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Arathi BP, Bound DJ, Ambedkar R, Venkateshappa S, Manjunath T, Paul B, Lakshminarayana R. Chemical Implications of apo-8, 6' Carotendial versus Intact Lycopene on Mechanism of Enhanced Cell-cell Communication and Apoptosis Induction in Breast Cancer Cells. Cell Biochem Biophys 2024; 82:3517-3533. [PMID: 39085671 DOI: 10.1007/s12013-024-01440-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2024] [Indexed: 08/02/2024]
Abstract
Investigation on carotenoids and its cleavage products is crucial to combat the development of chronic diseases, including cancer. Therefore, this study aimed to explore the effect of lycopene oxidative products versus equivalent concentration of lycopene (LYC) on major molecular events of cancer cells (MCF-7). Primarily, LYC-oxidized products were generated chemically, then collected its rich fraction. Based on cell-based assays, the antiproliferation potency of rich fraction of chemically-oxidized lycopene (COL) identified as apo-8, 6' carotendial was compared with LYC. Interestingly, the inhibition of cell migration by COL strongly demonstrated anti-metastatic activity. Further, the increased connexin-43 expression confirms enhanced gap-junctional communication activity of COL than LYC and control. Fortunately, apo-8, 6' carotendial did not affect normal breast epithelial cells. We anticipated that, the chemical properties of apo-8, 6'-carotendial is similar and mimic a model compound acrolein (α, β-conjugated aldehyde) which is involved in Michael addition/Schiff base formation with specific amino acids and regulates redox signaling, reactive oxygen species sensing and cellular buffering. The chemistry of apo-8, 6' carotendial reveals a greater insight into the mechanism of selective inhibition of cancer cells proliferation. In this context, speculations of putative action of lycopeneoids through chemical biology approach facilitate greater insights in tandem with synthetic chemistry.
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Affiliation(s)
- Bangalore Prabhashankar Arathi
- Department of Microbiology and Biotechnology, Jnana Bharathi Campus, Bangalore University, Bengaluru, 560 056, India
- Department of Biochemistry, Indian Institute of Science, Bengaluru, 560 012, India
| | - D James Bound
- Post-Graduate Department of Chemistry and Research Centre, NMKRV College, Jayanagar, Bengaluru, 560 011, India
- Department of Ophthalmology and Visual Sciences, University of Utah, 65 Mario Capecchi Drive, Moran Eye Center, Salt Lake City, UT, 84132, USA
| | - Rudrappa Ambedkar
- Department of Microbiology and Biotechnology, Jnana Bharathi Campus, Bangalore University, Bengaluru, 560 056, India
| | - Sowmya Venkateshappa
- Department of Microbiology and Biotechnology, Jnana Bharathi Campus, Bangalore University, Bengaluru, 560 056, India
| | - Tejaswini Manjunath
- Department of Microbiology and Biotechnology, Jnana Bharathi Campus, Bangalore University, Bengaluru, 560 056, India
| | - Bishwajit Paul
- Department of Chemistry, Jnana Bharathi Campus, Bangalore University, Bengaluru, 560 056, India
| | - Rangaswamy Lakshminarayana
- Department of Microbiology and Biotechnology, Jnana Bharathi Campus, Bangalore University, Bengaluru, 560 056, India.
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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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Chen QH, Wu BK, Pan D, Sang LX, Chang B. Beta-carotene and its protective effect on gastric cancer. World J Clin Cases 2021; 9:6591-6607. [PMID: 34447808 PMCID: PMC8362528 DOI: 10.12998/wjcc.v9.i23.6591] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/16/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Beta-carotene is an important natural pigment that is very beneficial to human health. It is widely found in vegetables and fruits. The three main functions are antioxidant effects, cell gap junction-related functions and immune-related functions. Because of its diverse functions, beta-carotene is believed to prevent and treat many chronic diseases. Gastric cancer is one of the most important diseases it can treat. Gastric cancer is a type of cancer with a high incidence. Its etiology varies, and the pathogenesis is complex. Gastric cancer seriously affects human health. The role of beta-carotene, a natural nutrient, in gastric cancer has been explored by many researchers, including molecular mechanisms and epidemiological studies. Molecular studies have mainly focused on oxidative stress, cell cycle, signal transduction pathways and immune-related mechanisms of beta-carotene in gastric cancer. Many epidemiological surveys and cohort studies of patients with gastric cancer have been conducted, and the results of these epidemiological studies vary due to the use of different research methods and analysis of different regions. This paper will summarize the results of these studies, mainly in terms of molecular mechanisms and epidemiological research results, which will provide a systematic basis for future studies of the treatment and prognosis of gastric cancer. This paper will help researchers identify new research directions.
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Affiliation(s)
- Qian-Hui Chen
- Department of Intensive Care Unit, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bao-Kang Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Dan Pan
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Burton GW, Mogg TJ, Riley WW, Nickerson JG. β-Carotene oxidation products - Function and safety. Food Chem Toxicol 2021; 152:112207. [PMID: 33891992 DOI: 10.1016/j.fct.2021.112207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/09/2021] [Indexed: 10/21/2022]
Abstract
β-Carotene oxidation products have newly discovered bioactivity in plants and animals. Synthetic fully oxidized β-carotene (OxBC) has application in supporting livestock health, with potential human applications. The safety of synthetic OxBC has been evaluated. An Ames test showed weak-to-moderate mutagenicity in only one cell line at high concentrations. A mouse micronucleus assay established a non-toxic dose of 1800 mg/kg body weight, and no bone marrow micronuclei were induced. Plant sources of β-carotene inevitably contain varying levels of natural OxBC. Vegetable powders and dried forages can be especially rich. Intakes of natural OxBC for humans and livestock alike have been estimated. The exposure range for humans (1-22 mg/serving) is comparable to the safe intake of β-carotene (<15 mg/d). In livestock, OxBC in alfalfa can contribute ~550-850 mg/head/d for dairy cattle but in forage-deficient poultry feed much less (~1 ppm). Livestock intake of supplemental synthetic OxBC is comparable to OxBC potentially available from traditional plant sources. Human intake of synthetic OxBC in meat from livestock fed OxBC is similar to a single serving of food made with carrot powder. It is concluded that consumption of synthetic OxBC at levels comparable to natural OxBC is safe for humans and animals.
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Affiliation(s)
- Graham W Burton
- Avivagen Inc., 100 Sussex Drive, Ottawa, Ontario, K1A 0R6, Canada.
| | - Trevor J Mogg
- Avivagen Inc., 100 Sussex Drive, Ottawa, Ontario, K1A 0R6, Canada
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Luo KJ, Chen CX, Yang JP, Huang YC, Cardenas ER, Jiang JX. Connexins in Lung Cancer and Brain Metastasis. Front Oncol 2020; 10:599383. [PMID: 33425756 PMCID: PMC7786366 DOI: 10.3389/fonc.2020.599383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/11/2020] [Indexed: 01/20/2023] Open
Abstract
Connexins (Cxs) are involved in the brain metastasis of lung cancer cells. Thus, it is necessary to determine whether gap junction-forming Cxs are involved in the communication between lung cancer cells and the host cells, such as endothelial cells, forming the brain-blood-barrier, and cells in the central nervous system. Data from multiple studies support that Cxs function as tumor suppressors during lung cancer occurrence. However, recent evidence suggests that during metastasis to the brain, cancer cells establish communication with the host. This review discusses junctional or non-junctional hemichannel studies in lung cancer development and brain metastasis, highlighting important unanswered questions and controversies.
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Affiliation(s)
- Kai-Jun Luo
- School of Life Sciences, Yunnan University, Kunming, China
- Key Laboratory of the University in Yunnan Province for International Cooperation in Intercellular Communications and Regulations, Yunnan University, Kunming, China
| | - Chang-Xu Chen
- School of Life Sciences, Yunnan University, Kunming, China
- Key Laboratory of the University in Yunnan Province for International Cooperation in Intercellular Communications and Regulations, Yunnan University, Kunming, China
| | - Jia-Peng Yang
- Department of Thoracic Surgery I, The Third Affiliated Hospital of Kunming Medical University/Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming, China
- Joint International Research Laboratory of Regional Tumor in High Altitude Area, Kunming, China
| | - Yun-Chao Huang
- Department of Thoracic Surgery I, The Third Affiliated Hospital of Kunming Medical University/Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming, China
- Joint International Research Laboratory of Regional Tumor in High Altitude Area, Kunming, China
| | - Eduardo R. Cardenas
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States
| | - Jean X. Jiang
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States
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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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Fang WL, Lai SY, Lai WA, Lee MT, Liao CF, Ke FC, Hwang JJ. CRTC2 and Nedd4 ligase involvement in FSH and TGFβ1 upregulation of connexin43 gap junction. J Mol Endocrinol 2015; 55:263-75. [PMID: 26508620 DOI: 10.1530/jme-15-0076] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The major mission of the ovarian follicle is the timely production of the mature fertilizable oocyte, and this is achieved by gonadotropin-regulated, gap junction-mediated cell-cell communication between the oocyte and surrounding nurturing granulosa cells. We have demonstrated that FSH and transforming growth factor beta 1 (TGFβ1) stimulate Gja1 gene-encoded connexin43 (Cx43) gap junction formation/function in rat ovarian granulosa cells is important for their induction of steroidogenesis; additionally, cAMP-protein kinase A (PKA)- and calcium-calcineurin-sensitive cAMP response element-binding (CREB) coactivator CRTC2 plays a crucial role during steroidogenesis. This study was to explore the potential molecular mechanism whereby FSH and TGFβ1 regulate Cx43 synthesis and degradation, particularly the involvement of CRTC2 and ubiquitin ligase Nedd4. Primary culture of granulosa cells from ovarian antral follicles of gonadotropin-primed immature rats was used. At 48 h post-treatment, FSH plus TGFβ1 increased Cx43 level and gap junction function in a PKA- and calcineurin-dependent manner, and TGFβ1 acting through its type I receptor modulated FSH action. Chromatin-immunoprecipitation analysis reveals FSH induced an early-phase (45 min) and FSH+TGFβ1 further elicited a late-phase (24 h) increase in CRTC2, CREB and CBP binding to the Gja1 promoter. Additionally, FSH+TGFβ1 increased the half-life of hyper-phosphorylated Cx43 (Cx43-P2). Also, the proteasome inhibitor MG132 prevented the brefeldin A (blocker of protein transport through Golgi)-reduced Cx43-P2 level and membrane Cx43 gap junction plaque. This is associated with FSH+TGFβ1-attenuated Cx43 interaction with Nedd4 and Cx43 ubiquitination. In all, this study uncovers that FSH and TGFβ1 upregulation of Cx43 gap junctions in ovarian granulosa cells critically involves enhancing CRTC2/CREB/CBP-mediated Cx43 expression and attenuating ubiquitin ligase Nedd4-mediated proteosomal degradation of Cx43 protein.
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Affiliation(s)
- Wei-Ling Fang
- School of MedicineInstitute of Physiology, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, TaiwanDepartment of NursingHsin-Sheng College of Medical Care and Management, Taoyuan, TaiwanInstitute of Biological ChemistryInstitute of Cellular and Organismic BiologyAcademia Sinica, Taipei, TaiwanCollege of Life ScienceInstitute of Molecular and Cellular Biology, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan School of MedicineInstitute of Physiology, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, TaiwanDepartment of NursingHsin-Sheng College of Medical Care and Management, Taoyuan, TaiwanInstitute of Biological ChemistryInstitute of Cellular and Organismic BiologyAcademia Sinica, Taipei, TaiwanCollege of Life ScienceInstitute of Molecular and Cellular Biology, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan
| | - Si-Yi Lai
- School of MedicineInstitute of Physiology, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, TaiwanDepartment of NursingHsin-Sheng College of Medical Care and Management, Taoyuan, TaiwanInstitute of Biological ChemistryInstitute of Cellular and Organismic BiologyAcademia Sinica, Taipei, TaiwanCollege of Life ScienceInstitute of Molecular and Cellular Biology, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan
| | - Wei-An Lai
- School of MedicineInstitute of Physiology, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, TaiwanDepartment of NursingHsin-Sheng College of Medical Care and Management, Taoyuan, TaiwanInstitute of Biological ChemistryInstitute of Cellular and Organismic BiologyAcademia Sinica, Taipei, TaiwanCollege of Life ScienceInstitute of Molecular and Cellular Biology, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan
| | - Ming-Ting Lee
- School of MedicineInstitute of Physiology, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, TaiwanDepartment of NursingHsin-Sheng College of Medical Care and Management, Taoyuan, TaiwanInstitute of Biological ChemistryInstitute of Cellular and Organismic BiologyAcademia Sinica, Taipei, TaiwanCollege of Life ScienceInstitute of Molecular and Cellular Biology, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan
| | - Ching-Fong Liao
- School of MedicineInstitute of Physiology, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, TaiwanDepartment of NursingHsin-Sheng College of Medical Care and Management, Taoyuan, TaiwanInstitute of Biological ChemistryInstitute of Cellular and Organismic BiologyAcademia Sinica, Taipei, TaiwanCollege of Life ScienceInstitute of Molecular and Cellular Biology, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan
| | - Ferng-Chun Ke
- School of MedicineInstitute of Physiology, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, TaiwanDepartment of NursingHsin-Sheng College of Medical Care and Management, Taoyuan, TaiwanInstitute of Biological ChemistryInstitute of Cellular and Organismic BiologyAcademia Sinica, Taipei, TaiwanCollege of Life ScienceInstitute of Molecular and Cellular Biology, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan
| | - Jiuan-Jiuan Hwang
- School of MedicineInstitute of Physiology, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, TaiwanDepartment of NursingHsin-Sheng College of Medical Care and Management, Taoyuan, TaiwanInstitute of Biological ChemistryInstitute of Cellular and Organismic BiologyAcademia Sinica, Taipei, TaiwanCollege of Life ScienceInstitute of Molecular and Cellular Biology, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan
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Combination of β-carotene and quercetin against benzo[a]pyrene-induced pro-inflammatory reaction accompanied by the regulation of antioxidant enzyme activity and NF-κB translocation in Mongolian gerbils. Eur J Nutr 2014; 54:397-406. [DOI: 10.1007/s00394-014-0719-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 05/12/2014] [Indexed: 01/05/2023]
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Changes in antioxidant capacity and colour associated with the formation of β-carotene epoxides and oxidative cleavage derivatives. Food Chem 2014; 147:160-9. [DOI: 10.1016/j.foodchem.2013.09.106] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 09/11/2013] [Accepted: 09/17/2013] [Indexed: 11/20/2022]
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Abdul-Hamid M, Moustafa N. Amelioration of alloxan-induced diabetic keratopathy by beta-carotene. ACTA ACUST UNITED AC 2013; 66:49-59. [PMID: 24129090 DOI: 10.1016/j.etp.2013.08.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Revised: 07/22/2013] [Accepted: 08/30/2013] [Indexed: 12/25/2022]
Abstract
This study was undertaken to assess the anti-keratopathy activity of β-carotene in experimentally-induced diabetic animal model. The rats were divided into four groups as following: G1, normal control group; G2, β-carotene control group (50 mg/kg b.wt.); G3, diabetic group which was injected intraperitoneally with a single dose (100 mg/kg b. wt) of alloxan (ALX) and G4, diabetic rats treated with β-carotene which was injected with ALX as G3, and then received a daily oral dose of β-carotene (50 mg/kg b.wt.) for 3 months. ALX injection caused elevated levels of serum glucose in diabetic group. Moreover, histopathology revealed relatively thick corneal epithelium, ill-defined Bowman's membrane, widely spaced stromal layers and relatively thick Descemet's membrane. Electron microscopic studies showed vacuolated cytoplasm, partial loss of hemi-desmosomes and disorganized collagen fibrils with focal lysis of stromal layer. Oral gavage of β-carotene to diabetic rats for 3 months significantly decreased serum glucose level and ameliorated histopathological, immunohistochemical and ultrastructural results. Consequently, β-carotene exerted anti-keratopathy effects and ameliorated the corneal changes in diabetic rats via its hypoglycemic and antioxidant mechanisms.
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Affiliation(s)
- Manal Abdul-Hamid
- Department of Zoology, Faculty of Science, Beni-Suef University, Egypt.
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Novo R, Azevedo PS, Minicucci MF, Zornoff LAM, Paiva SAR. Effect of beta-carotene on oxidative stress and expression of cardiac connexin 43. Arq Bras Cardiol 2013; 101:233-9. [PMID: 23917457 PMCID: PMC4032303 DOI: 10.5935/abc.20130160] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 05/27/2013] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Intervention studies have shown an increased mortality in patients who received beta-carotene. However, the mechanisms involved in this phenomenon are still unknown. OBJECTIVE Evaluate the influence of beta-carotene on oxidative stress and the expression of connexin 43 in rat hearts. METHODS Wistar rats, weighing approximately 100 g, were allocated in two groups: CONTROL GROUP (n=30), that received the diet routinely used in our laboratory, and Beta-Carotene Group (n = 28), which received beta-carotene (in crystal form, added and mixed to the diet) at a dose of 500 mg of beta-carotene/kg of diet. The animals received the treatment until they reached 200-250 g, when they were sacrificed. Samples of blood, liver and heart were collected to perform Western blotting and immunohistochemistry for connexin 43; morphometric studies, dosages of beta-carotene by high-performance liquid chromatography as well as reduced glutathione, oxidized glutathione and lipids hydroperoxides were performed by biochemical analysis. RESULTS Beta-carotene was detected only in the liver of Beta-Carotene Group animals (288 ± 94.7 µg/kg). Levels of reduced/oxidized glutathione were higher in the liver and heart of Beta-Carotene Group animals (liver - CONTROL GROUP 42.60 ± 1.62; liver - Beta-Carotene Group: 57.40 ± 5.90; p = 0.04; heart: - CONTROL GROUP 117.40 ± 1.01; heart - Beta-Carotene Group: 121.81 ± 1.32 nmol/mg protein; p = 0.03). The content of total connexin 43 was larger in Beta-Carotene Group. CONCLUSION Beta-carotene demonstrated a positive effect, characterized by the increase of intercellular communication and improvement of anti-oxidizing defense system. In this model, mechanism does not explain the increased mortality rate observed with the beta-carotene supplementation in clinical studies.
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Affiliation(s)
| | | | | | - Leonardo A. M. Zornoff
- Mailing Address: Leonardo A. M. Zornoff, Internal Medicine Department,
Rubião Jr. Postal Code 18618-970, Botucatu, SP - Brazil. E-mail:
,
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Nguyen TTT, Shaw PN, Parat MO, Hewavitharana AK. Anticancer activity ofCarica papaya: A review. Mol Nutr Food Res 2012; 57:153-64. [DOI: 10.1002/mnfr.201200388] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 09/16/2012] [Accepted: 10/09/2012] [Indexed: 12/20/2022]
Affiliation(s)
- Thao T. T. Nguyen
- School of Pharmacy,; The University of Queensland; Brisbane; Australia
| | - Paul N. Shaw
- School of Pharmacy,; The University of Queensland; Brisbane; Australia
| | - Marie-Odile Parat
- School of Pharmacy,; The University of Queensland; Brisbane; Australia
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Deng F, Olesen P, Foldbjerg R, Dang DA, Guo X, Autrup H. Silver nanoparticles up-regulate Connexin43 expression and increase gap junctional intercellular communication in human lung adenocarcinoma cell line A549. Nanotoxicology 2010; 4:186-95. [DOI: 10.3109/17435390903576451] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Huang CS, Fan YE, Lin CY, Hu ML. Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1. J Nutr Biochem 2007; 18:449-56. [PMID: 17049831 DOI: 10.1016/j.jnutbio.2006.08.007] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2006] [Revised: 08/09/2006] [Accepted: 08/22/2006] [Indexed: 11/26/2022]
Abstract
The carotenoid lycopene has been associated with decreased risks of several types of cancer, such as hepatoma. Although lycopene has been shown to inhibit metastasis, its mechanism of action is poorly understood. Here, we used SK-Hep-1 cells (from a human hepatoma) to test whether lycopene exerts its anti-invasion activity via down-regulation of the expression of matrix metalloproteinase (MMP)-9, an important enzyme in the degradation of basement membrane in cancer invasion. The activity and expressions of MMP-9 protein and mRNA were detected by gelatin zymography, Western blotting and RT-PCR, respectively. The binding abilities of nuclear factor-kappa B (NF-kappaB), activator protein-1 and stimulatory protein-1 (Sp1) to the binding sites in the MMP-9 promoter were measured by the electrophoretic mobility shift assay. We showed that lycopene (1-10 microM) significantly inhibited SK-Hep-1 invasion (P<.05) and that this effect correlated with the inhibition of MMP-9 at the levels of enzyme activity (r(2)=.94, P<.001), protein expression (r(2)=.80, P=.007) and mRNA expression (r(2)=.94, P<.001). Lycopene also significantly inhibited the binding abilities of NF-kappaB and Sp1 and decreased, to some extent, the expression of insulin-like growth factor-1 receptor (IGF-1R) and the intracellular level of reactive oxygen species (P<.05). The antioxidant effect of lycopene appeared to play a minor role in its inhibition of MMP-9 and invasion activity of SK-Hep-1 cells because coincubation of cells with lycopene plus hydrogen peroxide abolished the antioxidant effect but did not significantly affect the anti-invasion ability of lycopene. Thus, lycopene decreases the invasive ability of SK-Hep-1 cells by inhibiting MMP-9 expression and suppressing the binding activity of NF-kappaB and Sp1. These effects of lycopene may be related to the down-regulation of IGF-1R, while the antioxidant activity of lycopene appears to play a minor role.
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Affiliation(s)
- Chin-Shiu Huang
- Department of Food Science and Biotechnology, National Chung-Hsing University, Taichung 402, Taiwan, Republic of China
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Magesh V, Venugopal R, Bhavani KD, Sakthiseka D. Effect of Crocetin on Benzo (a) Pyrene Induced Lung Carcinogenesis in Swiss Albino Mice. ACTA ACUST UNITED AC 2007. [DOI: 10.3923/ijcr.2007.143.150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Salameh A, Dhein S. Pharmacology of gap junctions. New pharmacological targets for treatment of arrhythmia, seizure and cancer? BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2005; 1719:36-58. [PMID: 16216217 DOI: 10.1016/j.bbamem.2005.09.007] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2005] [Revised: 08/25/2005] [Accepted: 09/06/2005] [Indexed: 11/26/2022]
Abstract
Intercellular communication in many organs is maintained via intercellular gap junction channels composed of connexins, a large protein family with a number of isoforms. This gap junction intercellular communication (GJIC) allows the propagation of action potentials (e.g., in brain, heart), and the transfer of small molecules which may regulate cell growth, differentiation and function. The latter has been shown to be involved in cancer growth: reduced GJIC often is associated with increased tumor growth or with de-differentiation processes. Disturbances of GJIC in the heart can cause arrhythmia, while in brain electrical activity during seizures seems to be propagated via gap junction channels. Many diseases or pathophysiological conditions seem to be associated with alterations of gap junction protein expression. Thus, depending on the target disease opening or closure of gap junctions may be of interest, or alteration of connexin expression. GJIC can be affected acutely by changing gap junction conductance or--more chronic--by altering connexin expression and membrane localisation. This review gives an overview on drugs affecting GJIC.
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Affiliation(s)
- Aida Salameh
- Clinic I for Internal Medicine, Department of Cardiology, University of Leipzig, Johannisallee 32, 04103 Leipzig, Germany.
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Hix LM, Frey DA, McLaws MD, Østerlie M, Lockwood SF, Bertram JS. Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative. Carcinogenesis 2005; 26:1634-41. [PMID: 15888493 DOI: 10.1093/carcin/bgi121] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Carotenoids have been implicated in numerous epidemiological studies as being protective against cancer at many sites, and their chemopreventive properties have been confirmed in laboratory studies. Astaxanthin (AST), primarily a carotenoid of marine origin, responsible for the pink coloration of salmon, shrimp and lobster, has received relatively little attention. As with other carotenoids, its highly lipophilic properties complicate delivery to model systems. To overcome this issue we have synthesized a novel tetrasodium diphosphate astaxanthin (pAST) derivative with aqueous dispersibility of 25.21 mg/ml. pAST was delivered to C3H/10T1/2 cells in an aqueous/ethanol solution and compared with non-esterified AST dissolved in tetrahydrofuran. We show pAST to (i) upregulate connexin 43 (Cx43) protein expression; (ii) increase the formation of Cx43 immunoreactive plaques; (iii) upregulate gap junctional intercellular communication (GJIC); and (iv) cause 100% inhibition of methylcholanthrene-induced neoplastic transformation at 10(-6) M. In all these assays, pAST was superior to non-esterified AST itself; in fact, pAST exceeded the potency of all other previously tested carotenoids in this model system. Cleavage of pAST to non-esterified (free) AST and uptake into cells was also verified by HPLC; however, levels of free AST were approximately 100-fold lower than in cells treated with AST itself, suggesting that pAST possesses intrinsic activity. The dual properties of water dispersibility (enabling parenteral administration in vivo) and increased potency should prove extremely useful in the future development of cancer chemopreventive agents.
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Affiliation(s)
- Laura M Hix
- Department of Cell and Molecular Biology, University of Hawaii at Manoa, Honolulu, HI 96822, USA
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