A review on anti-inflammation activity of phenol compound paeonol

Abstract

Paeonol is a bioactive phenol present in Dioscorea japonica, Paeonia suffruticosa and Paeonia lactiflora. It is the main active ingredient in the traditional Chinese medicines Mudanpi and Xu Changqing. Clinical applications of paeonol are mainly focused on anti-inflammatory effects due to its ability to act as an antioxidant, a regulator of inflammatory enzyme activities, a modulator of inflammatory signaling pathways and a regulator of adhesion molecules to modulate inflammation through molecular mechanisms of action. In addition, paeonol also regulates inflammation by regulating the metabolism of gut microbes. In this review, we searched PubMed, Web of Science, ESI and other websites using “paeonol” “inflammation” “oxidative stress” “signaling pathways” and “gut microbiota” as keywords. We mainly referred to the relevant literature in the last decade and systematically summarized the studies on the anti-inflammatory effects of paeonol to provide a reference for new drug development and clinical application of paeonol.

Keywords

paeonol / inflammation / molecular mechanisms / gut microbes

References

[1] Medzhitov R. Origin and physiological roles of inflammation[J]. Nature, 2008, 454 (7203): 428-435.

[2] Mourits MP, Prummel MF, Wiersinga WM, et al. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy[J]. Clin Endocrinol (Oxf), 1997, 47 (1): 9-14.

[3] Semerano L, Julia C, Aitisha O, et al. Nutrition and chronic inflammatory rheumatic disease[J]. Joint Bone Spine, 2017, 84 (5): 547-552.

[4] Sharma D, Malik A, Guy CS, et al. Pyrin inflammasome regulates tight junction integrity to restrict colitis and tumorigenesis[J]. Gastroenterology, 2018, 154 (4): 948-964.e8.

[5] Wolf D, Ley K. Immunity and inflammation in atherosclerosis[J]. Circ Res, 2019, 124 (2): 315-327.

[6] Soysal P, Arik F, Smith L, et al. Inflammation, frailty and cardiovascular disease[J]. Adv Exp Med Biol, 2020, 1216: 55-64.

[7] Han X, Krempski JW, Nadeau K. Advances and novel developments in mechanisms of allergic inflammation[J]. Allergy, 2020, 75 (12): 3100-3111.

[8] Khandia R, Munjal A. Interplay between inflammation and cancer[J]. Adv Protein Chem Struct Biol, 2020, 119: 199-245.

[9] Galea E, Graeber MB. Neuroinflammation: The abused concept[J]. ASN Neuro, 2023, 15: 17590914231197523.

[10] Lyons JJ, Yi T. Mast cell tryptases in allergic inflammation and immediate hypersensitivity[J]. Curr Opin Immunol, 2021, 72: 94-106.

[11] Zhou Y, Zhang H, Yao Y, et al. CD4(+) T cell activation and inflammation in NASH-related fibrosis[J]. Front Immunol, 2022, 13: 967410.

[12] Hagen M, Derudder E. Inflammation and the alteration of B-cell physiology in aging[J]. Gerontology, 2020, 66 (2): 105-113.

[13] Kucuksezer UC, Aktas Cetin E, Esen F, et al. The role of natural killer cells in autoimmune diseases[J]. Front Immunol, 2021, 12: 622306.

[14] Singhal A, Kumar S. Neutrophil and remnant clearance in immunity and inflammation[J]. Immunology, 2022, 165 (1): 22-43.

[15] Hassanshahi A, Moradzad M, Ghalamkari S, et al. Macrophage-mediated inflammation in skin wound healing[J]. Cells, 2022, 11 (19): 2953.

[16] Zhao M, Wang Y, Li L, et al. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance[J]. Theranostics, 2021, 11 (4): 1845-1863.

[17] Daenen K, Andries A, Mekahli D, et al. Oxidative stress in chronic kidney disease[J]. Pediatr Nephrol, 2019, 34 (6): 975-991.

[18] Zhang Y, Cui J, Lu Y, et al. Selenium deficiency induces inflammation via the iNOS/NF-κB pathway in the brain of pigs[J]. Biol Trace Elem Res, 2020, 196 (1): 103-109.

[19] Denny WA. Inhibitors and activators of the p38 mitogen- activated MAP kinase (MAPK) family as drugs to treat cancer and inflammation[J]. Curr Cancer Drug Targets, 2022, 22 (3): 209-220.

[20] Wells JM, Gaggar A, Blalock JE. MMP generated matrikines[J]. Matrix Biol, 2015, 44-46: 122-129.

[21] He Z, Tao D, Xiong J, et al. Phosphorylation of 5-LOX: The potential set-point of inflammation[J]. Neurochem Res, 2020, 45 (10): 2245-2257.

[22] Yu T, Lao X, Zheng H. Influencing COX-2 activity by COX related pathways in inflammation and cancer[J]. Mini Rev Med Chem, 2016, 16 (15): 1230-1243.

[23] Capece D, Verzella D, Flati I, et al. NF-κB: Blending metabolism, immunity, and inflammation[J]. Trends Immunol, 2022, 43 (9): 757-775.

[24] Sarapultsev A, Gusev E, Komelkova M, et al. JAK-STAT signaling in inflammation and stress-related diseases: Implications for therapeutic interventions[J]. Mol Biomed, 2023, 4 (1): 40.

[25] Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro- inflammatory signaling[J]. Cell Mol Life Sci, 2021, 78 (4): 1233-1261.

[26] Acosta-Martinez M, Cabail MZ. The PI3K/Akt pathway in Meta-inflammation[J]. Int J Mol Sci, 2022, 23 (23): 5330.

[27] O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation[J]. Nature, 2013, 493 (7432): 346-355.

[28] Jang DI, Lee AH, Shin HY, et al. The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics[J]. Int J Mol Sci, 2021, 22 (5): 2719.

[29] Lee CW, Hu SC, Yen FL, et al. Magnolol nanoparticles exhibit improved water solubility and suppress TNF-α- induced VCAM-1 expression in endothelial cells[J]. J Biomed Nanotechnol, 2017, 13 (3): 255-268.

[30] Bacchi S, Palumbo P, Sponta A, et al. Clinical pharmacology of non-steroidal anti-inflammatory drugs: A review[J]. Antiinflamm Antiallergy Agents Med Chem, 2012, 11 (1): 52-64.

[31] Laveti D, Kumar M, Hemalatha R, et al. Anti- inflammatory treatments for chronic diseases: A review[J]. Inflamm Allergy Drug Targets, 2013, 12 (5): 349-361.

[32] Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: Challenges and opportunities[J]. Science, 2013, 339 (6116): 166-172.

[33] Gouda NA, Alshammari SO, Abourehab MAS, et al. Therapeutic potential of natural products in inflammation: underlying molecular mechanisms, clinical outcomes, technological advances, and future perspectives[J]. Inflammopharmacology, 2023, 31 (6): 2857-2883.

[34] Li P, Shen J, Wang Z, et al. Genus paeonia: A comprehensive review on traditional uses, phytochemistry, pharmacological activities, clinical application, and toxicology[J]. J Ethnopharmacol, 2021, 269: 113708.

[35] Adki KM, Kulkarni YA. Chemistry, pharmacokinetics, pharmacology and recent novel drug delivery systems of paeonol[J]. Life Sci, 2020, 250: 117544.

[36] Zhang L, Li DC, Liu LF. Paeonol: Pharmacological effects and mechanisms of action[J]. Int Immunopharmacol, 2019, 72: 413-421.

[37] Harada M, Yamashita A. Pharmacological studies on the root bark of paeonia moutan. I. Central effects of paeonol[J]. Yakugaku Zasshi, 1969, 89 (9): 1205-1211.

[38] Sies H, Berndt C, Jones DP. Oxidative stress[J]. Annu Rev Biochem, 2017, 86: 715-748.

[39] Ďuračková Z. Some current insights into oxidative stress[J]. Physiol Res, 2010, 59 (4): 459-469.

[40] Poyton RO, Ball KA, Castello PR. Mitochondrial generation of free radicals and hypoxic signaling[J]. Trends Endocrinol Metab, 2009, 20 (7): 332-340.

[41] Wang C, Schuller Levis GB, Lee EB, et al. Platycodin D and D3 isolated from the root of platycodon grandiflorum modulate the production of nitric oxide and secretion of TNF-alpha in activated RAW 264.7 cells[J]. Int Immunopharmacol, 2004, 4 (8): 1039-1049.

[42] Reuter S, Gupta SC, Chaturvedi MM, et al. Oxidative stress, inflammation, and cancer: How are they linked?[J]. Free Radic Biol Med, 2010, 49 (11): 1603-1616.

[43] Prabhakar O. Cerebroprotective effect of resveratrol through antioxidant and anti-inflammatory effects in diabetic rats[J]. Naunyn Schmiedebergs Arch Pharmacol, 2013, 386 (8): 705-710.

[44] Jin X, Wang J, Xia ZM, et al. Anti-inflammatory and anti-oxidative activities of paeonol and its metabolites through blocking MAPK/ERK/p38 signaling pathway[J]. Inflammation, 2016, 39 (1): 434-446.

[45] Jensen JS, Fan X, Guidot DM. Alcohol causes alveolar epithelial oxidative stress by inhibiting the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element signaling pathway[J]. Am J Respir Cell Mol Biol, 2013, 48 (4): 511-517.

[46] Zhang X, Yu Y, Lei H, et al. The Nrf-2/HO-1 signaling axis: A ray of hope in cardiovascular diseases[J]. Cardiol Res Pract, 2020, 2020: 5695723.

[47] Guo S, Zhang Q. Paeonol protects melanocytes against hydrogen peroxide-induced oxidative stress through activation of Nrf2 signaling pathway[J]. Drug Dev Res, 2021, 82 (6): 861-869.

[48] Morsy MA, Ibrahim YF, Abdel Hafez SMN, et al. Paeonol attenuates hepatic ischemia/reperfusion injury by modulating the Nrf2/HO-1 and TLR4/MYD88/NF-κB signaling pathways[J]. Antioxidants (Basel), 2022, 11 (9): 1687.

[49] Liu MH, Lin AH, Lee HF, et al. Paeonol attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling[J]. Mediators Inflamm, 2014, 2014: 651890.

[50] Tayanloo-Beik A, Kiasalari Z, Roghani M. Paeonol ameliorates cognitive deficits in streptozotocin murine model of sporadic Alzheimer’s disease via attenuation of oxidative stress, inflammation, and mitochondrial dysfunction[J]. J Mol Neurosci, 2022, 72 (2): 336-348.

[51] Chae HS, Kang OH, Lee YS, et al. Inhibition of LPS- induced iNOS, COX-2 and inflammatory mediator expression by paeonol through the MAPKs inactivation in RAW 264.7 cells[J]. Am J Chin Med, 2009, 37 (1): 181-194.

[52] Ahmed S, Kim Y. Prostaglandin catabolism in Spodoptera exigua, a lepidopteran insect[J]. J Exp Biol, 2020, 223 (Pt 21): jeb233221.

[53] Yang Z, Fang K. Research progress of inducible nitric oxide synthase/cyclooxygenas-2 in female stress urinary incontinence[J]. Journal of Medical Research & Combat Trauma Care, 2015, 28 (3): 323-328.

[54] Gorica E, Calderone V. Arachidonic acid derivatives and neuroinflammation[J]. CNS Neurol Disord Drug Targets, 2022, 21 (2): 118-129.

[55] Ye JM, Deng T, Zhang JB. Influence of paeonol on expression of COX-2 and p27 in HT-29 cells[J]. World J Gastroenterol, 2009, 15 (35): 4410-4414.

[56] Liu H, Zhang C. Paeonol induces antitumor effects in hepatocellular carcinoma cells through survivin via the cyclooxygenase-2/prostaglandin E2 signaling pathway[J]. Transl Cancer Res, 2020, 9 (11): 7183-7195.

[57] He LX, Tong X, Zeng J, et al. Paeonol suppresses neuroinflammatory responses in LPS-activated microglia cells[J]. Inflammation, 2016, 39 (6): 1904-1917.

[58] Bao MH, Zhang YW, Zhou HH. Paeonol suppresses oxidized low-density lipoprotein induced endothelial cell apoptosis via activation of LOX-1/p38MAPK/NF-κB pathway[J]. J Ethnopharmacol, 2013, 146 (2): 543-551.

[59] Sharma JN, Mohammed LA. The role of leukotrienes in the pathophysiology of inflammatory disorders: Is there a case for revisiting leukotrienes as therapeutic targets?[J]. Inflammopharmacology, 2006, 14 (1-2): 10-16.

[60] Mangge H, Becker K, Fuchs D, et al. Antioxidants, inflammation and cardiovascular disease[J]. World J Cardiol, 2014, 6 (6): 462-477.

[61] Gong Z, Liu S. Research progress on the relationship between nitric oxide and intestinal inflammation[J]. Modern Interventional Diagnosis and Treatment in Gastroenterology, 2020, 25 (1): 136-138.

[62] Virág L, Szabó E, Gergely P, et al. Peroxynitrite- induced cytotoxicity: Mechanism and opportunities for intervention[J]. Toxicol Lett, 2003, 140-141: 113-124.

[63] Niu Y, Qin D, Jin Y, et al. Effect of paeonol on M1 polarization of macrophages induced by polarization[J]. The Chinese Journal of Clinical Pharmacology, 2023, 39 (5): 649-653.

[64] Mehana EE, Khafaga AF, El-Blehi SS. The role of matrix metalloproteinases in osteoarthritis pathogenesis: An updated review[J]. Life Sci, 2019, 234: 116786.

[65] Cui N, Hu M, Khalil RA. Biochemical and biological attributes of matrix metalloproteinases[J]. Prog Mol Biol Transl Sci, 2017, 147: 1-73.

[66] Ozeki N, Yamaguchi H, Kawai R, et al. Cytokines induce MMP-3-regulated proliferation of embryonic stem cell- derived odontoblast-like cells[J]. Oral Dis, 2014, 20 (5): 505-513.

[67] Wang Q, Xu X, Kang Z, et al. Paeonol prevents IL-1β- induced inflammatory response and degradation of type II collagen in human primary chondrocytes[J]. Artif Cells Nanomed Biotechnol, 2019, 47 (1): 2139-2145.

[68] Chen S, Luo K, Bian S, et al. Paeonol ameliorates abdominal aortic aneurysm progression by the NF-κB pathway[J]. Ann Vasc Surg, 2021, 77: 255-262.

[69] Zhao H, Wu L, Yan G, et al. Inflammation and tumor progression: Signaling pathways and targeted intervention[J]. Signal Transduct Target Ther, 2021, 6 (1): 263.

[70] Yeung YT, Aziz F, Guerrero-Castilla A, et al. Signaling pathways in inflammation and anti-inflammatory therapies[J]. Curr Pharm Des, 2018, 24 (14): 1449-1484.

[71] Barnabei L, Laplantine E, Mbongo W, et al. NF-κB: At the borders of autoimmunity and inflammation[J]. Front Immunol, 2021, 12: 716469.

[72] Shih VF, Tsui R, Caldwell A, et al. A single NFκB system for both canonical and non-canonical signaling[J]. Cell Res, 2011, 21 (1): 86-102.

[73] Ruland J, Hartjes L. CARD-BCL-10-MALT1 signalling in protective and pathological immunity[J]. Nat Rev Immunol, 2019, 19 (2): 118-134.

[74] Zhang P, Yin X, Wang X, et al. Paeonol protects against acute pancreatitis by Nrf2 and NF-κB pathways in mice[J]. J Pharm Pharmacol, 2022, 74 (11): 1618-1628.

[75] Li J, Li Y, Pan S, et al. Paeonol attenuates ligation-induced periodontitis in rats by inhibiting osteoclastogenesis via regulating Nrf2/NF-κB/NFATc1 signaling pathway[J]. Biochimie, 2019, 156: 129-137.

[76] Huang IH, Chung WH, Wu PC, et al. JAK-STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review[J]. Front Immunol, 2022, 13: 1068260.

[77] Yi JH, Park SW, Kapadia R, et al. Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage[J]. Neurochem Int, 2007, 50 (7-8): 1014-1027.

[78] Zhang L, Chen WX, Li LL, et al. Paeonol suppresses proliferation and motility of non-small-cell lung cancer cells by disrupting STAT3/NF-κB signaling[J]. Front Pharmacol, 2020, 11: 572616.

[79] Ishiguro K, Ando T, Maeda O, et al. Paeonol attenuates TNBS-induced colitis by inhibiting NF-kappaB and STAT1 transactivation[J]. Toxicol Appl Pharmacol, 2006, 217 (1): 35-42.

[80] Mitra A, Fallen RS, Lima HC. Cytokine-based therapy in psoriasis[J]. Clin Rev Allergy Immunol, 2013, 44 (2): 173-182.

[81] Meng Y, Wang M, Xie X, et al. Paeonol ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/ C mice by inhibiting the maturation and activation of dendritic cells[J]. Int J Mol Med, 2017, 39 (5): 1101-1110.

[82] Chang L, Karin M. Mammalian MAP kinase signaling cascades[J]. Nature, 2001, 410 (6824): 37-40.

[83] Mayor Jr F, Jurado-Pueyo M, Campos PM, et al. Interfering with MAP kinase docking interactions: Implications and perspective for the p38 route[J]. Cell Cycle, 2007, 6 (5): 528-533.

[84] Behl T, Rana T, Alotaibi GH, et al. Polyphenols inhibiting MAPK signalling pathway mediated oxidative stress and inflammation in depression[J]. Biomed Pharmacother, 2022, 146: 112545.

[85] Tang Y, Huang W, Song Q, et al. Paeonol ameliorates ovalbumin-induced asthma through the inhibition of TLR4/NF-κB and MAPK signaling[J]. Evid Based Complement Alternat Med, 2018, 2018: 3063145.

[86] Du Q, Feng GZ, Shen L, et al. Paeonol attenuates airway inflammation and hyperresponsiveness in a murine model of ovalbumin-induced asthma[J]. Can J Physiol Pharmacol, 2010, 88 (10): 1010-1016.

[87] Himaya SW, Ryu B, Qian ZJ, et al. Paeonol from Hippocampus kuda Bleeler suppressed the neuro- inflammatory responses in vitro via NF-κB and MAPK signaling pathways[J]. Toxicol in Vitro, 2012, 26 (6): 878-887.

[88] Chacón MR, Ceperuelo-Mallafré V, Maymó-Masip E, et al. Grape-seed procyanidins modulate inflammation on human differentiated adipocytes in vitro[J]. Cytokine, 2009, 47 (2): 137-142.

[89] Huo D, Liu Z, Cui S, et al. Tanshinone II-A inhibits LPS-induced cell inflammation by regulating the TLR4/IκBα/ NFκB signaling pathway[J]. Chinese Pharmacological Bulletin, 2021, 37 (2): 210-214.

[90] Dou F, Liu Y, Liu L, et al. Aloe-emodin ameliorates renal fibrosis via inhibiting PI3K/Akt/mTOR signaling pathway in vivo and in vitro[J]. Rejuvenation Res, 2019, 22 (3): 218-229.

[91] Li Y, Li P, Lin SH, et al. Paeonol inhibited TNFα-induced GM-CSF expression in fibroblast-like synoviocytes[J]. Int J Clin Pharmacol Ther, 2014, 52 (11): 986-996.

[92] Xiong XQ, Geng Z, Zhou B, et al. FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in obesity[J]. Metabolism, 2018, 83: 31-41.

[93] Qi Y, Shang L, Liao Z, et al. Intracerebroventricular injection of resveratrol ameliorated Aβ-induced learning and cognitive decline in mice[J]. Metab Brain Dis, 2019, 34 (1): 257-266.

[94] Beurel E, Michalek SM, Jope RS. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3)[J]. Trends Immunol, 2010, 31 (1): 24-31.

[95] Golpich M, Amini E, Hemmati F, et al. Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson’s disease[J]. Pharmacol Res, 2015, 97: 16-26.

[96] Kim S, Joe Y, Kim HJ, et al. Endoplasmic reticulum stress-induced IRE1α activation mediates cross-talk of GSK-3β and XBP-1 to regulate inflammatory cytokine production[J]. J Immunol, 2015, 194 (9): 4498-4506.

[97] Liu CM, Yang HX, Ma JQ, et al. Role of AMPK pathway in lead-induced endoplasmic reticulum stress in kidney and in paeonol-induced protection in mice[J]. Food Chem Toxicol, 2018, 122: 87-94.

[98] Sans M, Panés J, Ardite E, et al. VCAM-1 and ICAM-1 mediate leukocyte-endothelial cell adhesion in rat experimental colitis[J]. Gastroenterology, 1999, 116 (4): 874-883.

[99] Jander S, Heidenreich F, Stoll G. Serum and CSF levels of soluble intercellular adhesion molecule-1 (ICAM-1) in inflammatory neurologic diseases[J]. Neurology, 1993, 43 (9): 1809-1813.

[100] Yousef H, Czupalla CJ, Lee D, et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1[J]. Nat Med, 2019, 25 (6): 988-1000.

[101] Singh V, Kaur R, Kumari P, et al. ICAM-1 and VCAM-1: Gatekeepers in various inflammatory and cardiovascular disorders[J]. Clin Chim Acta, 2023, 548: 117487.

[102] Song A, Wu H, Dai M. Paeonol attenuates progression of atherosclerotic lesion formation through lipid regulation, anti-inflammatory and antioxidant activities[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27 (8): 565-575.

[103] Pan LL, Dai M. Paeonol from paeonia suffruticosa prevents TNF-alpha-induced monocytic cell adhesion to rat aortic endothelial cells by suppression of VCAM-1 expression[J]. Phytomedicine, 2009, 16 (11): 1027-1032.

[104] Adak A, Khan MR. An insight into gut microbiota and its functionalities[J]. Cell Mol Life Sci, 2019, 76 (3): 473-493.

[105] Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease[J]. Nature, 2016, 535 (7610): 75-84.

[106] Shi X, Huang H, Zhou M, et al. Paeonol attenuated vascular fibrosis through regulating Treg/Th17 balance in a gut microbiota-dependent manner[J]. Front Pharmacol, 2021, 12: 765482.

[107] Liu Y, Wu H, Wang T, et al. Paeonol reduces microbial metabolite α-hydroxyisobutyric acid to alleviate the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in atherosclerosis mice[J]. Chin J Nat Med, 2023, 21 (10): 759-774.

[108] Wu J, Wu D, Ma K, et al. Paeonol ameliorates murine alcohol liver disease via mycobiota-mediated Dectin-1/ IL-1β signaling pathway[J]. J Leukoc Biol, 2020, 108 (1): 199-214.

[109] Zhao M, Xie X, Xu B, et al. Paeonol alleviates ulcerative colitis in mice by increasing short-chain fatty acids derived from Clostridium butyricum[J]. Phytomedicine, 2023, 120: 155056.

[110] Zheng J, Li H, Zhang P, et al. Paeonol ameliorates ulcerative colitis in mice by modulating the gut microbiota and metabolites[J]. Metabolites, 2022, 12 (10): 956.