DOI QR코드

DOI QR Code

Molecular targets of exercise mimetics and their natural activators

  • Jang, Young Jin (Major of Food Science & Technology, Seoul Women's University) ;
  • Byun, Sanguine (Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University)
  • 투고 : 2021.09.23
  • 심사 : 2021.11.24
  • 발행 : 2021.12.31

초록

Physical exercise can be effective in preventing or ameliorating various diseases, including diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. However, not everyone may be able to participate in exercise due to illnesses, age-related frailty, or difficulty in long-term behavior change. An alternative option is to utilize pharmacological interventions that mimic the positive effects of exercise training. Recent studies have identified signaling pathways associated with the benefits of physical activity and discovered exercise mimetics that can partially simulate the systemic impact of exercise. This review describes the molecular targets for exercise mimetics and their effect on skeletal muscle and other tissues. We will also discuss the potential advantages of using natural products as a multi-targeting agent for mimicking the health-promoting effects of exercise.

키워드

과제정보

This research was supported by a research grant from Seoul Women's University (2020-0452) and the Yonsei University Research Fund of 2020-22-0073.

참고문헌

  1. Gubert C and Hannan AJ (2021) Exercise mimetics: harnessing the therapeutic effects of physical activity. Nat Rev Drug Discov 20, 862-879 https://doi.org/10.1038/s41573-021-00217-1
  2. Fan W and Evans RM (2017) Exercise mimetics: impact on health and performance. Cell Metab 25, 242-247 https://doi.org/10.1016/j.cmet.2016.10.022
  3. O'Gorman DJ, Karlsson HK, McQuaid S et al (2006) Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes. Diabetologia 49, 2983-2992 https://doi.org/10.1007/s00125-006-0457-3
  4. Ernst C, Olson AK, Pinel JP, Lam RW and Christie BR (2006) Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis? J Psychiatry Neurosci 31, 84-92
  5. Wang M, Baker JS, Quan W, Shen S, Fekete G and Gu Y (2020) A preventive role of exercise across the Coronavirus 2 (SARS-CoV-2) pandemic. Front Physiol 11, 572718 https://doi.org/10.3389/fphys.2020.572718
  6. Ahn J, Ha TY, Ahn J et al (2020) Undaria pinnatifida extract feeding increases exercise endurance and skeletal muscle mass by promoting oxidative muscle remodeling in mice. FASEB J 34, 8068-8081 https://doi.org/10.1096/fj.201902399RR
  7. Egan B and Zierath JR (2013) Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab 17, 162-184 https://doi.org/10.1016/j.cmet.2012.12.012
  8. Fan W, Waizenegger W, Lin CS et al (2017) PPARdelta promotes running endurance by preserving glucose. Cell Metab 25, 1186-1193 e1184 https://doi.org/10.1016/j.cmet.2017.04.006
  9. Hughes DC, Ellefsen S and Baar K (2018) Adaptations to endurance and strength training. Cold Spring Harb Perspect Med 8, a029769 https://doi.org/10.1101/cshperspect.a029769
  10. Bandy WD, Lovelace-Chandler V and McKitrick-Bandy B (1990) Adaptation of skeletal muscle to resistance training. J Orthop Sports Phys Ther 12, 248-255 https://doi.org/10.2519/jospt.1990.12.6.248
  11. Warburton DE, Nicol CW and Bredin SS (2006) Health benefits of physical activity: the evidence. CMAJ 174, 801-809 https://doi.org/10.1503/cmaj.051351
  12. Mercken EM, Carboneau BA, Krzysik-Walker SM and de Cabo R (2012) Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res Rev 11, 390-398 https://doi.org/10.1016/j.arr.2011.11.005
  13. Li S and Laher I (2017) Exercise mimetics: running without a road map. Clin Pharmacol Ther 101, 188-190 https://doi.org/10.1002/cpt.533
  14. Carey AL and Kingwell BA (2009) Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with 'exercise mimetics'. Diabetologia 52, 2015-2026 https://doi.org/10.1007/s00125-009-1420-x
  15. Hawley JA, Joyner MJ and Green DJ (2021) Mimicking exercise: what matters most and where to next? J Physiol 599, 791-802 https://doi.org/10.1113/JP278761
  16. Lee JH and Jun HS (2019) Role of myokines in regulating skeletal muscle mass and function. Front Physiol 10, 42 https://doi.org/10.3389/fphys.2019.00042
  17. Hartwig S, Raschke S, Knebel B et al (2014) Secretome profiling of primary human skeletal muscle cells. Biochim Biophys Acta 1844, 1011-1017 https://doi.org/10.1016/j.bbapap.2013.08.004
  18. Chen N, Li Q, Liu J and Jia S (2016) Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review. Diabetes Metab Res Rev 32, 51-59 https://doi.org/10.1002/dmrr.2660
  19. Liu L, Guo J, Chen X, Tong X, Xu J and Zou J (2021) The role of irisin in exercise-mediated bone health. Front Cell Dev Biol 9, 668759 https://doi.org/10.3389/fcell.2021.668759
  20. Lira VA, Benton CR, Yan Z and Bonen A (2010) PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab 299, E145-E161 https://doi.org/10.1152/ajpendo.00755.2009
  21. Bostrom P, Wu J, Jedrychowski MP et al (2012) A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463-468 https://doi.org/10.1038/nature10777
  22. Reza MM, Subramaniyam N, Sim CM et al (2017) Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy. Nat Commun 8, 1104 https://doi.org/10.1038/s41467-017-01131-0
  23. He W, Wang P, Chen Q and Li C (2020) Exercise enhances mitochondrial fission and mitophagy to improve myopathy following critical limb ischemia in elderly mice via the PGC1a/FNDC5/irisin pathway. Skelet Muscle 10, 25 https://doi.org/10.1186/s13395-020-00245-2
  24. Korta P, Pochec E and Mazur-Bialy A (2019) Irisin as a multifunctional protein: implications for health and certain diseases. Medicina (Kaunas) 55, 485 https://doi.org/10.3390/medicina55080485
  25. Mazur-Bialy AI, Bilski J, Pochec E and Brzozowski T (2017) New insight into the direct anti-inflammatory activity of a myokine irisin against proinflammatory activation of adipocytes. Implication for exercise in obesity. J Physiol Pharmacol 68, 243-251
  26. Otero-Diaz B, Rodriguez-Flores M, Sanchez-Munoz V et al (2018) Exercise induces white adipose tissue browning across the weight spectrum in humans. Front Physiol 9, 1781 https://doi.org/10.3389/fphys.2018.01781
  27. Castillo-Quan JI (2012) From white to brown fat through the PGC-1alpha-dependent myokine irisin: implications for diabetes and obesity. Dis Model Mech 5, 293-295 https://doi.org/10.1242/dmm.009894
  28. Wrann CD, White JP, Salogiannnis J et al (2013) Exercise induces hippocampal BDNF through a PGC-1alpha/ FNDC5 pathway. Cell Metab 18, 649-659 https://doi.org/10.1016/j.cmet.2013.09.008
  29. Islam MR, Valaris S, Young MF et al (2021) Exercise hormone irisin is a critical regulator of cognitive function. Nat Metab 3, 1058-1070 https://doi.org/10.1038/s42255-021-00438-z
  30. Liu PZ and Nusslock R (2018) Exercise-mediated neurogenesis in the Hippocampus via BDNF. Front Neurosci 12, 52 https://doi.org/10.3389/fnins.2018.00052
  31. Gomez-Pinilla F, Ying Z, Roy RR, Molteni R and Edgerton VR (2002) Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 88, 2187-2195 https://doi.org/10.1152/jn.00152.2002
  32. Soya H, Nakamura T, Deocaris CC et al (2007) BDNF induction with mild exercise in the rat hippocampus. Biochem Biophys Res Commun 358, 961-967 https://doi.org/10.1016/j.bbrc.2007.04.173
  33. Nilsson J, Ekblom O, Ekblom M et al (2020) Acute increases in brain-derived neurotrophic factor in plasma following physical exercise relates to subsequent learning in older adults. Sci Rep 10, 4395 https://doi.org/10.1038/s41598-020-60124-0
  34. Bishop-Bailey D (2013) Mechanisms governing the health and performance benefits of exercise. Br J Pharmacol 170, 1153-1166 https://doi.org/10.1111/bph.12399
  35. Yu T, Chang Y, Gao XL, Li H and Zhao P (2017) Dynamic expression and the role of BDNF in exercise-induced skeletal muscle regeneration. Int J Sports Med 38, 959-966 https://doi.org/10.1055/s-0043-118343
  36. Zhang Z, Wang B and Fei A (2019) BDNF contributes to the skeletal muscle anti-atrophic effect of exercise training through AMPK-PGC1alpha signaling in heart failure mice. Arch Med Sci 15, 214-222 https://doi.org/10.5114/aoms.2018.81037
  37. So B, Kim HJ, Kim J and Song W (2014) Exercise-induced myokines in health and metabolic diseases. Integr Med Res 3, 172-179 https://doi.org/10.1016/j.imr.2014.09.007
  38. Motamedi S, Karimi I and Jafari F (2017) The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): kill two birds with one stone. Metab Brain Dis 32, 651-665 https://doi.org/10.1007/s11011-017-9997-0
  39. Munoz-Canoves P, Scheele C, Pedersen BK and Serrano AL (2013) Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J 280, 4131-4148 https://doi.org/10.1111/febs.12338
  40. Pedersen BK, Steensberg A, Fischer C et al (2003) Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 24, 113-119 https://doi.org/10.1023/A:1026070911202
  41. Pedersen BK and Fischer CP (2007) Beneficial health effects of exercise--the role of IL-6 as a myokine. Trends Pharmacol Sci 28, 152-156 https://doi.org/10.1016/j.tips.2007.02.002
  42. Pedersen BK and Febbraio MA (2008) Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 88, 1379-1406 https://doi.org/10.1152/physrev.90100.2007
  43. Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH et al (2019) Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab 29, 844-855 e843 https://doi.org/10.1016/j.cmet.2018.12.007
  44. Febbraio MA, Hiscock N, Sacchetti M, Fischer CP and Pedersen BK (2004) Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53, 1643-1648 https://doi.org/10.2337/diabetes.53.7.1643
  45. Carey AL, Steinberg GR, Macaulay SL et al (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688-2697 https://doi.org/10.2337/db05-1404
  46. Bowen KK, Dempsey RJ and Vemuganti R (2011) Adult interleukin-6 knockout mice show compromised neurogenesis. Neuroreport 22, 126-130 https://doi.org/10.1097/WNR.0b013e3283430a44
  47. Fan W, Atkins AR, Yu RT, Downes M and Evans RM (2013) Road to exercise mimetics: targeting nuclear receptors in skeletal muscle. J Mol Endocrinol 51, T87-T100
  48. Richter EA and Ruderman NB (2009) AMPK and the biochemistry of exercise: implications for human health and disease. Biochem J 418, 261-275 https://doi.org/10.1042/BJ20082055
  49. Fujii N, Seifert MM, Kane EM et al (2007) Role of AMP-activated protein kinase in exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle -insight from analysis of a transgenic mouse model. Diabetes Res Clin Pract 77 Suppl 1, S92-S98 https://doi.org/10.1016/j.diabres.2007.01.040
  50. Narkar VA, Downes M, Yu RT et al (2008) AMPK and PPARdelta agonists are exercise mimetics. Cell 134, 405-415 https://doi.org/10.1016/j.cell.2008.06.051
  51. Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M and Holloszy JO (2000) Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol (1985) 88, 2219-2226 https://doi.org/10.1152/jappl.2000.88.6.2219
  52. Guerrieri D, Moon HY and van Praag H (2017) Exercise in a pill: the latest on exercise-mimetics. Brain Plast 2, 153-169 https://doi.org/10.3233/bpl-160043
  53. Buhl ES, Jessen N, Pold R et al (2002) Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes 51, 2199-2206 https://doi.org/10.2337/diabetes.51.7.2199
  54. Kirchner J, Brune B and Namgaladze D (2018) AICAR inhibits NFkappaB DNA binding independently of AMPK to attenuate LPS-triggered inflammatory responses in human macrophages. Sci Rep 8, 7801 https://doi.org/10.1038/s41598-018-26102-3
  55. Kobilo T, Yuan C and van Praag H (2011) Endurance factors improve hippocampal neurogenesis and spatial memory in mice. Learn Mem 18, 103-107 https://doi.org/10.1101/lm.2001611
  56. Kobilo T, Guerrieri D, Zhang Y, Collica SC, Becker KG and van Praag H (2014) AMPK agonist AICAR improves cognition and motor coordination in young and aged mice. Learn Mem 21, 119-126 https://doi.org/10.1101/lm.033332.113
  57. Guerrieri D and van Praag H (2015) Exercise-mimetic AICAR transiently benefits brain function. Oncotarget 6, 18293-18313 https://doi.org/10.18632/oncotarget.4715
  58. Zizola C, Kennel PJ, Akashi H et al (2015) Activation of PPARdelta signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction. Am J Physiol Heart Circ Physiol 308, H1078-H1085 https://doi.org/10.1152/ajpheart.00679.2014
  59. Braissant O, Foufelle F, Scotto C, Dauca M and Wahli W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPARalpha, -beta, and -gamma in the adult rat. Endocrinology 137, 354-366 https://doi.org/10.1210/en.137.1.354
  60. Greene NP, Fluckey JD, Lambert BS, Greene ES, Riechman SE and Crouse SF (2012) Regulators of blood lipids and lipoproteins? PPARdelta and AMPK, induced by exercise, are correlated with lipids and lipoproteins in overweight/obese men and women. Am J Physiol Endocrinol Metab 303, E1212-E1221 https://doi.org/10.1152/ajpendo.00309.2012
  61. Reilly SM and Lee CH (2008) PPAR delta as a therapeutic target in metabolic disease. FEBS Lett 582, 26-31 https://doi.org/10.1016/j.febslet.2007.11.040
  62. Tanaka T, Yamamoto J, Iwasaki S et al (2003) Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A 100, 15924-15929 https://doi.org/10.1073/pnas.0306981100
  63. Oliver WR Jr, Shenk JL, Snaith MR et al (2001) A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A 98, 5306-5311 https://doi.org/10.1073/pnas.091021198
  64. Cheng L, Ding G, Qin Q et al (2004) Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 10, 1245-1250 https://doi.org/10.1038/nm1116
  65. Badin PM, Vila IK, Sopariwala DH et al (2016) Exercise-like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db/db mice. Sci Rep 6, 26442 https://doi.org/10.1038/srep26442
  66. Matsakas A, Macharia R, Otto A et al (2012) Exercise training attenuates the hypermuscular phenotype and restores skeletal muscle function in the myostatin null mouse. Exp Physiol 97, 125-140 https://doi.org/10.1113/expphysiol.2011.063008
  67. Fan W, He N, Lin CS et al (2018) ERRgamma promotes angiogenesis, mitochondrial biogenesis, and oxidative remodeling in PGC1alpha/beta-deficient muscle. Cell Rep 22, 2521-2529 https://doi.org/10.1016/j.celrep.2018.02.047
  68. Narkar VA, Fan W, Downes M et al (2011) Exercise and PGC-1alpha-independent synchronization of type I muscle metabolism and vasculature by ERRgamma. Cell Metab 13, 283-293 https://doi.org/10.1016/j.cmet.2011.01.019
  69. Rangwala SM, Wang X, Calvo JA et al (2010) Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity. J Biol Chem 285, 22619-22629 https://doi.org/10.1074/jbc.M110.125401
  70. Matsakas A, Yadav V, Lorca S and Narkar V (2013) Muscle ERRgamma mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming. FASEB J 27, 4004-4016 https://doi.org/10.1096/fj.13-228296
  71. Kim DK, Kim JR, Koh M et al (2011) Estrogen-related receptor gamma (ERRgamma) is a novel transcriptional regulator of phosphatidic acid phosphatase, LIPIN1, and inhibits hepatic insulin signaling. J Biol Chem 286, 38035-38042 https://doi.org/10.1074/jbc.M111.250613
  72. Kim DK, Kim YH, Jang HH et al (2013) Estrogen-related receptor gamma controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol. Gut 62, 1044-1054 https://doi.org/10.1136/gutjnl-2012-303347
  73. Kim DK, Jeong JH, Lee JM et al (2014) Inverse agonist of estrogen-related receptor gamma controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat Med 20, 419-424 https://doi.org/10.1038/nm.3483
  74. Byun S, Lim S, Mun JY et al (2015) Identification of a dual inhibitor of janus kinase 2 (JAK2) and p70 ribosomal S6 kinase1 (S6K1) pathways. J Biol Chem 290, 23553-23562 https://doi.org/10.1074/jbc.M115.662445
  75. Shin EJ, Lee JS, Hong S, Lim TG and Byun S (2019) Quercetin directly targets JAK2 and PKCdelta and prevents UV-induced photoaging in human skin. Int J Mol Sci 20, 5262 https://doi.org/10.3390/ijms20215262
  76. Jiang Q, Cheng X, Cui Y et al (2019) Resveratrol regulates skeletal muscle fibers switching through the AdipoR1-AMPK-PGC-1alpha pathway. Food Funct 10, 3334-3343 https://doi.org/10.1039/C8FO02518E
  77. Wicinski M, Malinowski B, Weclewicz MM, Grzesk E and Grzesk G (2017) Resveratrol increases serum BDNF concentrations and reduces vascular smooth muscle cells contractility via a NOS-3-independent mechanism. Biomed Res Int 2017, 9202954 https://doi.org/10.1155/2017/9202954
  78. Seo DY, Lee SR, Heo JW et al (2018) Ursolic acid in health and disease. Korean J Physiol Pharmacol 22, 235-248 https://doi.org/10.4196/kjpp.2018.22.3.235
  79. Bang HS, Seo DY, Chung YM et al (2014) Ursolic Acid-induced elevation of serum irisin augments muscle strength during resistance training in men. Korean J Physiol Pharmacol 18, 441-446 https://doi.org/10.4196/kjpp.2014.18.5.441
  80. Jang YJ, Son HJ, Choi YM, Ahn J, Jung CH and Ha TY (2017) Apigenin enhances skeletal muscle hypertrophy and myoblast differentiation by regulating Prmt7. Oncotarget 8, 78300-78311 https://doi.org/10.18632/oncotarget.20962
  81. Chen L, Xie W, Xie W, Zhuang W, Jiang C and Liu N (2017) Apigenin attenuates isoflurane-induced cognitive dysfunction via epigenetic regulation and neuroinflammation in aged rats. Arch Gerontol Geriatr 73, 29-36 https://doi.org/10.1016/j.archger.2017.07.004
  82. Choi WH, Son HJ, Jang YJ, Ahn J, Jung CH and Ha TY (2017) Apigenin ameliorates the obesity-induced skeletal muscle atrophy by attenuating mitochondrial dysfunction in the muscle of obese mice. Mol Nutr Food Res 61, 1700218 https://doi.org/10.1002/mnfr.201700218
  83. Zhang H, Chi M, Chen L et al (2021) Daidzein alleviates cisplatin-induced muscle atrophy by regulating Glut4/AMPK/FoxO pathway. Phytother Res 35, 4363-4376 https://doi.org/10.1002/ptr.7132
  84. Tan J, Huang C, Luo Q et al (2019) Soy isoflavones ameliorate fatty acid metabolism of visceral adipose tissue by increasing the AMPK activity in male rats with diet-induced obesity (DIO). Molecules 24, 2809 https://doi.org/10.3390/molecules24152809
  85. Zhao Y, Chen B, Shen J et al (2017) The beneficial effects of quercetin, curcumin, and resveratrol in obesity. Oxid Med Cell Longev 2017, 1459497 https://doi.org/10.1155/2017/1459497
  86. Rahvar M, Owji AA and Mashayekhi FJ (2018) Effect of quercetin on the brain-derived neurotrophic factor gene expression in the rat brain. Bratisl Lek Listy 119, 28-31
  87. Dyle MC, Ebert SM, Cook DP et al (2014) Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. J Biol Chem 289, 14913-14924 https://doi.org/10.1074/jbc.M114.556241
  88. Kuo CY, Huang WC, Liou CJ, Chen LC, Shen JJ and Kuo ML (2017) Tomatidine attenuates airway hyperresponsiveness and inflammation by suppressing Th2 cytokines in a mouse model of asthma. Mediators Inflamm 2017, 5261803 https://doi.org/10.1155/2017/5261803
  89. Wu SJ, Huang WC, Yu MC et al (2021) Tomatidine ameliorates obesity-induced nonalcoholic fatty liver disease in mice. J Nutr Biochem 91, 108602 https://doi.org/10.1016/j.jnutbio.2021.108602
  90. Fang EF, Waltz TB, Kassahun H et al (2017) Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci Rep 7, 46208 https://doi.org/10.1038/srep46208
  91. Ahn J, Kim MJ, Yoo A et al (2021) Identifying Codium fragile extract components and their effects on muscle weight and exercise endurance. Food Chem 353, 129463 https://doi.org/10.1016/j.foodchem.2021.129463
  92. Ahn J, Son HJ, Seo HD et al (2021) Gamma-oryzanol improves exercise endurance and muscle strength by upregulating PPARdelta and ERRgamma activity in aged mice. Mol Nutr Food Res 65, e2000652
  93. Jang YJ, Ahn J, Son HJ, Jung CH, Ahn J and Ha TY (2019) Hydrangea serrata tea enhances running endurance and skeletal muscle mass. Mol Nutr Food Res 63, e1801149
  94. Malaguarnera L (2019) Influence of resveratrol on the immune response. Nutrients 11, 946 https://doi.org/10.3390/nu11050946
  95. Kunkel SD, Suneja M, Ebert SM et al (2011) mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell Metab 13, 627-638 https://doi.org/10.1016/j.cmet.2011.03.020
  96. Choi WH, Jang YJ, Son HJ, Ahn J, Jung CH and Ha TY (2018) Apigenin inhibits sciatic nerve denervation-induced muscle atrophy. Muscle Nerve 58, 314-318 https://doi.org/10.1002/mus.26133
  97. Wang D, Yang Y, Zou X, Zhang J, Zheng Z and Wang Z (2020) Antioxidant apigenin relieves age-related muscle atrophy by inhibiting oxidative stress and hyperactive mitophagy and apoptosis in skeletal muscle of mice. J Gerontol A Biol Sci Med Sci 75, 2081-2088 https://doi.org/10.1093/gerona/glaa214
  98. Salehi B, Venditti A, Sharifi-Rad M et al (2019) The therapeutic potential of apigenin. Int J Mol Sci 20, 1305 https://doi.org/10.3390/ijms20061305
  99. Ahmed T, Javed S, Tariq A et al (2017) Daidzein and its effects on brain. Curr Med Chem 24, 365-375 https://doi.org/10.2174/0929867323666161101140214
  100. Ogawa M, Kitano T, Kawata N et al (2017) Daidzein down-regulates ubiquitin-specific protease 19 expression through estrogen receptor beta and increases skeletal muscle mass in young female mice. J Nutr Biochem 49, 63-70 https://doi.org/10.1016/j.jnutbio.2017.07.017
  101. Sakamoto Y, Naka A, Ohara N, Kondo K and Iida K (2014) Daidzein regulates proinflammatory adipokines thereby improving obesity-related inflammation through PPARgamma. Mol Nutr Food Res 58, 718-726 https://doi.org/10.1002/mnfr.201300482
  102. Liu X, Suzuki N, Santosh Laxmi YR, Okamoto Y and Shibutani S (2012) Anti-breast cancer potential of daidzein in rodents. Life Sci 91, 415-419 https://doi.org/10.1016/j.lfs.2012.08.022
  103. Das D, Sarkar S, Bordoloi J, Wann SB, Kalita J and Manna P (2018) Daidzein, its effects on impaired glucose and lipid metabolism and vascular inflammation associated with type 2 diabetes. Biofactors 44, 407-417 https://doi.org/10.1002/biof.1439
  104. Le NH, Kim CS, Park T et al (2014) Quercetin protects against obesity-induced skeletal muscle inflammation and atrophy. Mediators Inflamm 2014, 834294 https://doi.org/10.1155/2014/834294
  105. Anhe GF, Okamoto MM, Kinote A et al (2012) Quercetin decreases inflammatory response and increases insulin action in skeletal muscle of ob/ob mice and in L6 myotubes. Eur J Pharmacol 689, 285-293 https://doi.org/10.1016/j.ejphar.2012.06.007
  106. Otsuka Y, Egawa K, Kanzaki N, Izumo T, Rogi T and Shibata H (2019) Quercetin glycosides prevent dexamethasone-induced muscle atrophy in mice. Biochem Biophys Rep 18, 100618
  107. Ghafouri-Fard S, Shabestari FA, Vaezi S et al (2021) Emerging impact of quercetin in the treatment of prostate cancer. Biomed Pharmacother 138, 111548 https://doi.org/10.1016/j.biopha.2021.111548
  108. Geng L, Liu Z, Wang S et al (2019) Low-dose quercetin positively regulates mouse healthspan. Protein Cell 10, 770-775 https://doi.org/10.1007/s13238-019-0646-8
  109. Kanzaki N, Takemoto D, Ono Y et al (2019) Quercetin glycosides improve motor performance and muscle weight in adult mice. J Nutr Food Sci 9, 760
  110. Davis JM, Murphy EA, Carmichael MD and Davis B (2009) Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul Integr Comp Physiol 296, R1071-R1077 https://doi.org/10.1152/ajpregu.90925.2008
  111. Daneshvar P, Hariri M, Ghiasvand R et al (2013) Effect of eight weeks of quercetin supplementation on exercise performance, muscle damage and body muscle in male badminton players. Int J Prev Med 4, S53-S57
  112. Dajas F, Abin-Carriquiry JA, Arredondo F et al (2015) Quercetin in brain diseases: Potential and limits. Neurochem Int 89, 140-148 https://doi.org/10.1016/j.neuint.2015.07.002
  113. Kim TI, Kim YJ and Kim K (2021) Extract of seaweed Codium fragile inhibits integrin alphaIIbbeta3-induced outside-in signaling and arterial thrombosis. Front Pharmacol 12, 685948 https://doi.org/10.3389/fphar.2021.685948
  114. Yang Y, Lim J, Li C, Lee S and Hong S (2021) Effects of sulfated polysaccharides isolated from Codium fragile on inflammatory cytokine gene expression and Edwardsiella tarda infection in rockfish, Sebastes schlegelii. Fish Shellfish Immunol 112, 125-134 https://doi.org/10.1016/j.fsi.2021.03.001
  115. Park HB, Hwang J, Zhang W et al (2020) Polysaccharide from Codium fragile induces anti-cancer immunity by activating natural killer cells. Mar Drugs 18, 626 https://doi.org/10.3390/md18120626
  116. Monmai C, Rod-In W, Jang AY et al (2020) Immune-enhancing effects of anionic macromolecules extracted from Codium fragile coupled with arachidonic acid in RAW264.7 cells. PLoS One 15, e0239422 https://doi.org/10.1371/journal.pone.0239422
  117. Kolsi RBA, Jardak N, Hajkacem F et al (2017) Anti-obesity effect and protection of liver-kidney functions by Codium fragile sulphated polysaccharide on high fat diet induced obese rats. Int J Biol Macromol 102, 119-129 https://doi.org/10.1016/j.ijbiomac.2017.04.017
  118. Etman SM, Mehanna RA, Bary AA, Elnaggar YSR and Abdallah OY (2021) Undaria pinnatifida fucoidan nanoparticles loaded with quinacrine attenuate growth and metastasis of pancreatic cancer. Int J Biol Macromol 170, 284-297 https://doi.org/10.1016/j.ijbiomac.2020.12.109
  119. Li L, Wang Y, Yuan J, Liu Z, Ye C and Qin S (2020) Undaria pinnatifida improves obesity-related outcomes in association with gut microbiota and metabolomics modulation in high-fat diet-fed mice. Appl Microbiol Biotechnol 104, 10217-10231 https://doi.org/10.1007/s00253-020-10954-9
  120. Maqueshudul Haque Bhuiyan M, Mohibbullah M, Hannan MA et al (2015) Undaria pinnatifida promotes spinogenesis and synaptogenesis and potentiates functional presynaptic plasticity in hippocampal neurons. Am J Chin Med 43, 529-542 https://doi.org/10.1142/S0192415X15500330
  121. Lee HH, Cho Y, Kim GH and Cho H (2020) Undaria pinnatifida fucoidan-rich extract recovers immunity of immunosuppressed mice. J Microbiol Biotechnol 30, 439-447 https://doi.org/10.4014/jmb.1908.08026
  122. Oh JH, Kim J and Lee Y (2016) Anti-inflammatory and anti-diabetic effects of brown seaweeds in high-fat diet-induced obese mice. Nutr Res Pract 10, 42-48 https://doi.org/10.4162/nrp.2016.10.1.42
  123. Rungratanawanich W, Cenini G, Mastinu A et al (2019) Gamma-oryzanol improves cognitive function and modulates hippocampal proteome in mice. Nutrients 11, 753 https://doi.org/10.3390/nu11040753
  124. Araujo SM, Bortolotto VC, Poetini MR et al (2021) Gamma-oryzanol produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in Drosophila melanogaster. Stress 24, 282-293 https://doi.org/10.1080/10253890.2020.1790519
  125. De Mattei L, Francisqueti-Ferron FV, Garcia JL et al (2021) Antioxidant and anti-inflammatory properties of gamma- oryzanol attenuates insulin resistance by increasing GLUT- 4 expression in skeletal muscle of obese animals. Mol Cell Endocrinol 537, 111423 https://doi.org/10.1016/j.mce.2021.111423
  126. Wang L, Lin Q, Yang T et al (2017) Oryzanol modifies high fat diet-induced obesity, liver gene expression profile, and inflammation response in mice. J Agric Food Chem 65, 8374-8385 https://doi.org/10.1021/acs.jafc.7b03230
  127. Shin SY, Kim HW, Jang HH et al (2017) Gamma-oryzanolrich black rice bran extract enhances the innate immune response. J Med Food 20, 855-863 https://doi.org/10.1089/jmf.2017.3966
  128. Eslami S, Esa NM, Marandi SM, Ghasemi G and Eslami S (2014) Effects of gamma oryzanol supplementation on anthropometric measurements & muscular strength in healthy males following chronic resistance training. Indian J Med Res 139, 857-863
  129. Han HS, Lee HH, Gil HS et al (2021) Standardized hot water extract from the leaves of Hydrangea serrata (Thunb.) Ser. alleviates obesity via the AMPK pathway and modulation of the gut microbiota composition in high fat diet-induced obese mice. Food Funct 12, 2672-2685 https://doi.org/10.1039/D0FO02185G
  130. Myung DB, Han HS, Shin JS et al (2019) Hydrangenol isolated from the leaves of hydrangea serrata attenuates wrinkle formation and repairs skin moisture in uvbirradiated hairless mice. Nutrients 11, 2354 https://doi.org/10.3390/nu11102354