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DOI: 10.1055/a-2735-8069
Effect of Herbal Products and Their Active Constituents on Angiogenesis in Diabetic Wounds
Authors
Research was funded by the Warsaw University of Technology within the Excellence Initiative: Research University (IDUB) program [POSTDOC PW edition V, grant number CPR-IDUB/367/Z01/Z10/2023].
Abstract
Angiogenesis plays a key role in tissue regeneration by delivering oxygen and nutrients to the injury site. In diabetes mellitus, various factors, including hyperglycemia, neuropathy, increased reactive oxygen species, and proinflammatory cytokines, decrease the levels of proangiogenic factors and increase levels of antiangiogenic factors, hamper angiogenesis, and hinder wound healing. Reconstruction of the vasculature of the wound bed is crucial for promoting diabetic wound healing and improving the quality of life of patients. Given the urgent need for innovative therapies to promote angiogenesis and accelerate the repair of diabetic wounds, researchers have increasingly focused on identifying herbal products and their active constituents with promising proangiogenic activity.
The aim of this review is to present verified data on the current knowledge on the effect of herbal products and their active constituents on angiogenesis processes in diabetic wounds.
The electronic databases were searched for articles published from 2014 to the present. The 38 articles comparing topically used herbal products/active constituents on angiogenesis in diabetic wound healing treatment versus control treatments (placebo or active therapy) were selected.
Herbal products and their active constituents are rich sources of novel angio-modulators that may affect the angiogenesis process in diabetic wound healing via different mechanisms of action, including stimulation of VEGF and HRMs and activation of the Nrf2, PI3K/AKT, and HIF-1α signaling pathways. Topical applications of herbal products and their active constituents, especially when incorporated into wound dressings, show promising proangiogenic activity and represent a potential alternative for the treatment of diabetic wounds.
Publication History
Received: 06 July 2025
Accepted after revision: 30 October 2025
Accepted Manuscript online:
30 October 2025
Article published online:
17 November 2025
© 2025. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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References
- 1 Velander P, Theopold C, Hirsch T, Bleiziffer O, Zuhaili B, Fossum M, Hoeller D, Gheerardyn R, Chen M, Visovatti S, Svensson H, Yao F, Eriksson E. Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia. Wound Repair Regener 2008; 16: 288-293
- 2 Shaikh-Kader A, Houreld NN, Rajendran NK, Abrahamse H. The link between advanced glycation end products and apoptosis in delayed wound healing. Cell Biochem Funct 2019; 37: 432-442
- 3 Ngo BT, Hayes KD, Dimiao DJ, Srinivasan SK, Huerter CJ, Rendell MS. Manifestations of cutaneous diabetic microangiopathy. Am J Clin Dermatol 2005; 6: 6225-6237
- 4 Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother 2019; 112: 108615
- 5 Kalan LR, Meisel JS, Loesche MA, Horwinski J, Soaita I, Chen X, Kalan LR, Meisel JS, Loesche MA, Horwinski J, Soaita I, Chen X, Uberoi A, Gardner SE, Grice EA. Strain-and species-level variation in the microbiome of diabetic wounds is associated with clinical outcomes and therapeutic efficacy. Cell Host Microbe 2019; 25: 641-655
- 6 Soares R. Angiogenesis in diabetes. Unraveling the angiogenic paradox. Open Circ Vasc J 2010; 3: 3-9
- 7 Nishikori Y, Shiota N, Okunishi H. The role of mast cells in cutaneous wound healing in streptozotocin-induced diabetic mice. Arch Dermatol Res 2014; 306: 823-835
- 8 Tellechea A, Leal EC, Kafanas A, Auster ME, Kuchibhotla S, Ostrovsky Y, Tellechea A, Leal EC, Kafanas A, Auster ME, Kuchibhotla S, Ostrovsky Y, Tecilazich F, Baltzis D, Zheng Y, Carvalho E, Zabolotny JM, Weng Z, Petra A, Patel A, Panagiotidou S, Pradhan-Nabzdyk L, Theoharides TC, Veves A. Mast cells regulate wound healing in diabetes. Diabetes 2016; 65: 2006-2019
- 9 Greenhalgh DG, Sprugel KH, Murray MJ, Ross R. PDGF and FGF stimulate wound healing in the genetically diabetic mouse. Am J Pathol 1990; 136: 1235
- 10 Liu L, Marti GP, Wei X, Zhang X, Zhang H, Liu YV, Nastai M, Semenza GL, Harmon JW. Age-dependent impairment of HIF-1α expression in diabetic mice: correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J Cell Physiol 2008; 217: 319-327
- 11 Sharma K, Ziyadeh FN. Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes 1995; 44: 1139-1146
- 12 Schönborn M, Łączak P, Pasieka P, Borys S, Płotek A, Maga P. Pro-and anti-angiogenic factors: Their relevance in diabetic foot syndrome-a review. Angiology 2022; 73: 299-311
- 13 Okonkwo UA, DiPietro LA. Diabetes and wound angiogenesis. Int J Mol Sci 2017; 18: 1419
- 14 Bouïs D, Kusumanto Y, Meijer C, Mulder NH, Hospers GA. A review on pro-and anti-angiogenic factors as targets of clinical intervention. Pharmacol Res 2006; 53: 89-103
- 15 Herman A, Herman AP. Herbal products and their active constituents for diabetic wound healing-preclinical and clinical studies: A systematic review. Pharmaceutics 2023; 15: 281
- 16 Sultana A, Borgohain R, Rayaji A, Saha D, Das BK. Promising phytoconstituents in diabetes-related wounds: Mechanistic insights and implications. Curr Diabetes Rev 2025; 21: e270224227477
- 17 Li J, Li R, Wu X, Zheng C, Shiu PHT, Rangsinth P, Lee SMY, Leung GPH. An update on the potential application of herbal medicine in promoting angiogenesis. Front Pharmacol 2022; 13: 928817
- 18 Liu Y, Zhang X, Yang L, Zhou S, Li Y, Shen Y, Lu S, Zhou J, Liu Y. Proteomics and transcriptomics explore the effect of mixture of herbal extract on diabetic wound healing process. Phytomedicine 2023; 116: 154892
- 19 Hou Q, He WJ, Chen L, Hao HJ, Liu JJ, Dong L, Tong C, Li MR, Zhou ZZ, Han WD, Fu XB. Effects of the four-herb compound ANBP on wound healing promotion in diabetic mice. Int J Low Extrem Wounds 2015; 14: 335-342
- 20 Al-Rawaf HA, Gabr SA, Alghadir AH. Circulating hypoxia responsive microRNAs (HRMs) and wound healing potentials of green tea in diabetic and nondiabetic rat models. Evid Based Complement Alternat Med 2019; 1: 9019253
- 21 Qiu F, Fan S, Diao Y, Liu J, Li B, Li K, Zhang W. The mechanism of Chebulae fructus immaturus promote diabetic wound healing based on network pharmacology and experimental verification. J Ethnopharmacol 2024; 322: 117579
- 22 Xu C, Hu L, Zeng J, Wu A, Deng S, Zhao Z, Geng K, Luo J, Wang L, Zhou X, Huang W, Long Y, Song J, Zheng S, Wu J, Chen Q. Gynura divaricata (L.) DC. promotes diabetic wound healing by activating Nrf2 signaling in diabetic rats. J Ethnopharmacol 2024; 323: 117638
- 23 Muhammad AA, Arulselvan P, Cheah PS, Abas F, Fakurazi S. Evaluation of wound healing properties of bioactive aqueous fraction from Moringa oleifera Lam on experimentally induced diabetic animal model. Drug Des Devel Ther 2016; 10: 1715
- 24 Park DH, Park JY, Shin MS, Hwang GS. Wound healing effect of 20 (S)-protopanaxadiol of ginseng involves VEGF-ERK pathways in HUVECs and diabetic mice. Processes 2023; 11: 692
- 25 Zhang EY, Gao B, Shi HL, Huang LF, Yang L, Wu XJ, Wang ZT. 20 (S)-Protopanaxadiol enhances angiogenesis via HIF-1α-mediated VEGF secretion by activating p 70S6 kinase and benefits wound healing in genetically diabetic mice. Exp Mol Med 2017; 49: e387
- 26 Liu Y, Li Z, Li W, Chen X, Yang L, Lu S, Zhou S, Li M, Xiong W, Zhang X, Liu Y, Zhou J. Discovery of β-sitosterolʼs effects on molecular changes in rat diabetic wounds and its impact on angiogenesis and macrophages. Int Immunopharmacol 2024; 126: 111283
- 27 Xiao K, Wang S, Li G, Chen W, Chen B, Li X. Resveratrol promotes diabetic wound healing by inhibiting ferroptosis in vascular endothelial cells. Burns 2024; 50: 107198
- 28 Xue C, Dou J, Zhang S, Yu H, Zhang S. Shikonin potentiates skin wound healing in Sprague–Dawley rats by stimulating fibroblast and endothelial cell proliferation and angiogenesis. J Gene Med 2014; 26: e3633
- 29 Phang SJ, Arumugam B, Kuppusamy UR, Fauzi MB, Looi ML. A review of diabetic wound models-novel insights into diabetic foot ulcer. J Tissue Eng Regen Med 2021; 15: 1051-1068
- 30 Bandyk DF. The diabetic foot: Pathophysiology, evaluation, and treatment. Semin Vasc Surg 2018; 31: 43-48
- 31 Mohajeri G, Safaee M, Sanei MH. Effects of topical kiwifruit on healing of neuropathic diabetic foot ulcer. J Res Med Sci 2014; 19: 520-524
- 32 Song Y, Zhang S, Fan T, Yang Z, Li P, Zhang L, Gao N, Mei W. Exploring the efficacy of Catha edulis extract-loaded nanofibrous scaffolds seeded with bone marrow-derived stem cells for diabetic wound healing: A preclinical investigation. J Bioact Compatible Polym 2024; 39: 264-278
- 33 Soheilifar MH, Dastan D, Masoudi-Khoram N, Keshmiri Neghab H, Nobari S, Tabaie SM, Amini R. In vitro and in vivo evaluation of the diabetic wound healing properties of saffron (Crocus Sativus L.) petals. Sci Rep 2024; 14: 19373
- 34 Tan M, Liu Y, Xu Y, Yan G, Zhou N, Chen H, Jiang Z, Peng L. Plant-derived exosomes as novel nanotherapeutics contrive glycolysis reprogramming-mediated angiogenesis for diabetic ulcer healing. Biomater Res 2024; 28: 0035
- 35 Yadollah-Damavandi S, Chavoshi-Nejad M, Jangholi E, Nekouyian N, Hosseini S, Seifaee A, Rafiee S, Karimi H, Ashkani-Esfahani S, Parsa Y, Mohsenikia M. Topical Hypericum perforatum improves tissue regeneration in full-thickness excisional wounds in diabetic rat model. Evid Based Complement Alternat Med 2015; 2015: 245328
- 36 Almasian A, Najafi F, Eftekhari M, Ardekani MRS, Sharifzadeh M, Khanavi M. Polyurethane/carboxymethylcellulose nanofibers containing Malva sylvestris extract for healing diabetic wounds: Preparation, characterization, in vitro and in vivo studies. Mater Sci Eng C Mater Biol Appl 2020; 114: 111039
- 37 Sulistyoningrum E, Rosmelia R, Fidianingsih I, Narantika SG, Cleopatra NN, Azzahra F. Wound healing activity of topical Phaleria macrocarpa extract in type 2 diabetic rats. Univ Med 2024; 43: 136-147
- 38 Liao TT, Sukpat S, Chansriniyom C, Patumraj S. Topical combined Phyllanthus emblica Linn. and simvastatin improves wound healing in diabetic mice by enhancing angiogenesis and reducing neutrophil infiltration. Biomed Rep 2023; 18: 31
- 39 Savekar PL, Nadaf SJ, Killedar SG, Kumbar VM, Hoskeri JH, Bhagwat DA, Gurav SS. Citric acid cross-linked pomegranate peel extract-loaded pH-responsive β-cyclodextrin/carboxymethyl tapioca starch hydrogel film for diabetic wound healing. Int J Biol Macromol 2024; 274: 133366
- 40 Wang S, Zhang Y, Shi Y, He Q, Tan Q, Peng Z, Liu Y, Li D, Li X, Ke D, Wang J. Rhubarb charcoal-crosslinked chitosan/silk fibroin sponge scaffold with efficient hemostasis, inflammation, and angiogenesis for promoting diabetic wound healing. Int J Biol Macromol 2023; 253: 126796
- 41 Algandaby MM, Esmat A, Nasrullah MZ, Alhakamy NA, Abdel-Naim AB, Rashad OM, Elhady SS, Eltamany EE. LC–MS based metabolic profiling and wound healing activity of a chitosan nanoparticle-loaded formula of Teucrium polium in diabetic rats. Biomed Pharmacother 2023; 168: 115626
- 42 Zhao Z, Han S, Feng W, Zhang Z, Shen S, Huang H, Wu J. Xanthium strumarium/gelatin methacryloyl based hydrogels with anti-inflammatory and antioxidant properties for diabetic wound healing via akt/mtor pathway. Int J Biol Macromol 2025; 300: 140186
- 43 Zeng Z, Zhu BH. Arnebin-1 promotes the angiogenesis of human umbilical vein endothelial cells and accelerates the wound healing process in diabetic rats. J Ethnopharmacol 2014; 154: 653-662
- 44 Xiong W, Zhang X, Hu J, Zou X, Huang H, Qu W, Cai S, Li C, Wei Y, Zhong X, Cai Z, Huang Z. PF–PEG@ASIV-EXO hydrogel accelerates diabetic wound healing by ferroptosis resistance and promoting angiogenesis. ACS Biomater Sci Eng 2024; 10: 6263-6285
- 45 Chen Y, Li Y, Song H, Liu X, Zhang H, Jiang J, Liu H, Zhuo R, Cheng G, Fang J, Xu L, Qi Y, Sun D. Injectable nanocomposite hydrogel for accelerating diabetic wound healing through inflammatory microenvironment regulation. Int J Nanomedicine 2025; 20: 1679-1696
- 46 Fan X, Huang J, Zhang W, Su Z, Li J, Wu Z, Zhang P. A multifunctional, tough, stretchable, and transparent curcumin hydrogel with potent antimicrobial, antioxidative, anti-inflammatory, and angiogenesis capabilities for diabetic wound healing. ACS Appl Mater Interfaces 2024; 16: 9749-9767
- 47 Ranjbar-Mohammadi M, Rabbani S, Bahrami SH, Joghataei MT, Moayer F. Antibacterial performance and in vivo diabetic wound healing of curcumin loaded gum tragacanth/poly (ε-caprolactone) electrospun nanofibers. Mater Sci Eng C Mater Biol Appl 2016; 69: 1183-1191
- 48 Han Z, Li A, Xue Z, Guan SB, Yin G, Zheng X. Eugenol-loaded polyurethane gelatin dressing for efficient angiogenesis and antibacterial effects in refractory diabetic wound defect healing. Int J Biol Macromol 2024; 271: 132619
- 49 Gao SQ, Chang C, Li JJ, Li Y, Niu XQ, Zhang DP, Li LJ, Gao JQ. Codelivery of deferoxamine and hydroxysafflor yellow A to accelerate diabetic wound healing via enhanced angiogenesis. Drug Deliv 2018; 25: 1779-1789
- 50 Hao M, Wei S, Su S, Tang Z, Wang Y. A Multifunctional hydrogel fabricated by direct self-assembly of natural herbal small molecule mangiferin for treating diabetic wounds. ACS Appl Mater Interfaces 2024; 16: 24221-24234
- 51 Yang Y, Wang F, Yin D, Fang Z, Huang L. Astragulus polysaccharide-loaded fibrous mats promote the restoration of microcirculation in/around skin wounds to accelerate wound healing in a diabetic rat model. Colloids Surf B: Biointerfaces 2015; 136: 111-118
- 52 Xu N, Wang L, Guan J, Tang C, He N, Zhang W, Fu S. Wound healing effects of a Curcuma zedoaria polysaccharide with platelet-rich plasma exosomes assembled on chitosan/silk hydrogel sponge in a diabetic rat model. Int J Biol Macromol 2018; 117: 102-107
- 53 Liu W, Lei L, Ma F, Zhan M, Zhu J, Khan MZH, Liu X. A Dioscorea opposita polysaccharide-calcium carbonate microsphere-doped hydrogel for accelerated diabetic wound healing via synergistic glucose-responsive hypoglycemic and anti-inflammatory effects. ACS Biomater Sci Eng 2025; 11: 415-428
- 54 Xin C, Cheng Z, Liu W, Li W, Zhu H. The antibacterial and hemostatic activity of Gastrodia elata polysaccharide-based hydrogel embedded with drug-carrying microspheres accelerates diabetic wound healing. Chem Eng J 2024; 492: 152403
- 55 Wang T, Liao Q, Wu Y, Wang X, Fu C, Geng F, Qu Y, Zhang J. A composite hydrogel loading natural polysaccharides derived from Periplaneta americana herbal residue for diabetic wound healing. Int J Biol Macromo 2010; 164: 3846-3857
- 56 Lihao Q, Tingting L, Jiawei Z, Yifei B, Zheyu T, Jingyan L, Tongqing X, Zhongzhi J. 3D bioprinting of salvianolic acid B-sodium alginate-gelatin skin scaffolds promotes diabetic wound repair via antioxidant, anti-inflammatory, and proangiogenic effects. Biomed Pharmacother 2024; 171: 116168
- 57 Zhang J, Wang W, Liu D, Shi H, Song X, Gao Y, Zhou X, Liu X, Chen Z, Guo J. A hydrogel based on Bletilla striata polysaccharide and hyaluronic acid topically administers tetramethylpyrazine for diabetic wound therapy. Eur Polym J 2024; 215: 113209
- 58 Tan WS, Arulselvan P, Ng S, Norma C, Taib M, Sarian MN. Improvement of diabetic wound healing by topical application of Vicenin-2 hydrocolloid film on Sprague Dawley rats. BMC Complement Altern Med 2019; 19: 20
- 59 Brumberg V, Astrelina T, Malivanova T, Samoilov A. Modern wound dressings: hydrogel dressings. Biomedicines 2021; 9: 1235
- 60 Liu Y, Li C, Feng Z, Han B, Yu DG, Wang K. Advances in the preparation of nanofiber dressings by electrospinning for promoting diabetic wound healing. Biomolecules 2022; 12: 1727
- 61 Li K, Zhu Z, Zhai Y, Chen S. Recent advances in electrospun nanofiber-based strategies for diabetic wound healing application. Pharmaceutics 2023; 15: 2285
- 62 Awasthi A, Gulati M, Kumar B, Kaur J, Vishwas S, Khursheed R, Porwal O, Alam A, Arya KR, Corrie L, Kumar R, Kumar A, Kaushik M, Jha NK, Gupta PK, Chellappan DK, Gupta G, Dua K, Gupta S, Gundamaraju R, Rao PV, Singh SK. Recent progress in development of dressings used for diabetic wounds with special emphasis on scaffolds. Biomed Res Int 2022; 1: 1659338
- 63 Shi L, Song D, Meng C, Cheng Y, Wang B, Yang Z. Opportunities and challenges of engineered exosomes for diabetic wound healing. Giant 2024; 18: 100251
- 64 Jin W, Li Y, Yu M, Ren D, Han C, Guo S. Advances of exosomes in diabetic wound healing. Burns Trauma 2025; 13: tkae078
- 65 Li D, Wu N. Mechanism and application of exosomes in the wound healing process in diabetes mellitus. Diabetes Res Clin Pract 2022; 187: 109882
- 66 Duran CL, Howell DW, Dave JM, Smith RL, Torrie ME, Essner JJ, Bayless KJ. Molecular regulation of sprouting angiogenesis. Compr Physio 2018; 8: 153-235
- 67 Mentzer SJ, Konerding MA. Intussusceptive angiogenesis: Expansion and remodeling of microvascular networks. Angiogenesis 2014; 17: 499-509
- 68 Dudley AC, Griffioen AW. Pathological angiogenesis: Mechanisms and therapeutic strategies. Angiogenesis 2023; 26: 313-347
- 69 Cébe-Suarez S, Zehnder-Fjällman A, Ballmer-Hofer K. The Role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci 2006; 63: 601-615
- 70 Mustonen T, Alitalo K. Endothelial receptor tyrosine kinases involved in angiogenesis. J Cell Biol 1995; 129: 895-898
- 71 Mace KA, Yu DH, Paydar KZ, Boudreau N, Young DM. Sustained expression of HIF‐1α in the diabetic environment promotes angiogenesis and cutaneous wound repair. Wound Repair Regen 2007; 15: 636-645
- 72 Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996; 16: 4604-4613
- 73 Li D, Landén NX. MicroRNAs in skin wound healing. Eur J Dermatol 2017; 27: 12-14
- 74 Rane S, He M, Sayed D, Vashistha H, Malhotra A, Sadoshima J, Vatner DE, Vatner SF, Abdellatif M. Downregulation of MiR-199a derepresses hypoxia-inducible factor-1α and sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes. Circ Res 2009; 104: 879-886
- 75 Jere SW, Houreld NN, Abrahamse H. Role of the PI3K/AKT (mTOR and GSK3β) signaling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev 2019; 50: 52-59
- 76 Jere SW, Houreld NN, Abrahamse H. Photobiomodulation activates the PI3K/AKT pathway in diabetic fibroblast cells in vitro . J Photochem Photobiol B: Biol 2022; 237: 112590
- 77 Somanath PR, Chen J, Byzova TV. Akt1 is necessary for the vascular maturation and angiogenesis during cutaneous wound healing. Angiogenesis 2008; 11: 277-288
- 78 Jiang BH, Liu LZ. AKT signaling in regulating angiogenesis. Curr Cancer Drug Targets 2008; 8: 19-26
- 79 Süntar I, Çetinkaya S, Panieri E, Saha S, Buttari B, Profumo E, Saso L. Regulatory role of Nrf2 signaling pathway in wound healing process. Molecules 2021; 26: 2424
- 80 Kaussikaa S, Prasad MK, Ramkumar KM. Nrf2 activation in keratinocytes: A central role in diabetes‐associated wound healing. Exp Dermatol 2024; 33: e15189
- 81 Long M, Rojo de la Vega M, Wen Q, Bharara M, Jiang T, Zhang R, Zhou S, Wong PK, Wondrak GT, Zheng H, Zhang DD. An essential role of NRF2 in diabetic wound healing. Diabetes 2016; 65: 780-793
- 82 Li L, Pan H, Wang H, Li X, Bu X, Wang Q, Gao Y, Wen G, Zhou Y, Cong Z, Yang Y, Tang C, Liu Z. Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension. Sci Rep 2016; 6: 37338
- 83 Huang Y, Mao Y, Li H, Shen G, Nan G. Knockdown of Nrf2 inhibits angiogenesis by downregulating VEGF expression through PI3K/Akt signaling pathway in cerebral microvascular endothelial cells under hypoxic conditions. Biochem Cell Biol 2018; 96: 475-482
- 84 Yang XD, Yang YY. Ferroptosis as a novel therapeutic target for diabetes and its complications. Front Endocrinol 2022; 13: 853822
- 85 Joshi BS, Kaul PN. Alternative medicine: Herbal drugs and their critical appraisal – Part I. Prog Drug Res 2001; 56: 1-76
- 86 Huxtable RJ. The myth of beneficent nature: The risks of herbal preparations. Ann Intern Med 1992; 117: 165-166
- 87 De Smet PA. Health risks of herbal remedies: An update. Clin Pharmacol Ther 2004; 76: 1-17
- 88 Ernst E. Adverse effects of herbal drugs in dermatology. Br J Dermatol 2000; 143: 923-929
- 89 Bedi MK, Shenefelt PD. Herbal therapy in dermatology. Arch Dermatol 2002; 138: 232-242
