Mechanisms of medicinal plants in the treatment of diabetic wound

Abstract

Wound repair is noticeably prolonged in a diabetic state due to a faulty inflammatory process and an underlying neuropathy. Several medicinal plants and their products have been of prime importance for the management of wounds over the years. Various mechanisms whereby medicinal plants elicit their action in wound repair are revealed and some plants are proven to be experimentally effective in enhancing wound closure and achieving healing. The mechanisms identified include hyperglycemic control, alleviation of physiological inflammation, controlled oxidative stress, infection control, and influence on gene expression. Information in this review was sourced from research and review articles in electronic databases such as Web of Science, Scopus, PubMed, and Google Scholar.

Keywords

Diabetes / Infection / Inflammation / Medicinal plants / Wound healing / Oxidative stress

Conflict of interest statement

All authors declare no conflict of interest.

Funding

The authors received no extramural funding for this study.

Authors’ contributions

OVA contributed to design, literature search, and manuscript preparation and editing. SAA and GO contributed to conceptualization, design and manuscript reviewing. All authors read and agreed to the published version of this manuscript.

References

[1] Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138: 271-281.

[2] International Diabetes Federation. IDF Diabetes Atlas. 10th ed. Brussels, Belgium; 2022.

[3] Banday MZ, Sameer AS, Nissar S. Pathophysiology of diabetes; An overview. Avicenna J Med 2020; 10(4): 174-188.

[4] Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, et al. Diabetic foot ulcers: Part I. Pathophysiology and prevention. J Am Acad Dermatol 2014; 70(1): 1-18.

[5] Pengzi Z, Jing L, Yali J, Sunyinyan T, Dalong Z, Yan B. Global epidemiology of diabetic foot ulceration: A systematic review and meta-analysis. Ann Med 2017; 49: 106-116.

[6] Roy R, Zayas J, Mohamed MF, Aboonabi A, Delgado K, Wallace J, et al. IL-10 dysregulation underlies chemokine insufficiency, delayed macrophage response, and impaired healing in diabetic wounds. J Invest Dermatol 2022; 142(3): 692-704.

[7] 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. doi: 10.1016/j.biopha.2019.108615.

[8] Forsythe RO, Brownrigg J, Hinchliffe RJ. Peripheral arterial disease and revascularization of the diabetic foot. Diabetes Obes Metab 2015; 17: 435-444.

[9] Park S, Kang HJ, Jeon JH, Kim MJ, Lee IK. Recent advances in the pathogenesis of microvascular complications in diabetes. Arch Pharm Res 2019; 42(3): 252-262.

[10] Pan D, Xu L, Guo M. The role of protein kinase C in diabetic microvascular complications. Front Endocrinol 2022; 13. doi: 10.3389/fendo.2022.973058.

[11] Gianino E, Miller C, Gilmore J. Smart wound dressings for diabetic chronic Wounds. Bioengineering 2018; 5: 51.

[12] Watson JC, Dyck PJ. Peripheral neuropathy: A practical approach to diagnosis and symptom management. Mayo Clin Proc 2015; 90: 940-951.

[13] Wilkinson HN, Hardman MJ. Wound healing: Cellular mechanisms and pathological outcomes. Open Biol 2020; 10(9). doi: 10.1098/rsob.200223.

[14] Portou MJ, Baker D, Abraham D, Tsui J. The innate immune system, toll-like receptors and dermal wound healing: A review. Vascul Pharmacol 2015; 71: 31-36.

[15] Singh MR, Saraf S, Vyas A, Jain V, Singh D. Innovative approaches in wound healing: Trajectory and advances. Artif Cell Nanomed Biotechnol 2013; 41: 202-212.

[16] Kasuya A, Tokura Y. Attempts to accelerate wound healing. J Dermatol Sci 2014; 76: 169-172.

[17] Houreld NN, Ayuk SM, Abrahamse H. Cell adhesion molecules are mediated by photobiomodulation at 660 nm in diabetic wounded fibroblast cells. Cells 2018; 7(4): 30.

[18] Mendes JJ, Leandro C, Corte-Real S, Barbosa R, Cavaco-Silva P, Melo-Cristino J, et al. Wound healing potential of topical bacteriophage therapy on diabetic cutaneous wounds. Wound Repair Regen 2013; 21: 595-603.

[19] Clinton A, Carter T. Chronic wound biofilms: Pathogenesis and potential therapies. Lab Med 2015; 46: 277-284.

[20] Qiu YY, Tang LQ, Wei W. Berberine exerts renoprotective effects by regulating the AGEs-RAGE signaling pathway in mesangial cells during diabetic nephropathy. Mol Cell Endocrinol 2017; 443: 89-105.

[21] National diabetes fact sheet. National estimates and general information on diabetes and prediabetes in the United States, GA. United States: Centers for Disease Control and Prevention; 2013.

[22] Kavitha KV, Tiwari S, Purandare VB, Khedkar S, Bhosale SS, Unnikrishnan AG. Choice of wound care in diabetic foot ulcer: A practical approach. World J Diabetes 2014; 5: 546-556.

[23] Wang C, Mai L, Yang C, Liu D, Sun K, Song W, et al. Reducing major lower extremity amputations after the introduction of a multidisciplinary team in patient with diabetes foot ulcer. BMC Endocr Disord 2016; 16: 38.

[24] Perez-Favila A, Martinez-Fierro ML, Rodriguez-Lazalde JG, Cid-Baez MA, Zamudio-Osuna MJ, Martinez-Blanco MD, et al. Current therapeutic strategies in diabetic foot ulcers. Medicina 2019; 55: 714.

[25] Ertugrul BM, Lipsky BA, Guvenc U. An assessment of intra-lesional epidermal growth factor for treating diabetic foot wounds. The first experiences in Turkey. J Am Podiatr Med Assoc 2017; 107: 17-29.

[26] Sofowora A, Ogunbodede E, Onayade A. The role and place of medicinal plants in the strategies for disease prevention. Afr J Tradit Complement Altern Med 2013; 10: 210-229.

[27] Adeleke O, Oboh G, Adefegha S, Osesusi A. Effect of aqueous extract from root and leaf of Sphenocentrum jollyanum Pierre on wounds of diabetic rats: Influence on wound tissue cytokines, vascular endothelial growth factor and microbes. J Ethnopharmacol 2022; 29. doi: 10.1016/j.jep.2022.115266.

[28] Sharma A, Khanna S, Kaur G, Singh I. Medicinal plants and their components for wound healing applications. Future J Pharm Sci 2021; 7: 53.

[29] Albahri G, Badran A, Hijazi A, Daou A, Baydoun E, Nasser M, et al. The therapeutic wound healing bioactivities of various medicinal plants. Life 2020; 13(2): 317.

[30] Sanchez MC, Lancel S, Boulanger E, Neviere R. Targeting oxidative stress and mitochondrial dysfunction in the treatment of impaired wound healing: A systematic review. Antioxidants 2018; 7: 98.

[31] Blakely M. The use of best practice in the treatment of a complex diabetic foot ulcer: A case report. Healthcare (Basel) 2016; 4: 18.

[32] Adeleke OV, Adefegha SA, Oboh G. Sphenocentrum jollyanum root and leaf extracts enhanced wound closure by improving the glycemic state of diabetic rats induced by high fat diet/streptozotocin. Comp Clin Pathol 2021; 30: 881-889.

[33] Garaniya N, Bapodra A. Ethno botanical and phytopharmacological potential of Abrus precatorius L: A review. Asian Pac J Trop Biomed 2014; 4(Suppl 1): S27-S34.

[34] Vistoli G, De Maddis D, Cipak A, Zarkovic N, Carini M, Aldini G. Advanced glycoxidation and lipoxidation end products (ages and ales): An overview of their mechanisms of formation. Free Radic Res 2013; 47(1): 3-27.

[35] Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: Clinical insights and vascular mechanisms. Can J Cardiol 2018; 34(5): 575-584.

[36] Singh A, Bajpai S, Singh N, Kumara V, Gour JK, Singh PK, et al. Wound healing activity of standardized extract of Curculigo orchioides in streptozotocin-induced diabetic mice. Asian Pac J Trop Dis 2014; 4: S48-S53.

[37] Qing C. The molecular biology in wound healing and non-healing wound. Chin J Traumatol 2017; 20: 189-193.

[38] Anushree U, Punj P, Vasumathi, Bharati S. Phosphorylated chitosan accelerates dermal wound healing in diabetic wistar rats. Glycoconj J 2023; 40: 19-31.

[39] Lemarchand M, Thoulin K, De Serres-Berard T, Bellenfant S, Cadau S, Berthod F. In vitro glycation of a tissue-engineered wound healing model to mimic diabetic ulcers. Biotechnol Bioeng 2023; 120(6): 1657-1666.

[40] Adefegha SA, Oboh G. Phytochemistry and mode of action of some tropical spices in the management of type-2 diabetes and hypertension. Afr J Pharm Pharmacol 2013; 7(7): 332-346.

[41] Nair SS, Kavrekar V, Mishra A. In vitro studies on α-amylase and α glucosidase inhibitory activities of selected plant extracts. Eur J Exp Biol 2013; 3(1): 128-132.

[42] Ademiluyi AO, Oboh G. Soybean phenolic rich extracts inhibits key-enzymes linked to diabetes (α-amylase and α-glucosidase) and hypertension (Angiotensin-Ⅰ-converting enzyme ACE) in vitro. Exp Toxicol Pathol 2013; 65(3): 305-309.

[43] Oboh G, Ademosun AO, Akinleye M, Omojokun OS, Boligon AA, Athayde ML. Starch composition, glycemic indices, phenolic constituents, and antioxidative and antidiabetic properties of some common tropical fruits. J Ethn Foods 2015; 2: 64-73.

[44] Adefegha SA, Oboh G, Omojokun OS, Jimoh TO, Oyeleye SI. In vitro antioxidant activities of African birch (Anogeissus leiocarpus) leaf and its effect on α-amylase and α-glucosidase inhibitory properties of Acarbose. J Taibah Uni Medical Sci 2016; 11(3): 236-242.

[45] Adefegha SA, Oboh G, Adefegha OM. Ashanti pepper attenuates carbohydrate hydrolyzing, blood pressure regulating and cholinergic enzymes in experimental type 2 diabetes rat model. J Basic Clin Physiol Pharmacol 2017; 28(1): 19-30.

[46] Hoffmann MH, Griffiths HR. The dual role of ROS in autoimmune and inflammatory diseases: Evidence from preclinical models. Free Radic Biol Med 2018; 125: 62-71.

[47] Lazarevic-Pasti T, Leskovac A, Vasic V. Myeloperoxidase inhibitors as potential drugs. Curr Drug Metab 2015; 16(3): 168-190.

[48] De Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: Going forward in reverse. Nature Rev Immunol 2016; 16(6): 378-391.

[49] David JA, Rifkin WJ, Rabbani PS, Ceradini DJ. The Nrf2/Keap 1/ARE pathway and oxidative stress as a therapeutic target in type Ⅱ diabetes mellitus. J Diabetes Res 2017; 2017. doi: 10.1155/2017/4826724.

[50] Katakami N. Mechanism of development of atherosclerosis and cardiovascular disease in Diabetes Mellitus. J Atheroscler Thromb 2018; 25: 27-39.

[51] Golebiewska EM, Poole AW. Platelet secretion: From hemostasis to wound healing and beyond. Blood Rev 2015; 29: 153-162.

[52] Kunkemoeller B, Kyriakides TR. Redox signaling in diabetic wound healing regulates extracellular matrix deposition. Antioxid Redox Signal 2017; 27: 823-838.

[53] Ashrafizadeh M, Ahmadi Z, Mohammadinejad R, Farkhondeh T, Samarghandian S. Curcumin activates the Nrf2 pathway and induces cellular protection against oxidative injury. Curr Mol Med 2020; 20: 116-133.

[54] Kumari A, Raina N, Wahi A, Goh KW, Sharma P, Nagpal R, et al. Wound healing effects of curcumin and its nanoformulations: A comprehensive review. Pharmaceutics 2022; 14(11): 2288.

[55] Tie L, An Y, Han J, Xiao Y, Xiaokaiti Y, Fan S, et al. Genistein accelerates refractory wound healing by suppressing superoxide and FoxO1/iNOS pathway in type 1 diabetes. J Nutr Biochem 2013; 24: 88-96.

[56] Tam JCW, Ko CH, Lau KM, To MH, Kwok HF, Chan YW, et al. A Chinese 2-herb formula (NF3) promotes hind-limb ischemia-induced neovascularization and wound healing of diabetic rats. J Diabetes Complicat 2014; 28: 436-447.

[57] Lodhi S, Singhai AK. Wound healing effect of flavonoid rich fraction and luteolin isolated from Martynia annua Linn on streptozotocin induced diabetic rats. Asian Pac J Trop Med 2013; 6(4): 253-259.

[58] Xiao J, Li J, Cai L, Chakrabarti S, Li X. Cytokines and diabetes research. J Diabetes Res 2014; 2014. doi: 10.1155/2014/920613.

[59] Khezri K, Farahpour MR, Rad SM. Accelerated infected wound healing by topical application of encapsulated Rosemary essential oil into nanostructured lipid carriers. Artif Cells Nanomed Biotechnol 2019; 47(1): 980-988.

[60] Emiroglu G, Ozergin CZ, Kalkan Y, Celebi EO, Tumkaya L, Terzi S, et al. The effects of curcumin on wound healing in a rat model of nasal mucosal trauma. Evid Based Complement Altern Med 2017; 2017. doi: 10.1155/2017/9452392.

[61] Larijani B, Heshmat R, Bahrami A, Delshad H, Ranjbar OG, Mohammad K, et al. Effect of intravenous Semelil (ANGIPARSTM) on diabetic foot ulcers healing: A multicenter clinical trial. Daru J Pharm Sci 2008; 16: 35-40.

[62] Chen Y, Ding H, Wu H, Chen HL. The relationship between osteomyelitis complication and drug-resistant infection risk in diabetic foot ulcer: A meta-analysis. Int J Low Extrem Wounds 2017; 16: 183-190.

[63] Kalan L, Loesche M, Hodkinson BP, Heilmann K, Ruthel G, Gardner SE, et al. Redefining the chronic-wound microbiome: Fungal communities are prevalent, dynamic, and associated with delayed healing. MBio 2016; 7: e01058-e01116.

[64] Franco-Zorrilla JM, Lopez-Vidriero I, Carrasco JL, Godoy M, Vera P, Solano R. DNA-binding specificities of plant transcription factors and their potential to define target genes. Proc Natl Acad Sci USA 2014; 111(6): 2367-2372.

[65] Ambrozova N, Ulrichova J, Galandakova A. Models for the study of skin wound healing, the role of Nrf2 and NF-κB. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2017; 16(1): 1-13.

[66] Panossian A, Seo E, Efferth T. Effects of anti-inflammatory and adaptogenic herbal extracts on gene expression of eicosanoids signaling pathways in isolated brain cells. Phytomedicine 2019; 60. doi: 10.1016/j.phymed.2019.152881.

[67] Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodeling. The J Pathol 2013; 229(2): 176-185.

[68] Wang T, He R, Zhao J, Mei JC, Shao MZ, Pan Y, et al. Negative pressure wound therapy inhibits inflammation and up-regulates activating transcription factor-3 and down-regulates nuclear factor-kappa b in diabetic patients with foot ulcerations. Diabetes Metab Res Rev 2017; 33(4). doi: 10.1002/dmrr.2871.

[69] Kant V, Kumar D, Kumar D, Prasad R, Gopal A, Pathak N, et al. Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats. Cytokine 2015; 73: 144-155.

[70] Kandhare AD, Ghosh P, Bodhankar SL. Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats. Chem Biol Interact 2014; 219: 101-112.

[71] Kant V, Gopal A, Pathak NN, Kumar P, Tandan SK, Kumar D. Antioxidant and anti-inflammatory potential of curcumin accelerated the cutaneous wound healing in streptozotocin induced diabetic rats. Int Immunopharmacol 2014; 20: 322-330.

[72] Zhang X, Ma Z, Wang Y, Li Y, Sun B, Guo X, et al. The four-herb chinese medicine formula Tuo-Li-Xiao-Du-San accelerates cutaneous wound healing in streptozotocin induced diabetic rats through reducing inflammation and increasing angiogenesis. J Diabetes Res 2016; 5: 11.

[73] Kwon AH, Qiu Z, Hashimoto M, Yamamoto K, Kimura T. Effects of medicinal mushroom (Sparassis crispa) on wound healing in streptozotocin-induced diabetic rats. Am J Surg 2009; 197: 503-509.