Review Article

Resveratrol as a Potential Protective Compound Against Metabolic Inflammation

Abstract

Although the exact mechanism linking obesity to type 2 diabetes (T2D) remains unknown, accumulating evidence suggests that low-grade chronic metabolic inflammation or ‘metainflammation’ plays a pivotal role. Adipose tissue is the primary site of meta-inflammation, and overproduction of pro-inflammatory cytokines in this tissue affects other organs such as the liver, skeletal muscle, pancreas, and brain. This leads to the development of insulin resistance and metabolic irregularities in these tissues. Therefore, strategies targeting metainflammation could be effective in treating T2D and related metabolic traits. Resveratrol, a polyphenol, is suggested to possess anti-inflammatory and immunomodulatory activities. The anti-inflammatory effect of resveratrol is mediated through several mechanisms including the suppression of nuclear factor kB (NF-kB), down-regulation of extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) signaling, suppression of toll-like receptor (TLR)-mediated pathway; inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, reduction of reactive oxygen species (ROS) generation, suppression of immune cell infiltration into tissues; and inhibition of pro-inflammatory cytokines production. This review will examine the evidence on the role of resveratrol in modulating inflammation in various organs affected by obesity such as liver, skeletal muscle, kidney, heart and brain.

1. Organization, W.H., Obesity: preventing and managing the global epidemic. 2000: World Health Organization.
2. Ng, M., T. Fleming, M. Robinson, B. Thomson, N. Graetz, C. Margono, et al., Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet, 2014. 384(9945): p. 766-81.
3. Rosa, F.T., M.Á. Zulet, J.S. Marchini, and J.A. Martínez, Bioactive compounds with effects on inflammation markers in humans. International journal of food sciences and nutrition, 2012. 63(6): p. 749-765.
4. Ferrante, A., Obesity‐induced inflammation: a metabolic dialogue in the language of inflammation. Journal of internal medicine, 2007. 262(4): p. 408-414.
5. Meshkani, R. and S. Vakili, Tissue resident macrophages: Key players in the pathogenesis of type 2 diabetes and its complications. Clinica Chimica Acta, 2016.
6. Bisht, K., K.-H. Wagner, and A.C. Bulmer, Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto-and DNA-protective dietary compounds. Toxicology, 2010. 278(1): p. 88-100.
7. Zamani‐Garmsiri, F., S. Emamgholipour, S. Rahmani Fard, G. Ghasempour, R. Jahangard Ahvazi, and R. Meshkani, Polyphenols: potential anti‐inflammatory agents for treatment of metabolic disorders. Phytotherapy Research, 2022. 36(1): p. 415-432.
8. Tehrani, S.S., G. Goodarzi, G. Panahi, F. Zamani-Garmsiri, and R. Meshkani, The combination of metformin with morin alleviates hepatic steatosis via modulating hepatic lipid metabolism, hepatic inflammation, brown adipose tissue thermogenesis, and white adipose tissue browning in high-fat diet-fed mice. Life Sciences, 2023. 323: p. 121706.
9. Golnaz Goodarzi, S.S.T., Ghodratollah Panahi, Arash Bahramzadeh, Reza Meshkani, Combination therapy of metformin and p-coumaric acid mitigates metabolic dysfunction associated with obesity and nonalcoholic fatty liver disease in high-fat diet obese C57BL/6 mice. The Journal of Nutritional Biochemistry, 2023. 118: p. 109369.
10. Leiherer, A., A. Mündlein, and H. Drexel, Phytochemicals and their impact on adipose tissue inflammation and diabetes. Vascular pharmacology, 2013. 58(1): p. 3-20.
11. Dali-Youcef, N., M. Mecili, R. Ricci, and E. Andrès, Metabolic inflammation: connecting obesity and insulin resistance. Annals of medicine, 2013. 45(3): p. 242-253.
12. Lumeng, C.N. and A.R. Saltiel, Inflammatory links between obesity and metabolic disease. The Journal of clinical investigation, 2011. 121(6): p. 2111-2117.
13. Khodabandehloo, H., S. Gorgani-Firuzjaee, G. Panahi, and R. Meshkani, Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Translational Research, 2016. 167(1): p. 228-256.
14. Gerner, R.R., V. Wieser, A.R. Moschen, and H. Tilg, Metabolic inflammation: role of cytokines in the crosstalk between adipose tissue and liver 1. Canadian journal of physiology and pharmacology, 2013. 91(11): p. 867-872.
15. Lontchi-Yimagou, E., E. Sobngwi, T.E. Matsha, and A.P. Kengne, Diabetes mellitus and inflammation. Current diabetes reports, 2013. 13(3): p. 435-444.
16. Liu, L., M. Mei, S. Yang, and Q. Li, Roles of chronic low-grade inflammation in the development of ectopic fat deposition. Mediators of inflammation, 2014. 2014.
17. Mraz, M. and M. Haluzik, The role of adipose tissue immune cells in obesity and low-grade inflammation. Journal of Endocrinology, 2014. 222(3): p. R113-R127.
18. Pereira, S.S. and J.I. Alvarez-Leite, Low-Grade Inflammation, Obesity, and Diabetes. Current obesity reports, 2014. 3(4): p. 422-431.
19. Roya Jahangard , S.S.S.E., Akram Vatannejad, Reza Meshkani Autophagy protects peripheral blood mononuclear cells from high glucose-induced inflammation and apoptosis. Acta Biochimica Iranica, 2023. 1(1): p. 40-49.
20. Olefsky, J.M. and C.K. Glass, Macrophages, inflammation, and insulin resistance. Annual review of physiology, 2010. 72: p. 219-246.
21. Anderson, E.K., D.A. Gutierrez, and A.H. Hasty, Adipose tissue recruitment of leukocytes. Current opinion in lipidology, 2010. 21(3): p. 172.
22. Chen, Y., J. Tian, X. Tian, X. Tang, K. Rui, J. Tong, et al., Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PloS one, 2014. 9(3): p. e92450.
23. Nima Taghizadeh , S.M., Vahid Saeedi, Ladan Haghighi, Mona Nourbakhsh, Mitra Nourbakhsh, Maryam Razzaghy Azar, Association between Steroid Hormones and Insulin Resistance in Patients with Polycystic Ovary Syndrome. Acta Biochimica Iranica, 2023. 1: p. 1.
24. Chmelar, J., K.-J. Chung, and T. Chavakis, The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance. Thromb Haemost, 2013. 109(3): p. 399-406.
25. Artaud-Wild, S.M., S. Connor, G. Sexton, and W. Connor, Differences in coronary mortality can be explained by differences in cholesterol and saturated fat intakes in 40 countries but not in France and Finland. A paradox. Circulation, 1993. 88(6): p. 2771-2779.
26. de Ligt, M., S. Timmers, and P. Schrauwen, Resveratrol and obesity: can resveratrol relieve metabolic disturbances? Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2015. 1852(6): p. 1137-1144.
27. Kulkarni, S.S. and C. Cantó, The molecular targets of resveratrol. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2015. 1852(6): p. 1114-1123.
28. Sattar Gorgani-Firuzjaee, R.M., Resveratrol reduces high glucose-induced de-novo lipogenesis through mTOR mediated induction of autophagy in HepG2 cells. Acta Biochimica Iranica, 2023. 1(1): p. 32-39.
29. Baur, J.A. and D.A. Sinclair, Therapeutic potential of resveratrol: the in vivo evidence. Nature reviews Drug discovery, 2006. 5(6): p. 493-506.
30. Borriello, A., D. Bencivenga, I. Caldarelli, A. Tramontano, A. Borgia, V. Zappia, et al., Resveratrol: from basic studies to bedside, in Advances in Nutrition and Cancer. 2014, Springer. p. 167-184.
31. Soleas, G.J., E.P. Diamandis, and D.M. Goldberg, Resveratrol: a molecule whose time has come? And gone? Clinical biochemistry, 1997. 30(2): p. 91-113.
32. R Neves, A., M. Lucio, J. LC Lima, and S. Reis, Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug-delivery, and membrane interactions. Current medicinal chemistry, 2012. 19(11): p. 1663-1681.
33. Smoliga, J.M., J.A. Baur, and H.A. Hausenblas, Resveratrol and health–a comprehensive review of human clinical trials. Molecular nutrition & food research, 2011. 55(8): p. 1129-1141.
34. Szkudelski, T. and K. Szkudelska, Anti‐diabetic effects of resveratrol. Annals of the New York Academy of Sciences, 2011. 1215(1): p. 34-39.
35. Liu, K., R. Zhou, B. Wang, and M.T. Mi, Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. Am J Clin Nutr, 2014. 99(6): p. 1510-9.
36. Palsamy, P. and S. Subramanian, Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. Biomed Pharmacother, 2008. 62(9): p. 598-605.
37. Liu, K., R. Zhou, B. Wang, and M.-T. Mi, Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. The American journal of clinical nutrition, 2014. 99(6): p. 1510-1519.
38. Koushki, M., N.A. Dashatan, and R. Meshkani, Effect of Resveratrol Supplementation on Inflammatory Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin Ther, 2018. 40(7): p. 1180-1192.e5.
39. Alarcon De La Lastra, C. and I. Villegas, Resveratrol as an anti‐inflammatory and anti‐aging agent: Mechanisms and clinical implications. Molecular nutrition & food research, 2005. 49(5): p. 405-430.
40. Zordoky, B.N., I.M. Robertson, and J.R. Dyck, Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim Biophys Acta, 2015. 1852(6): p. 1155-77.
41. Carreras, A., S. Zhang, E. Peris, Z. Qiao, Y. Wang, I. Almendros, et al., Effect of resveratrol on visceral white adipose tissue inflammation and insulin sensitivity in a mouse model of sleep apnea. International Journal of Obesity, 2015. 39(3): p. 418-423.
42. Jeon, B.T., E.A. Jeong, H.J. Shin, Y. Lee, D.H. Lee, H.J. Kim, et al., Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet. Diabetes, 2012. 61(6): p. 1444-1454.
43. Carreras, A., S.X. Zhang, I. Almendros, Y. Wang, E. Peris, Z. Qiao, et al., Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice. Endocrinology, 2014. 156(2): p. 437-443.
44. Nøhr, M.K., A. Dudele, M.M. Poulsen, L.H. Ebbesen, Y. Radko, L.P. Christensen, et al., LPS-enhanced glucose-stimulated insulin secretion is normalized by resveratrol. PloS one, 2016. 11(1).
45. Lv, Z.m., Q. Wang, Y.h. Chen, S.h. Wang, and D.q. Huang, Resveratrol attenuates inflammation and oxidative stress in epididymal white adipose tissue: Implications for its involvement in improving steroidogenesis in diet‐induced obese mice. Molecular reproduction and development, 2015. 82(4): p. 321-328.
46. Gómez-Zorita, S., A. Fernández-Quintela, A. Lasa, E. Hijona, L. Bujanda, and M.P. Portillo, Effects of resveratrol on obesity-related inflammation markers in adipose tissue of genetically obese rats. Nutrition, 2013. 29(11): p. 1374-1380.
47. Ølholm, J., S. Paulsen, K. Cullberg, B. Richelsen, and S.B. Pedersen, Anti-inflammatory effect of resveratrol on adipokine expression and secretion in human adipose tissue explants. International Journal of Obesity, 2010. 34(10): p. 1546-1553.
48. Krawczyk, S.A., J.F. Haller, T. Ferrante, R.A. Zoeller, and B.E. Corkey, Reactive oxygen species facilitate translocation of hormone sensitive lipase to the lipid droplet during lipolysis in human differentiated adipocytes. PloS one, 2012. 7(4): p. e34904.
49. Sun, Y., J. Li, N. Xiao, M. Wang, J. Kou, L. Qi, et al., Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1. Pharmacological research, 2014. 89: p. 19-28.
50. Jimenez-Gomez, Y., J.A. Mattison, K.J. Pearson, A. Martin-Montalvo, H.H. Palacios, A.M. Sossong, et al., Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell metabolism, 2013. 18(4): p. 533-545.
51. Lin, Q.-Q., C.-F. Yan, R. Lin, J.-Y. Zhang, W.-R. Wang, L.-N. Yang, et al., SIRT1 regulates TNF-α-induced expression of CD40 in 3T3-L1 adipocytes via NF-κB pathway. Cytokine, 2012. 60(2): p. 447-455.
52. Zagotta, I., E.Y. Dimova, J.-B. Funcke, M. Wabitsch, T. Kietzmann, and P. Fischer-Posovszky, Resveratrol suppresses PAI-1 gene expression in a human in vitro model of inflamed adipose tissue. Oxidative medicine and cellular longevity, 2013. 2013.
53. Li, X., J. Li, L. Wang, A. Li, Z. Qiu, L.w. Qi, et al., The role of metformin and resveratrol in the prevention of hypoxia‐inducible factor 1α accumulation and fibrosis in hypoxic adipose tissue. British journal of pharmacology, 2016. 173(12): p. 2001-2015.
54. Kim, S., Y. Jin, Y. Choi, and T. Park, Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice. Biochemical pharmacology, 2011. 81(11): p. 1343-1351.
55. Ahn, J., H. Lee, S. Kim, and T. Ha, Resveratrol inhibits TNF-α-induced changes of adipokines in 3T3-L1 adipocytes. Biochemical and biophysical research communications, 2007. 364(4): p. 972-977.
56. Yen, G.-C., Y.-C. Chen, W.-T. Chang, and C.-L. Hsu, Effects of polyphenolic compounds on tumor necrosis factor-α (TNF-α)-induced changes of adipokines and oxidative stress in 3T3-L1 adipocytes. Journal of agricultural and food chemistry, 2010. 59(2): p. 546-551.
57. Zagotta, I., E.Y. Dimova, K.-M. Debatin, M. Wabitsch, T. Kietzmann, and P. Fischer-Posovszky, Obesity and inflammation: reduced cytokine expression due to resveratrol in a human in vitro model of inflamed adipose tissue. Frontiers in pharmacology, 2015. 6.
58. Zhu, J., W. Yong, X. Wu, Y. Yu, C. Liu, X. Mao, et al., Anti-inflammatory effect of resveratrol on TNF-α-induced MCP-1 expression in adipocytes. Biochemical and biophysical research communications, 2008. 369(2): p. 471-477.
59. Chuang, C.-C., K. Martinez, G. Xie, A. Kennedy, A. Bumrungpert, A. Overman, et al., Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-α–mediated inflammation and insulin resistance in primary human adipocytes. The American journal of clinical nutrition, 2010. 92(6): p. 1511-1521.
60. Lee, H.J., Y. Lim, and S.J. Yang, Involvement of resveratrol in crosstalk between adipokine adiponectin and hepatokine fetuin-A in vivo and in vitro. The Journal of nutritional biochemistry, 2015. 26(11): p. 1254-1260.
61. Lettieri Barbato, D., G. Tatulli, K. Aquilano, and M.R. Ciriolo, Inhibition of age-related cytokines production by ATGL: a mechanism linked to the anti-inflammatory effect of resveratrol. Mediators of inflammation, 2014. 2014.
62. Li, A., S. Zhang, J. Li, K. Liu, F. Huang, and B. Liu, Metformin and resveratrol inhibit Drp1-mediated mitochondrial fission and prevent ER stress-associated NLRP3 inflammasome activation in the adipose tissue of diabetic mice. Molecular and Cellular Endocrinology, 2016.
63. Meshkani, R. and K. Adeli, Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clinical biochemistry, 2009. 42(13): p. 1331-1346.
64. Zamani-Garmsiri, F., S.M.R. Hashemnia, M. Shabani, M. Bagherieh, S. Emamgholipour, and R. Meshkani, Combination of metformin and genistein alleviates non-alcoholic fatty liver disease in high-fat diet-fed mice. J Nutr Biochem, 2021. 87: p. 108505.
65. Yang, S.J. and Y. Lim, Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation. Metabolism, 2014. 63(5): p. 693-701.
66. Faghihzadeh, F., P. Adibi, R. Rafiei, and A. Hekmatdoost, Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutrition research, 2014. 34(10): p. 837-843.
67. Chen, S., X. Zhao, L. Ran, J. Wan, X. Wang, Y. Qin, et al., Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Digestive and Liver Disease, 2015. 47(3): p. 226-232.
68. Nishikawa, K., K. Iwaya, M. Kinoshita, Y. Fujiwara, M. Akao, M. Sonoda, et al., Resveratrol increases CD68+ Kupffer cells colocalized with adipose differentiation‐related protein and ameliorates high‐fat‐diet‐induced fatty liver in mice. Molecular nutrition & food research, 2015. 59(6): p. 1155-1170.
69. Wan, J., M. Benkdane, F. Teixeira‐Clerc, S. Bonnafous, A. Louvet, F. Lafdil, et al., M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology, 2014. 59(1): p. 130-142.
70. Chan, C.C., L.Y. Cheng, C.L. Lin, Y.H. Huang, H.C. Lin, and F.Y. Lee, The protective role of natural phytoalexin resveratrol on inflammation, fibrosis and regeneration in cholestatic liver injury. Molecular nutrition & food research, 2011. 55(12): p. 1841-1849.
71. Chan, C.C., K.C. Lee, Y.H. Huang, C.K. Chou, H.C. Lin, and F.Y. Lee, Regulation by resveratrol of the cellular factors mediating liver damage and regeneration after acute toxic liver injury. Journal of gastroenterology and hepatology, 2014. 29(3): p. 603-613.
72. Kessoku, T., K. Imajo, Y. Honda, T. Kato, Y. Ogawa, W. Tomeno, et al., Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Scientific reports, 2016. 6.
73. Jeong, J.H., Y.R. Lee, H.G. Park, and W.L. Lee, The effects of either resveratrol or exercise on macrophage infiltration and switching from M1 to M2 in high fat diet mice. Journal of exercise nutrition & biochemistry, 2015. 19(2): p. 65.
74. Pan, Q.-R., Y.-L. Ren, W.-X. Liu, Y.-J. Hu, J.-S. Zheng, Y. Xu, et al., Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats. Nutrition Research, 2015. 35(7): p. 576-584.
75. Chang, C.-C., C.-Y. Chang, J.-P. Huang, and L.-M. Hung, Effect of resveratrol on oxidative and inflammatory stress in liver and spleen of streptozotocin-induced type 1 diabetic rats. Chin J Physiol, 2012. 55(3): p. 192-201.
76. Albertoni, G. and N. Schor, Resveratrol plays important role in protective mechanisms in renal disease-mini-review. Jornal Brasileiro de Nefrologia, 2015. 37(1): p. 106-114.
77. Tung, B.T., E. Rodríguez-Bies, E. Talero, E. Gamero-Estévez, V. Motilva, P. Navas, et al., Anti-inflammatory effect of resveratrol in old mice liver. Experimental gerontology, 2015. 64: p. 1-7.
78. Russo, G.T., C.B. Giorda, S. Cercone, A. Nicolucci, and D. Cucinotta, Factors Associated with Beta-Cell Dysfunction in Type 2 Diabetes: The BETADECLINE Study. PLoS One, 2014. 9(10).
79. Ehses, J.A., A. Perren, E. Eppler, P. Ribaux, J.A. Pospisilik, R. Maor-Cahn, et al., Increased number of islet-associated macrophages in type 2 diabetes. Diabetes, 2007. 56(9): p. 2356-2370.
80. Li, Z.-D., Q.-Y. Ma, and C.-A. Wang, Effect of resveratrol on pancreatic oxygen free radicals in rats with severe acute pancreatitis. World Journal of Gastroenterology, 2006. 12(1): p. 137.
81. Tsang, S.W., Y.F. Guan, J. Wang, Z.X. Bian, and H.J. Zhang, Inhibition of pancreatic oxidative damage by stilbene derivative dihydro-resveratrol: implication for treatment of acute pancreatitis. Sci Rep, 2016. 6.
82. Lee, S.-M., H. Yang, D. Tartar, B. Gao, X. Luo, S. Ye, et al., Prevention and treatment of diabetes with resveratrol in a non-obese mouse model of type 1 diabetes. Diabetologia, 2011. 54(5): p. 1136-1146.
83. Khalafani, Z., F. Zamani-Garmsiri, G. Panahi, and R. Meshkani, Metformin-chlorogenic acid combination reduces skeletal muscle inflammation in c57BL/6 mice on high-fat diets. Mol Biol Rep, 2023. 50(3): p. 2581-2589.
84. Khodabandehloo, H., S. Gorgani-Firuzjaee, G. Panahi, and R. Meshkani, Molecular and cellular mechanisms linking inflammation to insulin resistance and beta-cell dysfunction. Transl Res, 2016. 167(1): p. 228-56.
85. Timmers, S., E. Konings, L. Bilet, R.H. Houtkooper, T. van de Weijer, G.H. Goossens, et al., Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab, 2011. 14(5): p. 612-22.
86. Centeno-Baez, C., P. Dallaire, and A. Marette, Resveratrol inhibition of inducible nitric oxide synthase in skeletal muscle involves AMPK but not SIRT1. American Journal of Physiology-Endocrinology and Metabolism, 2011. 301(5): p. E922-E930.
87. Sadeghi, A., S.S. Seyyed Ebrahimi, A. Golestani, and R. Meshkani, Resveratrol Ameliorates Palmitate-Induced Inflammation in Skeletal Muscle Cells by Attenuating Oxidative Stress and JNK/NF-kappaB Pathway in a SIRT1-Independent Mechanism. J Cell Biochem, 2017. 118(9): p. 2654-2663.
88. Olesen, J., L. Gliemann, R. Bienso, J. Schmidt, Y. Hellsten, and H. Pilegaard, Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men. J Physiol, 2014. 592(8): p. 1873-86.
89. Jeong, J.H., H.G. Park, Y.R. Lee, and W.L. Lee, Moderate exercise training is more effective than resveratrol supplementation for ameliorating lipid metabolic complication in skeletal muscle of high fat diet-induced obese mice. J Exerc Nutrition Biochem, 2015. 19(2): p. 131-7.
90. van der Heijden, R.A., J. Bijzet, W.C. Meijers, G.K. Yakala, R. Kleemann, T.Q. Nguyen, et al., Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis. Scientific reports, 2015. 5.
91. Tang, J., H. Yan, and S. Zhuang, Inflammation and oxidative stress in obesity-related glomerulopathy. International journal of nephrology, 2012. 2012.
92. Guebre-Egziabher, F., E. Kalbacher, and D. Fouque, [Insulin resistance and inflammation in chronic kidney diseases]. Nephrologie & therapeutique, 2009. 5: p. S346-52.
93. Mora, C. and J.F. Navarro, Inflammation and diabetic nephropathy. Current diabetes reports, 2006. 6(6): p. 463-468.
94. Lim, A.K. and G.H. Tesch, Inflammation in diabetic nephropathy. Mediators of inflammation, 2012. 2012.
95. Biswas, S.K. and J.B. Lopes de Faria, Hypertension induces oxidative stress but not macrophage infiltration in the kidney in the early stage of experimental diabetes mellitus. American journal of nephrology, 2006. 26(5): p. 415-422.
96. Lee, V.W.S., Y.M. Wang, Y. Wang, D. Zheng, T. Polhill, Q. Cao, et al., Regulatory immune cells in kidney disease. American Journal of Physiology-Renal Physiology, 2008. 295(2): p. F335-F342.
97. Hartner, A., R. Veelken, M. Wittmann, N. Cordasic, and K.F. Hilgers, Effects of diabetes and hypertension on macrophage infiltration and matrix expansion in the rat kidney. BMC nephrology, 2005. 6(1): p. 1.
98. Wada, J. and H. Makino, Innate immunity in diabetes and diabetic nephropathy. Nature Reviews Nephrology, 2015.
99. Roubicek, T., M. Bartlova, J. Krajickova, D. Haluzikova, M. Mraz, Z. Lacinova, et al., Increased production of proinflammatory cytokines in adipose tissue of patients with end-stage renal disease. Nutrition, 2009. 25(7): p. 762-768.
100. Egido, J., M. Gomez-Chiarri, A. Ortiz, C. Bustos, J. Alonso, C. Gomez-Guerrero, et al., Role of tumor necrosis factor-alpha in the pathogenesis of glomerular diseases. Kidney international. Supplement, 1993. 39: p. S59-64.
101. Patel, N.S., P.K. Chatterjee, R. Di Paola, E. Mazzon, D. Britti, A. De Sarro, et al., Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion. Journal of Pharmacology and Experimental Therapeutics, 2005. 312(3): p. 1170-1178.
102. Lan, H.Y., M. Bacher, N. Yang, W. Mu, D.J. Nikolic-Paterson, C. Metz, et al., The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. The Journal of experimental medicine, 1997. 185(8): p. 1455-1466.
103. Zhang, L., S. Pang, B. Deng, L. Qian, J. Chen, J. Zou, et al., High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-kappaB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol. Int J Biochem Cell Biol, 2012. 44(4): p. 629-38.
104. Palsamy, P. and S. Subramanian, Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2–Keap1 signaling. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2011. 1812(7): p. 719-731.
105. Kim, M.Y., J.H. Lim, H.H. Youn, Y.A. Hong, K.S. Yang, H.S. Park, et al., Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1alpha axis in db/db mice. Diabetologia, 2013. 56(1): p. 204-17.
106. Sharma, S., M. Anjaneyulu, S. Kulkarni, and K. Chopra, Resveratrol, a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats. Pharmacology, 2006. 76(2): p. 69-75.
107. Zhou, Y., S. Lin, L. Zhang, and Y. Li, Resveratrol prevents renal lipotoxicity in high-fat diet-treated mouse model through regulating PPAR-alpha pathway. Mol Cell Biochem, 2016. 411(1-2): p. 143-50.
108. Wu, M., J. Gu, S. Mei, D. Xu, Y. Jing, Q. Yao, et al., Resveratrol delays polycystic kidney disease progression through attenuation of nuclear factor κB-induced inflammation. Nephrology Dialysis Transplantation, 2016: p. gfw058.
109. Kolgazi, M., G. Şener, Ş. Çetinel, N. Gedik, and I.n. Alican, Resveratrol reduces renal and lung injury caused by sepsis in rats. Journal of Surgical Research, 2006. 134(2): p. 315-321.
110. Şener, G., H. Tuğtepe, M. Yüksel, Ş. Çetinel, N. Gedik, and B.Ç. Yeğen, Resveratrol improves ischemia/reperfusion-induced oxidative renal injury in rats. Archives of medical research, 2006. 37(7): p. 822-829.
111. Chen, L., S. Yang, E.E. Zumbrun, H. Guan, P.S. Nagarkatti, and M. Nagarkatti, Resveratrol attenuates lipopolysaccharide‐induced acute kidney injury by suppressing inflammation driven by macrophages. Molecular nutrition & food research, 2015. 59(5): p. 853-864.
112. Castilla, P., A. Davalos, J.L. Teruel, F. Cerrato, M. Fernandez-Lucas, J.L. Merino, et al., Comparative effects of dietary supplementation with red grape juice and vitamin E on production of superoxide by circulating neutrophil NADPH oxidase in hemodialysis patients. Am J Clin Nutr, 2008. 87(4): p. 1053-61.
113. Castilla, P., R. Echarri, A. Davalos, F. Cerrato, H. Ortega, J.L. Teruel, et al., Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects. Am J Clin Nutr, 2006. 84(1): p. 252-62.
114. Laslett, L.J., P. Alagona, Jr., B.A. Clark, 3rd, J.P. Drozda, Jr., F. Saldivar, S.R. Wilson, et al., The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol, 2012. 60(25 Suppl): p. S1-49.
115. Yaser Mohassel , S.A., Shayan Mostafae , Mohammad Taghi Goodarzi Assessing the Possible Association between Polymorphism of C677T MTHFR with Preeclampsia Risk: A Systematic Review and Bayesian Hierarchical Meta-Analysis. Acta Biochimica Iranica, 2023. 1(1): p. 3-11.
116. Libby, P., P.M. Ridker, and A. Maseri, Inflammation and atherosclerosis. Circulation, 2002. 105(9): p. 1135-43.
117. Wakabayashi, I. and Y. Takeda, Inhibitory effects of resveratrol on MCP-1, IL-6, and IL-8 production in human coronary artery smooth muscle cells. Naunyn Schmiedebergs Arch Pharmacol, 2013. 386(9): p. 835-9.
118. Zhong, M., G.F. Cheng, W.J. Wang, Y. Guo, X.Y. Zhu, and J.T. Zhang, Inhibitory effect of resveratrol on interleukin 6 release by stimulated peritoneal macrophages of mice. Phytomedicine, 1999. 6(2): p. 79-84.
119. Song, R., W.Q. Li, J.L. Dou, L. Li, Y.J. Hu, J.Z. Guo, et al., [Resveratrol reduces inflammatory cytokines via inhibiting nuclear factor-kappaB and mitogen-activated protein kinase signal pathway in a rabbit atherosclerosis model]. Zhonghua Xin Xue Guan Bing Za Zhi, 2013. 41(10): p. 866-9.
120. Pervaiz, S., Resveratrol: from grapevines to mammalian biology. Faseb j, 2003. 17(14): p. 1975-85.
121. Deng, Y.H., D. Alex, H.Q. Huang, N. Wang, N. Yu, Y.T. Wang, et al., Inhibition of TNF-alpha-mediated endothelial cell-monocyte cell adhesion and adhesion molecules expression by the resveratrol derivative, trans-3,5,4'-trimethoxystilbene. Phytother Res, 2011. 25(3): p. 451-7.
122. Kim, S.W., C.E. Kim, and M.H. Kim, Flavonoids inhibit high glucose-induced up-regulation of ICAM-1 via the p38 MAPK pathway in human vein endothelial cells. Biochem Biophys Res Commun, 2011. 415(4): p. 602-7.
123. Scoditti, E., N. Calabriso, M. Massaro, M. Pellegrino, C. Storelli, G. Martines, et al., Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer. Arch Biochem Biophys, 2012. 527(2): p. 81-9.
124. Buttari, B., E. Profumo, L. Segoni, D. D'Arcangelo, S. Rossi, F. Facchiano, et al., Resveratrol counteracts inflammation in human M1 and M2 macrophages upon challenge with 7-oxo-cholesterol: potential therapeutic implications in atherosclerosis. Oxid Med Cell Longev, 2014. 2014: p. 257543.
125. Csiszar, A., N. Labinskyy, A. Podlutsky, P.M. Kaminski, M.S. Wolin, C. Zhang, et al., Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. American Journal of Physiology-Heart and Circulatory Physiology, 2008. 294(6): p. H2721-H2735.
126. Latruffe, N., A. Lancon, R. Frazzi, V. Aires, D. Delmas, J.J. Michaille, et al., Exploring new ways of regulation by resveratrol involving miRNAs, with emphasis on inflammation. Ann N Y Acad Sci, 2015. 1348(1): p. 97-106.
127. Li, J., C. Xie, J. Zhuang, H. Li, Y. Yao, C. Shao, et al., Resveratrol attenuates inflammation in the rat heart subjected to ischemia-reperfusion: role of the TLR4/NF-κB signaling pathway. Molecular medicine reports, 2015. 11(2): p. 1120-1126.
128. Dong, W., R. Yang, J. Yang, J. Yang, J. Ding, H. Wu, et al., Resveratrol pretreatment protects rat hearts from ischemia/reperfusion injury partly via a NALP3 inflammasome pathway. Int J Clin Exp Pathol, 2015. 8(8): p. 8731-41.
129. Cheng, L., Z. Jin, R. Zhao, K. Ren, C. Deng, and S. Yu, Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway. International journal of clinical and experimental medicine, 2015. 8(7): p. 10420.
130. McMurray, J.J. and M.A. Pfeffer, Heart failure. Lancet, 2005. 365(9474): p. 1877-89.
131. Gupta, P.K., D.J. DiPette, and S.C. Supowit, Protective effect of resveratrol against pressure overload-induced heart failure. Food Sci Nutr, 2014. 2(3): p. 218-29.
132. Yoshida, Y., T. Shioi, and T. Izumi, Resveratrol ameliorates experimental autoimmune myocarditis. Circulation Journal, 2007. 71(3): p. 397-404.
133. Tome-Carneiro, J., M. Larrosa, M.J. Yanez-Gascon, A. Davalos, J. Gil-Zamorano, M. Gonzalvez, et al., One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res, 2013. 72: p. 69-82.
134. Tome-Carneiro, J., M. Gonzalvez, M. Larrosa, M.J. Yanez-Gascon, F.J. Garcia-Almagro, J.A. Ruiz-Ros, et al., Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc Drugs Ther, 2013. 27(1): p. 37-48.
135. Tomé-Carneiro, J., M. Larrosa, M.J. Yánez-Gascón, A. Dávalos, J. Gil-Zamorano, M. Gonzálvez, et al., One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacological research, 2013. 72: p. 69-82.
136. Tomé-Carneiro, J., M. Gonzálvez, M. Larrosa, M.J. Yáñez-Gascón, F.J. García-Almagro, J.A. Ruiz-Ros, et al., Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovascular Drugs and Therapy, 2013. 27(1): p. 37-48.
137. Tomé-Carneiro, J., M. Gonzálvez, M. Larrosa, M.J. Yáñez-Gascón, F.J. García-Almagro, J.A. Ruiz-Ros, et al., One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. The American journal of cardiology, 2012. 110(3): p. 356-363.
138. Magyar, K., R. Halmosi, A. Palfi, G. Feher, L. Czopf, A. Fulop, et al., Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clinical hemorheology and microcirculation, 2012. 50(3): p. 179-187.
139. Franco, R. and D. Fernandez-Suarez, Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol, 2015. 131: p. 65-86.
140. Minogue, A.M., Role of infiltrating monocytes/macrophages in acute and chronic neuroinflammation: Effects on cognition, learning and affective behaviour. Prog Neuropsychopharmacol Biol Psychiatry, 2017. 79(Pt A): p. 15-18.
141. Zhang, F., J. Liu, and J.-S. Shi, Anti-inflammatory activities of resveratrol in the brain: role of resveratrol in microglial activation. European journal of pharmacology, 2010. 636(1): p. 1-7.
142. Choi, D.K., S. Koppula, and K. Suk, Inhibitors of microglial neurotoxicity: focus on natural products. Molecules, 2011. 16(2): p. 1021-1043.
143. Fang, L., H. Gao, W. Zhang, W. Zhang, and Y. Wang, Resveratrol alleviates nerve injury after cerebral ischemia and reperfusion in mice by inhibiting inflammation and apoptosis. International journal of clinical and experimental medicine, 2015. 8(3): p. 3219.
144. Im Jeong, S., J.A. Shin, S. Cho, H.W. Kim, J.Y. Lee, J.L. Kang, et al., Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice. Neurobiology of Aging, 2016. 44: p. 74-84.
145. Gatson, J.W., M.-M. Liu, K. Abdelfattah, J.G. Wigginton, S. Smith, S. Wolf, et al., Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury. Journal of Trauma and Acute Care Surgery, 2013. 74(2): p. 470-475.
146. Hoda, U., N.B. Agarwal, D. Vohora, S. Parvez, and S. Raisuddin, Resveratrol suppressed seizures by attenuating IL-1β, IL1-Ra, IL-6, and TNF-α in the hippocampus and cortex of kindled mice. Nutritional neuroscience, 2016: p. 1-8.
147. Tian, X., Y. Liu, G. Ren, L. Yin, X. Liang, T. Geng, et al., Resveratrol limits diabetes-associated cognitive decline in rats by preventing oxidative stress and inflammation and modulating hippocampal structural synaptic plasticity. Brain Research, 2016. 1650: p. 1-9.
148. Hoda, U., N.B. Agarwal, D. Vohora, S. Parvez, and S. Raisuddin, Resveratrol suppressed seizures by attenuating IL-1β, IL1-Ra, IL-6, and TNF-α in the hippocampus and cortex of kindled mice. Nutritional neuroscience, 2017. 20(9): p. 497-504.
149. Mishra, V., B. Shuai, M. Kodali, G.A. Shetty, B. Hattiangady, X. Rao, et al., Resveratrol treatment after status epilepticus restrains neurodegeneration and abnormal neurogenesis with suppression of oxidative stress and inflammation. Scientific reports, 2015. 5: p. 17807.
150. Ge, L., L. Liu, H. Liu, S. Liu, H. Xue, X. Wang, et al., Resveratrol abrogates lipopolysaccharide-induced depressive-like behavior, neuroinflammatory response, and CREB/BDNF signaling in mice. European journal of pharmacology, 2015. 768: p. 49-57.
151. Tiwari, V. and K. Chopra, Resveratrol prevents alcohol‐induced cognitive deficits and brain damage by blocking inflammatory signaling and cell death cascade in neonatal rat brain. Journal of neurochemistry, 2011. 117(4): p. 678-690.
152. Steiner, N., R. Balez, N. Karunaweera, J.M. Lind, G. Münch, and L. Ooi, Neuroprotection of Neuro2a cells and the cytokine suppressive and anti-inflammatory mode of action of resveratrol in activated RAW264. 7 macrophages and C8–B4 microglia. Neurochemistry international, 2016. 95: p. 46-54.
153. Abraham, J. and R.W. Johnson, Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation research, 2009. 12(6): p. 445-453.
154. Zhong, L.-M., Y. Zong, L. Sun, J.-Z. Guo, W. Zhang, Y. He, et al., Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PloS one, 2012. 7(2): p. e32195.
155. Bureau, G., F. Longpré, and M.G. Martinoli, Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation. Journal of neuroscience research, 2008. 86(2): p. 403-410.
156. Wyss-Coray, T. and L. Mucke, Inflammation in neurodegenerative disease—a double-edged sword. Neuron, 2002. 35(3): p. 419-432.
157. Rudge, J.S., D. Morrissey, R.M. Lindsay, and E.M. Pasnikowski, Regulation of ciliary neurotrophic factor in cultured rat hippocampal astrocytes. European Journal of Neuroscience, 1994. 6(2): p. 218-229.
158. Kim, Y.A., G.-Y. Kim, K.-Y. Park, and Y.H. Choi, Resveratrol inhibits nitric oxide and prostaglandin E2 production by lipopolysaccharide-activated C6 microglia. Journal of medicinal food, 2007. 10(2): p. 218-224.
159. White, K.A., S.R. Hutton, J.M. Weimer, and P.A. Sheridan, Diet-induced obesity prolongs neuroinflammation and recruits CCR2+ monocytes to the brain following herpes simplex virus (HSV)-1 latency in mice. Brain, Behavior, and Immunity, 2016.
160. Beilharz, J., J. Maniam, and M. Morris, Short-term exposure to a diet high in fat and sugar, or liquid sugar, selectively impairs hippocampal-dependent memory, with differential impacts on inflammation. Behavioural brain research, 2016. 306: p. 1-7.
161. Spagnuolo, M.S., M.P. Mollica, B. Maresca, G. Cavaliere, C. Cefaliello, G. Trinchese, et al., High Fat Diet and Inflammation–Modulation of Haptoglobin Level in Rat Brain. Frontiers in cellular neuroscience, 2015. 9.
162. Miller, A.A. and S.J. Spencer, Obesity and neuroinflammation: a pathway to cognitive impairment. Brain, behavior, and immunity, 2014. 42: p. 10-21.
163. Cai, D., Neuroinflammation and neurodegeneration in overnutrition-induced diseases. Trends in Endocrinology & Metabolism, 2013. 24(1): p. 40-47.
164. Kumar, A. and S.S. Sharma, NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochem Biophys Res Commun, 2010. 394(2): p. 360-5.
165. Vinik, A.I. and A. Mehrabyan, Diabetic neuropathies. Med Clin North Am, 2004. 88(4): p. 947-99, xi.
166. Ramadori, G., L. Gautron, T. Fujikawa, C.R. Vianna, J.K. Elmquist, and R. Coppari, Central administration of resveratrol improves diet-induced diabetes. Endocrinology, 2009. 150(12): p. 5326-5333.
167. Thomas, J., M.L. Garg, and D.W. Smith, Dietary resveratrol supplementation normalizes gene expression in the hippocampus of streptozotocin-induced diabetic C57Bl/6 mice. The Journal of nutritional biochemistry, 2014. 25(3): p. 313-318.
168. Kumar, A. and S.S. Sharma, NF-κB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochemical and Biophysical Research Communications, 2010. 394(2): p. 360-365.
169. Kumar, A., R.K. Kaundal, S. Iyer, and S.S. Sharma, Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life sciences, 2007. 80(13): p. 1236-1244.
170. Sharma, S.S., A. Kumar, M. Arora, and R.K. Kaundal, Neuroprotective potential of combination of resveratrol and 4-amino 1, 8 naphthalimide in experimental diabetic neuropathy: focus on functional, sensorimotor and biochemical changes. Free radical research, 2009. 43(4): p. 400-408.
171. Anekonda, T.S., Resveratrol—A boon for treating Alzheimer's disease? Brain Research Reviews, 2006. 52(2): p. 316-326.
172. Zhuang, H., Y.-S. Kim, R.C. Koehler, and S. DorÉ, Potential Mechanism by Which Resveratrol, a Red Wine Constituent, Protects Neurons. Annals of the New York Academy of Sciences, 2003. 993(1): p. 276-286.
173. Clark, D., U.I. Tuor, R. Thompson, A. Institoris, A. Kulynych, X. Zhang, et al., Protection against Recurrent Stroke with Resveratrol: Endothelial Protection. PLOS ONE, 2012. 7(10): p. e47792.
174. Huang, S.S., M.C. Tsai, C.L. Chih, L.M. Hung, and S.K. Tsai, Resveratrol reduction of infarct size in Long-Evans rats subjected to focal cerebral ischemia. Life Sciences, 2001. 69(9): p. 1057-1065.
Files
IssueVol 1 No 2 (2023) QRcode
SectionReview Article(s)
DOI https://doi.org/10.18502/abi.v1i2.14101
Keywords
Resveratrol Adipose tissue Macrophage Type 2 diabetes Metabolic inflammation

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Ghahremani H, Bahramzadeh A, Bolandnazar K, Emamgholipor S, Hosseini H, Meshkani R. Resveratrol as a Potential Protective Compound Against Metabolic Inflammation. ABI. 2023;1(2):50-64.