胰腺癌SMO靶标治疗研究启示：从中药中发现新药

doi:10.3736/jcim20120303

Abstract

Smoothened (SMO) is a member of sonic hedgehog homology (SHH) signaling pathway. It plays a key role as a bridge between patched-1 (PTCH-1) and Gli. Aberrant SHH expression can be detected in various malignant tissues, and the expression in pancreatic cancer stem cells is higher apparently. SHH signals are closely associated with self-duplication of cancer stem cells, formation of tumor vessels as well as matrixes. SMO antagonists such as cyclopamine, GDC-0449 and so on show potential to inhibit activity of SHH signaling, and arrest the growth as well as metastases of tumors. Recently, a few of SMO antagonists have been studied in phase Ⅰ clinical trials and some are in phase Ⅱ, meanwhile, phase Ⅰ or Ⅱ trials of SMO antagonists to treat pancreatic cancer are performed currently. As the classical SMO antagonist, cyclopamine is extracted from a medicinal plant. Perhaps researchers may be able to determine more effective SMO-targeting drugs from herbal medicines in the future.

Key words: pancreatic neoplasms, neoplastic stem cells, smoothened, hedgehog proteins, signal transduction, plants, medicinal, review

Jin-bin Han, Yong-qiang Hua, Lian-yu Chen, Lu-ming Liu . Advances in Smoothened-targeting therapies for pancreatic cancer: Implication for drug discovery from herbal medicines. Journal of Chinese Integrative Medicine, 2012, 10(3): 256-263.

/ / Recommend

Add to citation manager EndNote| Reference Manager|ProCite|BibTeX|RefWorks

URL: http://www.jcimjournal.com/EN/10.3736/jcim20120303

http://www.jcimjournal.com/EN/Y2012/V10/I3/256

TrendMD

References 49

[1]	Simeone DM . Pancreatic cancer stem cells : implications for the treatment of pancreatic cancer. Clin Cancer Res. 2008; 14(18):5646-5648. doi: 10.1158/1078-0432.CCR-08-0584
[2]	Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ, Basler K . Dispatched, a novel sterol-sensing modified hedgehog from signaling cells. Cell. 1999; 99(7):803-815. doi: 10.1016/S0092-8674(00)81677-3
[3]	Taipale J, Cooper MK, Maiti T, Beachy PA . Patched acts catalytically to suppress the activity of Smoothened. Nature. 2002; 418(6900):892-897. doi: 10.1038/nature00989
[4]	Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon AP . The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell. 2006; 10(5):647-656. doi: 10.1016/j.devcel.2006.04.004
[5]	Stecca B , Ruiz I Altaba A. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J Mol Cell Biol. 2010; 2(2):84-95. doi: 10.1093/jmcb/mjp052
[6]	Ruiz I Altaba A . Catching a Gli-mpse of Hedgehog. Cell. 1997; 90(2):193-196. doi: 10.1016/S0092-8674(00)80325-6
[7]	Price MA, Kalderon D . Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by glycogen synthase kinase 3 and vasein kinase 1. Cell. 2002; 108(6) : 823-835. doi: 10.1016/S0092-8674(02)00664-5
[8]	Cheng SY, Bishop JM . Suppressor of fused represses Cli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci USA. 2002; 99(8):5442-5447. doi: 10.1073/pnas.082096999
[9]	Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE . Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996; 85(6) : 841-851. doi: 10.1016/S0092-8674(00)81268-4
[10]	Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ . Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998; 391(6662):90-92. doi: 10.1038/34201
[11]	Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D . Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002; 31(3):306-310. doi: 10.1038/ng916
[12]	Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez- del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M . Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003; 425(6960) : 851-856. doi: 10.1038/nature02009
[13]	JiaJ, Tong C, Jiang J . Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes Dev. 2003; 17(21) : 2709-2720. doi: 10.1101/gad.1136603
[14]	May SR, Ashique AM, Karlen M, Wang B, Shen Y, Zarbalis K, Reiter J, Ericson J, Peterson AS . Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol. 2005; 287(2):378-389. doi: 10.1016/j.ydbio.2005.08.050
[15]	Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, Wright CV, Hebrok M, Lewis BC . Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA. 2007; 104(12) : 5103-5108 doi: 10.1073/pnas.0701158104
[16]	Kawahira H, Scheel DW, Smith SB, German MS, Hebrok M . Hedgehog signaling regulates expansion of pancreatic epithelial cells. Dev Biol. 2005; 280(1):111-121. doi: 10.1016/j.ydbio.2005.01.008
[17]	Kayed H, Kleeff J, Osman T, Keleg S, Biichler MW, Friess H . Hedgehog signaling in the normal and diseased pancreas. Pancreas. 2006 ; 32(2) : 119-129. doi: 10.1097/01.mpa.0000202937.55460.0c
[18]	Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio- Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW . Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008; 321(5897):1801-1806. doi: 10.1126/science.1164368
[19]	Feldmann G, Habbe N, Dhara S, Bisht S, Alvarez H, Fendrich V, Beaty R, Mullendore M, Karikari C, Bardeesy N, Ouellette MM, Yu W, Maitra A . Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut. 2008; 57(10):1420-1430. doi: 10.1136/gut.2007.148189
[20]	Feldmann G, Fendrich V, McGovern K, Bedja D, Bisht S, Alvarez H, Koorstra JB, Habbe N, Karikari C, Mullendore M, Gabrielson KL, Sharma R, Matsui W, Maitra A . An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol Cancer Ther. 2008; 7(9) : 2725-2735. doi: 10.1158/1535-7163.MCT-08-0573
[21]	Ohuchida K, Mizumoto K, Fujita H, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M . Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms : clinical implications of mRNA levels in pancreatic juice. J Pathol. 2006; 210(1):42-48. doi: 10.1002/(ISSN)1096-9896
[22]	Tian H, Callahan CA , DuPree KJ, Darbonne WC, Ahn CP, Scales SJ, de Sauvage FJ. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA. 2009 ; 106(11) : 4254-4259. doi: 10.1073/pnas.0813203106
[23]	Asai J, Takenaka H, Kusano KF, Ii M, Luedemann C, Curry C, Eaton E, Iwakura A, Tsutsumi Y, Hamada H, Kishimoto S, Thorne T, Kishore R, Losordo DW . Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling. Circulation. 2006; 113(20) : 2413-2424. doi: 10.1161/CIRCULATIONAHA.105.603167
[24]	Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Riickert F, Griitzmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA . Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009; 324(5933) : 1457-1461. doi: 10.1126/science.1171362
[25]	Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters JC, Rubin LL, de Sauvage FJ . A paracrine requirement for hedgehog signalling in cancer. Nature. 2008; 455(7211) : 406-410. doi: 10.1038/nature07275
[26]	Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, Ouellette MM, Hollingsworth MA . Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res. 2008; 14(19):5995-6004. doi: 10.1158/1078-0432.CCR-08-0291
[27]	Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz I, Altaba A . HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol. 2007 ; 17(2) : 165-172. doi: 10.1016/j.cub.2006.11.033
[28]	Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS . Hedgehog signaling and Bmi- 1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006; 66(12) : 6063-6071. doi: 10.1158/0008-5472.CAN-06-0054
[29]	Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, Watkins DN, Matsui W . Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA. 2007 ; 104(10) : 4048-4053. doi: 10.1073/pnas.0611682104
[30]	Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM . Identification of pancreatic cancer stem cells. Cancer Res. 2007; 67(3) : 1030-1037. doi: 10.1158/0008-5472.CAN-06-2030
[31]	Nakamura K, Sasajima J, Mizukami Y, Sugiyama Y, Yamazaki M, Fujii R, Kawamoto T, Koizumi K, Sato K, Fujiya M, Sasaki K, Tanno S, Okumura T, Shimizu N, Kawabe J, Karasaki H, Kono T, Ii M, Bardeesy N, Chung DC, Kohgo Y . Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro- angiogenic cells. PLoS One. 2010; 5(1):e8824. doi: 10.1371/journal.pone.0008824
[32]	Chen JK, Taipale J, Cooper MK, Beachy PA . Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002; 16(21):2743-2748. doi: 10.1101/gad.1025302
[33]	Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio- Donahue C, Jimeno A, Gabrielson KL, Matsui W, Maitra A . Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases : a new paradigm for combination therapy in solid cancers. Cancer Res. 2007; 67(5) : 2187-2196. doi: 10.1158/0008-5472.CAN-06-3281
[34]	Lee SW, Moskowitz MA, Sims JR . Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts. Int J Mol Med. 2007 ; 19(3):445-451.
[35]	Rafii S, Lyden D . Therapeutic stem and progenitor cell transplantation for organ vasculatization and regencration. Nat Med. 2003; 9(6):702-712. doi: 10.1038/nm0603-702
[36]	Evangelista M, Tian H, de Sauvage FJ . The hedgehog signaling pathway in cancer. Clin Cancer Res. 2006; 12(20 Pt 1) : 5924-5928. doi: 10.1158/1078-0432.CCR-06-1736
[37]	Yamazaki M, Nakamura K, Mizukami Y, Ii M, Sasajima J, Sugiyama Y, Nishikawa T, Nakano Y, Yanagawa N, Sato K, Maemoto A, Tanno S, Okumura T, Karasaki H, Kono T, Fujiya M, Ashida T, Chung DC, Kohgo Y . Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells. Cancer Sci. 2008; 99(6) : 1131-1138. doi: 10.1111/cas.2008.99.issue-6
[38]	Kim SK, Melton DA . Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc Natl Acad Sci U S A. 1998; 95(22):13036-13041. doi: 10.1073/pnas.95.22.13036
[39]	Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA . Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003; 425(6960):846-851. doi: 10.1038/nature01972
[40]	Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, Hann CL, Gould SE, Low JA, Rudin CM, de Sauvage FJ . Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009 ; 326(5952) : 572-574. doi: 10.1126/science.1179386
[41]	Dijkgraaf GJ, Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D, Goldsmith R, Robarge K, Sutherlin D, Scales SJ, Gould SE, Yauch RL, de Sauvage FJ . Small molecule inhibition of GDC- 0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2010 ; 71(2):435-444.
[42]	LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Chang I, Darbonne WC, Graham RA, Zerivitz KL, Low JA, Von Hoff DD . Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011; 17(8) : 2502-2511. doi: 10.1158/1078-0432.CCR-10-2745
[43]	LoRusso PM, Rudin CM, Borad MJ, Vernillet L, Darbonne WC, Mackey H, DiMartino JF, de Sauvage F, Low JA, Von Hoff DD . A first-in-human, first-in- class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors. J Clin Oncol (Meeting Abstracts). 2008; 26(15 Suppl) : 3516. doi: 10.1200/jco.2008.26.15_suppl.3516
[44]	Berlin J , et al. A phase 2 A phase 2, randomized, double-blind, placebo-controlled study of hedgehog pathway inhibitor (HPI) GDC-0449 in patients with previously untreated metastatic colorectal cancer (mCRC) . Presented at 35 th European Society for Medical Oncology ESMO Congress October 8, 2010, Milan Italy (Vol. 21 Suppl 8, p. Abstract LBA21). [2011-08-15]. .
[45]	Merchant AA, Matsui W . Targeting Hedgehog — a cancer stem cell pathway. Clin Cancer Res. 2010 ; 16(12) : 3130-3140. doi: 10.1158/1078-0432.CCR-09-2846
[46]	Kelleher FC . Hedgehog signaling and therapeutics in pancreatic cancer. Carcinogenesis. 2010 ; 32(4) : 445-451.
[47]	Ailles L, Siu LL . Targeting the Hedgehog pathway in cancer : can the spines be smoothened? Clin Cancer Res. 2011; 17(8) : 2071-2073. doi: 10.1158/1078-0432.CCR-11-0211
[48]	Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, Peaceman D, Ozdemirli M, Rodriguez O, Macdonald TJ, Albanese C, Toretsky JA, Uren A . Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011; 121(1):148-160. doi: 10.1172/JCI42874
[49]	Mazumdar T, Devecchio J, Agyeman A, Shi T, Houghton JA . Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells. Cancer Res. 2011; 71(17):5904-5914. doi: 10.1158/0008-5472.CAN-10-4173

Metrics

Viewed

Full text

Abstract

Cited

Shared

Discussed

Comments

Recommended 10

[1]	Dong Yang, Yong-ping Du, Qing Shen, Wei Chen, Yan Yu, Guang-lei Chen. Expression of alpha-smooth muscle actin in renal tubulointerstitium in patients with kidney collateral stasis. Journal of Chinese Integrative Medicine, 2008, 6(1): 41-44
[2]	Hai-feng Wei, Bai-liu Ya, Ling Zhao, Cui-fei Ye, Li Zhang, Lin Li. Evaluation of tongue manifestation of blood stasis syndrome and its relationship with blood rheological disorder in a rat model of transient brain ischemia. Journal of Chinese Integrative Medicine, 2008, 6(1): 73-76
[3]	Xi Lin, Jian-ping Liu. Herbal medicines for viral myocarditis. Journal of Chinese Integrative Medicine, 2008, 6(1): 76
[4]	Xi Lin, Jian-ping Liu. Tai chi for treating rheumatoid arthritis. Journal of Chinese Integrative Medicine, 2008, 6(1): 82
[5]	Liang-ping Hu, Hui Gao. Discrimination of errors in statistical analysis of medical papers published in the first issue of 2006 in Journal of Chinese Integrative Medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 98-106
[6]	Yan-bo Zhu , Qi Wang, Cheng-yu Wu, Guo-ming Pang, Jian-xiong Zhao, Shi-lin Shen, Zhong-yuan Xia , Xue Yan . Logistic regression analysis on relationships between traditional Chinese medicine constitutional types and overweight or obesity. Journal of Chinese Integrative Medicine, 2010, 8(11): 1023-1035
[7]	Wei Xu, Meng Shi, Jian-gang Liu, Cheng-long Wang . Collagen protein expressions in ischemic myocardium of rats with acute myocardial infarction and effects of qi-tonifying, yin-tonifying and blood-activating herbs and detoxifying and blood-activating herbs. Journal of Chinese Integrative Medicine, 2010, 8(11): 1041-1047
[8]	Tao Wang , Feng Qin. Effects of Chinese herbal medicine Xiaoyao Powder on monoamine neurotransmitters in hippocampus of rats with postpartum depression. Journal of Chinese Integrative Medicine, 2010, 8(11): 1075-1079
[9]	Ying Xu , Chang-chun Zeng , Xiu-yu Cai , Rong-ping Guo , Guang Nie , Ying Jin. Chromaticity and optical spectrum colorimetry of the tongue color in different syndromes of primary hepatic carcinoma. Journal of Chinese Integrative Medicine, 2012, 10(11): 1263-1271
[10]	Xiang-ying Mao , Qin Bian , Zi-yin Shen. Analysis of the osteogenetic effects exerted on mesenchymal stem cell strain C3H10T1/2 by icariin via MAPK signaling pathway in vitro. Journal of Chinese Integrative Medicine, 2012, 10(11): 1272-1278

Advances in Smoothened-targeting therapies for pancreatic cancer: Implication for drug discovery from herbal medicines

RichHTML

PDF (PC)

Like

Abstract

Cite this article

Share this article

TrendMD

References 49

Related Articles 15

Metrics

Comments

Recommended 10

[1]	Ming-min Xu, Pei Guo, Qing-yu Ma, Xuan Zhou, Yu-long Wei, Lu Wang, Yue Chen, Yu Guo. Can acupuncture enhance therapeutic effectiveness of antidepressants and reduce adverse drug reactions in patients with depression? A systematic review and meta-analysis. Journal of Integrative Medicine, 2022, 20(4): 305-320.
[2]	Ting-ting Lu, Cun-cun Lu, Mei-xuan Li, Li-xin Ke, Hui Cai, Ke-hu Yang. Reporting and methodological quality of meta-analyses of acupuncture for patients with migraine: A methodological investigation with evidence map. Journal of Integrative Medicine, 2022, 20(3): 213-220.
[3]	Witoo Dilokthornsakul, Ramanya Kosiyaporn, Rattanamanee Wuttipongwaragon, Piyameth Dilokthornsakul. Potential effects of propolis and honey in COVID-19 prevention and treatment: A systematic review of in silico and clinical studies. Journal of Integrative Medicine, 2022, 20(2): 114-125.
[4]	Jun-peng Yao, Li-ping Chen, Xian-jun Xiao, Ting-hui Hou, Si-yuan Zhou, Ming-min Xu, Kai Wang, Yu-jun Hou, Lin Zhang, Ying Li. Effectiveness and safety of acupuncture for treating functional constipation: An overview of systematic reviews. Journal of Integrative Medicine, 2022, 20(1): 13-25.
[5]	Yi Yuan, Rui-Ting Wang, Jun Xia, Hui-Juan Cao. Interventions for preventing influenza: an overview of Cochrane systematic reviews and a Bayesian network meta-analysis. Journal of Integrative Medicine, 2021, 19(6): 503-514.
[6]	Meng-zhu Zhao, Chen Zhao, Shuang-shuang Tu, Xu-xu Wei, Hong-cai Shang. Evaluating the methodology of studies conducted during the global COVID-19 pandemic: A systematic review of randomized controlled trials. Journal of Integrative Medicine, 2021, 19(4): 317-326.
[7]	Liang Dai, Ka Kei Chan, Jian-chun Mao, Yu Tian, Jun-hua Gu, Jun Zhou, Linda L.D. Zhong. Modified Zhibai Dihuang pill, a traditional Chinese medicine formula, on steroid withdrawal in systemic lupus erythematosus: A systematic review and meta-analysis. Journal of Integrative Medicine, 2020, 18(6): 478-491.
[8]	Arthur Yin Fan, Sherman Gu, Sarah Faggert Alemi, Research Group for Evidence-based Chinese Medicine. Chinese herbal medicine for COVID-19: Current evidence with systematic review and meta-analysis. Journal of Integrative Medicine, 2020, 18(5): 385-394.
[9]	Johannes Loeser, Brigitte Layer, Christopher Plata, Klaus-Maria Perrar, Tim Hucho, Rebecca Kulbida. Hirudotherapy attenuates arthritic pain in patients with various chronic pain syndromes: A retrospective analysis. Journal of Integrative Medicine, 2020, 18(5): 425-433.
[10]	Xian-jun Xiao, Lei-xiao Zhang, Yun-zhou Shi, Jun-peng Yao, Wei Cao, Ying Liu, Zi-hao Zou, Si-yuan Zhou, Ming-ling Chen, Chun-xiao Li, Qian-hua Zheng, Ying Li. Cupping therapy for patients with chronic urticaria: A systematic review and meta-analysis. Journal of Integrative Medicine, 2020, 18(4): 303-312.
[11]	Dong-dong Yu, Liang-zhen You, Wan-qiu Huang, Hui Cao, Fan-jing Wang, Xiu-qin Tang, Zhao-hui Fang, Guo-ming Shen, Yu-xiang Guan. Effects of traditional Chinese exercises on blood glucose and hemoglobin A1c levels in patients with prediabetes: A systematic review and meta-analysis. Journal of Integrative Medicine, 2020, 18(4): 292-302.
[12]	Kayode Ezekiel Adewole. Nigerian antimalarial plants and their anticancer potential: A review. Journal of Integrative Medicine, 2020, 18(2): 92-113.
[13]	Yogesh Subhash Biradar, Swathi Bodupally, Harish Padh. Evaluation of antiplasmodial properties in 15 selected traditional medicinal plants from India. Journal of Integrative Medicine, 2020, 18(1): 80-85.
[14]	Dona Nirmani Ann Wijewickrama Samarakoon, Deepthi Inoka Uluwaduge, Malith Aravinda Siriwardhene. Mechanisms of action of Sri Lankan herbal medicines used in the treatment of diabetes: A review. Journal of Integrative Medicine, 2020, 18(1): 13-20.
[15]	Rebecca Kulbida, Alexander Mathes, Johannes Loeser. Beneficial effects of hirudotherapy in a chronic case of complex regional pain syndrome. Journal of Integrative Medicine, 2019, 17(5): 383-386.