http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, Early Online: 1–6 ! 2015 Informa UK Ltd. DOI: 10.3109/09546634.2015.1021663

REVIEW ARTICLE

Triterpenes with healing activity: A systematic review Lais C. Agra1*, Jamylle N. S. Ferro1*, Fabiano T. Barbosa2, and Emiliano Barreto1 Laborato´rio de Biologia Celular, Universidade Federal de Alagoas, Maceio´-AL, Brazil and 2Faculdade de Medicina, Universidade Federal de Alagoas, Maceio´-AL, Brazil

J Dermatolog Treat Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.

1

Abstract

Keywords

The purpose of this review was to systematically evaluate the literature on the efficacy of triterpenes for wound healing. We searched for original studies in the Medline, SCIDIRECT and LILACS databases published from 1910 to 2013. For each study, the title, abstract and full article were evaluated by two reviewers. We identified 2181 studies; however, after application of the inclusion and exclusion criteria, only 12 studies were subjected to further review. In surgical wounds, the triterpenes induced a reduction in time to closure, and this effect was reported in virtually all wound types. Triterpenes also modulate the production of ROS in the wound microenvironment, accelerating the process of tissue repair. Triterpenes may also induce cell migration, cell proliferation and collagen deposition. Although the pharmacological effects of triterpenes are well characterized, little is known about their effects in cells involved in healing, such as keratinocytes and fibroblasts. In addition, the lack of studies on the risks associated with the therapeutic use of triterpenes is worrisome. Our study reveals that triterpenes seem to favor wound healing; however, toxicological studies with these compounds are required. Taken together, these findings show that the triterpenes are a class of molecules with significant promise that leads for the development of new drugs to treat skin injury.

Skin, systematic review, triterpenes, wound healing

Introduction Cutaneous injury can significantly affect a person’s life by leading to prolonged periods of discomfort, in addition to causing pain (1). Efforts are being made all over the world to develop agents able to promote healing and thereby reduce the cost of treatment and prevent severe complications. Such agents expedite the healing process and contribute to rapid and effective healing of wounds without scar formation. A large number of plants and plant-derived products have been used in traditional medicinal practices worldwide for the treatment of cuts, wounds and burns (2). It has been estimated that more than 40% of medicines have their origins in active natural products (3). Several studies suggest that plant-derived products, such as secondary metabolites, are capable of promoting wound healing in various animal models (4–6). A group of secondary metabolites, attracting much attention are the pentacyclic triterpenoids (7). Pentacyclic triterpenoids are a class of C30 isoprenoid compounds found widely in distinct parts of plant, such as the leaves, pollen, seeds and fruits (8). They help wound-healing mainly due to their effects on the production and activity of inflammatory mediators and growth factors, and thus produce *Both authors contributed equally to this work. Correspondence: Prof. Fabiano T. Barbosa, Faculdade de Medicina, Universidade Federal de Alagoas, Campus A.C. Simo˜es, s/n. Tabuleiro dos Martins, CEP 57072-970, Maceio´-AL, Brazil. Tel: +55 82 3214 1704. E-mail: [email protected] Dr Emiliano Barreto, Laborato´rio de Biologia Celular, Nu´cleo de Pesquisa Multidisciplinar, Universidade Federal de Alagoas, Campus A.C. Simo˜es, s/n. Tabuleiro dos Martins, CEP 57072-970, Maceio´-AL, Brazil. E-mail: [email protected]

History Received 1 August 2014 Revised 1 November 2014 Accepted 25 January 2015 Published online 23 March 2015

wound contraction and increase the rate of epithelialization (9). Despite their demonstrated therapeutic effects, there are no reviews of published studies on the effects of triterpenoids in wound healing. Therefore, the aim of the present systematic review was to summarize the current knowledge about the healing effects of the triterpenoids on superficial burns and wounds.

Methods Sources We performed a systematic electronic search for peer-reviewed articles in English in three major databases: MEDLINE (PubMed 1969 through February 2014), SCIDIRECT (1910 through February 2014) and LILACS (1995 to February 2014). Study selection For our search strategy, the databases were searched using combinations of the following terms: triterterpene(s), triterpenoid(s), wound healing, wound and healing. Review articles, duplicate articles and articles in which the outcomes were not of interest were excluded. The manuscript selection was based on the following inclusion criteria: articles with keywords in the title, abstract or full text, as well as studies with isolated triterpenes (natural or synthetic) and studies examining cutaneous wound healing in experimental animal models. This article selection step was performed by two independent reviewers (L.C.A and J.N.S.F), who checked the papers selected for review for discrepancies, which were resolved through discussion. Any disagreement was resolved through a consensus between the independent reviewers. The selected articles were manually

2

L. C. Agra et al.

J Dermatolog Treat, Early Online: 1–6

J Dermatolog Treat Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.

Figure 1. Trial flow depicting the selection process of studies included in this study.

reviewed with the goal of identifying and excluding works that did not fit the criteria described above.

Results and discussion A total of 2181 articles were identified: 749 from PubMed, 827 from SCIDIRECT and 605 from LILACS. However, of the 2181 articles, 628 studies were excluded due to duplication in multiple databases. After the initial screening, 12 articles were selected (Figure 1). Although most studies on triterpenes have utilized natural compounds, we selected 10 articles that studied synthetic triterpenes, including asiaticoside, astragaloside IV, bacoside A, cycloastragenol, cyclocanthoside E, ginsenoside Rd, lupeol, madecoside, oleanolic acid and ursolic acid. Thus, we evaluated the healing activity of all compounds of potential interest with the chemical characteristics of triterpenes. Of the final 12 selected studies, most were conducted in China (33.4%) and India (33.4%), followed by Korea (8.3%), Japan (8.3%), Turkey (8.3%) and Peru (8.3%). India and China are recognized for secular traditional practices that are able to offer valuable information concerning plants used in the treatment of wounds and burns (10). Among the 10 triterpenes identified in this review, seven were isolated from medicinal plants: asiaticoside and madecosside from Centella asiatica, bacoside A from Bacopa monnieri, a ginsenoside from Panax ginseng, lupeol from Celastrus paniculatus, oleanolic acid from Andereda diffusa and ursolic acid from Shorea robusta. The triterpenes astragaloside IV, cyclocanthoside E and cycloastragenol were obtained commercially for their respective studies. In four articles, the authors used different doses of triterpene astragaloside IV, as well as various formulations and time points for evaluation of biological effects. Two articles studied asiaticoside in distinct experimental models: wound healing in burns and skin wounds associated with diabetes. We identified six different animal models that have been used to evaluate the healing activity of triterpenes: excision (EW), incision (IW), dead space (DSW), breaking strength (BSW), burns (BW) and laser burns excision (LBEW). These data show that, regardless of the experimental model used to induce wounds, triterpenes were able to accelerate skin injury healing. Of the reviewed publications, 83% (10/12) of studies used EW model. Therefore, the EW model has been the main model used to evaluate the healing effect of triterpenes. In these studies, both macroscopic and microscopic approaches were used. The primary

advantages of the EW model are rapid injury induction and relatively rapid wound closure. Moreover, this model is easy to use and inexpensive in comparison with other wound models (11,12). Similar evidence was found in the recent study of Barreto and colleagues (13), who found that the EW model was most frequently used to evaluate the healing effects of monoterpenes and iridoid derivatives. In this review, we found that most studies used the topical route of administration (91.7%) to evaluate the healing effects of triterpenes. This preference for the topical route seems to be related to its many advantages, including non-invasive methodology and its ease of application in comparison with systemic treatments (14). However, only a single study evaluated the healing effects of triterpenes by the oral route of administration. Several studies have demonstrated that faster rates of wound closure are achieved when therapeutic agents are serially delivered over an extended period (15–17). Our work highlights the apparently universal wound healing effects of triterpenes, which are common to the studied compounds despite their structural diversity. However, the molecular mechanisms involved in triterpene-induced healing need to be better understood. No studies have assessed the structure–activity relationship for the healing effects of triterpenes; therefore, more research on the mechanisms of action of these compounds on wound healing is necessary. Moreover, there are no reports on the possible side effects of triterpene use. Thus, in vitro and in vivo toxicological studies must be performed before triterpenes can be extensively applied in clinical settings. The triterpenes identified by this systematic review that have been demonstrated to have healing effects on skin wounds are presented in Table 1 along with the general pharmacological aspects. Triterpenes with healing effects and the related mechanisms Asiaticoside Asiaticoside is a triterpene glycoside isolated from Centella asiatica (family Umbelliferae). Shukla and collaborators (18) used the EW model to demonstrate the ability of asiaticoside to reduce edema, leukocyte infiltration and necrosis, and to increase fibroblast proliferation, collagen synthesis and angiogenesis, after treatment with oral or topical asiaticoside for seven consecutive days. In the same study, the authors reported that topical treatment

Triterpenes induces wound healing

DOI: 10.3109/09546634.2015.1021663

3

Table 1. Description of the pharmacological aspects of the triterpenes included in this systematic review.

Source

Injury

Animal

Results

Country

Reference

Asiaticoside

Extract of Centella asiatica

EW

Topical or oral for 7 days (0.05–0.2%; 0.5–10 mg/kg or 0.2–0.4%)

Rat and Guinea pigs

India

(18)

Asiaticoside

Extracts of Centella asiatica

BWH

Topical ointment for 20 days (10 8% and 10 12%, w/w)

Mice

Japan

(6)

Astragaloside IV

Bionorm Natural Products Zhejiang Institute of Food and Drug Control

EW

Topical gel for 14 days (2.5–10%) Topical hydrogel for 14 days (0.5 mg)

Rat

Induces high collagen synthesis, angiogenesis, epithelization and high tissue tensile strength. Induces production of mediators (VEGF, IL-1b and MCP-1) and macrophage accumulation in tissue. Mechanism unknown.

Turkey

(20)

China

(15)

China

(5)

China

(16)

Astragaloside IV

Zhejiang Institute of Food and Drug Control

EW

Topical for 30 days (0.5%)

Rat

Astragaloside IV

Zhejiang Institute of Food and Drug Control

EW

Topical gel for 12 days, 3–7 weeks (0.5%)

Rat

Bacoside A

Extracts of Bacopa monnieri

EW IW DSW

Topical or oral for 16 days on EW or 10 days on IW (0.2% w/w or 4 mg/kg)

Rat

Cycloastragenol

Bionorm Natural ProductsÕ Bionorm Natural ProductsÕ Extract of Panax ginseng Extracts of Celastrus paniculatus

EW

Topical gel for 14 days (2.5–5%) Topical gel for 14 days (2.5–5%) Topical for 10 days (0.1% or 0.5%) Topical or oral for 16 days (0.2% w/v; 8 mg/kg) Oral for 20 days (6, 12 and 24 mg/kg)

Rat

Induces a high rate of re-epithelialization in the wound with the presence of TGF-b. Induces re-epithelization, angiogenesis and remodeling in the wound. Stimulates the proliferation and migration of keratinocytes. Enhances the proliferation and migration of keratinocytes by contributing to collagen deposition. Decreases the period of epithelialization and increases wound contraction. Increases the breaking strength of the granulation tissue. Mechanism unknown.

Rat

Mechanism unknown.

Turkey

(20)

Mice

Stimulates PKA signaling. Induces expression of beta-catenin.

Korea

(24)

India

(32)

Increases antioxidant activity and enhances collagen synthesis and angiogenesis. Mechanism unknown.

China

(38)

Peru

(48)

India

(3)

Astragaloside IV

J Dermatolog Treat Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.

Administration (dose or concentration)

Triterpenoid

Cyclocanthoside E Ginsenoside Lupeol Madecosside

Extracts of Centella asiatica

Oleanolic acid

Extracts of Anredera diffusa Extracts of Shorea robusta

Ursolic acid

EW

EW LBEW EW IW DSW BWH

IW WBS EW IW DSW WBS

Topical for 48 h (7.5–15 mg/ml) Topical ointment for 10 or 21 days (0.25%)

Rat

Rat Mice

Mice Rat

Induces modulation of the inflammatory mediators

India

(25)

Turkey

(20)

BWH, burn wound healing; EW, excision wound; IW, incision wound; DSW, dead space wound; WBS, wound breaking strength; LBEW, laser burn excision wound.

with asiaticoside increased the tensile strength of tissue more effectively than oral asiaticoside treatment (18). In India, asiaticoside has been used as a memory enhancing and psychoactive drug for millions of years. In addition, asiaticoside has been reported to have many other activities, including anti-inflammatory and neuroprotective effects (19). In a more recent study, Kimura et al. (6) investigated the mechanisms by which asiaticoside seems to promote its effects. Kimura used a burn wound (BW) model to demonstrate that

topical application of asiaticoside increased the production of vascular endothelial growth factor (VEGF), interleucin-1b (IL-1b) and monocyte chemoattractant protein-1 (MCP-1) (6). Astragaloside IV Astragaloside IV is a cycloartane-type triterpene glycoside capable of promoting wound healing in the skin. This triterpene is a major bioactive compound isolated from the roots of

J Dermatolog Treat Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.

4

L. C. Agra et al.

Astragalus species, which are used in traditional Chinese medicine for their antiperspirant, tonic and diuretic effects (20). Three articles were identified in which the healing activity of astragaloside IV was evaluated. First, Sevimli-Gu¨r and colleagues (20) reported the effect of treatment with astragaloside IV on reepithelization and keratinocyte proliferation, and showed that this triterpene improved the tensile strength of the skin and induced regeneration of cutaneous appendages. In another study, Chen et al. (5) sought to understand the underlying mechanisms of action of astragaloside IV by evaluating angiogenesis, extracellular matrix remodeling, and proliferation and migration of keratinocytes. Chen and colleagues showed that astragaloside IV promoted the formation of new vessels and balanced the synthesis and disposition of collagens. In addition, astragaloside IV decreased TGF-b1 secretion and collagen production (5). In another study, the authors used a hydrogel made from highly absorbent constituents with the aim of controlling the release of astragaloside IV in skin repair applications In this pharmaceutical formulation, the astragaloside IV-containing hydrogel enhanced the effects of astragaloside IV on wound re-epithelialization, TGF-b1 secretion, formation of skin appendages, collagen deposition and skin tensile strength. However, as in previous studies presented in this systematic review, the molecular mechanism of action for this triterpene was not identified. In a more recent study, Chen et al. (16) reported the need to seek other pharmaceutical matrices for topical application of astragaloside IV. Astragaloside IV was incorporated in solid lipid nanoparticles (SLN) enriched with carbomer gel, and this formulation produced angiogenic effects in a wound repair model and inhibited scar complications in adult tissues (16). Bacoside A Bacoside A is a triterpenoid saponin isolated from the methanolic extract of Bacopa monnieri Wettest (Family Scrophulariaceae). Bacoside A has been shown to have potent inhibitory effects on superoxide production (21). Moreover, administration of bacoside A has been reported to inhibit the effects of stressful conditions by modulating expression of heat shock protein 70 (hsp70), and to enhance ROS scavenging by influencing the activity of cytochrome P450 enzymes and superoxide dismutase (SOD) (22,23). In addition, Janani et al. (24) showed that bacoside A has a potent anti-metastatic effect against hepatocellular carcinoma by reducing the activity and expression of MMP-2 and MMP-9. Together, these findings indicate the potential modulatory effect of bacoside A on tissue remodeling events. Another study revealed that topical treatment with bacoside A in an EW model accelerated wound closure, induced epithelialization and increased the tensile strength of scar tissue. Moreover, bacoside A inhibited metalloprotease activity, indicating the potential of this triterpene as a lead in the development of novel healing agents (25). Cycloastragenol and cyclocanthoside E Cycloartanes occupy a special position among molecular bioregulators because they are produced only by photosynthesizing organisms. An important representative of this group of compounds is cycloartenol, which serves as a key link in the biosynthesis of phytosterols. Plant species in the genus Astragalus have proved to be the richest source of cycloartanes (26,27). Two cycloartane saponins, cycloastragenol and cyclocanthoside E, are major chemical constituents of Turkish Astragalus species, which may possess healing activity, and have been shown to increase fibroblast proliferation and cell migration in vitro (20). Furthermore, Sevimli-Gu¨r et al. (20) showed that cycloastragenol

J Dermatolog Treat, Early Online: 1–6

increased cell density and thus improved dermal organization, and also induced formation of blood vessels in skin wounds in rats. Similarly, cyclocanthoside E promoted epithelization of lesions, allowing the structure of papillae and scar tissue to be observed in some regions (20). Taken together, these pharmacological reports show that cycloartanes enhance wound healing, but further studies are needed to identify their mechanisms of action. Ginsenoside Rd Ginsenoside Rd is a triterpenoid that was isolated from ethanolic extract of Panax ginseng leaves. In pre-clinical studies, Ginsenoside Rd prevented glutamate/oxygen-glucose deprivation (OGD)-induced apoptosis in cultured neurons (28), and reduced infarction volume after transient focal ischemia in rats (29), suggesting that this triterpene has neuroprotective effects. In vitro, ginsenoside Rd increased proliferation and migration keratinocyte progenitor cells (KPCs) by increasing phosphorylation of ERK and Akt. Moreover, molecular analyses showed that ginsenoside Rd stimulated proliferation and migration of KPCs by inducing PKA signaling. Kim et al. (30) showed that ginsenoside Rd increased the expression of mRNA encoding collagen type 1 in fibroblasts by mechanisms that involved increased cAMP generation and CREB phosphorylation. This report shows that cAMP-mediated signaling is involved in the healing effects of ginsenoside in laser-induced wounds. Lupeol Lupeol is a triterpene found in the leaves of Celastrus paniculatus Willd. (Family Celastraceae). Previous studies reported that lupeol possesses several bioactivities, including anti-inflammatory (31) and antioxidant effects (32). In particular, lupeol has been shown to interfere with the cell proliferation in vitro via several mechanisms of action, including differentiation induction (33), p38 mitogen-activated protein kinases (MAPK) activation (34), and actin cytoskeleton remodeling (37). These biological effects appear to be involved in the healing effects of lupeol. Harish et al. (36) showed that topical treatment with lupeol accelerated skin wound closure, which promoted faster tissue epithelialization by inducing granulation tissue formation, while inhibiting macrophage infiltration and increasing collagen deposition. Madecosside Madecosside is a triterpene found in Centella asiatica (Family Umbellifeare). Extracts of medicinal plants containing madecosside have antioxidant properties and neuroprotective effects against damage caused by ischemia-reperfusion injuries (37). Oral administration of madecosside significantly enhanced skin repair in rats subjected to burn injury (38). Furthermore, Liu et al. (38) showed that madecosside inhibited recruitment of inflammatory cells to injury sites and increased fibroblast proliferation and angiogenesis, which favored the formation of granulation tissue and epithelialization. These authors also reported greater synthesis and deposition of collagen in animals treated with madecosside, as determined by increased tissue levels of hydroxyproline. Oleanolic acid Oleanolic acid has been identified in more than 120 plant species, including Anredera diffusa, a plant that has attracted interest because of its multiple bioactive components. The numerous beneficial effects of oleanolic acid include cardioprotective (39), antiatherosclerotic (40), anti-inflammatory and immunomodulatory properties, and it is effective against hypersensitivity

DOI: 10.3109/09546634.2015.1021663

reactions, such as allergic asthma, as well as experimental models of colitis and multiple sclerosis (41–44). In addition, oleanolic acid produces gastroprotective effects against gastric ulcers in different experimental models in rats and mice (45,46). In addition, Rodrı´guez et al. (47) demonstrated that oleanolic acid promoted healing of acetic acid-induced chronic gastric lesions in rats. These results support the findings presented by Moura-Letts and colleagues (48), who reported that oleanolic acid accelerated wound closure and improved the tensile strength of healing tissue.

J Dermatolog Treat Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.

Ursolic acid Ursolic acid is a natural pentacyclic triterpenoid widely distributed in various plants that have become an integral part of the human diet (49). Increasing evidence, both in vitro and in vivo, suggests that ursolic acid has a variety of biological activities, including anti-inflammatory, anti-oxidative, antimutagenic, anti-carcinogenic, anti-microbial, anti-atherosclerotic and anti-hyperlipidemic effects (50). Moreover, Murkherjee and colleagues (4) isolated ursolic acid from methanolic extract of Shorea robusta leaves and reported healing activity in rats using distinct wound models. The authors found that ursolic acid treatment increased skin strength, expedited epithelization, increased the weight of granulation tissue and increased tissue hydroxyproline content.

Conclusion Our study suggests that all of the triterpenes evaluated in the literature, which were assessed using a range of doses, might expedite the wound healing process and increase the rate of success of healing, the rate of epithelialization and collagen deposition in tissue, in comparison with conventional treatments. In addition, the incorporation of triterpenes in pharmaceutical formulations seems to be a viable strategy to accelerate the healing process due to long-term delivery of incorporated active principles. However, further studies are required to better clarify the molecular targets through which triterpenes mediate healing effects, as well as to assess the toxicity associated with topical or systemic treatment with these compounds. Taken together, these findings show that the triterpenes are a class of molecules with significant promise as leads for the development of new drugs for the treatment of skin injury, but their molecular mechanisms of action and potential side effects require further study.

Acknowledgements This systemic review was carried out using the recommendations and protocols of the Cochrane Collaboration. The authors would like to thank MSc. Paulo Se´rgio de Melo Carvalho (UFAL) for their generous support. They also thank CAPES and CNPq for the scholarships and research grant provided.

Declaration of interest The authors have neither conflict of interest nor competing interest concerning this paper.

References 1. Meirelles RP, Hochman B, Helene Junior A, et al. Experimental model of cutaneous radiation injury in rabbits. Acta Cir Bras. 2013; 28:751–5. 2. Marinho PC, Neto-Ferreira R, Jose de Carvalho J. Evaluation of therapeutic intervention with a natural product in cutaneous wound healing: the use of capybara oil. J Evid-Based Complem Altern Med. 2013;2013:217198. 3. Ngo LT, Okogun JI, Folk WR. 21st Century natural product research and drug development and traditional medicines. Nat Prod Rep. 2013;30:584–92.

Triterpenes induces wound healing

5

4. Mukherjee H, Ojha D, Bharitkar YP, et al. Evaluation of the wound healing activity of Shorea robusta, an Indian ethnomedicine, and its isolated constituent(s) in topical formulation. J Ethnopharmacol. 2013;149:335–43. 5. Chen X, Peng LH, Li N, et al. The healing and anti-scar effects of astragaloside IV on the wound repair in vitro and in vivo. J Ethnopharmacol. 2012;139:721–7. 6. Kimura Y, Sumiyoshi M, Samukawa K, et al. Facilitating action of asiaticoside at low doses on burn wound repair and its mechanism. Eur J Pharmacol. 2008;584:415–23. 7. Salvador JA, Moreira VM, Goncalves BM, et al. Ursane-type pentacyclic triterpenoids as useful platforms to discover anticancer drugs. Nat Prod Rep. 2012;29:1463–79. 8. Mahato SB, Garai S. Triterpenoid saponins. Proge Chem Organic Natural Prod. 1998;74:1–196. 9. Byun-McKay A, Godard KA, Toudefallah M, et al. Wound-induced terpene synthase gene expression in Sitka spruce that exhibit resistance or susceptibility to attack by the white pine weevil. Plant Physiol. 2006;140:1009–21. 10. Kumar B, Vijayakumar M, Govindarajan R, et al. Ethnopharmacological approaches to wound healing – exploring medicinal plants of India. J Ethnopharmacol. 2007;114:103–13. 11. Davidson JM. Animal models for wound repair. Arch Dermatol Res 1998;290:S1–11. 12. Ansell DM, Holden KA, Hardman MJ. Animal models of wound repair: are they cutting it? Exp Dermatol. 2012;21:581–5. 13. Barreto RS, Albuquerque-Junior RL, Araujo AA, et al. A systematic review of the wound-healing effects of monoterpenes and iridoid derivatives. Molecules. 2014;19:846–62. 14. Dias AM, Braga ME, Seabra IJ, et al. Development of natural-based wound dressings impregnated with bioactive compounds and using supercritical carbon dioxide. Int J Pharm. 2011;408:9–19. 15. Peng LH, Chen X, Chen L, et al. Topical astragaloside IV-releasing hydrogel improves healing of skin wounds in vivo. Biol Pharm Bull. 2012;35:881–8. 16. Chen X, Peng LH, Shan YH, et al. Astragaloside IV-loaded nanoparticle-enriched hydrogel induces wound healing and anti-scar activity through topical delivery. Int J Pharm. 2013;447:171–81. 17. Khan MN, Davies CG. Advances in the management of leg ulcers – the potential role of growth factors. Int Wound J. 2006;3:113–20. 18. Shukla A, Rasik AM, Jain GK, et al. In vitro and in vivo wound healing activity of asiaticoside isolated from Centella asiatica. J Ethnopharmacol. 1999;65:1–11. 19. Chen S, Yin ZJ, Jiang C, et al. Asiaticoside attenuates memory impairment induced by transient cerebral ischemia-reperfusion in mice through anti-inflammatory mechanism. Pharmacol Biochem Behav. 2014;122C:7–15. 20. Sevimli-Gu¨r C, Onbasilar I, Atilla P, et al. In vitro growth stimulatory and in vivo wound healing studies on cycloartane-type saponins of Astragalus genus. J Ethnopharmacol. 2011;134:844–50. 21. Pawar R, Gopalakrishnan C, Bhutani KK. Dammarane triterpene saponin from Bacopa monniera as the superoxide inhibitor in polymorphonuclear cells. Planta Med. 2001;67:752–4. 22. Anbarasi K, Kathirvel G, Vani G, et al. Cigarette smoking induces heat shock protein 70 kDa expression and apoptosis in rat brain: modulation by bacoside A. Neuroscience. 2006;138:1127–35. 23. Chowdhuri DK, Parmar D, Kakkar P, et al. Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain. Phytother Res. 2002;16:639–45. 24. Janani P, Sivakumari K, Geetha A, et al. Bacoside A downregulates matrix metalloproteinases 2 and 9 in DEN-induced hepatocellular carcinoma. Cell Biochem Funct. 2010;28:164–9. 25. Sharath R, Harish BG, Krishna V, et al. Wound healing and protease inhibition activity of Bacoside-A, isolated from Bacopa monnieri wettest. Phytother Res. 2010;24:1217–22. 26. Bedir E, Calis I, Aquino R, et al. Cycloartane triterpene glycosides from the roots of Astragalus brachypterus and Astragalus microcephalus. J Nat Prod. 1998;61:1469–72. 27. Kim JS, Yean MH, Lee EJ, et al. Two new cycloartane saponins from the roots of Astragalus membranaceus. Chem Pharm Bull. 2008;56:105–8. 28. Li XY, Liang J, Tang YB, et al. Ginsenoside Rd prevents glutamateinduced apoptosis in rat cortical neurons. Clin Exp Pharmacol Physiol. 2010;37:199–204.

J Dermatolog Treat Downloaded from informahealthcare.com by Kainan University on 04/28/15 For personal use only.

6

L. C. Agra et al.

29. Xie R, Li X, Ling Y, et al. Alpha-lipoic acid pre- and post-treatments provide protection against in vitro ischemia-reperfusion injury in cerebral endothelial cells via Akt/mTOR signaling. Brain Res. 2012; 1482:81–90. 30. Kim WK, Song SY, Oh WK, et al. Wound-healing effect of ginsenoside Rd from leaves of Panax ginseng via cyclic AMPdependent protein kinase pathway. Eur J Pharmacol. 2013;702: 285–93. 31. Geetha T, Varalakshmi P. Anti-inflammatory activity of lupeol and lupeol linoleate in rats. J Ethnopharmacol. 2001;76:77–80. 32. Prasad S, Kalra N, Shukla Y. Hepatoprotective effects of lupeol and mango pulp extract of carcinogen induced alteration in Swiss albino mice. Mol Nutr Food Res. 2007;51:352–9. 33. Hata K, Ishikawa K, Hori K, Konishi T. Differentiation-inducing activity of lupeol, a lupane-type triterpene from Chinese dandelion root (Hokouei-kon), on a mouse melanoma cell line. Biol Pharm Bull. 2000;23:962–7. 34. Hata K, Hori K, Takahashi S. Role of p38 MAPK in lupeol-induced B16 2F2 mouse melanoma cell differentiation. J Biochem. 2003; 134:441–5. 35. Hata K, Hori K, Murata J, Takahashi S. Remodeling of actin cytoskeleton in lupeol-induced B16 2F2 cell differentiation. J Biochem. 2005;138:467–72. 36. Harish BG, Krishna V, Santosh Kumar HS, et al. Wound healing activity and docking of glycogen-synthase-kinase-3-beta-protein with isolated triterpenoid lupeol in rats. Phytomedicine. 2008;15:763–7. 37. Hashim P, Sidek H, Helan MH, et al. Triterpene composition and bioactivities of Centella asiatica. Molecules. 2011;16:1310–22. 38. Liu M, Dai Y, Li Y, et al. Madecassoside isolated from Centella asiatica herbs facilitates burn wound healing in mice. Planta Med. 2008;74:809–15. 39. Somova LO, Nadar A, Rammanan P, Shode FO. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine: Int J Phytother Phytopharmacol. 2003;10:115–21.

J Dermatolog Treat, Early Online: 1–6

40. Somova LI, Shode FO, Ramnanan P, Nadar A. Antihypertensive, antiatherosclerotic and antioxidant activity of triterpenoids isolated from Olea europaea, subspecies Africana leaves. J Ethnopharmacol. 2003;84:299–305. 41. Rios JL. Effects of triterpenes on the immune system. J Ethnopharmacol. 2010;128:1–14. 42. Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol. 1995;49:57–68. 43. Giner-Larza EM, Manez S, Recio MC, et al. Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity. Eur J Pharmacol. 2001;428: 137–43. 44. Martin R, Hernandez M, Cordova C, Nieto ML. Natural triterpenes modulate immune-inflammatory markers of experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis. Brit J Pharmacol. 2012;166:1708–23. 45. Matsuda H, Li Y, Murakami T, et al. Protective effects of oleanolic acid oligoglycosides on ethanol- or indomethacin-induced gastric mucosal lesions in rats. Life Sci. 1998;63:PL245–50. 46. Astudillo L, Rodriguez JA, Schmeda-Hirschmann G. Gastroprotective activity of oleanolic acid derivatives on experimentally induced gastric lesions in rats and mice. J Pharm Pharmacol. 2002;54:583–8. 47. Rodrı´guez JA, Astudillo L, Schmeda-Hirschmann G. Oleanolic acid promotes healing of acetic acid-induced chronic gastric lesions in rats. Pharmacol Res. 2003;48:291–4. 48. Moura-Letts G, Villegas LF, Marcalo A, et al. In vivo woundhealing activity of oleanolic acid derived from the acid hydrolysis of Anredera diffusa. J Nat Prod. 2006;69:978–9. 49. Zhang Y, Kong C, Zeng Y, et al. Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro. Mol Carcinog. 2010;49:374–85. 50. e Silva Mde L, David JP, Silva LC, et al. Bioactive oleanane, lupane and ursane triterpene acid derivatives. Molecules. 2012;17: 12197–205.

Triterpenes with healing activity: A systematic review.

The purpose of this review was to systematically evaluate the literature on the efficacy of triterpenes for wound healing. We searched for original st...
207KB Sizes 3 Downloads 6 Views