A Comprehensive Review of Plants and Their Active Constituents With Wound Healing Activity in Traditional Iranian Medicine

Introduction. Wound healing is a complex cascade of events with various cellular and biochemical processes that result in reconstruction and regeneration of damaged tissue. The objective of the current study was to scientifically evaluate the medicinal plants said to produce wound healing activity in traditional Iranian medicine (TIM). Material and Methods. Electronic databases were searched for the names of medicinal plants claimed in TIM literature for having wound healing activity. Articles were evaluated to obtain any in vitro, animal, or clinical evidence of their efficacy and possible mechanisms involved in would healing. Results. Mechanisms of action for some of these plants, including Tamarix spp., Rosa spp., Piper betle, Plantago major, Oxalis spp., Olea europaea, Malva spp., Linum usitatissimum, and Tamarindus indica, have not been yet clarified. In contrast, some herbs such as Vitis vinifera, Quercus spp., Punica granatum, Pinus spp., Polygonum spp., Lilium spp., Gentiana lutea, Arnebia euchroma, Aloe spp., and Caesalpinia spp. have various biological and pharmacological mechanisms that have been verified for wound healing activity. Conclusions. Overall, TIM resources have introduced various medicinal plants for wounds with confirmed effectiveness according to current pharmacological studies. These herbal remedies could be considered as future drugs for healing of wounds. Further pharmacological and clinical investigations are recommended for exploring safety, exact mechanisms, and efficacy of these herbal remedies.

Wounds are defined as the disruption of anatomical and functional integrity of living tissue. Wound healing is an intricate and continual cascade of events, with various cellular and biochemical processes, ultimately resulting in the reconstruction and regeneration of damaged tissue.¹ Subsequent to wound occurrence, inflammation is induced due to the release of leukotrienes, prostaglandins, and free radicals. Cellular proliferation is the next stage and encompasses collagen deposition, epithelization, and angiogenesis which is regulated by growth factors. Finally, tissue remodeling with proliferation of fibroblasts and synthesis/accumulation of collagen fibers occurs.^2-4 Antioxidants play a determining role in the progression of wound healing.^5,6 In addition, anti-inflammatory agents act as a key role in the wound healing process and preventing exacerbating wound conditions.² Antimicrobial agents are also useful in the management of microbial infection which may concomitantly occur in severe and chronic wounds.⁷ The large number of patients with serious chronic wounds is now a worldwide concern. Globally, approximately 6 million patients have chronic wounds including diabetic foot ulcers, decubitus ulcers, venous stasis ulcers, and nonhealing surgical wounds.^7,8 Studies on medicinal plants confirmed that herbal drugs exhibit fewer side effects in comparison with chemical agents, and are more cost-effective.^7,8 Just 1%-3% of chemicals listed in Western pharmacopoeia are indicated for use in treating wounds and skin disease, while more than 30% of herbal medicaments are considered beneficial.^7,8 Traditional medicine worldwide, especially traditional Iranian medicine (TIM), has recently made progress in the management of some diseases.^9-11 The current study was conducted to review medicinal herbs considered as wound healing agents in TIM literature, and also to collect evidence for their effectiveness and pharmacological mechanisms in modern literature.

 The authors searched the TIM literature for medicinal plants with wound healing activity.^12,13 Electronic databases including Scirus, PubMed, Scopus, Web of Science, Google Scholar, and the Cochrane library were searched for each of these plants between 1966 and 2013. All retrieved articles were evaluated for inclusion of any in vitro, animal, or clinical evidence for their efficacy and pharmacological mechanisms related to wound healing properties. The studies chosen to include in this current research either exhibited apparent efficiency of these remedies or demonstrated their effectiveness indirectly on the mechanisms involved in wound healing activity. Only published articles that were also in English were included in this review. The search terms were “wound healing” or “inflammation” or “antioxidant” in title and abstract, and the name of each mentioned plant in the whole text. Primary search results were screened by 2 independent investigators. Articles with languages other than English, review articles, articles that studied mixture of the plant with agents other than herbs, experimental studies on the plants without relevant biological effects (ie, wound healing, inflammation, antioxidant), case reports, and case control studies were excluded. References of final included articles were reviewed for more relevant studies. Included articles were reviewed for mention of plant scientific names, part, and extract of the plants, active components, type of experimental wound, animal model for in vivo, and type of cell line for in vitro studies. The authors looked for differences between test group and control group in wound contraction, period of epithelialization, neovascularization, collagenation, keratinization, inflammatory reactions, number of inflammatory cells, antioxidant activity, local and systemic biomarkers of tissue damage, and total microbial count. Results are abstracted in Table 1 and continued, 2A, 2B, 2C, 2D, 2E, 2F, 2G, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, and 4 In human studies, study design, number of patients, interventions, duration of treatment, and data related to the efficacy and tolerability of the patients to the herbal treatment were also collected.

The study resulted in a list of medicinal plants with wound healing activity in TIM, and all evidence found for their effectiveness in the modern medical literature.

  Achillea melifolium. Aerial part showed significant healing activity on burn wounds with enhancement of contraction, granulation, epithelization, and arrangement of collagen fiber.¹⁴ The aerial part of A. biebersteinii demonstrated wound healing activity on excision and incision wounds specifically related to enhancement of tensile strength and contraction rate, which was comparable to the positive control in each study. The aerial part of this plant also enhanced the growth of fibroblast, mature hair follicles, and collagen formation and arrangement.¹⁵A. melifolium flower heads showed significant anti-inflammatory activity in the Paw edema test.¹⁶ Also, aerial parts showed antioxidant and inhibition of lipid peroxidation (LPO) activity as well as antimicrobial activity in vitro.¹⁷

  Aloe spp. Glycoproteins from its gel showed significant wound healing activity in vivo with enhancement of granulation and epithelialization, as well as wound healing activity in vitro via cell proliferation activity, and enhancement of epidermal tissue, proliferation markers (fibronectin and keratin), epidermal growth factor receptor, and fibronectin receptor.¹⁸A. littoralis gel exhibited significant wound healing activity on incisional-induced and thermal-induced wound models, as well as anti-inflammatory activity on carrageenan-induced paw edema.¹⁹ It demonstrated anti-inflammatory activity via inhibition of matrix metalloproteinase-9 (MMP-9) on peripheral blood mononuclear cells.²⁰ Furthermore, the leaf skin and flower of this plant showed antioxidant activity in vitro.²¹ Aloe produces 2 substances, gel and latex, which are used for medicinal purposes. Aloe gel is the clear, jelly-like substance found in the inner part of the Aloe plant leaf. Aloe latex comes from just under the plant’s skin and is yellow in color. A. barbadensis leaf latex (ie, the yellow substance found under the leaf’s skin) demonstrated antibacterial property.²²

  Arnebia euchroma. The roots possess significant wound healing activity on bilateral round skin wounds with enhancement of fibroblasts’ cell, collagen, and capillary tissue production, and also basic fibroblast growth factor (bFGF) expression.²³ Furthermore, in a clinical trial on full-thickness wounds, wound healing activity has been proven;²⁴ it also showed antibacterial activity.²⁵ The root of A. hispidissima, another species from the genus Arnebia, showed significant anti-inflammatory activity on carrageenan-induced paw edema and complete Freund’s adjuvant-induced chronic arthritis which is related to isolated components: arnebin-5, arnebin-6, teracryl shikonin, arnebinonem, and acetyl shikonin.²⁶ Moreover, shikonin possesses antioxidant activity in vitro.²⁷

  Blechnum spp. B. orientale leaves showed wound healing activity on an excision model with enhancement of epithelization, collagen synthesis, tissue regeneration, fibroblasts cell production, and angiogenesis.²⁸B. occidentale leaves showed anti-inflammatory activity on rat paw edema and inhibit carrageenan-induced neutrophil migration to the peritoneal cavity.²⁹B. orientale leaves demonstrated antioxidant and antibacterial activity in vitro.³⁰

  Boswellia spp. B. serrata oleo-gum-resin showed wound healing activity on excision wound models, demonstrating significant wound contraction and tensile strength.³¹ B. carterii oleo-gum-resin showed significant anti-inflammatory activity on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema. Triterpene acids, especially boswelic acid-related compounds are responsible for this action.³² Furthermore, B. serrata gum demonstrated anti-inflammatory activity in vitro, by reducing tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), IL-6, and nitric oxide (NO) production, and also suppressing inducible nitric oxide synthase (iNOS) expression on human mononuclear cells and mouse macrophage.³³ Its antioxidant activity has been proven in vitro,³⁴ and Al-Saidi et al³⁵ demonstrated antibacterial activity of B. sacra gum.

  Caesalpinia spp. C. benthamiana leaves demonstrated significant wound healing in incision and excision wounds by the enhancement of epithelization, tensile strength, percentage of closure, hydroxyproline content, and antioxidant function.³⁶C. sappan heartwood possesses anti-inflammatory activity in vitro with inhibition of pro-inflammatory cytokines (IL-1β and TNF-α), suppression of cyclooxygenase-2 (COX-2) transcription, NO synthesis, and iNOS mRNA expression in IL-1β-stimulated osteoarthritis chondrocytes and lipopolysaccharide (LPS)-stimulated macrophages.³⁷ Moreover, C. crista seeds demonstrated healing activity on excision, incision, and dead space wound models.³⁸C. benthamiana root bark also showed antibacterial and antioxidant activity in vitro.³⁹

  Cassia spp. C. fistula leaves exhibit significant wound healing activity on full-thickness wound models with enhancement of wound closure, tissue DNA, protein and collagen content, tissue epithelialization and regeneration, metalloproteinases expression, and new blood vessel formation. Moreover, it has proven antibacterial function.⁴⁰ Pulps and seeds showed antioxidant activity in vitro.⁴¹C. siamea stem bark demonstrated significant anti-inflammatory activity on carrageenan-induced paw edema.⁴²

  Cedrus spp. C. libani cones demonstrated wound healing activity on linear incision and circular excision wound models with enhancement of wound contraction, tensile strength, reepithelization, and remodeling of tissue. It also showed significant anti-inflammatory activity on acetic acid-induced mouse capillary permeability.⁴³C. deodara wood exhibited significant anti-inflammatory activity on nystatin-induced rat paw edema.⁴⁴C. deodara hard wood possesses antibacterial activity.⁴⁵ Pine needles showed antioxidant activity in vitro.⁴⁶

  Centaurea spp. The aerial part of C. sadleriana showed significant wound healing activity on wounds inflicted by branding iron.⁴⁷ The aerial part of C. ainetensis demonstrated anti-inflammatory activity in vitro via inhibition of endotoxin- induced IL-6 levels in mammary epithelial cells and IL-1-induced COX enzyme levels in intestinal epithelial cells. Salograviolide A was shown to be responsible for this activity.⁴⁸ Salograviolide from C. ainetensis possesses anti-inflammatory activity in vitro via inhibition of COX-2 expression and nuclear factor-κB (NF-κB) translocation in intestinal epithelial cells induced by IL-1.⁴⁹ Centaurepensin, chlorojanerin, and 13-acetylsolstitialin A from the aerial part of C. solstitialis possesses antimicrobial activity.⁵⁰ The aerial parts of C. cariensis and C. cadmea possess antioxidant activity in vitro.⁵¹

  Commiphora spp. C. molmol oleo-gum-resin possesses wound healing activity on severe skin injury model via proliferation and differentiation of leukocytes and tissue cells.⁵²C. erythraea oleo-gum-resin showed significant anti-inflammatory activity on croton oil-induced ear edema.⁵³ Furthermore, C. mukul oleo-gum-resin exhibited anti-inflammatory activity in vitro via inhibition of interferon-γ (IFN-γ), IL-12, TNF-α, IL-1β, and NO levels in peripheral blood mononuclear cells.⁵⁴ Mansumbinone, 3,4-seco-mansumbinoic acid, β–elemene, and T-cadinol from C. molmol oleo-gum-resin demonstrated antibacterial activity in vitro.⁵⁵ In addition, C. erythraea oleo-gum-resin demonstrated antioxidant activity.⁵³

  Coriandrum sativum L. The leaves of Coriandrum sativum possess protective activity on human keratinocytes against H2O2-induced oxidative stress in vitro via enhancement of antioxidant activity.⁵⁶ The stem and leaf of this plant also possess anti-inflammatory activity in vitro via suppression of NO, prostaglandin E2 (PGE2), IL-1β, TNF-α n, iNOS, and COX-2, as well as NF-κB translocation induced by lipopolysaccharide (LPS) in macrophage cells.⁵⁷ Also, the fruits of the plant demonstrated antibacterial activity.⁵⁸

  Curcuma zedoaria (Christm.) Roscoe. C. inodora rhizome showed significant wound healing activity on excision wounds, demonstrating an increase in wound contraction, tissue epithelialization, and proliferation of collagen fiber. It also exhibited significant anti-inflammatory activity and inhibited carrageenan- and formalin-induced paw edema.⁵⁹ Furanodiene and furanodienone from C. zedoaria rhizome demonstrated anti-inflammatory activity on TPA-induced ear edema, which is comparable to indomethacin.⁶⁰ Curcuminoids from a C. domestica rhizome demonstrated significant anti-inflammatory activity on TPA-induced ear edema.⁶¹C. zedoaria and C. domestica rhizomes revealed antioxidant activity and antibacterial activity in vitro.⁶²

  Daucus carota L. The roots have shown significant wound healing activity on excision and incision wound models, demonstrating improvement of scar width, epithelization, wound contraction, tensile strength, hydroxyproline content, and protein content.⁶³ Luteolin, luteolin 3’-O-β-D-glucopyranoside, and luteolin 4’-O-β-D-glucopyranoside from seeds exhibited antioxidant and antibacterial activity in vitro.⁶⁴

  Elaeagnus angustifolia L. Fruits of Elaeagnus angustifolia L. showed wound healing activity on excision wounds with significant enhancement of wound contraction, hydroxyproline content, reepithelialization, and collagen deposition.⁶⁵ Fruits and endocarp significantly reduced rats’ paw inflammation.⁶⁶E. multiflora fruit seeds and flesh showed anti-inflammatory activity via suppression of COX-2 expression on cell culture.⁶⁷E. angustifolia bark exhibited antioxidant and also antibacterial activity in vitro.^68,69

  Equisetum arvense L. The aerial part of Equisetum arvense L. demonstrated significant wound healing activity on an incision wound model, demonstrating enhancement of wound contraction, epithelization, wound closure, fibroblast and fibrocytes proliferation, and inhibition of inflammatory agents.⁷⁰ Its stems showed anti-inflammatory activity on rat paw edema.⁷¹ Moreover, antioxidant and antibacterial activity of the aerial part of this plant have been demonstrated in vitro.⁷²

  Ficus carica L. F. benghalensis bark demonstrated significant wound healing activity on excision and incision wound models with improvement of wound contraction, duration of complete epithelialization, and tensile strength.⁷³ Moreover, F. racemosa roots demonstrated significant wound healing activity on excision and incision wound models with enhancement of wound contraction, tensile strength, fibroblast cells, collagen fibers, and blood vesicles, and a decrease in duration of epithelization.⁷⁴F. racemosa leaves demonstrated reduction in carrageenan-, serotonin-, histamine-, and dextran-induced hind paw edema and also significantly reduced granuloma weight in cotton pellet-induced chronic inflammatory test, which indicates its anti-inflammatory activity.⁷⁵F. racemosa bark exhibited anti-inflammatory activity in vitro via inhibition of COX-1 and 5-lipooxygenase enzymes and improvement of antioxidant activity.⁷⁶ In addition, Ficus carica fruits showed antioxidant activity in vitro,⁷⁷ and F. racemosa bark demonstrated antibacterial activity.⁷⁸

  Gentiana lutea L. The rhizomes showed significant wound healing activity on excision, incision, and dead space wound models with enhancement of wound contraction, tensile strength, tissue granulation, fibroblast proliferation, collagen content, and hydroxyproline content.⁷⁹ The root of this plant also demonstrated wound healing activity in vitro via enhancement of collagen production and mitotic activity. Gentiopicroside, sweroside, and swertiamarine were shown to be responsible for this action.⁸⁰ Moreover, rhizomes revealed significant anti-inflammatory activity on xylol-induced mouse ear edema, carrageenan-induced rat paw edema, and cotton pellet-induced chronic inflammatory model.⁷⁹ The flower and leaf exhibited antimicrobial activity,⁸¹ and the roots showed antioxidant activity in vitro.⁸²

  Hypericum perforatum L. The aerial part of this plant showed significant wound healing activity on full-thickness excision wounds with fibroblast and myofibroblast proliferation.⁸³ The flowering tops exhibited wound healing activity in a clinical trial on women with cesarean section scars.⁸⁴ Moreover, it revealed wound healing activity in vitro with fibroblast proliferation and collagen production in cultured chicken embryonic fibroblasts.⁸⁵ Its anti-inflammatory activity on acetic acid-induced mice capillary permeability has been proven.⁸⁶ Moreover, it showed antioxidant activity, LPO reduction, and antibacterial activity in vitro.^87,88

  Inula spp. The aerial part of I. viscosa showed significant wound healing activity with enhancement of epidermis organization, hair follicle formation, and reduction of inflammatory cells in full-thickness excision wounds.⁸⁹ The aerial part also demonstrated significant anti-inflammatory activity on mouse TPA-induced ear edema and on chronic dermatitis.⁹⁰ Sesquiterpenes from the I. graveolens aerial parts showed moderate antibacterial activity,⁹¹ and the I. viscosa aerial parts showed antibacterial and antioxidant activity.^92,93

  Lawsonia inermis L. L. inermis leaves showed significant wound healing activity in excision, incision, and dead space wound models with enhancement of wound contraction, tensile strength, granulation of tissue, hydroxyproline content, collagen organization, fibroblast cells, and reduction in the period of epithelialization and inflammatory cells.⁹⁴ Oral and topical administration of L. alba leaves and its isolated compound, lawsone, showed wound healing activity in excision and incision wound models.⁹⁵L. inermis leaves showed antibacterial activity.⁹⁶ Lawsochylin A, lawsonaphthoate A, luteolin, apigenin, 4S-4-hydroxy-a-tetralone, and 2-butoxysuccinic acid isolated from the L. inermis stem and leaves possess anti-inflammatory activity in vitro via reduction of elastase release and superoxide anion generation induced by cytochalasin B on human neutrophils.⁹⁷ Additionally, p-coumaric acid, 2-methoxy-3-methyl-1,4-naphthoquinone, apiin, lawsone, apigenin, luteolin, and cosmosiin from L. inermis leaves showed antioxidant activity in vitro.⁹⁸

  Lilium spp. L. longiflorum bulbs revealed wound healing activity with enhancement of dermal fibroblast migration, transforming growth factor-β1 (TGF-β1) mRNA expression and NO production, due to the presence of steroidal glycoalkaloids.⁹⁹ Moreover, roots demonstrated anti-inflammatory activity in vitro via inhibition of NO, PGE2, IL-6, and TNF-α production as well as iNOS and COX-2 expression, and also NF-κB activation in LPS-stimulated macrophage cells.¹⁰⁰ Bulbs demonstrated antioxidant activity in vitro,¹⁰¹ and L. candidum showed antibacterial activity.¹⁰²

  Linum usitatissimum L. The seeds of Linum usitatissimum demonstrated significant wound healing activity on incision and excision wounds with enhancement of wound contraction, tensile strength, reepithelialization, and inhibition of LPO.¹⁰³ They also exhibited significant anti-inflammatory activity on PGE2-, leukotriene (LT)-, histamine-, bradykinin-, and arachidonic acid-induced rat paw edema.¹⁰⁴ This plant’s antioxidant and antibacterial activity in vitro have also been proven.^105,106

  Malva spp. M. parviflora leaves and roots revealed anti-inflammatory activity in vitro via inhibition of COX-1 enzyme.¹⁰⁷M. sylvestris leaves showed anti-inflammatory activity on croton oil-induced ear edema.¹⁰⁸ The aerial part of M. sylvestris demonstrated antimicrobial activity on wound infection microorganisms in vitro.¹⁰⁹ Additionally, leaves exhibited antioxidant activity and inhibition of LPO in vitro.¹⁰⁸

  Myrtus communis L. The leaves of this plant possess significant wound healing activity on an excision wound model with enhancement of wound contraction and fibroblast cell proliferation.¹¹⁰ Moreover, the aerial part demonstrated significant anti-inflammatory activity on croton oil-induced ear edema and cotton pellet-induced granuloma via inhibition of myeloperoxidase (MPO) activity and leukocyte migration, and also reduction of TNF-α and IL-6 levels.¹¹¹ Leaves also exhibited antibacterial activity.¹¹² The M. communis leaf, stem, and flower showed antioxidant properties in vitro.¹¹³

  Olea europaea L. Leaves from this plant showed significant wound healing activity on incision and excision wounds with enhancement of wound contraction and tensile strength.¹¹⁴ Fruits exhibited anti-inflammatory activity on LPS-induced inflammation in mice as well as LPS-induced human monocyte cell line via reducing TNF-α.¹¹⁵ Leaves demonstrated antioxidant activity and antibacterial activity in vitro.^114,116

  Oxalis spp. O. Corniculata whole plants showed significant wound healing activity in excision, incision, and dead space wound models with enhancement of contraction rate, tensile strength, granuloma breaking strength, hydroxyproline content, and tissue epithelization.¹¹⁷ Moreover, O. corniculata leaves demonstrated antibacterial activity.¹¹⁸O. acetosella leaves showed antioxidant activity in vitro.¹¹⁹

  Pinus spp. P. brutia bark demonstrated significant wound healing activity on an incision wound model by the enhancement of vascularization and antioxidant activity, including a reduction on malondialdehyde (MDA) and an increase in superoxide dismutase (SOD) and catalase (CAT) activities. P. sylvestris leaf showed anti-inflammatory activity in vitro via inhibition of NO and iNOS mRNA production in murine macrophages induced by LPS and interferon-δ (IFN-δ). The extract did not show inhibitory activity against PGE2 and COX.¹²¹ Furthermore, P. morrisonicola pine needles revealed anti-inflammatory activity in vitro via antioxidant function, inhibition of NO production, iNOS, and COX-2 expression in macrophages induced by LPS.¹²² Pinosylvin from P. densiflora. showed antimicrobial activity.¹²³

  Piper betle L. The leaves of this plant showed significant wound healing activity on excision wounds with enhancement of wound contraction and epithelization.¹²⁴ The leaves also demonstrated anti-inflammatory activity on TPA-induced mouse ear edema.¹²⁵ Furthermore, antioxidant and antibacterial activity of the leaves have been demonstrated in vitro.^126,127

  Pistacia lentiscus L. and P. atlantica Desf. Virgin fatty oil from P. lentiscus showed significant wound healing activity on burn-induced wounds with enhancement of wound contraction and epithelization of tissue.¹²⁸P. lentiscus oleo-gum-resin possesses significant anti-inflammatory activity on carrageenan-induced rat paw edema and also cotton pellet-induced granuloma, by reducing TNF-α and IL-6.¹²⁹ Masticadienonic acid, masticadienolic acid, and morolic acid from P. terebinthus galls showed significant anti-inflammatory activity on TPA-induced mouse ear edema and phospholipase-A2 (PL-A2)- induced rat paw edema via inhibition of LT-B4 production in rat polymorphonuclear leukocytes.¹³⁰P. lentiscus and P. atlantica leaves demonstrated antioxidant and antimicrobial activity in vitro.¹³¹

  Plantago major L. This plant’s wound healing activity on an excision wound model with enhancement of reepithelialization and skin appendages has been proven.¹³² Seeds of the plant also revealed significant anti-inflammatory activity on carrageenan-induced paw edema.¹³³ Antioxidant activity of the aerial parts and antibacterial activity of leaves have been exhibited in vitro.^134,135

  Polygonum spp. The aerial part of P. cuspidatum exhibited significant wound healing activity in an excision wound model by the enhancement of tissue granulation, collagen, fibroblasts, and hair follicle content, by lessening inflammatory cells, and by increasing in TGF-β1 level.¹³⁶P. hydropiper leaves demonstrated anti-inflammatory activity in vitro via suppression of NO, PGE2, IL-1β, TNF-α production, iNOS, and COX-2 expression, and also NF-κB translocation induced by LPS in macrophage cells.¹³⁷P. minus leaves showed antioxidant activity in vitro.¹³⁸ Additionally, the whole P. capitatum plant exhibited antibacterial activity.¹³⁹

  Punica granatum L. Peels from the fruit of this plant demonstrated significant wound healing on excision wounds with enhancement of contraction rate, epithelialization, tensile strength, proteins, collagen, and DNA synthesis.¹⁴⁰ Fruits revealed significant anti-inflammatory activity with reducing paw swelling and suppressing PGE2 levels in mice serum. They also exhibited anti-inflammatory activity in vitro via inhibition of NO production, iNOS expression, PGE2 levels, and COX-2 expression in LPS-induced macrophage cells. The phenolic compounds granatin B, punicalagin, punicalin, and strictinin A seem to be responsible for this activity.¹⁴¹ Seeds exhibited antioxidant activity¹⁴² and the fruit rinds showed antibacterial activity.¹⁴³

  Quercus spp. Q. infectoria galls showed wound healing activity in excision, incision, and dead space wound models with improvement of tensile strength, percentage of wound closure, complete epithelization, and size of scar.¹⁴⁴ Furthermore, Q. persica fruits exhibited significant wound healing activity in an excision wound model with enhancement of collagen deposition and antioxidant activity.¹⁴⁵Q. infectoria galls inhibited carrageenan-, histamine-, serotonin- and PGE2-induced paw edema, dose dependently. It also suppressed phorbol-12-myristate-13-acetate (PMA)-induced ear edema. Moreover, it reduced LPS-stimulated PGE2 and NO production, iNOS expression, and also PMA-stimulated superoxide production on rat-isolated peritoneal macrophages, dose dependently.¹⁴⁶Q. persica fruits showed antibacterial activity.¹⁴⁵ In addition, Q. ilex leaves demonstrated antioxidant activity in vitro.¹⁴⁷

  Rosa spp. R. indica leaves revealed significant wound healing activity on excision wound model.¹⁴⁸R. canina fruits demonstrated significant anti-inflammatory activity on carrageenan-induced rat paw edema, which was similar to the effect of indomethacin. Also, its antioxidant activity has been proven in vitro.¹⁴⁹R. indica leaves exhibited antibacterial activity.¹⁴⁸

  Sambucus spp. S. ebulus leaves demonstrated significant wound healing activity in incision and excision wounds with enhancement of contraction value, tensile strength, reepithelialization, cell proliferation, and re-modeling of the tissue.¹⁵⁰ The aerial parts, leaves, and roots of S. ebulus showed significant reduction in carrageenan-induced rat paw edema.¹⁵¹ Fruits revealed significant antioxidant activity, NO scavenging function, and inhibition of LPO.¹⁵² Furthermore, the leaves showed antibacterial activity.¹⁵³

  Tamarindus indica L. T. indica seeds showed significant wound healing activity on epidermal circular wounds with enhancement of wound closure and antioxidant function.¹⁵⁴ The leaves of this plant also showed inhibition on carrageenan-induced paw edema via membrane stabilization and neutrophils and TNF-α synthesis inhibition.¹⁵⁵ Seed coats from T. indica revealed antibacterial activity,¹⁵⁶ and the flowers showed antioxidant and antibacterial activity in vitro.¹⁵⁷

  Tamarix spp. Leaves of T. aphylla showed significant wound healing activity in an excision wound model with enhancement of wound contraction. The leaves also demonstrated significant anti-inflammatory activity in carrageenan-induced paw edema.¹⁵⁸ The leaves and flowers of T. galica demonstrated antioxidant and antibacterial activity in vitro.¹⁵⁹

  Tragopogon graminifolious DC. Antioxidant activity of T. graminifolius aerial parts has been demonstrated in vitro,^160,161 and the essential oil of T. graminifolius demonstrated antibacterial activities.¹⁶¹T. graminifolius aerial parts showed protective activity against ethanol-induced ulcers in rat stomachs.¹⁶² Flavonoids including gallic acid, p-coumaric acid, catechin, ferulic acid, and caffeic acid are the main constituent of Tragopogon genus.^160,163,164 Caffeic acid demonstrated significant wound healing activity in an incision model via inhibition of MPO activity (ie, neutrophil infiltration), LPO activity, PL-A2 activity, and enhancement of tissue collagen-like polymer synthesis.¹⁶⁵ In addition, caffeic acid possesses anti-inflammatory activity in vitro via reduction of arachidonic acid, PGE2, and histamine production in cell culture.¹⁶⁵ Ferulic acid demonstrated significant wound healing activity on excision wounds in streptozotocin-induced diabetic rats via enhancement of epithelialization, hydroxyproline, and hexosamine content. Ferulic acid also affected the inhibition of LPO function and increased antioxidant enzymes CAT, SOD, glutathione (GSH), and NO levels, which indicate proliferation activity. Moreover, zinc and copper levels were elevated, which is related to the wound healing process.¹⁶⁶ This plant also demonstrated angiogenesis activity via enhancement of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), hypoxic-induced factor-1α (HIF-1α) mRNA, and protein expression in human umbilical vein endothelial cells.¹⁶⁷

  Vitis vinifera L. The seeds of this plant exhibited significant wound healing activity in an excision full-thickness wound model with reduction of wound area, enhancement of hydroxyproline content, tensile strength, tissue granulation, reconstruction of epidermis, and reduction of inflammatory agents.¹⁶⁸ Moreover, Sagliyan et al¹⁶⁹ proved wound healing activity of its oral administration via enhancement of wound contraction, reepithelization, granulation, collagen accumulation, angiogenesis, reduction in inflammatory agents, as well as antioxidant activity. This plant’s anti-inflammatory activity via inhibition of NO and PGE2 production, iNOS expression, and NF-κB translocation in macrophages stimulated by LPS plus IFN-γ has been proven.¹⁷⁰ In addition, its antioxidant and antibacterial activity have been demonstrated in vitro.^171,172

Traditional Iranian medicine resources encompass a wide range of virgin natural remedies and medicinal practice for management of complicated diseases that modern medicine has been unable to effectively treat. In previous studies, the authors identified efficacious medicinal plants used in TIM for the treatment of peptic ulcer,⁹ burn wounds,¹⁷³ inflammatory bowel disease,^11,174 irritable bowel disease,¹⁷⁵ and hemorrhoids.¹⁰ In the present paper, all of the remedies asserted to possess wound healing activity were gathered from TIM sources and any scientific evidence that demonstrated their efficiency was retrieved from electronic databases. The herbs with wound healing activity used in TIM are from various families and no exact relationship between the family of these plants and their efficacy was observed (Table 1 and continued). Various experimental studies for many of these plants highlight their efficacious and pharmacological aspects of wound healing function. These in vitro, in vivo, and human studies are summarized in Tables 2A, 2B, 2C, 2D, 2E, 2F, 2G, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, and 4, respectively. Only 2 clinical trials were found for wound healing activity of herbal remedies (Table 4); in one, topical administration of Hypericum perforatrum flower tops accelerated cesarean section wound healing significantly, alleviating the formation of a scar, pruritis ,and pain with no serious adverse events.²⁴ In another study, Arnebia euchroma root oil applied topically for a patient with a full-thickness skin deficiency caused wound surface contraction and had a healing effect on the damaged tissue.^24,84

  These remedies have shown their efficacious wound healing activity via various pharmacological mechanisms including anti-inflammatory activity and suppression of pro-inflammatory cytokines (ie, PGE2 and COX enzyme, NO and iNOS enzyme,IL-6, IL-12, IL-1β, TNF-α, IFN-γ), antioxidant activity, antibacterial activity on microorganisms involved in wound infection (ie, S. aureus, S. epidermis, B. cereus, B. subtillis, P. aeruginosa, and C. albicans), angiogenesis, growth factors enhancement, cellular proliferation, endothelial NO synthase (eNOS) and NO stimulation, collagen synthesis and arrangement, and remodeling of tissue. For some of these remedies including, Tamarix spp., Rosa spp., Piper betle, Plantago major, Oxalis spp., Olea europaea, Malva spp., Linum usitatissimum, and Tamarindus indica, complete pharmacological mechanism of action has not been observed. Additional pharmacological research for determining their perfect mechanism of action is suggested. In contrast, for many of these remedies, such as Vitis vinifera, Quercus spp., Punica granatum, Pinus spp., Polygonum spp., Lilium spp., Gentiana lutea, Arnebia euchroma, Aloe spp., and Caesalpinia spp., several mechanisms of action responsible for wound healing activity have been proved. In Figure 1, the structure of some compounds with wound healing activity is shown. Various chemical compounds from different phytochemical categories including phenolic compounds, essential oils, sesquiterpenoids, fatty acids, sterols, and alkaloids may be responsible for wound healing activities. The most reported phytochemicals with wound healing properties are phenolic compounds, especially phenolic acids and flavonoids.

  Overall, wound healing activities of several TIM medicinal herbs have been proved via modern scientific studies. Considering the paucity of clinical studies on the efficacy of mentioned medicinal plants despite numerous in vitro and animal evidence, advanced clinical trials are recommended for confirming efficacy and safety of the discussed herbal remedies.

Affiliations: Zahra Abbasabadi, PharmD is from Kermanshah University of Medical Sciences, Kermanshah, Iran. Mohammad Reza Shams-Ardekani, PharmD, PhD; and Roja Rahimi, PharmD, PhD are from Department of Pharmacy in Traditional Medicine, Faculty of Traditional Medicine and Persian Medicine, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. Mohammad Hosein Farzaei, PharmD, PhD Candidate is from the Kermanshah University of Medical Sciences, Kermanshah, Iran; and Department of Pharmacy in Traditional Medicine, Faculty of Traditional Medicine and Persian Medicine, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. Mohammad Abdollahi, PharmD, PhD is from Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Address correspondence to:
Roja Rahimi, PharmD, PhD
Faculty of Traditional Medicine
Tehran University of Medical Sciences
Tehran 1417653761, Iran
rojarahimi@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.