratinocyte Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:589365. [PMID: 23243457 PMCID: PMC3518788 DOI: 10.1155/2012/589365] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 09/26/2012] [Indexed: 01/19/2023]
Abstract
Though melatonin was known to regulate gap junctional intercellular communication (GJIC) in chick astrocytes and mouse hepatocytes, the underlying mechanism by melatonin was not elucidated in hydrogen peroxide- (H2O2-) treated HaCaT keratinocyte cells until now. In the current study, though melatonin at 2 mM and hydrogen peroxide (H2O2) at 300 μM showed weak cytotoxicity in HaCaT keratinocyte cells, melatonin significantly suppressed the formation of reactive oxygen species (ROS) in H2O2-treated HaCaT cells compared to untreated controls. Also, the scrape-loading dye-transfer assay revealed that melatonin enhances the intercellular communication by introducing Lucifer Yellow into H2O2-treated cells. Furthermore, melatonin significantly enhanced the expression of connexin 26 (Cx26) and connexin 43 (Cx43) at mRNA and protein levels, but not that of connexin 30 (Cx30) in H2O2-treated HaCaT cells. Of note, melatonin attenuated the phosphorylation of extracellular signal-regulated protein kinases (ERKs) more than p38 MAPK or JNK in H2O2-treated HaCaT cells. Conversely, ERK inhibitor PD98059 promoted the intercellular communication in H2O2-treated HaCaT cells. Furthermore, combined treatment of melatonin (200 μM) and vitamin C (10 μg/mL) significantly reduced ROS production in H2O2-treated HaCaT cells. Overall, these findings support the scientific evidences that melatonin facilitates gap junctional intercellular communication in H2O2-treated HaCaT keratinocyte cells via inhibition of connexin 26/43 and ERK as a potent chemopreventive agent.
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Chien YC, Huang GJ, Cheng HC, Wu CH, Sheu MJ. Hispolon attenuates balloon-injured neointimal formation and modulates vascular smooth muscle cell migration via AKT and ERK phosphorylation. JOURNAL OF NATURAL PRODUCTS 2012; 75:1524-1533. [PMID: 22967007 DOI: 10.1021/np3002145] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The pathological mechanism of restenosis is attributed primarily to excessive proliferation and migration of vascular smooth muscle cells (VSMC). The preventive effects of hispolon (1) on balloon injury-induced neointimal formation were investigated, and 1 showed potent activity in inhibiting fetal bovine serum-induced VSMC outgrowth. Hispolon (1) significantly inhibited VSMC migration, as shown by trans-well assays. Compound 1 decreased the expression and secretion of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The expression of the endogenous inhibitors of these proteins, namely, tissue inhibitors of MMP (TIMP-1 and TIMP-2), increased. The inhibition by noncytotoxic doses of 1 of VSMC migration was through its negative regulatory effects on FAK phosphorylation, ERK1/2 phosphorylation, and PI3K/AKT. These results demonstrate that 1 can inhibit the migration of VSMC by reduced expression of MMP-9 through the suppression of the FAK signaling pathway and of the activity of PI3K/AKT. The data obtained suggest that 1 might block balloon injury-induced neointimal hyperplasia via the inhibition of VSMC proliferation and migration, without inducing apoptosis.
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Affiliation(s)
- Yi-Chung Chien
- Department of Life Science and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan
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Antioxidant activity of Fragilariopsis pseudonana and protective effect against hydrogen peroxide-induced inhibition of gap junctional intercellular communication. Food Sci Biotechnol 2012. [DOI: 10.1007/s10068-012-0055-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Polysaccharides from Phellinus linteus inhibit cell growth and invasion and induce apoptosis in HepG2 human hepatocellular carcinoma cells. Biologia (Bratisl) 2012. [DOI: 10.2478/s11756-011-0160-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Huang GJ, Hsieh WT, Chang HY, Huang SS, Lin YC, Kuo YH. α-Glucosidase and aldose reductase inhibitory activities from the fruiting body of Phellinus merrillii. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2011; 59:5702-5706. [PMID: 21452825 DOI: 10.1021/jf2003943] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
The inhibitory activity from the isolated component of the fruiting body Phellinus merrillii (PM) was evaluated against α-glucosidase and lens aldose reductase from Sprague-Dawley male rats and compared to the quercetin as an aldose reductase inhibitor and acarbose as an α-glucosidase inhibitor. The ethanol extracts of PM (EPM) showed the strong α-glucosidase and aldose reductase activities. α-Glucosidase and aldose reductase inhibitors were identified as hispidin (A), hispolon (B), and inotilone (C), which were isolated from EtOAc-soluble fractions of EPM. The above structures were elucidated by their spectra and comparison with the literatures. Among them, hispidin, hispolon, and inotilone exhibited potent against α-glucosidase inhibitor activity with IC(50) values of 297.06 ± 2.06, 12.38 ± 0.13, and 18.62 ± 0.23 μg/mL, respectively, and aldose reductase inhibitor activity with IC(50) values of 48.26 ± 2.48, 9.47 ± 0.52, and 15.37 ± 0.32 μg/mL, respectively. These findings demonstrated that PM may be a good source for lead compounds as alternatives for antidiabetic agents currently used. The importance of finding effective antidiabetic therapeutics led us to further investigate natural compounds.
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Affiliation(s)
- Guan-Jhong Huang
- School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, Taichung, Taiwan.
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Harikrishnan R, Balasundaram C, Heo MS. Diet enriched with mushroom Phellinus linteus extract enhances the growth, innate immune response, and disease resistance of kelp grouper, Epinephelus bruneus against vibriosis. FISH & SHELLFISH IMMUNOLOGY 2011; 30:128-134. [PMID: 20883799 DOI: 10.1016/j.fsi.2010.09.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2010] [Revised: 09/18/2010] [Accepted: 09/20/2010] [Indexed: 05/29/2023]
Abstract
The effect of diet supplemented with Phellinus linteus fed for 30 days was investigated in grouper Epinephelus bruneus challenged with Vibrio anguillarum, Vibrio harveyi, Vibrio alginolyticus, and Vibrio carchariae; infected and treated fish had a significantly higher percent weight gain and feed efficiency. In groups fed with enriched diet and challenged with V. anguillarum and V. harveyi the mortality rate declined with a consequent rise in survival rate than with other pathogens. On the other hand, in groups fed with P. linteus enriched diet and challenged with V. anguillarum, V. harveyi, and V. alginolyticus the cellular and humoral immune responses, such as the alternative complement activity (ACH(50)), serum lysozyme activity, phagocytic activity (PA), phagocytic index (PI) significantly higher than in the control group. The respiratory bursts (RB), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities were found significantly enhanced when the groups fed with enriched diet against V. anguillarum and V. harveyi. The results reveal that kelp grouper fed for 30 days with P. linteus enriched diet had higher cellular and humoral immune response and disease protection from vibriosis than the group fed on basal diet with the protection linked to stimulation of immune system.
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Affiliation(s)
- Ramasamy Harikrishnan
- Marine Applied Microbes and Aquatic Organism Disease Control Lab, Department of Aquatic Biomedical Sciences, School of Marine Biomedical Sciences, College of Ocean Sciences and Marine and Environmental Research Institute, Jeju National University, Jeju 690-756, South Korea.
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Down-regulation of connexin43 gap junction by serum deprivation in human endothelial cells was improved by (-)-Epigallocatechin gallate via ERK MAP kinase pathway. Biochem Biophys Res Commun 2010; 404:217-22. [PMID: 21110950 DOI: 10.1016/j.bbrc.2010.11.096] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Accepted: 11/22/2010] [Indexed: 11/23/2022]
Abstract
Intercellular communication through gap junctions (GJIC) plays an essential role in maintaining the functional integrity of vascular endothelium. Despite emerging evidence suggests that (-)-Epigallocatechin gallate (EGCG) may improve endothelial function. However, its effect on Cx43 gap junction in endothelial cells remains unexplored. Here we investigated the effect of EGCG on connexin43 (Cx43) gap junction in endothelial cells. The levels of Cx43 protein in human umbilical vein endothelial cells (HUVECs) cultured under serum-deprivation 48 h decreased about 50%, accompanied by decreased GJIC. This reduction can be reversed by treatments with EGCG. In addition, EGCG activated ERK, P38, and JNK mitogen-activated protein kinases (MAPKs), which were supposed to participate in the regulation of Cx43. A MEK inhibitor PD98059, but not SB203580 (a p38 kinase inhibitor) or SP600125 (a JNK kinase inhibitor), abolished the effects of EGCG on Cx43 expression and GJIC. Moreover, although both Akt and eNOS phosphorylation were time-dependently augmented by EGCG, neither PI3K inhibitor LY294002 nor eNOS inhibitor L-NAME blocked the effects of EGCG on Cx43 gap junctions. Thus, EGCG attenuated Cx43 down-regulation and impaired GJIC induced by serum deprivation, ERK MAPK Signal transduction pathway appears to be involved in these processes.
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Quercetin, the active phenolic component in kiwifruit, prevents hydrogen peroxide-induced inhibition of gap-junction intercellular communication. Br J Nutr 2010; 104:164-70. [PMID: 20302682 DOI: 10.1017/s0007114510000346] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We evaluated the effects of the two main kiwifruit cultivars (gold kiwifruit (GOK) and green kiwifruit (GRK)) and their active phenolic compound, quercetin, on H2O2-induced inhibition of gap-junction intercellular communication (GJIC) in WB-F344 rat liver epithelial cells. We found that both GOK and GRK protect WB-F344 cells from H2O2-induced inhibition of GJIC. The extracellular signal-regulated protein kinase 1/2 (ERK1/2)-connexin 43 (Cx43) signalling pathway is crucial for the regulation of GJIC, and both GOK and GRK blocked the H2O2-induced phosphorylation of Cx43 and ERK1/2 in WB-F344 cells. Quercetin alone attenuated the H2O2-mediated ERK1/2-Cx43 signalling pathway and consequently reversed H2O2-mediated inhibition of GJIC in WB-F344 cells. A free radical-scavenging assay using 1,1-diphenyl-2-picrylhydrazyl showed that the scavenging activity of quercetin was higher than that of a synthetic antioxidant, butylated hydroxytoluene, per mol, suggesting that the chemopreventive effect of quercetin on H2O2-mediated inhibition of ERK1/2-Cx43 signalling and GJIC may be mediated through its free radical-scavenging activity. Since the carcinogenicity of reactive oxygen species such as H2O2 is attributable to the inhibition of GJIC, GOK, GRK and quercetin may have chemopreventive potential by preventing the inhibition of GJIC.
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Kim JH, Choi SH, Kim J, Lee BK, Lee KW, Lee HJ. Differential regulation of the hydrogen-peroxide-induced inhibition of gap-junction intercellular communication by resveratrol and butylated hydroxyanisole. Mutat Res 2009; 671:40-44. [PMID: 19720069 DOI: 10.1016/j.mrfmmm.2009.08.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2009] [Revised: 08/22/2009] [Accepted: 08/24/2009] [Indexed: 05/28/2023]
Abstract
The present study was performed to evaluate the effects of two different phenolic antioxidants, resveratrol (3,5,4'-trihydroxystilbene) and butylated hydroxyanisole (BHA), on the hydrogen peroxide (H2O2)-induced inhibition of gap-junction intercellular communication (GJIC) in WB-F344 rat liver epithelial cells (WB-F344). Resveratrol is a naturally occurring polyphenolic antioxidant; on the other hand, BHA is a synthetic phenolic compound. We found that only resveratrol protects WB-F344 cells from H2O2-induced inhibition of GJIC, and BHA has no effect. The extracellular-signal-regulated protein kinase 1/2 (ERK1/2)-connexin 43 (Cx43) signaling pathway is crucial for the regulation of GJIC in rat liver epithelial cells, and resveratrol, but not BHA, blocked the H2O2-induced phosphorylation of Cx43, a critical regulator of GJIC, and ERK1/2 in WB-F344 cells. Resveratrol appears to attenuate the H2O2-mediated ERK1/2-Cx43 signaling pathway and consequently reverses H2O2-mediated inhibition of GJIC. DPPH and ABTS radical-scavenging assays revealed that the protective effect of resveratrol on the H2O2-mediated inhibition of GJIC was not mediated through its free radical-scavenging activity.
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Affiliation(s)
- Jong Hun Kim
- Major in Biomodulation, Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, 599 Gwangak-ro, Gwanak-gu, Seoul 151-921, Republic of Korea
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Garry A, Edwards DH, Fallis IF, Jenkins RL, Griffith TM. Ascorbic acid and tetrahydrobiopterin potentiate the EDHF phenomenon by generating hydrogen peroxide. Cardiovasc Res 2009; 84:218-26. [PMID: 19592567 PMCID: PMC2761203 DOI: 10.1093/cvr/cvp235] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2009] [Revised: 07/01/2009] [Accepted: 07/02/2009] [Indexed: 12/11/2022] Open
Abstract
AIMS Our objective was to investigate whether pro-oxidant properties of ascorbic acid (AA) and tetrahydrobiopterin (BH(4)) modulate endothelium-dependent, electrotonically mediated arterial relaxation. METHODS AND RESULTS In studies with rabbit iliac artery (RIA) rings, NO-independent, endothelium-derived hyperpolarizing factor (EDHF)-type relaxations evoked by the sarcoplasmic endoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid and the G protein-coupled agonist acetylcholine (ACh) were enhanced by AA (1 mM) and BH(4) (200 microM), which generated buffer concentrations of H(2)O(2) in the range of 40-80 microM. Exogenous H(2)O(2) potentiated cyclopiazonic acid (CPA)- and ACh-evoked relaxations with a threshold of 10-30 microM, and potentiation by AA and BH(4) was abolished by catalase, which destroyed H(2)O(2) generated by oxidation of these agents in the organ chamber. Adventitial application of H(2)O(2) also enhanced EDHF-type dilator responses evoked by CPA and ACh in RIA segments perfused intraluminally with H(2)O(2)-free buffer, albeit with reduced efficacy. In RIA rings, both control relaxations and their potentiation by H(2)O(2) were overcome by blockade of gap junctions by connexin-mimetic peptides (YDKSFPISHVR and SRPTEK) targeted to the first and second extracellular loops of the dominant vascular connexins expressed in the RIA. Superoxide dismutase attenuated the potentiation of EDHF-type relaxations by BH(4), but not AA, consistent with findings demonstrating a differential role for superoxide anions in the generation of H(2)O(2) by the two agents. CONCLUSION Pro-oxidant effects of AA and BH(4) can enhance the EDHF phenomenon by generating H(2)O(2), which has previously been shown to amplify electrotonic hyperpolarization-mediated relaxation by facilitating Ca(2+) release from endothelial stores.
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Affiliation(s)
- Ambroise Garry
- Department of Diagnostic Radiology, Wales Heart Research Institute, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - David H. Edwards
- Department of Diagnostic Radiology, Wales Heart Research Institute, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Ian F. Fallis
- School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
| | - Robert L. Jenkins
- School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
| | - Tudor M. Griffith
- Department of Diagnostic Radiology, Wales Heart Research Institute, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
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Neergheen VS, Bahorun T, Taylor EW, Jen LS, Aruoma OI. Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention. Toxicology 2009; 278:229-41. [PMID: 19850100 DOI: 10.1016/j.tox.2009.10.010] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2009] [Revised: 10/06/2009] [Accepted: 10/09/2009] [Indexed: 02/08/2023]
Abstract
Natural phytochemicals derived from dietary sources or medicinal plants have gained significant recognition in the potential management of several human clinical conditions. Much research has also been geared towards the evaluation of plant extracts as effective prophylactic agents since they can act on specific and/or multiple molecular and cellular targets. Plants have been an abundant source of highly effective phytochemicals which offer great potential in the fight against cancer by inhibiting the process of carcinogenesis through the upregulation of cytoprotective genes that encode for carcinogen detoxifying enzymes and antioxidant enzymes. The mechanistic insight into chemoprevention further includes induction of cell cycle arrest and apoptosis or inhibition of signal transduction pathways mainly the mitogen-activated protein kinases (MAPK), protein kinases C (PKC), phosphoinositide 3-kinase (PI3K), glycogen synthase kinase (GSK) which lead to abnormal cyclooxygenase-2 (COX-2), activator protein-1 (AP-1), nuclear factor-kappaB (NF-κB) and c-myc expression. Effectiveness of chemopreventive agents reflects their ability to counteract certain upstream signals that leads to genotoxic damage, redox imbalances and other forms of cellular stress. Targeting malfunctioning molecules along the disrupted signal transduction pathway in cancer represent a rational strategy in chemoprevention. NF-κB and AP-1 provide mechanistic links between inflammation and cancer, and moreover regulate tumor angiogenesis and invasiveness, indicating that signaling pathways that mediate their activation provide attractive targets for new chemotherapeutic approaches. Thus cell signaling cascades and their interacting factors have become important targets of chemoprevention and phenolic phytochemicals and plant extracts seem to be promising in this endeavor.
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Affiliation(s)
- Vidushi S Neergheen
- Department of Health Sciences, Faculty of Science, University of Mauritius, Réduit, Mauritius.
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Liang CH, Syu JL, Mau JL. Antioxidant properties of solid-state fermented adlay and rice by Phellinus linteus. Food Chem 2009. [DOI: 10.1016/j.foodchem.2009.03.032] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Vinken M, Doktorova T, Decrock E, Leybaert L, Vanhaecke T, Rogiers V. Gap junctional intercellular communication as a target for liver toxicity and carcinogenicity. Crit Rev Biochem Mol Biol 2009; 44:201-22. [PMID: 19635038 DOI: 10.1080/10409230903061215] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Direct communication between hepatocytes, mediated by gap junctions, constitutes a major regulatory platform in the control of liver homeostasis, ranging from hepatocellular proliferation to hepatocyte cell death. Inherent to this pivotal task, gap junction functionality is frequently disrupted upon impairment of the homeostatic balance, as occurs during liver toxicity and carcinogenicity. In the present paper, the deleterious effects of a number of chemical and biological toxic compounds on hepatic gap junctions are discussed, including environmental pollutants, biological toxins, organic solvents, pesticides, pharmaceuticals, peroxides, metals and phthalates. Particular attention is paid to the molecular mechanisms that underlie the abrogation of gap junction functionality. Since hepatic gap junctions are specifically targeted by tumor promoters and epigenetic carcinogens, both in vivo and in vitro, inhibition of gap junction functionality is considered as a suitable indicator for the detection of nongenotoxic hepatocarcinogenicity.
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Affiliation(s)
- Mathieu Vinken
- Department of Toxicology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
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Mammalian sterile 20-like kinase 3 (MST3) mediates oxidative-stress-induced cell death by modulating JNK activation. Biosci Rep 2009; 29:405-15. [PMID: 19604147 DOI: 10.1042/bsr20090096] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
MST3 (mammalian sterile 20-like kinase 3) is a sterile 20 kinase reported to have a role in Fas-ligation- and staurosporine-induced cell death by unknown mechanism(s). We found that MST3-deficient cells are resistant to H2O2, which was reversed by reconstituting recombinant MST3. H2O2-induced JNK (c-Jun N-terminal kinase) activation was greatly enhanced in shMST3 cells (a cell line treated with short hairpin RNA against MST3). Suppression of JNK activity by the inhibitor SP600125 or by dominant-negative JNK2 re-sensitized cells to H2O2. Furthermore, c-Jun Ser-63 phosphorylation was augmented in shMST3 cells, whereas JunAA (dominant-negative c-Jun) reduced H2O2 resistance, implicating an AP-1 (activator protein 1) pathway in H2O2-induced survival signalling. Total cytoprotective HO-1 (haem oxygenase 1) expression, which was attenuated by JunAA, was induced up to 5-fold higher in shMST3 cells compared with controls. Zinc protoporphyrin IX, a potent inhibitor of HO reversed the H2O2-resistance of shMST3 cells. Our results reveal that H2O2-induced MST3-mediated cell death involves suppressing both a JNK survival pathway and up-regulation of HO-1.
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33
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Samchai S, Seephonkai P, Sangdee A, Puntumchai A, Klinhom U. Antioxidant, Cytotoxic and Antimalarial Activities from Crude Extracts of Mushroom Phellinus linteus. ACTA ACUST UNITED AC 2009. [DOI: 10.3923/jbs.2009.778.783] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Kim JH, Lee BK, Lee KW, Lee HJ. Resveratrol counteracts gallic acid-induced down-regulation of gap-junction intercellular communication. J Nutr Biochem 2009; 20:149-54. [DOI: 10.1016/j.jnutbio.2008.01.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2007] [Revised: 12/31/2007] [Accepted: 01/10/2008] [Indexed: 11/16/2022]
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Lee KM, Kwon JY, Lee KW, Lee HJ. Ascorbic acid 6-palmitate suppresses gap-junctional intercellular communication through phosphorylation of connexin 43 via activation of the MEK-ERK pathway. Mutat Res 2009; 660:51-56. [PMID: 19026667 DOI: 10.1016/j.mrfmmm.2008.10.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2008] [Revised: 10/01/2008] [Accepted: 10/14/2008] [Indexed: 05/27/2023]
Abstract
Although the health benefits of dietary antioxidants have been extensively studied, their potential negative effects remain unclear. L-Ascorbic acid 6-palmitate (AAP), a synthetic derivative of ascorbic acid (AA), is widely used as an antioxidant and preservative in foods, vitamins, drugs, and cosmetics. Previously, we found that AA exerted an antitumor effect by protecting inhibition of gap-junctional intercellular communication (GJIC), which is closely associated with tumor progression. In this study, we examined whether AAP, an amphipathic derivative of AA, has chemopreventive effects using a GJIC model. AAP and AA exhibited dose-dependent free radical-scavenging activities and inhibited hydrogen peroxide (H(2)O(2))-induced intracellular reactive oxygen species (ROS) production in normal rat liver epithelial cells. Unexpectedly, however, AAP did not protect against the inhibition of GJIC induced by H(2)O(2); instead, it inhibited GJIC synergistically with H(2)O(2). AAP inhibited GJIC in a dose-dependent and reversible manner. This inhibitory effect was not due to the conjugated lipid structure of AAP, as treatment with palmitic acid alone failed to inhibit GJIC under the same conditions. The inhibition of GJIC by AAP was restored in the presence of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126, but not in the presence of other signal inhibitors and antioxidant (PKC inhibitors, EGFR inhibitor, NADPH oxidase inhibitor, catalase, vitamin E, or AA), indicating the critical involvement of MEK signaling in the GJIC inhibitory activity of AAP. Phosphorylation of ERK and connexin 43 (Cx43) was observed following AAP treatment, and this was reversed by U0126. These results suggest that the AAP-induced inhibition of GJIC is mediated by the phosphorylation of Cx43 via activation of the MEK-ERK pathway. Taken together, our results indicate that AAP has a potent carcinogenic effect, and that the influence of dietary antioxidants on carcinogenesis may be paradoxical.
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Affiliation(s)
- Kyung Mi Lee
- Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea
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36
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Kang NJ, Lee KM, Kim JH, Lee BK, Kwon JY, Lee KW, Lee HJ. Inhibition of gap junctional intercellular communication by the green tea polyphenol (-)-epigallocatechin gallate in normal rat liver epithelial cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2008; 56:10422-10427. [PMID: 18828601 DOI: 10.1021/jf801981w] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
(-)-Epigallocatechin gallate (EGCG), a polyphenolic compound found in green tea, is a promising chemopreventive agent against cancer due to its strong antiproliferative effects on cancer cells; however, its possible toxicity and carcinogenicity must be investigated before EGCG can be used as a dietary supplement for chemoprevention. The inhibition of gap junctional intercellular communication (GJIC) is strongly associated with carcinogenesis, particularly the tumor promotion process; thus, we investigated the effects of EGCG on GJIC in WB-F344 normal rat liver epithelial (RLE) cells. EGCG, but not (-)-epicatechin (EC), another polyphenol found in green tea, inhibited GJIC in a dose-dependent and reversible manner in RLE cells. EGCG also induced the phosphorylation of connexin 43 (Cx43), a major regulator of GJIC. The phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) was also observed in EGCG-treated RLE cells. The inhibition of GJIC and phosphorylation of Cx43 and ERK1/2 by EGCG were completely blocked by U0126, a pharmacological inhibitor of mitogen-activated protein kinase/ERK kinase. EGCG generated a larger amount of hydrogen peroxide than EC in a dose-dependent manner. Furthermore, catalase partially inhibited the EGCG-induced inhibition of GJIC and the phosphorylation of Cx43 and ERK1/2. These results indicated that EGCG inhibited GJIC mainly due to its prooxidant activity.
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Affiliation(s)
- Nam Joo Kang
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea
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37
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Choi SY, Hwang JH, Park SY, Jin YJ, Ko HC, Moon SW, Kim SJ. Fermented guava leaf extract inhibits LPS-induced COX-2 and iNOS expression in Mouse macrophage cells by inhibition of transcription factor NF-kappaB. Phytother Res 2008; 22:1030-4. [PMID: 18618521 DOI: 10.1002/ptr.2419] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The goal of this study was to elucidate the antiinflammatory activities of Psidium guajava L. (guava) leaf. To improve the functionality of guava leaf, it was fermented with Phellinus linteus mycelia, Lactobacillus plantarum and Saccharomyces cerevisiae. The ethanol extract from fermented guava leaf inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production. Western blot analysis showed that fermented guava leaf extract decreased LPS-induced inducible nitric oxide synthase (iNOS) and the cyclooxygenase-2 (COX-2) protein level in RAW 264.7 cells. To investigate the mechanism involved, the study examined the effect of fermented guava leaf extract on LPS-induced nuclear factor-kappaB (NF-kappaB) activation. Fermented guava leaf extract significantly inhibited LPS-induced NF-kappaB transcriptional activity. Immunochemical analysis revealed that fermented guava leaf extract suppressed LPS-induced degradation of I-kappaBalpha. Taken together, the data indicate that fermented guava leaf extract is involved in the inhibition of iNOS and COX-2 via the down-regulation of NF-kappaB pathway, revealing a partial molecular basis for the antiinflammatory properties of fermented guava leaf extract.
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Affiliation(s)
- Soo-Youn Choi
- Technology Innovation Center for Life Science, Cheju National University, Jeju, 690-756, South Korea
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38
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Hwang JW, Jung JW, Lee YS, Kang KS. Indole-3-carbinol prevents H(2)O(2)-induced inhibition of gap junctional intercellular communication by inactivation of PKB/Akt. J Vet Med Sci 2008; 70:1057-63. [PMID: 18981661 DOI: 10.1292/jvms.70.1057] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Indole-3-carbinol (I3C) is a phytochemical found in cruciferous vegetables and possesses a variety of biological and biochemical effects. Despite a wealth of data about the chemopreventive properties of I3C, its effects on gap junctional intercellular communication (GJIC), which is associated with the promotion and progression phases of the multi-stage process of carcinogenesis, has not been studied. In this study, we examined the ability of I3C to prevent H(2)O(2)-induced inhibition of GJIC in WB-F344 rat liver epithelial cells (WB cells). The cells were preincubated with I3C for 48 hr, and then treated with 1 mM H(2)O(2) for 1 hr. We found that I3C could prevent the H(2)O(2)-induced inhibition of GJIC through prevention of the phosphorylated state of gap junction protein connexin 43 (Cx43) phosphorylation. Prevention of GJIC by I3C was dependent upon inactivation of Akt, but not MAPK, although inhibition of GJIC by H(2)O(2) leads to activation of both. Similar to I3C, modulation of Akt activation through the phosphoinositide-3 kinase inhibitor, LY294002, could also prevent H(2)O(2)-induced inhibition of GJIC and phosphorylation of Cx43. Our results suggest that I3C might exert its dietary chemopreventive effects by interfering with the Akt signaling pathway, which appears to be linked to modulating GJIC, a cellular mechanisms regulating cell proliferation, differentiation and apoptosis.
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Affiliation(s)
- Jae-Woong Hwang
- Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
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39
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Mukai M, Kasai A, Hiramatsu N, Hayakawa K, Okamura M, Tagawa Y, Yao J, Nakamura T, Kitamura M. Blockade of the aryl hydrocarbon receptor pathway triggered by dioxin, polycyclic aromatic hydrocarbons and cigarette smoke by Phellinus linteus. Biol Pharm Bull 2008; 31:1888-93. [PMID: 18827349 DOI: 10.1248/bpb.31.1888] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Environmental pollutants including halogenated and polycyclic aromatic hydrocarbons activate the aryl hydrocarbon receptor (AhR) and thereby cause a wide range of pathological changes. Development of AhR antagonists will be useful for prevention and treatment of diseases related to AhR activation. Towards this end, we aimed in the present study at seeking for potential inhibitors of the AhR pathway in mycelial extracts using the dioxin responsive element-based sensing via secreted alkaline phosphatase (DRESSA). Through the screening of 13 mycelia, extracts prepared from Phellinus linteus, Cordyceps militaris and Hericium erinaceum inhibited activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin, benzo[a]pyrene or 3-methylcholanthrene. Subsequent studies revealed that only Phellinus linteus suppressed activation of AhR and AhR-dependent gene expression triggered by all of these agonists. Cigarette smoke is known to contain a number of halogenated and polycyclic aromatic hydrocarbons. We found that Phellinus linteus has the potential to block activation of AhR and AhR-dependent gene expression triggered by cigarette smoke. Furthermore, the inhibitory effect of Phellinus linteus on the AhR pathway was independent of; 1) depression of AhR or AhR nuclear translocator, and 2) induction of AhR repressor. We conclude that Phellinus linteus contains potent inhibitor(s) of AhR activation and may be useful for prevention of pathologies associated with aberrant activation of AhR.
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Affiliation(s)
- Mai Mukai
- Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
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Lee JW, Baek SJ, Kim YS. Submerged Culture of Phellinus linteus for Mass Production of Polysaccharides. MYCOBIOLOGY 2008; 36:178-182. [PMID: 23997621 PMCID: PMC3755190 DOI: 10.4489/myco.2008.36.3.178] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2008] [Accepted: 09/19/2008] [Indexed: 06/02/2023]
Abstract
In order to increase the mycelial production of Phellinus linteus, which exhibits potent anticancer activity, some ingredients of the medium used to culture P. linteus were investigated. The optimal medium composition for the production of Phellinus linteus was determined to be as follows: fructose, 40 g/l; yeast extract, 20 g/l; K2HPO4, 0.46 g/l; KH2PO4, 1.00 g/l; MgSO4·7H2O, 0.50 g/l; FeCl2·62O, 0.01 g/l; MnCl2·4H2O, 0.036 g/l; ZnCl2, 0.03 g/l; and CuSO4·7H2O, 0.005 g/l. The optimal culture conditions were determined to be as follows: temperature, 28℃; initial pH, 5.5; aeration, 0.6 vvm; and agitation, 100 rpm, respectively. Under optimal composition and conditions, the maximum mycelial biomass achieved in a 5 l jar fermentor was 29.9 g/l.
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Affiliation(s)
- June Woo Lee
- Department of Food Processing and Cooking, Kyungbuk College, Yeongjusi 750-712, Korea
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41
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Kroening PR, Barnes TW, Pease L, Limper A, Kita H, Vassallo R. Cigarette smoke-induced oxidative stress suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 181:1536-47. [PMID: 18606709 PMCID: PMC2819390 DOI: 10.4049/jimmunol.181.2.1536] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
IL-12p70, a heterodimer composed of p35 and p40 subunits, is a key polarizing cytokine produced by maturing dendritic cells (DCs). We report that cigarette smoke extract (CSE), an extract of soluble cigarette smoke components, suppresses both p35 and p40 production by LPS or CD40L-matured DCs. Suppression of IL-12p70 production from maturing DCs was not observed in the presence of nicotine concentrations achievable in CSE or in the circulation of smokers. The suppressed IL-12p70 protein production by CSE-conditioned DCs was restored by pretreatment of DCs or CSE with the antioxidants N-acetylcysteine and catalase. Inhibition of DC IL-12p70 by CSE required activation of ERK-dependent pathways, since inhibition of ERK abrogated the suppressive effect of CSE on IL-12 secretion. Oxidative stress and sustained ERK phosphorylation by CSE enhanced nuclear levels of the p40 transcriptional repressor c-fos in both immature and maturing DCs. Suppression of the p40 subunit by CSE also resulted in diminished production of IL-23 protein by maturing DCs. Using a murine model of chronic cigarette smoke exposure, we observed that systemic and lung DCs from mice "smokers" produced significantly less IL-12p70 and p40 protein upon maturation. This inhibitory effect was selective, since production of TNF-alpha during DC maturation was enhanced in the smokers. These data imply that oxidative stress generated by cigarette smoke exposure suppresses the generation of key cytokines by maturing DCs through the activation of ERK-dependent pathways. Some of the cigarette smoke-induced inhibitory effects on DC function may be mitigated by antioxidants.
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Affiliation(s)
- Paula R Kroening
- Thoracic Diseases Research Unit, Division of Pulmonary Critical Care, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA
| | | | - Larry Pease
- Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA
| | - Andrew Limper
- Thoracic Diseases Research Unit, Division of Pulmonary Critical Care, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA
| | - Hirohito Kita
- Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA
- Division of Allergic diseases, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA
| | - Robert Vassallo
- Thoracic Diseases Research Unit, Division of Pulmonary Critical Care, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA
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Yang KL, Chang WT, Hung KC, Li EIC, Chuang CC. Inhibition of transforming growth factor-beta-induced liver fibrosis by a retinoic acid derivative via the suppression of Col 1A2 promoter activity. Biochem Biophys Res Commun 2008; 373:219-23. [PMID: 18558083 DOI: 10.1016/j.bbrc.2008.05.192] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2008] [Accepted: 05/02/2008] [Indexed: 12/15/2022]
Abstract
Transforming growth factor-beta1 (TGF-beta1) mediates expression of collagen 1A2 (Col 1A2) gene via a synergistic cooperation between Smad2/Smad3 and Sp1, both act on the Col 1A2 gene promoter. In our previous study, we reported that a retinoic acid derivative obtained from Phellinus linteus (designated PL) antagonizes TGF-beta-induced liver fibrosis through regulation of ROS and calcium influx. In this continuing study we seek further the effect of PL on the Smad signaling pathway. We used a Col 1A2 promoter-luciferase construct to study the action of PL on Smad through TGF-beta. We found that PL decreases the promoter activity of Col 1A2, hinders the translocalization of phosphorylated Smad2/3-Smad 4 complex from cytosol into nucleus and inhibits Sp1 binding activity. These results suggest that PL inhibits TGF-beta1-induced Col 1A2 promoter activity through blocking ROS and calcium influx as well as impeding Sp1 binding and translocalization of pSmad 2/3-Smad4 complex into nucleus.
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Affiliation(s)
- Kun-Lin Yang
- Institute of Basic Medical Sciences, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
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Lee YS, Kang YH, Jung JY, Kang IJ, Han SN, Chung JS, Shin HK, Lim SS. Inhibitory constituents of aldose reductase in the fruiting body of Phellinus linteus. Biol Pharm Bull 2008; 31:765-8. [PMID: 18379080 DOI: 10.1248/bpb.31.765] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In an effort to characterize active principles for diabetic complication from medicinal mushroom, aldose reductase inhibitors were isolated from the fruiting body of Phellinus linteus and identified as hispidin (5), phelligridimer A (6), davallialactone (7), methyldavallialactone (8), hypholomine B (9), interfungins A (10), and inoscavin A (11), together with protocatechuic acid (1), protocatechualdehyde (2), caffeic acid (3), and ellagic acid (4). Their structures were elucidated by spectroscopic analyses. Among them, davallialactone (7), hypholomine B (9), and ellagic acid (4) exhibited potent rat lens aldose reductase and human recombinant aldose reductase inhibitory activity with IC50 values of 0.33, 0.82, 0.63 microM and 0.56, 1.28, 1.37 microM, respectively.
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Affiliation(s)
- Yeon Sil Lee
- Department of Food Science and Nutrition, Hallym University, Chuncheon 200-702, Korea
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Bioconversion of starch processing waste to Phellinus linteus mycelium in solid-state cultivation. J Ind Microbiol Biotechnol 2008; 35:859-65. [DOI: 10.1007/s10295-008-0358-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2007] [Accepted: 04/01/2008] [Indexed: 10/22/2022]
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Kim JH, Kang NJ, Lee BK, Lee KW, Lee HJ. Gallic acid, a metabolite of the antioxidant propyl gallate, inhibits gap junctional intercellular communication via phosphorylation of connexin 43 and extracellular-signal-regulated kinase1/2 in rat liver epithelial cells. Mutat Res 2008; 638:175-183. [PMID: 18054051 DOI: 10.1016/j.mrfmmm.2007.10.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Revised: 10/07/2007] [Accepted: 10/08/2007] [Indexed: 05/25/2023]
Abstract
Propyl gallate and its metabolite, gallic acid, are widely used as antioxidants in the food industry, but they have been shown to exhibit liver toxicity and enhance carcinogenesis. In the present study, we investigated the possible undesirable effects of propyl gallate and gallic acid on gap junctional intercellular communication (GJIC), inhibition of which is closely linked to carcinogenesis. Gallic acid and propyl gallate exhibited dose-dependent free-radical-scavenging activities as determined by 1,1-diphenyl-2-picrylhydrazyl- or 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)-radical-scavenging assays, and the free-radical-scavenging activity of gallic acid was stronger than that of propyl gallate. However, using WB-F344 rat liver epithelial cells, gallic acid inhibited GJIC in a dose-dependent manner, while propyl gallate had no significant effect compared with untreated controls. The gallic-acid-induced inhibition of GJIC was reversible, with a recovery of nearly 65% after 120 min. Gallic acid induced the phosphorylation of connexin 43 (Cx43) and phosphorylation of extracellular-signal-regulated kinase1/2 (ERK1/2). The gallic-acid-induced inhibition of GJIC was attenuated by treatment with mitogen-activated protein kinase kinase inhibitors (U0126 and PD098059). U0126 blocked the gallic-acid-induced phosphorylation of Cx43 and ERK1/2, indicating that the gallic-acid-induced inhibition of GJIC is mediated by phosphorylation of Cx43 via activation of ERK1/2. In addition, gallic-acid-induced inhibition of GJIC was protected by ascorbic acid and quercetin, which might represent a simple example of the different effects of natural antioxidants in carcinogenesis.
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Affiliation(s)
- Jong Hun Kim
- Department of Agricultural Biotechnology and Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921, Republic of Korea
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Bellei B, Mastrofrancesco A, Briganti S, Aspite N, Ale-Agha N, Sies H, Picardo M. Ultraviolet A induced modulation of gap junctional intercellular communication by P38 MAPK activation in human keratinocytes. Exp Dermatol 2008; 17:115-24. [DOI: 10.1111/j.1600-0625.2007.00662.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Ye SF, Hou ZQ, Zhang QQ. Protective effects of Phellinus linteus extract against iron overload-mediated oxidative stress in cultured rat hepatocytes. Phytother Res 2008; 21:948-53. [PMID: 17602436 DOI: 10.1002/ptr.2182] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Phellinus linteus (PL) mushroom has been reported to possess antioxidant activity. The present study was designed to investigate whether an ethanol extract obtained from PL might ameliorate oxidative stress and enhance antioxidant enzyme activities in primary rat hepatocytes, which were overloaded with iron using ferric nitrilotriacetate (FeNTA) complex. FeNTA enables hepatocytes to accumulate substantially redox-active iron and stimulates the production of injurious hydroxyl radicals, which in turn, initiate oxidative stress-mediated cytotoxicity. The results showed that pretreatment of hepatocytes with PL extract (50, 100 and 200 microg/mL) for 24 h significantly reversed FeNTA-induced cell viability loss, lactate dehydrogenase leakage (LDH), lipid peroxidation (LPO) and protein carbonyl formation in a dose-dependent manner. It was further observed that PL extract produced an inhibitory effect on intracellular reactive oxygen species (ROS) formation caused by FeNTA. Concomitantly, the amount of GSH content and the activities of glutathione reductase (GSH Rd) and glutathione peroxidase (GSH Px) in hepatocytes pretreated with PL extract increased substantially compared with those treated with FeNTA alone. These results suggest that PL may be useful in protecting against FeNTA-induced oxidative damage and also be capable of attenuating cytotoxicity of other oxidants.
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Affiliation(s)
- She-Fang Ye
- Key Laboratory of Biomedical Engineering of Fujian, Medical College, Xiamen University, 361005, PR China
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Song TY, Lin HC, Yang NC, Hu ML. Antiproliferative and antimetastatic effects of the ethanolic extract of Phellinus igniarius (Linnearus: Fries) Quelet. JOURNAL OF ETHNOPHARMACOLOGY 2008; 115:50-56. [PMID: 17936529 DOI: 10.1016/j.jep.2007.09.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Revised: 08/20/2007] [Accepted: 09/04/2007] [Indexed: 05/25/2023]
Abstract
AIM OF THIS STUDY Phellinus igniarius (Linnearus: Fries) Quelet (Phellinus igniarius) has been used in oriental countries for treatment of various diseases including cancer. However, it is unclear how Phellinus igniarius exerts anticancer effects. MATERIALS AND METHODS In this study the ethanolic extract from the fruiting body of Phellinus igniarius (EEPI) was used to evaluate the antiproliferative and antimetastatic effects in human hepatocarcinoma SK-Hep-1 cells and rat heart vascular endothelial cells (RHE cells). RESULTS We found that EEPI inhibited the proliferation of both cell lines in a dose-dependent manner, and the IC50 values at 48 h were 72 and 103 microg/ml for SK-Hep-1 cells and RHE cells, respectively. EEPI at non- or sub-cytotoxic concentrations (25-100 microg/ml) markedly inhibited the migration and invasion of SK-Hep-1 cells. EEPI added at 25 microg/ml significantly decreased the secretion of matrix metalloproteinase-2 (MMP-2) (49%, p<0.01) and vascular endothelial growth factor (VEGF) (13%, p<0.05) in SK-Hep-1 cells. EEPI at 25 microg/ml completely inhibited matrigel-induced tube formation in RHE cells. Importantly, EEPI (25 or 50 microg/ml) in combination with oxaliplatin (Oxa) or 5-flurouracil (5-FU) synergistically inhibited the proliferation of SK-Hep-1 cells. CONCLUSION These results demonstrate the antiproliferative and antimetastatic effects of EEPI in vitro and the potential of EEPI as an adjuvant for chemotherapy.
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Affiliation(s)
- Tuzz-Ying Song
- Department of Nutrition and Health Science, Chungchou Institute of Technology, Changhua, Taiwan, ROC
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Yang KL, Chang WT, Chuang CC, Hung KC, Li EIC. Antagonizing TGF-beta induced liver fibrosis by a retinoic acid derivative through regulation of ROS and calcium influx. Biochem Biophys Res Commun 2007; 365:484-9. [PMID: 17997979 DOI: 10.1016/j.bbrc.2007.10.203] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2007] [Accepted: 10/31/2007] [Indexed: 01/19/2023]
Abstract
Transforming growth factor-beta1 (TGF-beta1) mediates the regulation of extracellular matrix via reactive oxygen species (ROS) and calcium influx, both are activators of hepatic stellate cells (HSC) which play a critical role in hepatic fibrogenesis. Hence one can use ROS assay as the main screening tool for molecules that might antagonize the process of liver fibrosis. A retinoic acid derivative isolated from the mycelium of Phellinus linteus that down-regulates ROS generation and calcium influx in HSC-T6 cells was thus obtained in our screening process. The retinoic acid derivative also reverses an early liver fibrosis, as assayed by liver contents of hydroxyproline, alpha-smooth muscle actin (alpha-SMA), and collagen 1A2, in an early liver fibrosis model we established previously where an inducible expression vector containing a TGF-beta gene was hydrodynamically transferred into a testing animal. Retinoic acid derivative thus acts both in vitro and in vivo to prevent liver fibrosis at an early phase.
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Affiliation(s)
- Kun-Lin Yang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
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Wang CM, Lincoln J, Cook JE, Becker DL. Abnormal connexin expression underlies delayed wound healing in diabetic skin. Diabetes 2007; 56:2809-17. [PMID: 17717278 DOI: 10.2337/db07-0613] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVE Dynamically regulated expression of the gap junction protein connexin (Cx)43 plays pivotal roles in wound healing. Cx43 is normally downregulated and Cx26 upregulated in keratinocytes at the edge of the wound as they adopt a migratory phenotype. We have examined the dynamics of Cx expression during wound healing in diabetic rats, which is known to be slow. RESEARCH DESIGN AND METHODS We induced diabetes with streptozotocin and examined Cx expression and communication in intact and healing skin. RESULTS We found that diabetes decreased Cx43 and Cx26 protein and communication in the intact epidermis and increased Cx43 protein and communication in the intact dermis. Diabetes also altered the dynamic changes of Cxs associated with wound healing. Within 24 h, Cx43 was upregulated in a thickened bulb of keratinocytes at the wound edge (rather than downregulated as in controls, which formed a thin process of migratory cells). Cx43 decline was delayed until 48 h, when reepithelialization began. Although Cx26 was upregulated as normal after wounding in diabetic skin, its distribution at the wound edge was abnormal, being more widespread. Application of Cx43-specific antisense gel to diabetic wounds prevented the abnormal upregulation of Cx43 and doubled the rate of reepithelialization, which exceeded control levels. CONCLUSIONS Cx expression in diabetic skin is abnormal, as is the dynamic response of Cx43 to injury, which may underlie the delayed healing of diabetic wounds. Preventing the upregulation of Cx43 in diabetic wounds significantly improves the rate of healing and clearly has potential therapeutic value.
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Affiliation(s)
- Chiuhui Mary Wang
- Department of Anatomy and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK
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