Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Modulation of Inflammatory Pathways and Adipogenesis by the Action of Gentisic Acid in RAW 264.7 and 3T3-L1 Cell Lines

  • Kang, Min-jae (Department of Microbiology, College of Natural Sciences, Pukyong National University) ;
  • Choi, Woosuk (UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA) ;
  • Yoo, Seung Hyun (Department of Microbiology, College of Natural Sciences, Pukyong National University) ;
  • Nam, Soo-Wan (Biomedical Engineering and Biotechnology Major, Division of Applied Bioengineering, College of Engineering, Dong-Eui University) ;
  • Shin, Pyung-Gyun (Himchan Agriculture Co., Ltd.) ;
  • Kim, Keun Ki (Department of Life Sciences and Environmental Biochemistry, College of Natural Resources and Life Sciences, Pusan National University) ;
  • Kim, Gun-Do (Department of Microbiology, College of Natural Sciences, Pukyong National University)
  • Received : 2021.05.06
  • Accepted : 2021.06.10
  • Published : 2021.08.28
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Abstract

Gentisic acid (GA), a benzoic acid derivative present in various food ingredients, has been shown to have diverse pharmaceutical activities such as anti-carcinogenic, antioxidant, and hepatoprotective effects. In this study, we used a co-culture system to investigate the mechanisms of the anti-inflammatory and anti-adipogenic effects of GA on macrophages and adipocytes, respectively, as well as its effect on obesity-related chronic inflammation. We found that GA effectively suppressed lipopolysaccharide-stimulated inflammatory responses by controlling the production of nitric oxide and pro-inflammatory cytokines and modulating inflammation-related protein pathways. GA treatment also inhibited lipid accumulation in adipocytes by modulating the expression of major adipogenic transcription factors and their upstream protein pathways. Furthermore, in the macrophage-adipocyte co-culture system, GA decreased the production of obesity-related cytokines. These results indicate that GA possesses effective anti-inflammatory and anti-adipogenic activities and may be used in developing treatments for the management of obesity-related chronic inflammatory diseases.

Keywords

Acknowledgement

This research was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry (IPET) through the Agro and Livestock Products Safety Flow Management Technology Development Program, funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA) [Grant No. 119077-2] and the Basic Science Research Program through the National Research Foundation of Korea (NRF) by the Ministry of Education [Grant No. NRF-2020R1A6A3A13072744].

References

  1. Tremmel M, Gerdtham U, Nilsson PM, Saha S. 2017. Economic burden of obesity: a systematic literature review. Int. J. Environ. Res. Public Health 14: 435. https://doi.org/10.3390/ijerph14040435
  2. Kopelman PG. 2000. Obesity as a medical problem. Nature 404: 635-643. https://doi.org/10.1038/35007508
  3. Ghoorah K, Campbell P, Kent A, Maznyczka A, Kunadian V. 2016. Obesity and cardiovascular outcomes: a review. Eur. Heart J. Acute Cardiovasc. Care 5: 77-85. https://doi.org/10.1177/2048872614523349
  4. Charlton M. 2009. Obesity, hyperlipidemia, and metabolic syndrome. Liver Transplant. 15: S83-S89.
  5. Castro A, Macedo-de la Concha L, Pantoja-Melendez C. 2017. Low-grade inflammation and its relation to obesity and chronic degenerative diseases. Rev. Med. Hosp. Gen. Mex. 80: 101-105.
  6. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. 2003. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112: 1821-1830. https://doi.org/10.1172/JCI200319451
  7. Monteiro R, Azevedo I. 2010. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm. 2010: 289645. https://doi.org/10.1155/2010/289645
  8. Wellen KE, Hotamisligil GS. 2003. Obesity-induced inflammatory changes in adipose tissue. J. Clin. Invest. 112: 1785-1788. https://doi.org/10.1172/JCI20514
  9. Shah A, Mehta N, Reilly MP. 2008. Adipose inflammation, insulin resistance, and cardiovascular disease. J. Parenter. Enteral Nutr. 32: 638-644. https://doi.org/10.1177/0148607108325251
  10. Suganami T, Nishida J, Ogawa Y. 2005. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor α. Arterioscler. Thromb. Vasc. Biol. 25: 2062-2068. https://doi.org/10.1161/01.ATV.0000183883.72263.13
  11. Nishimura S, Manabe I, Nagai R. 2009. Adipose tissue inflammation in obesity and metabolic syndrome. Discov. Med. 8: 55-60.
  12. Abedi F, Razavi BM, Hosseinzadeh H. 2020. A review on gentisic acid as a plant derived phenolic acid and metabolite of aspirin: comprehensive pharmacology, toxicology, and some pharmaceutical aspects. Phytother. Res. 34: 729-741. https://doi.org/10.1002/ptr.6573
  13. Russell WR, Labat A, Scobbie L, Duncan GJ, Duthie GG. 2009. Phenolic acid content of fruits commonly consumed and locally produced in Scotland. Food Chem. 115: 100-104. https://doi.org/10.1016/j.foodchem.2008.11.086
  14. Onyeneho SN, Hettiarachchy NS. 1992. Antioxidant activity of durum wheat bran. J. Agric. Food Chem. 40: 1496-1500. https://doi.org/10.1021/jf00021a005
  15. Lubaina A and K Murugan. 2012. Biochemical characterization of oxidative burst during interaction between sesame (Sesamum indicum L.) in response to Alternaria sesami, pp. 243-250. Prospects in Bioscience: Addressing the Issues, Springer, India.
  16. Soleas GJ, Dam J, Carey M, Goldberg DM. 1997. Toward the fingerprinting of wines: cultivar-related patterns of polyphenolic constituents in Ontario wines. J. Agric. Food Chem. 45: 3871-3880. https://doi.org/10.1021/jf970183h
  17. Hsieh H, Ju Y. 2018. Medicinal components in Termitomyces mushrooms. Appl. Microbiol. Biotechnol. 102: 4987-4994. https://doi.org/10.1007/s00253-018-8991-8
  18. Palacios I, Lozano M, Moro C, D'arrigo M, Rostagno M, Martinez J, et al. 2011. Antioxidant properties of phenolic compounds occurring in edible mushrooms. Food Chem. 128: 674-678. https://doi.org/10.1016/j.foodchem.2011.03.085
  19. Awtry EH, Loscalzo J. 2000. Aspirin. Circulation 101: 1206-1218. https://doi.org/10.1161/01.CIR.101.10.1206
  20. Li H, Lee H, Kim S, Moon B, Lee C. 2014. Antioxidant and anti-inflammatory activities of methanol extracts of Tremella fuciformis and its major phenolic acids. J. Food Sci. 79: C460-C468.
  21. Sharma S, Khan N, Sultana S. 2004. Study on prevention of two-stage skin carcinogenesis by Hibiscus rosa sinensis extract and the role of its chemical constituent, gentisic acid, in the inhibition of tumour promotion response and oxidative stress in mice. Eur. J. Cancer Prev. 13: 53-63. https://doi.org/10.1097/00008469-200402000-00009
  22. Peskin AV, Winterbourn CC. 2000. A microtiter plate assay for superoxide dismutase using a water-soluble tetrazolium salt (WST-1). Clin. Chim. Acta 293: 157-166. https://doi.org/10.1016/S0009-8981(99)00246-6
  23. Giustarini D, Rossi R, Milzani A, Dalle-Donne I. 2008. Nitrite and nitrate measurement by Griess reagent in human plasma: evaluation of interferences and standardization. Methods Enzymol. 440: 361-380. https://doi.org/10.1016/S0076-6879(07)00823-3
  24. Chait A, den Hartigh LJ. 2020. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front. Cardiovasc. Med. 7: 22. https://doi.org/10.3389/fcvm.2020.00022
  25. Clancy RM, Abramson SB. 1995. Nitric oxide: a novel mediator of inflammation. Proc. Soc. Exp. Biol. Med. 210: 93-101. https://doi.org/10.3181/00379727-210-43927AA
  26. Murakami A, Ohigashi H. 2007. Targeting NOX, INOS and COX-2 in inflammatory cells: chemoprevention using food phytochemicals. Int. J. Cancer 121: 2357-2363. https://doi.org/10.1002/ijc.23161
  27. Kawahara K, Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y. 2015. Prostaglandin E2-induced inflammation: relevance of prostaglandin E receptors. Biochim. Biophys. Acta Mol. Cell. Biol. Lipids 1851: 414-421.
  28. Al-Sadi R, Ye D, Boivin M, Guo S, Hashimi M, Ereifej L, Ma TY. 2014. Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLoS One 9: e85345. https://doi.org/10.1371/journal.pone.0085345
  29. Hirao LA, Grishina I, Bourry O, Hu WK, Somrit M, Sankaran-Walters S, et al. 2014. Early mucosal sensing of SIV infection by paneth cells induces IL-1β production and initiates gut epithelial disruption. PLoS Pathog. 10: e1004311. https://doi.org/10.1371/journal.ppat.1004311
  30. Al-Sadi R, Guo S, Ye D, Ma TY. 2013. TNF-α modulation of intestinal epithelial tight junction barrier is regulated by ERK1/2 activation of Elk-1. Am. J. Pathol. 183: 1871-1884. https://doi.org/10.1016/j.ajpath.2013.09.001
  31. Liu T, Zhang L, Joo D, Sun S. 2017. NF-κB signaling in inflammation. Signal. Transduct. Target. Ther. 2: 17023. https://doi.org/10.1038/sigtrans.2017.23
  32. Karin M. 1999. How NF-κB is activated: the role of the IκB kinase (IKK) complex. Oncogene 18: 6867-6874. https://doi.org/10.1038/sj.onc.1203219
  33. Christian F, Smith EL, Carmody RJ. 2016. The regulation of NF-κB subunits by phosphorylation. Cells 5: 12. https://doi.org/10.3390/cells5010012
  34. Kaminska B. 2005. MAPK signalling pathways as molecular targets for anti-inflammatory therapy-from molecular mechanisms to therapeutic benefits. Biochim. Biophys. Acta 1754: 253-262. https://doi.org/10.1016/j.bbapap.2005.08.017
  35. Kim EK, Choi E. 2010. Pathological roles of MAPK signaling pathways in human diseases. Biochim. Biophys. Acta 1802: 396-405. https://doi.org/10.1016/j.bbadis.2009.12.009
  36. Coskun M, Olsen J, Seidelin JB, Nielsen OH. 2011. MAP kinases in inflammatory bowel disease. Clin. Chim. Acta 412: 513-520. https://doi.org/10.1016/j.cca.2010.12.020
  37. Ali AT, Hochfeld WE, Myburgh R, Pepper MS. 2013. Adipocyte and adipogenesis. Eur. J. Cell Biol. 92: 229-236. https://doi.org/10.1016/j.ejcb.2013.06.001
  38. Kowalska K, Olejnik A, Rychlik J, Grajek W. 2015. Cranberries (Oxycoccus quadripetalus) inhibit lipid metabolism and modulate leptin and adiponectin secretion in 3T3-L1 adipocytes. Food Chem. 185: 383-388. https://doi.org/10.1016/j.foodchem.2015.03.152
  39. Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F. 2004. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 86: 839-848. https://doi.org/10.1016/j.biochi.2004.09.018
  40. Chirala SS, Wakil SJ. 2004. Structure and function of animal fatty acid synthase. Lipids 39: 1045-1053. https://doi.org/10.1007/s11745-004-1329-9
  41. Yu W, Chen Z, Zhang J, Zhang L, Ke H, Huang L, et al. 2008. Critical role of phosphoinositide 3-kinase cascade in adipogenesis of human mesenchymal stem cells. Mol. Cell. Biochem. 310: 11-18. https://doi.org/10.1007/s11010-007-9661-9
  42. Zhang HH, Huang J, Duvel K, Boback B, Wu S, Squillace RM, et al. 2009. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS One 4: e6189. https://doi.org/10.1371/journal.pone.0006189
  43. Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. 2009. Adipogenesis and WNT signalling. Trends Endocrinol. Metab. 20: 16-24. https://doi.org/10.1016/j.tem.2008.09.002
  44. Liu J, Farmer SR. 2004. Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J. Biol. Chem. 279: 45020-45027. https://doi.org/10.1074/jbc.M407050200
  45. Hsieh C, Chou M, Wang C. 2017. Lunasin attenuates obesity-related inflammation in RAW264. 7 cells and 3T3-L1 adipocytes by inhibiting inflammatory cytokine production. PLoS One 12: e0171969. https://doi.org/10.1371/journal.pone.0171969