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González A, Fullaondo A, Rodríguez J, Tirnauca C, Odriozola I, Odriozola A. Conjugated linoleic acid metabolite impact in colorectal cancer: a potential microbiome-based precision nutrition approach. Nutr Rev 2025; 83:e602-e614. [PMID: 38728013 PMCID: PMC11723137 DOI: 10.1093/nutrit/nuae046] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
Abstract
Colorectal cancer (CRC) is the second most deadly and the third most diagnosed cancer in both sexes worldwide. CRC pathogenesis is associated with risk factors such as genetics, alcohol, smoking, sedentariness, obesity, unbalanced diets, and gut microbiota dysbiosis. The gut microbiota is the microbial community living in symbiosis in the intestine, in a dynamic balance vital for health. Increasing evidence underscores the influence of specific gut microbiota bacterial species on CRC incidence and pathogenesis. In this regard, conjugated linoleic acid (CLA) metabolites produced by certain gut microbiota have demonstrated an anticarcinogenic effect in CRC, influencing pathways for inflammation, proliferation, and apoptosis. CLA production occurs naturally in the rumen, and human bioavailability is through the consumption of food derived from ruminants. In recent years, biotechnological attempts to increase CLA bioavailability in humans have been unfruitful. Therefore, the conversion of essential dietary linoleic acid to CLA metabolite by specific intestinal bacteria has become a promising process. This article reviews the evidence regarding CLA and CLA-producing bacteria as therapeutic agents against CRC and investigates the best strategy for increasing the yield and bioavailability of CLA. Given the potential and limitations of the present strategies, a new microbiome-based precision nutrition approach based on endogenous CLA production by human gut bacteria is proposed. A literature search in the PubMed and PubMed Central databases identified 794 papers on human gut bacteria associated with CLA production. Of these, 51 studies exploring association consistency were selected. After excluding 19 papers, due to health concerns or discrepancies between studies, 32 papers were selected for analysis, encompassing data for 38 CLA-producing bacteria, such as Bifidobacterium and Lactobacillus species. The information was analyzed by a bioinformatics food recommendation system patented by our research group, Phymofood (EP22382095). This paper presents a new microbiome-based precision nutrition approach targeting CLA-producing gut bacterial species to maximize the anticarcinogenic effect of CLA in CRC.
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Affiliation(s)
- Adriana González
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Bilbao, Spain
| | - Asier Fullaondo
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Bilbao, Spain
| | - Javier Rodríguez
- Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Cristina Tirnauca
- Departamento de Matemáticas, Estadística y Computación, Universidad de Cantabria, Santander, Spain
| | - Iñaki Odriozola
- Health Department of Basque Government, Gipuzkoa, Donostia-San Sebastián, Spain
| | - Adrian Odriozola
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country UPV/EHU, Bilbao, Spain
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Guo Y, Wei Z, Zhang Y, Cao J. The Effects of trans-10, cis-12 Conjugated Linoleic Acid on the Production Performance of Dairy Cows and the Expression and Transcription Regulation of Lipid Metabolism-Related Genes in Bovine Mammary Epithelial Cells. ACS OMEGA 2024; 9:34161-34174. [PMID: 39130591 PMCID: PMC11308042 DOI: 10.1021/acsomega.4c05532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 08/13/2024]
Abstract
Dietary fatty acids (FAs) determine the quality of dairy products. The trans-10, cis-12 conjugated linoleic acid (t10c12-CLA) is commonly considered an FA factor leading to milk fat depression syndrome (MFDs) in dairy cow. However, its effect on dairy cow performance and involvement in milk fat metabolism have been insufficiently explored. This study administered 136.17 g/day of rumen-protected CLA (RP-CLA) to dairy cows and found a diminution in milk fat percentage and a trend of increasing milk protein percentage on day 21 postpartum. Lactose content, milk yield, and net energy for lactation were unaffected. In the cell experiments, Oil Red O staining showed a notable increase in lipid droplets. Gene and protein expression analysis showed that 300 μM t10c12-CLA upregulated the expression of CD36, DGAT2, and ADRP, while downregulating the expression of ACACA, FASN, SREBP1, FABP3, FATP3, ACSL4, LPIN1, DGAT1, BTN1A1, XDH, SNAP23, and VAMP4. This provides a possible mechanistic pathway for the contradictory phenomenon of t10c12-CLA reducing milk fat while increasing lipid droplets. Overall, t10c12-CLA, as a long-chain fatty acid, can promote lipid droplet synthesis but may reduce milk fat by inhibiting lipid droplet fusion and secretion, FAs de novo synthesis, and triglyceride biosynthesis.
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Affiliation(s)
- Yuanyin Guo
- College
of Veterinary Medicine, China Agricultural
University, Beijing 100193, China
| | - Ziang Wei
- College
of Veterinary Medicine, China Agricultural
University, Beijing 100193, China
| | - Yi Zhang
- College
of Animal Science and Technology, China
Agricultural University, Beijing 100193, China
| | - Jie Cao
- College
of Veterinary Medicine, China Agricultural
University, Beijing 100193, China
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3
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Yu D, Cheng J, Wang N, Li Z, Chen X, Wu F, Yang F, Wang L. Application of Rh/MWCNT catalysts in the preparation of conjugated linoleic acid from linoleic acid. J FOOD PROCESS PRES 2021. [DOI: 10.1111/jfpp.15529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Dianyu Yu
- School of Food Science Northeast Agricultural University Harbin China
| | - Jie Cheng
- School of Food Science Northeast Agricultural University Harbin China
| | - Ning Wang
- School of Food Science Northeast Agricultural University Harbin China
| | - Ziyue Li
- School of Food Science Northeast Agricultural University Harbin China
| | - Xing Chen
- School of Food Science Northeast Agricultural University Harbin China
| | - Fei Wu
- School of Food Science Northeast Agricultural University Harbin China
| | - Fuming Yang
- School of Food Science Northeast Agricultural University Harbin China
| | - Liqi Wang
- School of Computer and Information Engineering Harbin University of Commerce Harbin China
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Abstract
Conjugated linoleic acids (CLA) are distinctive polyunsaturated fatty acids. They are present in food produced by ruminant animals and they are accumulated in seeds of certain plants. These naturally occurring substances have demonstrated to have anti-carcinogenic activity. Their potential effect to inhibit cancer has been shown in vivo and in vitro studies. In this review, we present the multiple effects of CLA isomers on cancer development such as anti-tumor efficiency, anti-mutagenic and anti-oxidant activity. Although the majority of the studies in vivo and in vitro summarized in this review have demonstrated beneficial effects of CLA on the proliferation and apoptosis of tumor cells, further experimental work is needed to estimate the true value of CLA as a real anti-cancer agent.
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Aranda-Olmedo I, Rubio LA. Dietary legumes, intestinal microbiota, inflammation and colorectal cancer. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103707] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Goat milk attenuates mimetic aging related memory impairment via suppressing brain oxidative stress, neurodegeneration and modulating neurotrophic factors in D-galactose-induced aging model. Biogerontology 2019; 21:203-216. [PMID: 31792648 DOI: 10.1007/s10522-019-09854-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 11/26/2019] [Indexed: 10/25/2022]
Abstract
One of the most significant hallmarks of aging is cognitive decline. D-galactose administration may impair memory and mimic the effects of natural aging. In this study, the efficiency of goat milk to protect against memory decline was tested. Fifty-two male Sprague-Dawley rats were randomly divided into four groups: (i) control group, (ii) goat milk treated group, (iii) D-galactose treated group, and (iv) goat milk plus D-galactose treated group. Subcutaneous injections of D-galactose at 120 mg/kg and oral administrations of goat milk at 1 g/kg were chosen for the study. Goat milk and D-galactose were administered concomitantly for 6 weeks, while the control group received saline. After 6 weeks, novel object recognition and T-maze tests were performed to evaluate memory of rats. Following behavioral tests, the animals were sacrificed, and right brain homogenates were analyzed for levels of lipid peroxidation, antioxidant enzymes and neurotrophic factors. The left brain hemisphere was used for histological study of prefrontal cortex and hippocampus. There was a significant memory impairment, an increase in oxidative stress and neurodegeneration and a reduction in antioxidant enzymes and neurotrophic factors levels in the brain of D-galactose treated rats compared to controls. Goat milk treatment attenuated memory impairment induced by D-galactose via suppressing oxidative stress and neuronal damage and increasing neurotrophic factors levels, thereby suggesting its potential role as a geroprotective food.
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Lipase Catalyzed Acidolysis for Efficient Synthesis of Phospholipids Enriched with Isomerically Pure cis-9,trans-11 and trans-10,cis-12 Conjugated Linoleic Acid. Catalysts 2019. [DOI: 10.3390/catal9121012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The production of phospholipid (PL) conjugates with biologically active compounds is nowadays an extensively employed approach. This type of phospholipids conjugates could improve bioavailability of many poorly absorbed active compounds such as isomers of conjugated linoleic acid (CLA), which exhibit versatile biological effects. The studies were carried out to elaborate an efficient enzymatic method for the synthesis of phospholipids with pure (>90%) cis-9,trans-11 and trans-10,cis-12 CLA isomers. For this purpose, three commercially available immobilized lipases were examined in respect to specificity towards CLA isomers in acidolysis of egg-yolk phosphatidylcholine (PC). Different incorporation rates were observed for the individual CLA isomers. Under optimal conditions: PC/CLA molar ratio 1:6; Rhizomucor miehei lipase loading 24% wt. based on substrates; heptane; DMF, 5% (v/v); water activity (aw), 0.11; 45 °C; magnetic stirring, 300 rpm; 48 h., effective incorporation (EINC) of CLA isomers into PC reached ca. 50%. The EINC of CLA isomers was elevated for 25–30% only by adding a water mimic (DMF) and reducing aw to 0.11 comparing to the reaction system performed at aw = 0.23. The developed method of phosphatidylcholine acidolysis is the first described in the literature dealing with isometrically pure CLA and allow to obtain very high effective incorporation.
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Verruck S, Balthazar CF, Rocha RS, Silva R, Esmerino EA, Pimentel TC, Freitas MQ, Silva MC, da Cruz AG, Prudencio ES. Dairy foods and positive impact on the consumer's health. ADVANCES IN FOOD AND NUTRITION RESEARCH 2019; 89:95-164. [PMID: 31351531 DOI: 10.1016/bs.afnr.2019.03.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The objective of the present chapter was to demonstrate the state of the art in the recent advances in nutritional and functional components of dairy products research. In this chapter, the main mechanisms responsible and essential for a better understanding of nutritional and functional values of the components of milk and dairy products are highlighted. It also includes a discussion about the positive impacts of fermented milk, cheese, butter, ice cream, and dairy desserts components on the consumer's health.
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Affiliation(s)
- Silvani Verruck
- Universidade Federal de Santa Catarina (UFSC), Departamento de Ciência e Tecnologia de Alimentos, Florianópolis, Brazil
| | | | - Ramon Silva Rocha
- Universidade Federal Fluminense (UFF), Faculdade de Veterinária, Niterói, Brazil; Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Departamento de Alimentos, Rio de Janeiro, Brazil
| | - Ramon Silva
- Universidade Federal Fluminense (UFF), Faculdade de Veterinária, Niterói, Brazil; Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Departamento de Alimentos, Rio de Janeiro, Brazil
| | | | | | | | - Marcia Cristina Silva
- Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Departamento de Alimentos, Rio de Janeiro, Brazil
| | - Adriano Gomes da Cruz
- Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Departamento de Alimentos, Rio de Janeiro, Brazil.
| | - Elane Schwinden Prudencio
- Universidade Federal de Santa Catarina (UFSC), Departamento de Ciência e Tecnologia de Alimentos, Florianópolis, Brazil
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Layered Double Hydroxides for the Catalytic Isomerization of Linoleic Acid to Conjugated Linoleic Acids (CLAs). CHEMENGINEERING 2019. [DOI: 10.3390/chemengineering3010030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Several hydrotalcite-type compounds with different divalent (Mg2+, Ni2+, Cu2+, Zn2+) and trivalent (Al3+, Cr3+) cations and different ratio compositions were tested for the isomerization of linoleic acid in order to study their role on the obtention of specific conjugated linoleic acids (CLAs) with anticarcinogenic and nutritional properties. This is a complex reaction due to the high number of possible isomers of linoleic acid together with the significant competition of the isomerization reaction with other secondary undesired reactions. All catalysts showed very high conversions of linoleic acid, but condensation products were mainly obtained, especially for the hydrotalcite-type compounds with higher Mg/Al ratios due to their higher Brønsted basicity and for the catalysts with higher Ni2+ content or with the presence of Cu2+, Zn2+ in the layers because of the influence of the higher acidity of these cations on the Brønsted basicity of the hydroxides. The best results were achieved for the catalysts with Mg/Al ratio around 2.5–3, resulting in 29–38% of selectivity to the identified CLAs.
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Cassiem W, de Kock M. The anti-proliferative effect of apricot and peach kernel extracts on human colon cancer cells in vitro. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:32. [PMID: 30696432 PMCID: PMC6352493 DOI: 10.1186/s12906-019-2437-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 01/14/2019] [Indexed: 12/01/2022]
Abstract
Background Colorectal malignant neoplasms is one of the leading causes of death in both men and women in the developed world and the incidence has recently increased markedly in South Africa. Studies have highlighted the beneficial effects of Amygdalin, a cyanogenic compound found in both peach and apricot kernels, in its ability to suppress the development of colon cancer. The focus of this study was to investigate the potential anti-proliferative properties of various apricot and peach kernels extractions from South Africa and China and to monitor alterations in cell cycle kinetics in colon cancer cells. Methods Studies were conducted on HT-29 colon cancer cells. The interactive role of three different kernel extractions on the modulation of cell proliferation, apoptosis and cell cycle progression was monitored over 24, 48 and 72 h periods. Results After 24 h, all extracts of the South African apricot kernels had a dose related bi-phasic proliferative effect on the HT-29 cells. It stimulated cell proliferation at the lowest and highest concentrations while at 500 μg/mL it inhibited cell proliferation. In contrast, after 72 h, the low concentration inhibited cell proliferation while the 500 μg/mL extracts stimulated cell proliferation. Morphological changes were observed in cells incubated with Chinese kernel extracts after 24 h and South African kernel treatment (1000 μg/mL) after 72 h. A possible intra-S-phase block after 24 and 48 h exposure to South African hydrophilic kernel extracts was observed. This transient block that is more concerned with tolerating and accommodating damage during replication rather than repairing it, could explain the initial anti-proliferative effects observed after 24 h exposure to the various Chinese kernel extract concentrations. Conclusion Abrogation of the block by exhaustion of the cyanide production, most likely allowed the cells to resume the cell cycle and continue into mitosis, whereas low ATP levels caused by the presence of amygdalin in the kernels, can also cause the induction of pycnosis or necrosis. These results highlight the possible mechanisms of growth inhibition by amygdalin containing extracts and may contribute towards the development of dietary anti-cancer therapies.
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In vitro–fermented raw and roasted walnuts induce expression of CAT and GSTT2 genes, growth inhibition, and apoptosis in LT97 colon adenoma cells. Nutr Res 2017; 47:72-80. [DOI: 10.1016/j.nutres.2017.09.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 07/18/2017] [Accepted: 09/13/2017] [Indexed: 12/21/2022]
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Niezgoda N, Gliszczyńska A, Kempińska K, Wietrzyk J, Wawrzeńczyk C. Synthesis and evaluation of cytotoxic activity of conjugated linoleic acid derivatives (esters, alcohols, and their acetates) toward cancer cell lines. EUR J LIPID SCI TECH 2017. [DOI: 10.1002/ejlt.201600470] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Natalia Niezgoda
- Department of Chemistry; Wrocław University of Environmental and Life Sciences; Wrocław Poland
| | - Anna Gliszczyńska
- Department of Chemistry; Wrocław University of Environmental and Life Sciences; Wrocław Poland
| | - Katarzyna Kempińska
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy; Polish Academy of Sciences; Wrocław Poland
| | - Joanna Wietrzyk
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy; Polish Academy of Sciences; Wrocław Poland
| | - Czesław Wawrzeńczyk
- Department of Chemistry; Wrocław University of Environmental and Life Sciences; Wrocław Poland
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Kumari S, Yong Meng G, Ebrahimi M. Conjugated linoleic acid as functional food in poultry products: A review. INTERNATIONAL JOURNAL OF FOOD PROPERTIES 2016. [DOI: 10.1080/10942912.2016.1168835] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Suriya Kumari
- Institute of Tropical Agriculture, Universiti Putra Malaysia, Persiaran UPM-Serdang, Serdang Selangor, Malaysia
| | - Goh Yong Meng
- Institute of Tropical Agriculture, Universiti Putra Malaysia, Persiaran UPM-Serdang, Serdang Selangor, Malaysia
- Faculty of Veterinary Medicine, Universiti Putra Malaysia, Persiaran UPM-Serdang, Serdang Selangor, Malaysia
| | - Mahdi Ebrahimi
- Faculty of Veterinary Medicine, Universiti Putra Malaysia, Persiaran UPM-Serdang, Serdang Selangor, Malaysia
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Aimola IA, Inuwa HM, Nok AJ, Mamman AI, Bieker JJ. Cis-vaccenic acid induces differentiation and up-regulates gamma globin synthesis in K562, JK1 and transgenic mice erythroid progenitor stem cells. Eur J Pharmacol 2016; 776:9-18. [PMID: 26879870 DOI: 10.1016/j.ejphar.2016.02.041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 02/11/2016] [Accepted: 02/11/2016] [Indexed: 12/27/2022]
Abstract
Gamma globin induction remains a promising pharmacological therapeutic treatment mode for sickle cell anemia and beta thalassemia, however Hydroxyurea remains the only FDA approved drug which works via this mechanism. In this regard, we assayed the γ-globin inducing capacity of Cis-vaccenic acid (CVA). CVA induced differentiation of K562, JK1 and transgenic mice primary bone marrow hematopoietic progenitor stem cells. CVA also significantly up-regulated γ-globin gene expression in JK-1 and transgenic mice bone marrow erythroid progenitor stem cells (TMbmEPSCs) but not K562 cells without altering cell viability. Increased γ-globin expression was accompanied by KLF1 suppression in CVA induced JK-1 cells. Erythropoietin induced differentiation of JK-1 cells 24h before CVA induction did not significantly alter CVA induced differentiation and γ-globin expression in JK-1 cells. Inhibition of JK-1 and Transgenic mice bone marrow erythroid progenitor stem cells Fatty acid elongase 5 (Elovl5) and Δ(9) desaturase suppressed the γ-globin inductive effects of CVA. CVA treatment failed to rescue γ-globin expression in Elovl5 and Δ(9)-desaturase inhibited cells 48 h post inhibition in JK-1 cells. The data suggests that CVA directly modulates differentiation of JK-1 and TMbmEPSCs, and indirectly modulates γ-globin gene expression in these cells. Our findings provide important clues for further evaluations of CVA as a potential fetal hemoglobin therapeutic inducer.
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Affiliation(s)
- Idowu A Aimola
- Department of Biochemistry, Ahmadu Bello University, Zaria 800001, Nigeria; Africa Center for Excellence on Neglected Tropical Diseases and Forensic Biotechnology, Ahmadu Bello University, Zaria 800001, Nigeria; Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
| | - Hajiya M Inuwa
- Department of Biochemistry, Ahmadu Bello University, Zaria 800001, Nigeria; Africa Center for Excellence on Neglected Tropical Diseases and Forensic Biotechnology, Ahmadu Bello University, Zaria 800001, Nigeria
| | - Andrew J Nok
- Department of Biochemistry, Ahmadu Bello University, Zaria 800001, Nigeria; Africa Center for Excellence on Neglected Tropical Diseases and Forensic Biotechnology, Ahmadu Bello University, Zaria 800001, Nigeria
| | - Aisha I Mamman
- Department of Hematology, Ahmadu Bello University Teaching Hospital, Zaria 800001, Nigeria
| | - James J Bieker
- Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA
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Lima A, Otaviano A, Laureano M, Galeazzi P, de Camargo GM, Thomazine R, Tonhati H. Partial genetic characterization of Stearoyl Coa-Desaturase’s structural region in Bubalus bubalis. ITALIAN JOURNAL OF ANIMAL SCIENCE 2016. [DOI: 10.4081/ijas.2007.s2.287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Niezgoda N, Gliszczyńska A, Gładkowski W, Chojnacka A, Kiełbowicz G, Wawrzeńczyk C. Production of concentrates of CLA obtained from sunflower and safflower and their application to the lipase‐catalyzed acidolysis of egg yolk phosphatidylcholine. EUR J LIPID SCI TECH 2016. [DOI: 10.1002/ejlt.201500589] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Natalia Niezgoda
- Department of ChemistryWroclaw University of Environmental and Life SciencesWrocławPoland
| | - Anna Gliszczyńska
- Department of ChemistryWroclaw University of Environmental and Life SciencesWrocławPoland
| | - Witold Gładkowski
- Department of ChemistryWroclaw University of Environmental and Life SciencesWrocławPoland
| | - Anna Chojnacka
- Department of ChemistryWroclaw University of Environmental and Life SciencesWrocławPoland
| | - Grzegorz Kiełbowicz
- Department of ChemistryWroclaw University of Environmental and Life SciencesWrocławPoland
| | - Czesław Wawrzeńczyk
- Department of ChemistryWroclaw University of Environmental and Life SciencesWrocławPoland
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Caredda M, Addis M, Ibba I, Leardi R, Scintu MF, Piredda G, Sanna G. Prediction of fatty acid content in sheep milk by Mid-Infrared spectrometry with a selection of wavelengths by Genetic Algorithms. Lebensm Wiss Technol 2016. [DOI: 10.1016/j.lwt.2015.08.048] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Induction of apoptosis in MCF-7 human breast cancer cells by Khz (fusion of Ganoderma lucidum and Polyporus umbellatus mycelium). Mol Med Rep 2015; 13:1243-9. [DOI: 10.3892/mmr.2015.4655] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 09/01/2015] [Indexed: 11/05/2022] Open
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Faghfoori Z, Pourghassem Gargari B, Saber Gharamaleki A, Bagherpour H, Yari Khosroushahi A. Cellular and molecular mechanisms of probiotics effects on colorectal cancer. J Funct Foods 2015; 18:463-472. [DOI: 10.1016/j.jff.2015.08.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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In vitro fermentation of nuts results in the formation of butyrate and c9,t11 conjugated linoleic acid as chemopreventive metabolites. Eur J Nutr 2015; 55:2063-73. [PMID: 26286349 DOI: 10.1007/s00394-015-1020-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 08/10/2015] [Indexed: 01/09/2023]
Abstract
PURPOSE The consumption of foods rich in dietary fiber and polyunsaturated fatty acids such as nuts can contribute to a healthy diet. Therefore, the formation of fermentation end-products which might exert chemopreventive effects regarding colon cancer was investigated after an in vitro simulated digestion and fermentation of nuts using human fecal microbiota. METHODS Fermentation supernatants (FS) and pellets (FP) were obtained after an in vitro fermentation of hazelnuts, almonds, macadamia, pistachios and walnuts. Short-chain fatty acids (SCFA) and bile acids (BA) in FS as well as fatty acids in FP were analyzed via gas chromatography. Malondialdehyde (MDA) levels in FS were determined photometrically. RESULTS Fermentation of nuts resulted in 1.9- to 2.8-fold higher concentrations of SCFA compared to the control and a shift of molar ratios toward butyrate production. In vitro fermentation resulted in the formation of vaccenic acid (C18:1t11, 32.1 ± 3.2 % FAME; fatty acid methyl ester) and conjugated linoleic acid (c9,t11 CLA, 2.4 ± 0.7 % FAME) exclusively in fermented walnut samples. Concentrations of secondary BA deoxycholic-/iso-deoxycholic acid (6.8-24.1-fold/4.9-10.9-fold, respectively) and levels of MDA (1.3-fold) were significantly reduced in fermented nut samples compared to the control. CONCLUSION This is the first study that demonstrates the ability of the human fecal microbiota to convert polyunsaturated fatty acids from walnuts to c9,t11 CLA as a potential chemopreventive metabolite. In addition, the production of butyrate and reduction in potential carcinogens such as secondary BA and lipid peroxidation products might contribute to the protective effects of nuts regarding colon cancer development.
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Abstract
The ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) are two major families of PUFAs present as essential cellular components which possess diverse bioactivities. The ω-3s, mainly found in seafood, are associated with many beneficial effects on human health, while the ω-6s are more abundant in our daily diet and could be implicated in many pathological processes including cancer development. Increasing evidence suggests that the adverse effects of ω-6s may be largely attributed to arachidonic acid (AA, a downstream ω-6) and the metabolite prostaglandin E2 (PGE2) that stems from its cyclooxygenase (COX)-catalyzed lipid peroxidation. On the other hand, two of AA's upstream ω-6s, γ-linolenic acid (GLA) and dihomo-γ-linolenic acid (DGLA), are shown to possess certain anti-cancer activities, including inducing cell apoptosis and inhibiting cell proliferation. In this paper, we review the documented anti-cancer activities of ω-6 PUFAs, including the recent findings regarding the anti-cancer effects of free radical-mediated DGLA peroxidation. The possible mechanisms and applications of DGLA (and other ω-6s) in inducing anti-cancer activity are also discussed. Considering the wide availability of ω-6s in our daily diet, the study of the potential beneficial effect of ω-6 PUFAs may guide us to develop an ω-6-based diet care strategy for cancer prevention and treatment.
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Affiliation(s)
| | - Steven Y Qian
- Department of Pharmaceutical Sciences, College of Pharmacy, Nursing and Allied Sciences, North Dakota State University, Fargo, ND, USA
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Niezgoda N, Gliszczyńska A, Gładkowski W, Kempińska K, Wietrzyk J, Wawrzeńczyk C. Phosphatidylcholine with cis-9,trans-11 and trans-10,cis-12 Conjugated Linoleic Acid Isomers: Synthesis and Cytotoxic Studies. Aust J Chem 2015. [DOI: 10.1071/ch14606] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Novel phosphatidylcholines and lysophosphatidylcholines with cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid (CLA) were synthesized in high yields (75–99 %). The in vitro cytotoxic activities of these compounds against three human cancer cell lines (HL-60, MCF-7, and HT-29) were evaluated. The results revealed that there are differences in the activity between phosphatidylcholine with cis-9,trans-11 and trans-10,cis-12 CLA acyl groups. 1,2-Di(9Z,11E)-octadecadienoyl-sn-glycero-3-phosphocholine was the most potent cytotoxic agent among all tested CLA derivatives and its IC50 (concentration of a compound that inhibits the proliferation of 50 % of the cancer cell population) was 29.4 µM against HL-60. Moreover, phosphatidylcholines with CLA acyls exhibited much lower cytotoxicity against non-cancer cells (Balb/3T3) than free CLA isomers.
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Khz-cp (crude polysaccharide extract obtained from the fusion of Ganoderma lucidum and Polyporus umbellatus mycelia) induces apoptosis by increasing intracellular calcium levels and activating P38 and NADPH oxidase-dependent generation of reactive oxygen species in SNU-1 cells. Altern Ther Health Med 2014; 14:236. [PMID: 25012725 PMCID: PMC4227278 DOI: 10.1186/1472-6882-14-236] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 07/01/2014] [Indexed: 12/05/2022]
Abstract
Background Khz-cp is a crude polysaccharide extract that is obtained after nuclear fusion in Ganoderma lucidum and Polyporus umbellatus mycelia (Khz). It inhibits the growth of cancer cells. Methods Khz-cp was extracted by solvent extraction. The anti-proliferative activity of Khz-cp was confirmed by using Annexin-V/PI-flow cytometry analysis. Intracellular calcium increase and measurement of intracellular reactive oxygen species (ROS) were performed by using flow cytometry and inverted microscope. SNU-1 cells were treated with p38, Bcl-2 and Nox family siRNA. siRNA transfected cells was employed to investigate the expression of apoptotic, growth and survival genes in SNU-1 cells. Western blot analysis was performed to confirm the expression of the genes. Results In the present study, Khz-cp induced apoptosis preferentially in transformed cells and had only minimal effects on non-transformed cells. Furthermore, Khz-cp was found to induce apoptosis by increasing the intracellular Ca2+ concentration ([Ca2+]i) and activating P38 to generate reactive oxygen species (ROS) via NADPH oxidase and the mitochondria. Khz-cp-induced apoptosis was caspase dependent and occurred via a mitochondrial pathway. ROS generation by NADPH oxidase was critical for Khz-cp-induced apoptosis, and although mitochondrial ROS production was also required, it appeared to occur secondary to ROS generation by NADPH oxidase. Activation of NADPH oxidase was shown by the translocation of the regulatory subunits p47phox and p67phox to the cell membrane and was necessary for ROS generation by Khz-cp. Khz-cp triggered a rapid and sustained increase in [Ca2+]i that activated P38. P38 was considered to play a key role in the activation of NADPH oxidase because inhibition of its expression or activity abrogated membrane translocation of the p47phox and p67phox subunits and ROS generation. Conclusions In summary, these data indicate that Khz-cp preferentially induces apoptosis in cancer cells and that the signaling mechanisms involve an increase in [Ca2+]i, P38 activation, and ROS generation via NADPH oxidase and mitochondria.
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Trans vaccenic acid (trans-11 18:1), a precursor of cis-9, trans-11-conjugated linoleic acid, exerts a direct anti-carcinogenic function in T47D breast carcinoma cells. Food Sci Biotechnol 2014. [DOI: 10.1007/s10068-014-0087-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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Luo X, Zhang L, Li H, Zhang S, Jiao Y, Wang S, Xue C, Fan R. Comparison of enzymatic activity of two linoleic acid isomerases expressed in E. coli. Mol Biol Rep 2013; 40:5913-9. [DOI: 10.1007/s11033-013-2698-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 09/14/2013] [Indexed: 11/29/2022]
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Tamari F, Tychowski J, Lorentzen L. Determination of tolerable fatty acids and cholera toxin concentrations using human intestinal epithelial cells and BALB/c mouse macrophages. J Vis Exp 2013:e50491. [PMID: 23748896 DOI: 10.3791/50491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
The positive role of fatty acids in the prevention and alleviation of non-human and human diseases have been and continue to be extensively documented. These roles include influences on infectious and non-infectious diseases including prevention of inflammation as well as mucosal immunity to infectious diseases. Cholera is an acute intestinal illness caused by the bacterium Vibrio cholerae. It occurs in developing nations and if left untreated, can result in death. While vaccines for cholera exist, they are not always effective and other preventative methods are needed. We set out to determine tolerable concentrations of three fatty acids (oleic, linoleic and linolenic acids) and cholera toxin using mouse BALB/C macrophages and human intestinal epithelial cells, respectively. We solubilized the above fatty acids and used cell proliferation assays to determine the concentration ranges and specific concentrations of the fatty acids that are not detrimental to human intestinal epithelial cell viability. We solubilized cholera toxin and used it in an assay to determine the concentration ranges and specific concentrations of cholera toxin that do not statistically decrease cell viability in BALB/C macrophages. We found the optimum fatty acid concentrations to be between 1-5 ng/μl, and that for cholera toxin to be < 30 ng per treatment. This data may aid future studies that aim to find a protective mucosal role for fatty acids in prevention or alleviation of cholera infections.
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Affiliation(s)
- Farshad Tamari
- Department of Biological Sciences, Kingsborough Community College, USA.
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Mohammadzadeh M, Faramarzi E, Mahdavi R, Nasirimotlagh B, Asghari Jafarabadi M. Effect of conjugated linoleic acid supplementation on inflammatory factors and matrix metalloproteinase enzymes in rectal cancer patients undergoing chemoradiotherapy. Integr Cancer Ther 2013; 12:496-502. [PMID: 23632235 DOI: 10.1177/1534735413485417] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES The aims of this study were to determine the effect of conjugated linoleic acid (CLA) supplementation on inflammatory factors and matrix metalloproteinase (MMP) enzymes in rectal cancer patients undergoing chemoradiothetrapy. METHOD AND MATERIAL In this randomized, double-blind, placebo-controlled pilot study, 34 volunteer patients with rectal cancer undergoing chemoradiotherapy assigned into the CLA group (n = 16), receiving 3 g CLA/d, and placebo group (n = 18) receiving placebo capsules (sunflower oil) for 6 weeks. The supplementation began 1 week before starting RT (loading period) and continued every day during treatment. Before and after intervention, serum tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, MMP-2, MMP-9, and high-sensitivity C-reactive protein (hsCRP) were measured by enzyme-linked immunosorbent assay (ELISA) kits and immunoturbidimetric method, respectively. Independent t tests and paired t tests were used to compare parameters between and within groups, respectively. RESULTS In the CLA group, the mean serum TNF-α, IL-1β, hsCRP, MMP-9, and MMP-2 levels reduced insignificantly. However, significant changes in TNF-α (P = 0.04), hsCRP (P = 0.03), and MMP-9 (P = 0.04) concentrations were observed in the CLA group when compared with the placebo group. The mean serum IL-6 level remained unchanged in the CLA group but increased remarkably in the placebo group. CONCLUSION According to our results, CLA supplementation improved inflammatory factors, MMP-2, and MMP-9 as biomarkers of angiogenesis and tumor invasion. It seems that CLA may provide new complementary treatment by reducing tumor invasion and resistance to cancer treatment in patients with rectal cancer.
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Trans-10, cis-12 conjugated linoleic acid induced cell death in human colon cancer cells through reactive oxygen species-mediated ER stress. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1831:759-68. [DOI: 10.1016/j.bbalip.2013.01.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 12/13/2012] [Accepted: 01/09/2013] [Indexed: 11/18/2022]
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Niezgoda N, Mituła P, Kempińska K, Wietrzyk J, Wawrzeńczyk C. Synthesis of Phosphatidylcholine with Conjugated Linoleic Acid and Studies on Its Cytotoxic Activity. Aust J Chem 2013. [DOI: 10.1071/ch12404] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Phospholipids with conjugated linoleic acid (CLA), which are potential lipid prodrugs, were synthesised. CLA was obtained by the alkali-isomerisation of linoleic acid and was subsequently used in the synthesis of 1,2-di(conjugated)linoleoyl-sn-glycero-3-phosphocholine in good (82 %) yield. 1-Palmitoyl-2-(conjugated)linoleoyl-sn-glycero-3-phosphocholine was obtained by a two-step synthesis in 87 % yield. All the compounds were tested in an in vitro cytotoxicity assay against two human cancer cell lines, HL-60 and MCF-7, and a mouse fibroblast cell line, Balb/3T3. The free form of CLA exhibited the highest activity against all cancer cell lines. Results obtained for the Balb/3T3 line proved that phosphatidylcholine derivatives decreased the cytotoxic effect of CLA against healthy cell lines.
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Kim TH, Kim JS, Kim ZH, Huang RB, Wang RS. Khz (fusion of Ganoderma lucidum and Polyporus umbellatus mycelia) induces apoptosis by increasing intracellular calcium levels and activating JNK and NADPH oxidase-dependent generation of reactive oxygen species. PLoS One 2012; 7:e46208. [PMID: 23056263 PMCID: PMC3466234 DOI: 10.1371/journal.pone.0046208] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 08/29/2012] [Indexed: 01/25/2023] Open
Abstract
Khz is a compound derived from the fusion of Ganoderma lucidum and Polyporus umbellatus mycelia that inhibits the growth of cancer cells. The results of the present study show that Khz induced apoptosis preferentially in transformed cells and had only minimal effects on non-transformed cells. Furthermore, Khz induced apoptosis by increasing the intracellular Ca2+ concentration ([Ca2+]i) and activating JNK to generate reactive oxygen species (ROS) via NADPH oxidase and the mitochondria. Khz-induced apoptosis was caspase-dependent and occurred via a mitochondrial pathway. ROS generation by NADPH oxidase was critical for Khz-induced apoptosis, and although mitochondrial ROS production was also required, it appeared to occur secondary to ROS generation by NADPH oxidase. Activation of NADPH oxidase was demonstrated by the translocation of regulatory subunits p47phox and p67phox to the cell membrane and was necessary for ROS generation by Khz. Khz triggered a rapid and sustained increase in [Ca2+]i, which activated JNK. JNK plays a key role in the activation of NADPH oxidase because inhibition of its expression or activity abrogated membrane translocation of the p47phox and p67phox subunits and ROS generation. In summary, these data indicate that Khz preferentially induces apoptosis in cancer cells, and the signaling mechanisms involve an increase in [Ca2+]i, JNK activation, and ROS generation via NADPH oxidase and mitochondria.
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Affiliation(s)
- Tae Hwan Kim
- Department of Radiotherapy, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Ju sung Kim
- Clinical Medicine, Harbin Medical University, Harbin, China
| | - Zoo haye Kim
- Graduate School of Information Science, Nagoya University, Nagoya, Japan
| | - Ren Bin Huang
- Graduate School of Pharmacology, Guangxi Medical University, Nanning, China
| | - Ren Sheng Wang
- Department of Radiotherapy, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
- * E-mail:
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Enhanced anticancer activity of gemcitabine coupling with conjugated linoleic acid against human breast cancer in vitro and in vivo. Eur J Pharm Biopharm 2012; 82:401-9. [PMID: 22728546 DOI: 10.1016/j.ejpb.2012.06.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 06/04/2012] [Accepted: 06/12/2012] [Indexed: 11/24/2022]
Abstract
Gemcitabine (GEM) is a nucleoside analog agent against a wide variety of tumors. To overcome its limitation of rapid metabolism in vivo that results in short circulation time and poor antitumor efficacy, a novel prodrug (CLA-GEM conjugate) has been developed through the covalent coupling of conjugated linoleic acid (CLA) to N(4)-amino group of GEM. The chemical structure of CLA-GEM conjugate was identified by NMR, FTIR and other methods. From in vitro tests, it was demonstrated that the linkage with CLA increased the plasma stability of GEM as well as the antitumor activity against human breast tumor cells (MCF-7). Importantly, it also altered the transport pattern of GEM across cell membrane (MCF-7 and MDA-MB-231), evidenced by the little effect of nucleoside transporter inhibitors (NBMPR and dipyridamole) on the IC(50) values of CLA-GEM, instead of the great effect on that of unmodified GEM. In vivo pharmacokinetic study showed that the CLA-GEM conjugate had a longer plasma half-life and a higher bioavailability compared to that of unmodified GEM. Significant stronger antitumor activity was observed in the nude mice xenografted MCF-7 breast tumor after treated with CLA-GEM than that of unmodified GEM, while no significant body weight loss was found in all treatments. In conclusion, the novel CLA-GEM conjugate prepared in this study would be a promising prodrug of gemcitabine for future clinical use.
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Abstract
The primary purpose of the present review was to determine if the scientific evidence available for potential human health benefits of conjugated linoleic acid (CLA) is sufficient to support health claims on foods based on milk naturally enriched with cis-9, trans-11-CLA (c9, t11-CLA). A search of the scientific literature was conducted and showed that almost all the promising research results that have emerged in relation to cancer, heart health, obesity, diabetes and bone health have been in animal models or in vitro. Most human intervention studies have utilised synthetic CLA supplements, usually a 50:50 blend of c9, t11-CLA and trans-10, cis-12-CLA (t10, c12-CLA). Of these studies, the only evidence that is broadly consistent is an effect on body fat and weight reduction. A previous review of the relevant studies found that 3.2 g CLA/d resulted in a modest body fat loss in human subjects of about 0.09 kg/week, but this effect was attributed to the t10, c12-CLA isomer. There is no evidence of a consistent benefit of c9, t11-CLA on any health conditions; and in fact both synthetic isomers, particularly t10, c12-CLA, have been suspected of having pro-diabetic effects in individuals who are already at risk of developing diabetes. Four published intervention studies using naturally enriched CLA products were identified; however, the results were inconclusive. This may be partly due to the differences in the concentration of CLA administered in animal and human studies. In conclusion, further substantiation of the scientific evidence relating to CLA and human health benefits are required before health claims can be confirmed.
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Wang T, Cai G, Qiu Y, Fei N, Zhang M, Pang X, Jia W, Cai S, Zhao L. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME JOURNAL 2011; 6:320-9. [PMID: 21850056 DOI: 10.1038/ismej.2011.109] [Citation(s) in RCA: 937] [Impact Index Per Article: 66.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite a long-suspected role in the development of human colorectal cancer (CRC), the composition of gut microbiota in CRC patients has not been adequately described. In this study, fecal bacterial diversity in CRC patients (n=46) and healthy volunteers (n=56) were profiled by 454 pyrosequencing of the V3 region of the 16S ribosomal RNA gene. Both principal component analysis and UniFrac analysis showed structural segregation between the two populations. Forty-eight operational taxonomic units (OTUs) were identified by redundancy analysis as key variables significantly associated with the structural difference. One OTU closely related to Bacteroides fragilis was enriched in the gut microbiota of CRC patients, whereas three OTUs related to Bacteroides vulgatus and Bacteroides uniformis were enriched in that of healthy volunteers. A total of 11 OTUs belonging to the genera Enterococcus, Escherichia/Shigella, Klebsiella, Streptococcus and Peptostreptococcus were significantly more abundant in the gut microbiota of CRC patients, and 5 OTUs belonging to the genus Roseburia and other butyrate-producing bacteria of the family Lachnospiraceae were less abundant. Real-time quantitative PCR further validated the significant reduction of butyrate-producing bacteria in the gut microbiota of CRC patients by measuring the copy numbers of butyryl-coenzyme A CoA transferase genes (Mann-Whitney test, P<0.01). Reduction of butyrate producers and increase of opportunistic pathogens may constitute a major structural imbalance of gut microbiota in CRC patients.
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Affiliation(s)
- Tingting Wang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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Hsu YC, Ip MM. Conjugated linoleic acid-induced apoptosis in mouse mammary tumor cells is mediated by both G protein coupled receptor-dependent activation of the AMP-activated protein kinase pathway and by oxidative stress. Cell Signal 2011; 23:2013-20. [PMID: 21821121 DOI: 10.1016/j.cellsig.2011.07.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 06/30/2011] [Accepted: 07/13/2011] [Indexed: 12/19/2022]
Abstract
Conjugated linoleic acid (CLA) has shown chemopreventive activity in several tumorigenesis models, in part through induction of apoptosis. We previously demonstrated that the t10,c12 isomer of CLA induced apoptosis of TM4t mouse mammary tumor cells through both mitochondrial and endoplasmic reticulum (ER) stress pathways, and that the AMP-activated protein kinase (AMPK) played a critical role in the apoptotic effect. In the current study, we focused on the upstream pathways by which AMPK was activated, and additionally evaluated the contributing role of oxidative stress to apoptosis. CLA-induced activation of AMPK and/or induction of apoptosis were inhibited by infection of TM4t cells with an adenovirus expressing a peptide which blocks the interaction between the G protein coupled receptor (GPCR) and Gα(q), by the phospholipase C (PLC) inhibitor U73122, by the inositol trisphosphate (IP(3)) receptor inhibitor 2-APB, by the calcium/calmodulin-dependent protein kinase kinase α (CaMKK) inhibitor STO-609 and by the intracellular Ca(2+) chelator BAPTA-AM. This suggests that t10,c12-CLA may exert its apoptotic effect by stimulating GPCR through Gα(q) signaling, activation of phosphatidylinositol-PLC, followed by binding of the PLC-generated IP(3) to its receptor on the ER, triggering Ca(2+) release from the ER and finally stimulating the CaMKK-AMPK pathway. t10,c12-CLA also increased oxidative stress and lipid peroxidation, and antioxidants blocked its apoptotic effect, as well as the CLA-induced activation of p38 MAPK, a downstream effector of AMPK. Together these data elucidate two major pathways by which t10,c12-CLA induces apoptosis, and suggest a point of intersection of the two pathways both upstream and downstream of AMPK.
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Affiliation(s)
- Yung-Chung Hsu
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
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35
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Heinze VM, Actis AB. Dietary conjugated linoleic acid and long-chain n-3 fatty acids in mammary and prostate cancer protection: a review. Int J Food Sci Nutr 2011; 63:66-78. [PMID: 21762028 DOI: 10.3109/09637486.2011.598849] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The role of dietary fatty acids on cancer is still controversial. To examine the current literature on the protective role of conjugated linoleic acid (CLA) and marine long-chain fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and the risk of breast and prostate cancer, data from 41 case-control and cohort studies and relevant in vitro and animal experiments were included in this 2000-2010 revision. Epidemiological studies on CLA intake or its tissue concentration related to breast and prostate tumorigenesis are not conclusive; EPA and DHA intake have shown important inverse associations just in some studies. Additional research on the analysed association is required.
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Affiliation(s)
- Verónica M Heinze
- Facultad de Ciencias de la Salud, Universidad Adventista del Plata, 25 de Mayo 99, 3103 Libertador San Martín, Entre Ríos, Argentina.
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Gebauer SK, Chardigny JM, Jakobsen MU, Lamarche B, Lock AL, Proctor SD, Baer DJ. Effects of ruminant trans fatty acids on cardiovascular disease and cancer: a comprehensive review of epidemiological, clinical, and mechanistic studies. Adv Nutr 2011; 2:332-54. [PMID: 22332075 PMCID: PMC3125683 DOI: 10.3945/an.111.000521] [Citation(s) in RCA: 176] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
There are 2 predominant sources of dietary trans fatty acids (TFA) in the food supply, those formed during the industrial partial hydrogenation of vegetable oils (iTFA) and those formed by biohydrogenation in ruminants (rTFA), including vaccenic acid (VA) and the naturally occurring isomer of conjugated linoleic acid, cis-9, trans-11 CLA (c9,t11-CLA). The objective of this review is to evaluate the evidence base from epidemiological and clinical studies to determine whether intake of rTFA isomers, specifically VA and c9,t11-CLA, differentially affects risk of cardiovascular disease (CVD) and cancer compared with iTFA. In addition, animal and cell culture studies are reviewed to explore potential pro- and antiatherogenic mechanisms of VA and c9,t11-CLA. Some epidemiological studies suggest that a positive association with coronary heart disease risk exists between only iTFA isomers and not rTFA isomers. Small clinical studies have been conducted to establish cause-and-effect relationships between these different sources of TFA and biomarkers or risk factors of CVD with inconclusive results. The lack of detection of treatment effects reported in some studies may be due to insufficient statistical power. Many studies have used doses of rTFA that are not realistically attainable via diet; thus, further clinical studies are warranted. Associations between iTFA intake and cancer have been inconsistent, and associations between rTFA intake and cancer have not been well studied. Clinical studies have not been conducted investigating the cause-and-effect relationship between iTFA and rTFA intake and risk for cancers. Further research is needed to determine the health effects of VA and c9,t11-CLA in humans.
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Affiliation(s)
- Sarah K. Gebauer
- USDA, Agricultural Research Service, Beltsville Human Nutrition Research Center, Beltsville, MD 20705
| | - Jean-Michel Chardigny
- Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63000 Clermont-Ferrand, France
| | - Marianne Uhre Jakobsen
- Department of Epidemiology, School of Public Health, Aarhus University, DK-8000 Aarhus, Denmark
| | - Benoît Lamarche
- Institute on Nutraceuticals and Functional Foods, Laval University, Québec, QC, Canada G1V 0A
| | - Adam L. Lock
- Department of Animal Science, Michigan State University, East Lansing, MI 48864
| | - Spencer D. Proctor
- Metabolic and Cardiovascular Laboratory, Alberta Institute for Human Nutrition and Alberta Diabetes Institute, University of Alberta, AB, Canada T6G2P5
| | - David J. Baer
- USDA, Agricultural Research Service, Beltsville Human Nutrition Research Center, Beltsville, MD 20705
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Trans-10, cis-12-conjugated linoleic acid modulates NF-κB activation and TNF-α production in porcine peripheral blood mononuclear cells via a PPARγ-dependent pathway. Br J Nutr 2010; 105:1329-36. [DOI: 10.1017/s000711451000499x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The activation of PPARγ by ligands, including conjugated linoleic acid (CLA) isomers, plays an important role in the immune response. Among CLA isomers, trans-10, cis-12 (t10c12)-CLA is known to participate in the modulation of pro-inflammatory cytokine secretion. The aim of the present study was to assess the effect of t10c12-CLA on PPARγ activation, NF-κB activation and TNF-α expression in lipopolysaccharide (LPS)-naive and LPS-stimulated porcine peripheral blood mononuclear cells (PBMC). In addition, the effect of PPARγ inhibition on NF-κB activation and TNF-α expression in porcine PBMC was examined. t10c12-CLA was found to increase TNF-α expression and NF-κB activity in LPS-naive porcine PBMC. In contrast, t10c12-CLA decreased TNF-α expression and NF-κB activity in LPS-stimulated porcine PBMC. t10c12-CLA up-regulated PPARγ activity and mRNA expression in both LPS-naive and LPS-stimulated porcine PBMC. GW9662, a PPARγ antagonist, completely negated the modulating effects of t10c12-CLA on TNF-α expression and NF-κB activity in both LPS-naive and LPS-stimulated porcine PBMC. These results suggest that t10c12-CLA can modulate TNF-α production and NF-κB activation by a PPARγ-dependent pathway in porcine PBMC.
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Jiang H, Liu N. Self-assembled β-lactoglobulin–conjugated linoleic acid complex for colon cancer-targeted substance. J Dairy Sci 2010; 93:3931-9. [DOI: 10.3168/jds.2010-3071] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2010] [Accepted: 03/28/2010] [Indexed: 11/19/2022]
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Shiraishi R, Iwakiri R, Fujise T, Kuroki T, Kakimoto T, Takashima T, Sakata Y, Tsunada S, Nakashima Y, Yanagita T, Fujimoto K. Conjugated linoleic acid suppresses colon carcinogenesis in azoxymethane-pretreated rats with long-term feeding of diet containing beef tallow. J Gastroenterol 2010; 45:625-35. [PMID: 20143104 DOI: 10.1007/s00535-010-0206-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Accepted: 01/12/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND We have indicated previously that long-term feeding of beef tallow increases colorectal cancer in rats. In this study, we investigated the effects of conjugated linoleic acid (CLA) on colon carcinogenesis in rats under long-term feeding of beef tallow diets, pretreated with azoxymethane (AOM). METHODS Six-week-old male Sprague-Dawley rats were fed with 10% beef tallow diet only, 10% beef tallow with 1% CLA in triglyceride form (CLA-TG), or 10% beef tallow with 1% CLA in free fatty acid form (CLA-FFA). Colon carcinogenesis was induced by two intraperitoneal injections of AOM. Aberrant crypt foci (ACFs) were examined at 12 weeks. Cancer, cell proliferation, apoptosis, Wnt signaling, and the arachidonic acid cascade were examined at 44 weeks. RESULTS At 12 weeks, CLA-TG and CLA-FFA attenuated the increase in ACFs induced by 10% beef tallow and AOM pretreatment. At 44 weeks, both forms of CLA attenuated multiple colon cancers, and CLA-FFA reduced the incidence of colon cancer to 50% of that seen with CLA-TG. CLA-TG and CLA-FFA decreased the number of 5-bromo-2'-deoxyuridine-positive cells in AOM-pretreated rats fed with 10% beef tallow. CLA-FFA increased the number of apoptotic cells and the activity of caspase-3 in the colon mucosa, and CLA-TG enhanced the activity of caspase-3. Both forms of CLA suppressed Wnt signaling and the arachidonic acid cascade in rats treated with beef tallow and AOM. CONCLUSION These results suggested that CLA-TG and CLA-FFA suppressed colon carcinogenesis in rats with long-term feeding of a 10% beef tallow diet, through several mechanisms. The results of the present study with rats might be applicable to humans.
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Affiliation(s)
- Ryosuke Shiraishi
- Department of Internal Medicine and Gastrointestinal Endoscopy, Saga Medical School, and Fujioka Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan
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Lau DSY, Archer MC. The 10t,12c isomer of conjugated linoleic acid inhibits fatty acid synthase expression and enzyme activity in human breast, colon, and prostate cancer cells. Nutr Cancer 2010; 62:116-21. [PMID: 20043266 DOI: 10.1080/01635580903191536] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The objective of this study was to determine whether downregulation of fatty acid synthase (FAS) expression and/or inhibition of its activity by the two major CLA isomers, 10t,12c and 9c,11t CLA, could contribute to their inhibitory effect on the growth of human breast (MCF-7), colon (HT-29) and prostate (LNCaP) cancer cell lines. We first confirmed and extended the results of others showing that the inhibitory action of CLA on proliferation is dependent on the cell type as well as the structure of the isomer, the 10,12 isomer being a more potent inhibitor than the 9,11 isomer in the concentration range 25-100 microM. By Western analysis, we showed that 10,12 CLA downregulated FAS expression in all of the cell lines in a concentration-dependent manner, but the 9,11 isomer had no effect. Both isomers inhibited FAS enzyme activity, but 10,12 CLA was again more potent than the 9,11 isomer. Our results suggest that downregulation of FAS by 10,12 CLA, but not by the 9,11 isomer, as well as inhibition of FAS enzyme activity by both isomers, may contribute to growth inhibition of cancer cells but only at relatively high concentrations.
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Cho HJ, Kwon GT, Park JHY. trans-10,cis-12 Conjugated linoleic acid induces depolarization of mitochondrial membranes in HT-29 human colon cancer cells: a possible mechanism for induction of apoptosis. J Med Food 2010; 12:952-8. [PMID: 19857056 DOI: 10.1089/jmf.2009.0056] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Conjugated linoleic acid (CLA), which is naturally present in a variety of foods such as milk fat and the meat of ruminant animals, has been demonstrated to exert chemoprotective effects in several tissues in experimental animals. CLA is a collective term, which denotes one or more positional and geometric isomers of octadecadienoic acid, with cis-9,trans-11 (c9t11) and trans-10,cis-12 CLA (t10c12) being the principal isomers in commercial preparations. We observed previously that physiological levels of CLA inhibited HT-29 cell growth, and the growth inhibitory effects of CLA were attributed to the effect of t10c12, but not c9t11. In the present study, we assessed the mechanisms by which physiological levels of CLA and t10c12 induce apoptosis in HT-29 cells. HT-29 cells were cultured for 3 days in serum-free medium in the presence of various concentrations of CLA (0-20 micromol/L) or t10c12 (0-4 micromol/L). Addition of CLA or t10c12 to culture medium resulted in a dose-dependent increase in the numbers of apoptotic cells. The results of western blot analysis of total cell lysates showed that CLA and t10c12 increased the levels of cleaved caspase-9, caspase-3, and poly(ADP-ribose) polymerase but did not alter the levels of Bcl-2 family member proteins. However, these fatty acids were shown to increase the translocation of Bad and Bax to the mitochondria, increase mitochondrial membrane permeability, and induce the release of cytochrome c and Smac/Diablo from the mitochondria. In addition, CLA and t10c12 diminished Akt content and Akt phosphorylation. These findings indicate that physiological levels of t10c12 induce apoptosis in HT-29 colon cancer cells, which is mediated via mitochondrion-mediated events associated with a decline in Akt activity, an increase in the translocation of the pro-apototic Bad and Bax to the mitochondria, and the subsequent disruption of normal mitochondrial membrane potential.
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Affiliation(s)
- Han Jin Cho
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Republic of Korea
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Bocca C, Bozzo F, Cannito S, Colombatto S, Miglietta A. CLA reduces breast cancer cell growth and invasion through ERalpha and PI3K/Akt pathways. Chem Biol Interact 2010; 183:187-93. [PMID: 19800873 DOI: 10.1016/j.cbi.2009.09.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2009] [Revised: 09/21/2009] [Accepted: 09/25/2009] [Indexed: 12/24/2022]
Abstract
We previously reported that conjugated linoleic acid (CLA), a naturally occurring fatty acid, inhibits the growth of ERalpha(+) MCF-7 and ERalpha(-) MDA-MB-231 human breast cancer cells by negative modulation of the ERK/MAPK pathway and apoptosis induction. Here we show that in these cell lines CLA also down-regulates the PI3K/Akt cascade. In MCF-7 cells CLA also triggers ERalpha/PP2A complex formation reducing the phosphorylation state and transcriptional activity of Eralpha whereas in MDA-MB-231 cells CLA does not induce PP2A activation. Moreover, CLA induces the expression of proteins involved in cell adhesion and inhibits cell migration and MMP-2 activity. These findings suggest that CLA may induce the down-regulation of ERalpha signalling and the reduction of cell invasion through the modulation of balancing between phosphatases and kinases.
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Affiliation(s)
- C Bocca
- Department of Experimental Medicine and Oncology, University of Torino, C.so Raffaello 30, 10125 Torino, Italy.
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Larsen AE, Crowe TC. Effects of conjugated linoleic acid on myogenic and inflammatory responses in a human primary muscle and tumor coculture model. Nutr Cancer 2010; 61:687-95. [PMID: 19838943 DOI: 10.1080/01635580902898750] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The antiproliferative and anti-inflammatory properties of conjugated linoleic acid (CLA) make it a potentially novel treatment in chronic inflammatory muscle wasting disease, particularly cancer cachexia. Human primary muscle cells were grown in coculture with MIA PaCa-2 pancreatic tumor cells and exposed to varying concentrations of c9,t11 and t10,c12 CLA. Expression of myogenic (Myf5, MyoD, myogenin, and myostatin) and inflammatory genes (CCL-2, COX-2, IL-8, and TNF-alpha) were measured by real-time PCR. The t10,c12 CLA isomer, but not the c9,t11 isomer, significantly decreased MIA PaCa-2 proliferation by between 15% and 19%. There was a marked decrease in muscle MyoD and myogenin expression (78% and 62%, respectively), but no change in either Myf5 or myostatin, in myotubes grown in coculture with MIA PaCa-2 cells. CLA had limited influence on these responses. A similar pattern of myogenic gene expression changes was observed in myotubes treated with TNF-alpha alone. Several-fold significant increases in CCL-2, COX-2, IL-8, and TNF-alpha expression in myotubes were observed with MIA PaCa-2 coculture. The c9,t11 CLA isomer significantly decreased basal expression of TNF-alpha in myotubes and could ameliorate its tumor-induced rise. The study provides insight into the anti-inflammatory and antiproliferative actions of CLA and its application as a therapeutic agent in inflammatory disease states.
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Affiliation(s)
- Amy E Larsen
- School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia
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Benjamin S, Spener F. Conjugated linoleic acids as functional food: an insight into their health benefits. Nutr Metab (Lond) 2009; 6:36. [PMID: 19761624 PMCID: PMC2754987 DOI: 10.1186/1743-7075-6-36] [Citation(s) in RCA: 159] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Accepted: 09/18/2009] [Indexed: 12/17/2022] Open
Abstract
This review evaluates the health benefits of the functional food, conjugated linoleic acids (CLA) - a heterogeneous group of positional and geometric isomers of linoleic acid predominantly found in milk, milk products, meat and meat products of ruminants. During the past couple of decades, hundreds of reports - principally based on in vitro, microbial, animal, and of late clinical trials on humans - have been accumulating with varying biological activities of CLA isomers. These studies highlight that CLA, apart form the classical nuclear transcription factors-mediated mechanism of action, appear to exhibit a number of inter-dependent molecular signalling pathways accounting for their reported health benefits. Such benefits relate to anti-obesitic, anti-carcinogenic, anti-atherogenic, anti-diabetagenic, immunomodulatory, apoptotic and osteosynthetic effects. On the other hand, negative effects of CLA have been reported such as fatty liver and spleen, induction of colon carcinogenesis and hyperproinsulinaemia. As far as human consumption is concerned, a definite conclusion for CLA safety has not been reached yet. Parameters such as administration of the type of CLA isomer and/or their combination with other polyunsaturated fatty acids, mode of administration (eg., as free fatty acid or its triglyceride form, liquid or solid), daily dose and duration of consumption, gender, age, or ethnic and geographical backgrounds remain to be determined. Yet, it appears from trials so far conducted that CLA are functional food having prevailing beneficial health effects for humans.
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Affiliation(s)
- Sailas Benjamin
- Department of Biochemistry, University of Münster, 48149 Münster, Germany.
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Lack of genoprotective effect of phytosterols and conjugated linoleic acids on Caco-2 cells. Food Chem Toxicol 2009; 47:1791-6. [DOI: 10.1016/j.fct.2009.04.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2009] [Revised: 04/08/2009] [Accepted: 04/19/2009] [Indexed: 01/09/2023]
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Yanagita T, Oku H. Branched-Chain Fatty Acid as a Functional Lipid. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2009. [DOI: 10.1201/9781420077070.ch18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Cho MH, Kang JH, Yang MP. Immunoenhancing effect of trans-10, cis-12 conjugated linoleic acid on the phagocytic capacity and oxidative burst activity of canine peripheral blood phagocytes. Res Vet Sci 2008; 85:269-78. [DOI: 10.1016/j.rvsc.2007.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Revised: 11/20/2007] [Accepted: 12/13/2007] [Indexed: 11/25/2022]
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Islam MA, Kim YS, Jang WJ, Lee SM, Kim HG, Kim SY, Kim JO, Ha YL. A mixture of trans, trans conjugated linoleic acid induces apoptosis in MCF-7 human breast cancer cells with reciprocal expression of Bax and Bcl-2. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2008; 56:5970-5976. [PMID: 18570428 DOI: 10.1021/jf8004977] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
The growth inhibitory effect of a mixture of trans, trans conjugated linoleic acid isomers (t, t CLA) was investigated in a human breast cancer cell line, MCF-7, with references to c9, t11 CLA, t10, c12 CLA, and linoleic acid. The t, t CLA treatment effectively induced a cytotoxic effect in a time-dependent (0-6 days) and concentration-dependent (0-40 microM) manner, as compared to the reference and control treatments. The apoptotic parameters were measured on cells treated with 40 microM t, t CLA for 4 days. The occurrence of the characteristic morphological changes and DNA fragmentation confirmed apoptosis. The t, t CLA treatment led to an increase in the level of p53 tumor suppressor protein and Bax protein, but suppressed the expression of Bcl-2 protein. In addition, cytochrome c was released from the mitochondria into the cytosol, and the activation of caspase-3 led to the cleavage of poly(ADP-ribose) polymerase (PARP). Moreover, the composition of the linoleic and arachidonic acids was decreased in cellular membranes. These findings suggest that incorporation of t, t CLA in the membrane induces a mitochondria-mediated apoptosis that can enhance the antiproliferative effect of t, t CLA in MCF-7 cells.
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Affiliation(s)
- Mohammad A Islam
- Division of Applied Life Sciences (BK21), Graduate School, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 660-701, Republic of Korea
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Yun HS, Do SH, Jeong WI, Yang HJ, Yuan DW, Hong IH, Lee HR, Lee IS, Kim YK, Choi MS, Kim HA, Jeong KS. Cytotoxic effects of the conjugated linoleic acid isomers t10c12, c9t11-CLA and mixed form on rat hepatic stellate cells and CCl4-induced hepatic fibrosis. J Nutr Biochem 2008; 19:175-83. [PMID: 17869086 DOI: 10.1016/j.jnutbio.2007.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2006] [Revised: 12/20/2006] [Accepted: 02/08/2007] [Indexed: 12/29/2022]
Abstract
Rat hepatic stellate cells (HSC-T6) were incubated for 24 h with 10-180 microM of t10c12 (98%), c9t11 (96%) and a mixed form (c9,t11:t10,c12; 41%:44%) of conjugated linoleic acid (CLA). The MTS dye reduction was measured to verify cell viability in a dose-dependent manner. Among the three CLAs, c9,t11-CLA exhibited the most intense cytotoxic effect on HSCs, the survival rate of which was reduced to 60% under 80 microM of treatment, while cell survival was slightly affected by the mixed form. Three CLA-induced cell deaths were determined by measuring DNA fragmentation using 4',6-diamidino-2-phenylindole staining. The degrees of DNA fragmentation were the most severe in HSC treated with 80 microM of c9,t11-CLA. The mitogen-activated protein kinase/extracellular signal-regulated kinase-kinase and mitogen-activated or extracellular signal-regulated protein kinase (MEK) 1 and 2 were not activated in the t10,c12-CLA treatment. This suggests that the MEK-dependent apoptosis signal is crucial in HSC, which is induced by c9,t11 and mixed CLA. In order to evaluate the protective effect of CLA on carbon tetrachloride (CCl4)-induced hepatic fibrosis in vivo, animals were treated with 10% CCl4 to induce hepatic fibrosis during all experimental periods. Rats were divided into two treatment groups: (1) control diet with tap water ad libitum (n=15) and (2) 1% CLA diet with tap water ad libitum (n=15). In the CLA-supplemented rat livers, alpha-smooth muscle actin-positive cells were significantly reduced around the portal vein. In addition, collagen fibers were not detected in the CLA-treated group. These results suggest that 9c,11t-CLA influences cytotoxic effect on HSC in an MEK-dependent manner and preserving liver from fibrosis.
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Affiliation(s)
- Hae-Sun Yun
- Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea
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