Aloe Gel Enhances Angiogenesis in Healing of Diabetic Wound

Djanggan Sargowo, Adeodatus Yuda Handaya, Mohammad Aris Widodo, Diana Lyrawati, Askandar Tjokroprawiro


BACKGROUND: Diabetic micro and macroangiophathy lead to the incident of diabetic foot ulcers characterized by an increased number of circulating endothelial cells (CECs) and decreased function of endothelial progenitor cells (EPCs). This fact is correlated with ischemia and diabetic wound healing failure. Aloe vera gel is known to be able to stimulate vascular endothelial growth factor (VEGF) expression and activity by enhancing nitric oxide (NO) production as a result of nitric oxide synthase (NOS) enzyme activity. Aloe vera is a potential target to enhancing angiogenesis in wound healing.

OBJECTIVE: The objective of this study was to explore the major role of Aloe vera gel in wound healing of diabetic ulcers by increasing the level of EPCs, VEGF, and endothelial nitric oxide synthase (eNOS), as well as by reducing the level of CECs involved in angiogenesis process of diabetic ulcers healing.

METHODS: The experimental groups was divided into five subgroups consisting of non diabetic wistar rats, diabetic rats without oral administration of aloe gel, and treatment subgroup (diabetic rats) with 30, 60 and 120 mg/day of aloe gel doses for 14 days. All subgroups were wounded and daily observation was done on the wounds areas. Measurement of the number of EPCs (CD34), and CECs (CD45 and CD146) was done by flowcytometry, followed by measurement of VEGF and eNOS expression on dermal tissue by immunohistochemical method on day 0 and day 14 after treatment. The quantitative data were analyzed by One-Way ANOVA and Linear Regression, with a cofidence interval 5% and significance level (p<0.05) using SPSS 16 software to compare the difference and correlation between wound diameters, number of EPCs and CECs as well as the levels of VEGF and eNOS.

RESULTS: The results of this study showed that aloe gel oral treatment in diabetic wistar rats was able to accelerate the wound healing process. It was shown by significant reduction of wound diameter (0.27±0.02); the increased number of CECs (0.42±0.57), respectively (p<0.05). On the other hand, the wound diameter and eNOS indicators showed significant differences at the dose of 60 mg, while the number of EPCs and CECs and the level of VEGF showed significantly different results at a dose of 120 mg. Aloe gel oral therapy showed a positive indication of wound healing acceleration at the optimum dose range 60-120 mg a day.

CONCLUSIONS: Aloe gel is potential to be a herbal therapy candidate for diabetic wound healing through enhancing EPCs homing, decreasing the CECs number, and stimulating the increase of VEGF and eNOS levels,hence proving to be a dominant factor in the angiogenesis process.

KEYWORDS: aloe gel, diabetes, wound healing, angiogenesis

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Goycheva P, Gadjeva V, Popov B. Oxidative stress and its complication in diabetes mellitus. Trakia Journal of Science. 2006; 4: 1-8, article.

Tjokroprawiro A. Clinical staging of hyperglicemia diabetic vasular complication. [n.p]: Endocrine and Diabetes Forum Regional Sumater; 2010.

Pradhan L, Andersen A, LoGerfo F, Veves A. Molecular targets for promoting wound healing in diabetes. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery. 2007; 1: 1-13, CrossRef.

Ralf L, Gregory S, Hendrik L. Proteases and the diabetic foot syndrome: mechanisms and therapeutic implications. Diabetes Care. 2005; 28: 461-71, CrossRef.

Loomans CJM, de Koning EJP, FJT Staal, Rookmaaker MB, Verseyden C, de Boer HC, et al. Endothelial progenitor cell dysfunction a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004; 53: 195-9, CrossRef.

Chen YH, Lin SJ, Lin FY, Wu TC, Tsao CR, Huang PH, et al. High glucose impairs early and late endothelial progenitor cells by modifying nitric oxide related but not oxidative stress-mediated mechanisms. Diabetes. 2007; 56: 1559-68, CrossRef.

McClung JA, Naseer N, Saleem M, Rossi GP, Weiss MB, Abraham NG, Kappas A. Circulating endothelial cells are elevated in patients with type 2 diabetes independently of HbA1c. Diabetologia. 2005; 48: 345-50, CrossRef.

Somboonwong J, Thanamittramanee S, Jariyapongskul A, Patumraj S. Therapeutic effects of Aloe vera on cutaneous microcirculation and wound healing in second degree burn model in rats. J Med Assoc Thai. 2000; 83: 417-25, PMID.

Gallagher J, Gray M. Is aloe vera effective for healing chronic wounds? J Wound Ostomy Continence Nurs. 2003; 30: 68-71, CrossRef.

Ramamoorthy L, Kemp MC, Tizard IR. Acemannan, a beta-(1,4)-acetylated mannan,induces nitric oxide production in macrophage cell line RAW 264.7. Mol Pharmacol. 1996; 50: 878-84, PMID.

Hamman JH. Composition and applications of aloe vera leaf gel. Molecules. 2008; 13: 1599-616, CrossRef.

Shane-McWhorter L. Biological complementary therapies: a focus on botanical products in diabetes. Diabetes Spectrum. 2002; 14: 199-208, CrossRef.

Nayak BS.Cecropia peltata L(Cecropiaceae) has wound-healing potential: a preclinical study in a sprague dawley rat model. Int J Low Extrem Wounds. 2006; 5: 20-6, CrossRef.

Padmadisastra Y, Sidik SA. Formulasi sediaan cair gel lidah buaya (aloe vera linn.) sebagai minuman kesehatan. Bandung: Universitas Padjajaran; 2003.

Kwack SJ, Kim KB, Lee BM. Estimation of tolerable upper intake level (UL) of active aloe. Toxicol Environ Health. 2009; 72: 1455-62, CrossRef.

Jia Y, Zhao G, Jia J. Preliminary evaluation: the effects of aloe ferox miller and aloe arborescens miller on wound healing. J Ethnopharmacol. 2008; 120: 181-9, CrossRef.

Liu LY, Chen XD, Wu BY, Jiang Q. Influence of aloe polysaccharide on proliferation and hyaluronic acid and hydroxyproline secretion of human fibroblasts in vitro. Ong Xi Yi Jie He Xue Bao. 2010; 8: 256-62, PMID.

Mendonça FAS, Passarini Jr JR, Esquisatto MAM, Mendonça JS, Franchini CC, dos Santos GMT. Effects of the application of aloe vera (L.) and microcurrent on the healing of wounds surgically induced in Wistar rats. Acta Cirúrgica Brasileira. 2009; 24 : 150-5, CrossRef.

Takzare N, Hosseini M, Hasanzadeh G, Mortazavi H, Takzare A, Habibi P. Influence of aloe vera gel on dermal wound healing process in rat. Toxicology Mechanisms and Methods. 2009; 9: 73-77, CrossRef.

Jettanacheawchankit S, Sasithanasate S, Sangvanich P, Banlunara W, Thunyakitpisal P. Acemannan stimulates gingival fibroblast proliferation; expressions of keratinocyte growth factor-1, vascular endothelial growth factor, and type I collagen; and wound healing. J Pharmacol Sci. 2009; 109, 525-31, CrossRef.

Albiero M, Menegazzo L, Boscaro E, Agostini C, Avogaro A, Fadini GP. Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice. Diabetologia. 2010; 54: 945-53, CrossRef.

Tepper OM, Carr J, Allen RJ, Chang CC, Lin CD, Tanaka R, et al. Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1-α mediated bone marrow mobilization impair diabetic tissue repair. Diabetes. 2010; 59: 1974-83, CrossRef.

Sibal L, Aldibbiat A, Agarwal SC, Mitchell G, Oates C, Razvi S, et al. Circulating endothelial progenitor cells, endothelial function,carotid intima-media thickness and circulating markers of endothelial dysfunction in people with type 1 Diabetes without macrovascular disease or microalbuminuria. Diabetologia. 2009; 52: 1464-73, CrossRef.

Spinetti G, Kraenkel N, Emanueli C, Madeddu P. Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies. Cardiovascular Research. 2008; 78: 265-73, CrossRef.

Heggers JP, Pelley RP, Robson MC. Beneficial effects of aloe in wound healing. Phytotherapy Research. 1993; 7: S48-52, CrossRef.

İnan A, Şen M, Koca C, Ergin M, Dener C. Effects of aloe vera on colonic anastomoses of rats. Surgical Practice. 2007; 11: 60-5, CrossRef.

Choi S, Kim KW, Choi JS, Han ST, Park YI, Lee SK, et al. Angiogenic activity of beta-sitosterol in the ischaemia/reperfusion-damaged brain of Mongolian gerbil. Planta-Med. 2002; 68: 330-5, CrossRef.

Duda GD, Dai F, Rakesh KJ. Role of eNOS in neovascularization: NO for endothelial progenitor cells. Trends in Molecular Medicine. 2004; 10: 143-5, CrossRef.

Enoch S, Grey JE, Harding KG. Recent advances and emerging treatments. BMJ. 2006; 332: 962-5, CrossRef.

Saaristo A, Tammela T, Fārkkilā A, Kärkkäinen M, Suominen E, Yla-Herttuala S, et al. Vascular endothelial growth factor-C accelerates diabetic wound healing. Am J Pathol. 2006; 169: 1080-7, CrossRef.

Emanueli C, Salis MB, Pinna A Graiani G, Manni L, Madeddu P. Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs. Circulation. 2002; 106; 2257-62, CrossRef.

Altavilla D, Saitta A, Cucinotta D, Galeano M, Deodato B, Colonna M, et al. Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse. Diabetes. 2001; 50: 667-4, CrossRef.

Krishnan STM, Quattrini C, Jeziorska M, Malik RA, Rayman G. Neurovascular factors in wound healing in the foot skin of type 2 diabetic subjects. Diabetes Care. 2007; 30: 3058-62, CrossRef.

Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF et al. VEGF-A promotes tissue repairassociated lymphatic vessel formation via VEGFR-2 and the α1β1 and α2β1 integrins. FASEB J. 2004; 10: 1096-1179, CrossRef.

Kim YM, Seung NK, Yun YG, Hong HD, Lee YC, Ha KS, et al. Water extract of korean red ginseng stimulates angiogenesis by activating the PI3K/Akt- dependent ERK1/2 and eNOS pathways in human umbilical vein endothelial cells. Biol Pharm Bull. 2007; 30:1674-9, CrossRef.

Dawson NS, Zawieja DC, Wu MH, Granger HJ. Signaling pathways mediating VEGF165-induced calcium transients and membrane depolarization in human endothelial cells. FASEB J. 2006; 20; 991-3, CrossRef.

Aramoto H, Breslin JW, Pappas PJ, Hobson II RW, Durán WN. Vascular endothelial growth factor stimulates differential signaling pathways in the in vivo microcirculation. Am J Physiol Heart Circ Physiol. 2004; 10: 1-35, CrossRef.

Tanimoto T, Jin ZG, Berk BC. Transactivation of vascular endothelial growth factor (VEGF) receptor Flk-1/KDR is involved in sphingosine 1-phosphatestimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). The Journal of Biological Chemistry. 2002; 277: 42997-3001, CrossRef.


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