Preclinical and clinical studies on Qin-Zhu-Liang-Xue decoction: insights from network pharmacology and implications for atopic dermatitis treatment

Abstract

To investigate the protective effects and underlying mechanisms of Qin-Zhu-Liang-Xue decoction (QZLX) in atopic dermatitis (AD) and glucocorticoid resistance, we conducted a single-blinded, randomized controlled clinical trial to evaluate the efficacy and safety of this concoction. Network pharmacology analysis was performed and validated through clinical studies. The efficacy, safety, and mechanism of action of QZLX and glucocorticoid receptor (GR) α recombinant protein were assessed in AD mice induced by 2,4-dinitrofluorobenzene (DNFB). Correlation analysis was performed to determine the clinical relevance of GRα. The trial demonstrated that patients who received QZLX showed considerable improvements in their Scoring Atopic Dermatitis (SCORAD) and Dermatology Life Quality Index (DLQI) scores compared with those who received mizolastine at week 4. Network pharmacological analysis identified GRα as a key target for QZLX in AD treatment. QZLX administration increased the serum GRα expression in AD patients, alleviated AD symptoms in mice, decreased inflammatory cytokine expression, and increased GRα expression without affecting liver or kidney function. In addition, GRα recombinant protein improved AD-like skin lesions in DNFB-induced mice. A negative correlation was observed between GRα expression and clinical parameters, including SCORAD, DLQI, and serum IgE levels. QZLX alleviates AD symptoms through the upregulation of GRα and thus presents a novel therapeutic strategy for the prevention of glucocorticoid resistance in AD management.

Keywords

Qin-Zhu-Liang-Xue decoction / atopic dermatitis / glucocorticoid receptor α / traditional Chinese medicine / network pharmacology

References

[1] Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet 2020; 396(10247): 345–360

[2] Barbarot S, Auziere S, Gadkari A, Girolomoni G, Puig L, Simpson EL, Margolis DJ, de Bruin-Weller M, Eckert L. Epidemiology of atopic dermatitis in adults: results from an international survey. Allergy 2018; 73(6): 1284–1293

[3] Silverberg JI, Barbarot S, Gadkari A, Simpson EL, Weidinger S, Mina-Osorio P, Rossi AB, Brignoli L, Saba G, Guillemin I, Fenton MC, Auziere S, Eckert L. Atopic dermatitis in the pediatric population. Ann Allergy Asthma Immunol 2021; 126(4): 417–428.e2

[4] Yang X, Kambe N, Takimoto-Ito R, Kabashima K. Advances in the pathophysiology of atopic dermatitis revealed by novel therapeutics and clinical trials. Pharmacol Ther 2021; 224: 107830

[5] Ratchataswan T, Banzon TM, Thyssen JP, Weidinger S, Guttman-Yassky E, Phipatanakul W. Biologics for treatment of atopic dermatitis: current status and future prospect. J Allergy Clin Immunol Pract 2021; 9(3): 1053–1065

[6] HenggeURRuzicka TSchwartzRACorkMJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol 2006; 54(1): 1–15, quiz 1–15

[7] Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol 2017; 17(4): 233–247

[8] Vandewalle J, Luypaert A, De Bosscher K, Libert C. Therapeutic mechanisms of glucocorticoids. Trends Endocrinol Metab 2018; 29(1): 42–54

[9] Inui S, Sumikawa Y, Asada H, Itami S. Glucocorticoid resistance in atopic dermatitis associated with decreased expression of glucocorticoid receptor-α in peripheral blood mononuclear cells: glucocorticoid receptor in atopic dermatitis. J Dermatol 2010; 37(5): 496–499

[10] Clayton M, Leung D, Surs W, Szefler S. Altered glucocorticoid receptor binding in atopic dermatitis. J Allergy Clin Immunol 1995; 96(3): 421–423

[11] Webster JC, Oakley RH, Jewell CM, Cidlowski JA. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative β isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci USA 2001; 98(12): 6865–6870

[12] Kubin ME, Hägg PM, Kokkonen N, Väyrynen JP, Haapasaari KM, Moilanen J, Kallioinen M, Hurskainen T, Tasanen K. Glucocorticoid receptors GRα and GRβ are expressed in inflammatory dermatoses. Eur J Dermatol 2016; 26(1): 21–27

[13] Yan F, Li F, Liu J, Ye S, Zhang Y, Jia J, Li H, Chen D, Mo X. The formulae and biologically active ingredients of Chinese herbal medicines for the treatment of atopic dermatitis. Biomed Pharmacother 2020; 127: 110142

[14] Li S, Chen J, Li B, Li F, Wang Y, Miao X. Efficacy of Qinzhu Liangxue decoction on subacute eczema treatment. World Clin Drugs 2016; 37: 173–176

[15] Ma T, Chai Y, Li S, Sun X, Wang Y, Xu R, Chen J, Zhou M, Zhou M, Li B, Xu W, Li X. Efficacy and safety of Qinzhuliangxue decoction for treating atopic eczema: a randomized controlled trial. Ann Palliat Med 2020; 9(3): 12

[16] Qu K, Luo Y, Yan X, Kuai L, Ru Y, Luo Y, Song J, Ji W, Li B, Xing M. Qinzhuliangxue mixture alleviates psoriasis-like skin lesions via inhibiting the IL6/STAT3 axis. J Ethnopharmacol 2021; 274: 114041

[17] Wang L. Baicalin ameliorates 2, 4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice through modulating skin barrier function, gut microbiota and JAK/STAT pathway. Bioorganic Chem 2022; 119: 105538

[18] Hou DD, Wang XX, Li SJ, Wang DC, Niu Y, Xu ZR, Jin ZQ. Glycyrrhizic acid suppresses atopic dermatitis-like symptoms by regulating the immune balance. J Cosmet Dermatol 2022; 21(12): 7090–7099

[19] Zhang R, Zhu X, Bai H, Ning K. Network pharmacology databases for traditional Chinese medicine: review and assessment. Front Pharmacol 2019; 10: 123

[20] Lin H, Wang X, Liu M, Huang M, Shen Z, Feng J, Yang H, Li Z, Gao J, Ye X. Exploring the treatment of COVID-19 with Yinqiao powder based on network pharmacology. Phytother Res 2021; 35(5): 2651–2664

[21] Chopra R, Vakharia PP, Sacotte R, Patel N, Immaneni S, White T, Kantor R, Hsu DY, Silverberg JI. Severity strata for Eczema Area and Severity Index (EASI), modified EASI, Scoring Atopic Dermatitis (SCORAD), objective SCORAD, Atopic Dermatitis Severity Index and body surface area in adolescents and adults with atopic dermatitis. Br J Dermatol 2017; 177(5): 1316–1321

[22] Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19(3): 210–216

[23] Zhang Y, Song J, Jiang J, Yin S, Luo Y, Luo Y, Ding X, Ru Y, Liu L, Li W, Kuai L, Li B. Modular pharmacology-based approach to identify hub genes and kernel pathways of taodan granules treated psoriasis. J Ethnopharmacol 2021; 280: 114485

[24] Zheng BW, Wang BY, Xiao WL, Sun YJ, Yang C, Zhao BT. Different molecular weight hyaluronic acid alleviates inflammation response in DNFB-induced mice atopic dermatitis and LPS-induced RAW 264.7 cells. Life Sci 2022; 301: 120591

[25] Qiu Z, Zhu Z, Liu X, Chen B, Yin H, Gu C, Fang X, Zhu R, Yu T, Mi W, Zhou H, Zhou Y, Yao X, Li W. A dysregulated sebum–microbial metabolite–IL-33 axis initiates skin inflammation in atopic dermatitis. J Exp Med 2022; 219(10): e20212397

[26] Luo Y, Ru Y, Zhao H, Liu L, Hong S, Sun X, Kuai L, Lu Y, Xing M, Chen X, Song J, Luo Y, Fei X, Zhou Y, Li H, Li B, Li X. Establishment of mouse models of psoriasis with blood stasis syndrome complicated with glucose and lipid metabolism disorders. Evid Based Complement Alternat Med 2019; 2019: 1–10

[27] Kuai L, Song J, Zhang R, Xing M, Luo Y, Ru Y, Ding X, Liu L, Lu Y, Sun X, Nian H, Li X, Li B. Uncovering the mechanism of Jueyin granules in the treatment of psoriasis using network pharmacology. J Ethnopharmacol 2020; 262: 113214

[28] Wollenberg A, Christen-Zäch S, Taieb A, Paul C, Thyssen JP, de Bruin-Weller M, Vestergaard C, Seneschal J, Werfel T, Cork MJ, Kunz B, Fölster-Holst R, Trzeciak M, Darsow U, Szalai Z, Deleuran M, von Kobyletzki L, Barbarot S, Heratizadeh A, Gieler U, Hijnen DJ, Weidinger S, De Raeve L, SvenssonÅ, Simon D, Stalder JF, Ring J; European Task Force on Atopic Dermatitis/EADV Eczema Task Force. ETFAD/EADV Eczema task force 2020 position paper on diagnosis and treatment of atopic dermatitis in adults and children. J Eur Acad Dermatol Venereol 2020; 34(12): 2717–2744

[29] Tan HY, Zhang AL, Chen D, Xue CC, Lenon GB. Chinese herbal medicine for atopic dermatitis: a systematic review. J Am Acad Dermatol 2013; 69(2): 295–304

[30] Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, Peng X, Estrada YD, Nakajima S, Honda T, Shin JU, Lee H, Krueger JG, Lee KH, Kabashima K, Guttman-Yassky E. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol 2015; 136(5): 1254–1264

[31] Choi EJ, Debnath T, Tang Y, Ryu YB, Moon SH, Kim EK. Topical application of Moringa oleifera leaf extract ameliorates experimentally induced atopic dermatitis by the regulation of Th1/Th2/Th17 balance. Biomed Pharmacother 2016; 84: 870–877

[32] Boguniewicz M, Beck LA, Sher L, Guttman-Yassky E, Thaçi D, Blauvelt A, Worm M, Corren J, Soong W, Lio P, Rossi AB, Lu Y, Chao J, Eckert L, Gadkari A, Hultsch T, Ruddy M, Mannent LP, Graham NMH, Pirozzi G, Chen Z, Ardeleanu M. Dupilumab improves asthma and sinonasal outcomes in adults with moderate to Severe Atopic Dermatitis. J Allergy Clin Immunol Pract 2021; 9(3): 1212–1223.e6

[33] Kulthanan K, Tuchinda P, Nitiyarom R, Chunharas A, Chantaphakul H, Aunhachoke K, Chularojanamontri L, Rajatanavin N, Jirapongsananuruk O, Vichyanond P, Chatchatee P, Sangsupawanich P, Wananukul S, Singalavanija S, Trakanwittayarak S, Rerkpattanapipat T, Thongngarm T, Wisuthsarewong W, Limpongsanurak W, Kamchaisatian W, Noppakun N. Clinical practice guidelines for the diagnosis and management of atopic dermatitis. Asian Pac J Allergy Immunol 2021; 39: 145–155

[34] Ghiciuc CM, Vicovan AG, Stafie CS, Antoniu SA, Postolache P. Marine-derived compounds for the potential treatment of glucocorticoid resistance in severe Asthma. Mar Drugs 2021; 19(11): 586

[35] Goleva E, Li L, Eves PT, Strand MJ, Martin RJ, Leung DYM. Increased glucocorticoid receptor β alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med 2006; 173(6): 607–616

[36] De Bosscher K, Haegeman G. Minireview: latest perspectives on antiinflammatory actions of glucocorticoids. Mol Endocrinol 2009; 23(3): 281–291

[37] Adcock IM, Ford PA, Bhavsar P, Ahmad T, Chung KF. Steroid resistance in asthma: mechanisms and treatment options. Curr Allergy Asthma Rep 2008; 8(2): 171–178

[38] Quax RA, Manenschijn L, Koper JW, Hazes JM, Lamberts SWJ, van Rossum EFC, Feelders RA. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol 2013; 9(11): 670–686

[39] Hägg PM, Hurskainen T, Palatsi R, Ilves M, Oikarinen A. Increased expression of glucocorticoid receptor β in lymphocytes of patients with severe atopic dermatitis unresponsive to topical corticosteroid. Br J Dermatol 2010; 162(2): 318–324

[40] Rupprecht M, Rupprecht R, Kornhuber J, Wodarz N, Koch HU, Riederer P, Hornstein OP. Elevated glucocorticoid receptor concentrations before and after glucocorticoid therapy in peripheral mononuclear leukocytes of patients with atopic dermatitis. Dermatology 1991; 183(2): 100–105

[41] Kino T, Manoli I, Kelkar S, Wang Y, Su YA, Chrousos GP. Glucocorticoid receptor (GR) β has intrinsic, GRα-independent transcriptional activity. Biochem Biophys Res Commun 2009; 381(4): 671–675

[42] Smoak KA, Cidlowski JA. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev 2004; 125(10–11): 697–706

[43] De Bosscher K, Beck IM, Dejager L, Bougarne N, Gaigneaux A, Chateauvieux S, Ratman D, Bracke M, Tavernier J, Vanden Berghe W, Libert C, Diederich M, Haegeman G. Selective modulation of the glucocorticoid receptor can distinguish between transrepression of NF-κB and AP-1. Cell Mol Life Sci 2014; 71(1): 143–163

[44] Dorrington MG, Fraser IDC. NF-κB signaling in macrophages: dynamics, crosstalk, and signal integration. Front Immunol 2019; 10: 705

[45] Sung YY, Kim HK. Crocin ameliorates atopic dermatitis symptoms by down regulation of Th2 response via blocking of NF-κB/STAT6 signaling pathways in mice. Nutrients 2018; 10(11): 1625

[46] Li G, Wu H, Sun L, Cheng K, Lv Z, Chen K, Qian F, Li Y. (-)-α-bisabolol alleviates atopic dermatitis by inhibiting MAPK and NF-κB signaling in mast cell. Molecules 2022; 27(13): 3985

[47] Choi DW, Jung SY, Lee SY, Shon DH, Shin HS. Rosae multiflorae fructus extract improves trimellitic anhydride-induced atopic dermatitis-like symptoms. J Med Food 2020; 23(12): 1287–1295

[48] Moon PD, Han NR, Lee JS, Kim HM, Jeong HJ. p-coumaric acid, an active ingredient of Panax ginseng, ameliolates atopic dermatitis-like skin lesions through inhibition of thymic stromal lymphopoietin in mice. J Ginseng Res 2021; 45(1): 176–182

[49] Fang F, Xie Z, Quan J, Wei X, Wang L, Yang L. Baicalin suppresses Propionibacterium acnes-induced skin inflammation by downregulating the NF-κB/MAPK signaling pathway and inhibiting activation of NLRP3 inflammasome. Braz J Med Biol Res 2020; 53(12): e9949

[50] Gao C, Du Q, Li W, Deng R, Wang Q, Xu A, Shen J. Baicalin modulates APPL2/glucocorticoid receptor signaling cascade, promotes neurogenesis, and attenuates emotional and olfactory dysfunctions in chronic corticosterone-induced depression. Mol Neurobiol 2018; 55(12): 9334–9348

[51] Baradaran Rahimi V, Askari VR, Hosseinzadeh H. Promising influences of Scutellaria baicalensis and its two active constituents, baicalin, and baicalein, against metabolic syndrome: a review. Phytother Res 2021; 35(7): 3558–3574

[52] Austin JR, Kirkpatrick BJ, Rodríguez RR, Johnson ME, Lantvit DD, Burdette JE. Baicalein is a phytohormone that signals through the progesterone and glucocorticoid receptors. Horm Cancer 2020; 11(2): 97–110

[53] Pegoraro NS, Camponogara C, Cruz L, Oliveira SM. Oleic acid exhibits an expressive anti-inflammatory effect in croton oil-induced irritant contact dermatitis without the occurrence of toxicological effects in mice. J Ethnopharmacol 2021; 1(267): 113486

[54] Khwaza V, Oyedeji OO, Aderibigbe BA. Ursolic acid-based derivatives as potential anti-cancer agents: an update. Int J Mol Sci 2020; 21(16): 5920

[55] Junco JJ, Cho J, Mancha A, Malik G, Wei SJ, Kim DJ, Liang H, DiGiovanni J, Slaga TJ. Role of AMPK and PPARα in the anti-skin cancer effects of ursolic acid. Mol Carcinog 2018; 57(12): 1698–1706

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82004359), Xinglin Youth Scholar of Shanghai University of Traditional Chinese Medicine (No. RY411.33.10), Youth Talent Promotion Project of China Association of Traditional Chinese Medicine (2021–2023) Category A (No. CACM-2021-QNRC2-A10), Health Young Talents of Shanghai Municipal Health Commission (No. 2022YQ026), “Chen Guang” project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (No. 22CGA50), The Clinical Research Plan of SHDC (No. SHDC22022302), High-level Chinese Medicine Key Discipline Construction Project (Integrative Chinese and Western Medicine Clinic) of National Administration of TCM (No. zyyzdxk-2023065), Shanghai Dermatology Research Center (No. 2023ZZ02017), Shanghai Dermatology Hospital Demonstration Research Ward Project (No. SHDC2023CRW009), Evidence-based Dermatology Base sponsored by State Administration of Traditional Chinese Medicine, Shanghai Municipal Project for the Construction of Traditional Chinese Medicine Expert Heritage Studio (No. 2020ZYGZS-002), Clinical Transformation Incubation Program in Hospital (No. lczh2023-01), Professional Technical Service Platform Construction Project of Shanghai Science and Technology Commission (No. 21DZ2294500), and Shanghai key Discipline Construction Project of Traditional Chinese Medicine (No. shzyyzdxk-2024104).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1101-7 and is accessible for authorized users.

Compliance with ethics guidelines

Keke Huang, Qingkai Liu, Ruoxi Zhang, Hua Nian, Ying Luo, Yue Luo, Xiaoya Fei, Le Kuai, Bin Li, Yimei Tan, Su Li, and Xin Ma declare that they have no conflicts of interest.

The study was approved by the Institutional Review Board of Yueyang Hospital and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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