Wound Healing: A Brief Look at the Inflammatory Stage and Role of Medicinal Plants and Their Derivations on Modulating the Inflammatory Responses: A Systematic Review.

Aims: Wound is believed to be a major disorder in certain organs and/or tissues, which could be transmitted to other tissues. Skin is constantly exposed to infections, injuries, scratches, and burns. Wound dressings are commonly utilized for the treatment of wound site and protect it from external contamination. The biological importance of natural agents, such as herbal medicines and their derivations including extracts, essential oils and active compounds in the wound healing process has attracted the attention of researchers and also some manufacturers of wound dressings. Such natural agents improve wound healing by their antioxidant and antibacterial properties. This novel review article was conducted to evaluate the effects of medicinal plants and their derivations on inflammatory responses in surgical wound infection. Methods: The data were collected from various databases using specific keywords. Results: The results revealed that different medicinal plants and their derivations decrease the inflammation in the wound healing process by modulating in gene expression of inflammatory cytokines and immune cells. Conclusion: Active compounds of medicinal plants can alleviate inflammation in the wound healing process, which must be taken into consideration in pharmaceutical industries.

Facile fabrication of carboxymethylcellulose/ZnO/g-C3N4 containing nutmeg extract with photocatalytic performance for infected wound healing.

New topical antibacterial agents are required to inhibit and development of bacteria and also promoting the wound healing process. This study was evaluating the healing effect of Myristica fragrans extract coated with carboxymethyl cellulose, zinc oxide and graphite carbon nitride (CMC/ZnO/g-C3N4/MyR) by photocatalytic process on the healing process of full-thickness infectious excision wounds in mice. Nanosheets were prepared and physicochemical properties were evaluated. Safety, in vitro release, antibacterial activities under in vitro and in vivo condition, wound contraction, histopathological properties and the protein expressions of tumor necrosis factor-α (TNF-α), collagen 1A (COL1A) and CD31 were also evaluated. Physicochemical properties confirmed their successful synthesis. Nanosheets exhibited antibacterial activity under in vitro and in vivo conditions. The formulations containing CMC/ZnO/g-C3N4/MyR, significantly (P < 0.05) competed with standard ointment of mupirocin for accelerating the wound healing process due to their effects on bacterial count and the expression of TNF-α and also accelerating the proliferative phase. This structure can be used as a safe structure in combination with other agents for accelerating the wound healing process following future clinical studies.

Quercus infectoria gall extract aids wound healing in a streptozocin-induced diabetic mouse model.

OBJECTIVE: Quercus infectoria galls have commonly been used for different therapeutic purposes. This study was conducted to investigate the effects of topical application of an ointment prepared from Quercus infectoria gall hydroethanolic extract on open wound healing in a streptozocin-induced diabetic BALB/c mouse model. METHOD: After induction of diabetes, two circular wounds (5mm) were created on the dorsum of the mice which were then divided into three groups. The mice were treated with soft yellow paraffin (control-sham group) and therapeutic doses of 5% and 10% of an ointment prepared from Quercus infectoria, respectively. To evaluate the effects of the therapeutic ointment on the wound healing process, wound area, histological parameters, mRNA levels of vascular endothelial growth factor (VEGF), Bcl-2 and p53, plasma levels of interleukin-6 (IL-6) and tumour necrosis factor (TNF)-α, and tissue antioxidant capacity were investigated. RESULTS: The mice (n=54) were divided into three equal groups. Wound area and concentrations of IL-6 and TNF-α were significantly decreased in both ointment-treated groups compared to the control group (p<0.05). Moreover, angiogenesis, fibroblast distribution per mm2 of wound tissue, collagen deposition, rapid re-epithelialisation, and the expression of VEGF, Bcl-2 and p53 mRNA, were significantly increased (p<0.05). The administration of the ointment reduced malondialdehyde concentration and increased total antioxidant capacity compared with the control group (p<0.05). CONCLUSION: Our study suggests that an ointment prepared from Quercus infectoria gall hydroethanolic extract accelerated open wound healing in a diabetic animal model by shortening the inflammatory phase, inducing apoptosis, up-regulating the expression of Bcl-2 and p53 mRNA, antioxidant properties and cellular proliferation.

The biological synthesis of gold/perlite nanocomposite using Urtica dioica extract and its chitosan-capped derivative for healing wounds infected with methicillin-resistant Staphylococcus aureus.

The preparation of ointments from natural compounds is essential for accelerating infected wounds. This study investigated the effects of topical uses of gold nanoparticles (Au)/perlite (Au/Perl) nanocomposites (NCs) by the help of Urtica dioica extract and its chitosan-capped derivative (Chit) on methicillin-resistant Staphylococcus aureus (MRSA)-infected wound healing in a mouse model. Furthermore, Au/Perl/Chit nanocomposite was prepared using protonated chitosan solution. The physicochemical properties of the as-synthesized nanocomposites were also investigated. The effects of Au/Perl/Chit NC were assessed by antibacterial, histopathological parameters as well as molecular evaluations. Then, they were compared with synthetic agent of mupirocin. The results revealed that Au/Perl NC was mesoporous and spherical in a range of 13-15 nm. Topical administration of Au/Perl/Chit ointment accelerated wound healing by reducing bacteria colonization and wound rate enhancing collagen biosynthesis and re-epithelialization, the expressions of IL-10, PI3K, AKT, bFGF, and COL1A genes, which is in agreement with the obtained results for mupirocin. In conclusion, the results strongly demonstrated that administration of ointments prepared from Au/Perl and Au/Perl/Chit nanocomposites stimulates MRSA-infected wound healing by decreasing the length of healing time and regulating PI3K/AKT/bFGF signaling pathway and is a promising candidate in stimulating MRSA-infected wound regeneration.

The effectiveness of Rutin for prevention of surgical induced endometriosis development in a rat model.

Apoptosis and antioxidant mechanisms are pathways for the treatment of endometriosis (Endo). Rutin (Rtn) is an antioxidant flavonol that induces apoptosis. This study, for first time, was conducted to evaluate the effects of rutin on Endo through apoptosis and antioxidant mechanisms. The experimental Endo was induced in 24 rats and then the animals were subdivided into Endo-sole, 3000 and 6000 µg/kg rutin (Rtn-3000 and Rtn-6000) and vitamin C groups. After 4 weeks, the expression of Bcl2, Bax, anti Pro Caspase-9, cleaved Caspase-9, pro PARP, pro Cleaved PARP, Pro PARP, pro mTOR and mTOR were assessed by western blotting technique. The protein concentrations of malondialdehyde (MDA), total antioxidant capacity, and super oxide dismutase and gutathione peroxidase were also evaluated. TUNEL staining was also used for the detection of apoptosis. Caspase-9 and concentration of antioxidants were higher in the treated groups compared to Endo-sole group (P < 0.05). The results also showed that rutin decreased the expression of Bcl2 and MDA concentration (P < 0.05). The results for TUNEL staining showed that the animals treated with Rtn-6000 and vitamin C showed higher apoptosis. Rutin induces apoptosis by the expression of Bcl-2, Bax and caspase and also antioxidant activity by increasing antioxidants concentrations.

Accelerative effect of topical Zataria multiflora essential oil against infected wound model by modulating inflammation, angiogenesis, and collagen biosynthesis.

CONTEXT: Zataria multiflora Boiss (Lamiaceae) essential oil (ZME) is believed to be a bactericide herbal medicine and might alleviate negative effects of infection. OBJECTIVE: This study evaluates the effects of an ointment prepared from ZME (ZMEO) on infected wounds. MATERIALS AND METHODS: A full-thickness excisional skin wound was surgically created in each mouse and inoculated with 5 × 107 suspension containing Pseudomonas aeruginosa and Staphylococcus aureus. The BALB/c mice (n = 72) were divided into four groups: (1) negative control that received base ointment (NCG), (2) positive control that daily received Mupirocin® (MG), (3) therapeutic ointment containing 2% ZMEO and (4) therapeutic ointment containing 4% ZMEO, for 21 days. Wound contraction, total bacterial count, histopathological parameters, antioxidant activity, qRT-PCR analysis for expression of IL-1ß, TNF-α, VEGF, IGF-1, TGF-ß, IL-10, and FGF-2 mRNA levels were assessed on days 3, 7, and 14 following the wounding. RESULTS: Topical administration of ZMEO significantly decreased the total bacterial count and wound area and also expression of IL-1ß and TNF-α compared to the control groups (p < 0.05) in all days. This could also increase significantly the expression of TGF-ß, IL-10 IGF-1, FGF-2, and VEGF, and also angiogenesis, fibroblasts, fibrocytes, epithelialization ratio, and collagen deposition and improve antioxidant status compared to the control group (p < 0.05). DISCUSSION AND CONCLUSION: ZMEO accelerated the healing process of infected wounds by shortening the inflammatory factors and increasing proliferative phase. Applying ZMEO only and/or in combination with chemical agents for the treatment of wound healing could be suggested.

The Effect of Topical Administration of an Ointment Prepared From Trifolium repens Hydroethanolic Extract on the Acceleration of Excisional Cutaneous Wound Healing.

INTRODUCTION: Natural agents with antioxidant and anti-inflammatory properties are safer than synthetic agents and may improve wound healing. OBJECTIVE: The purpose of this study is to evaluate the in vivo wound healing potential of an ointment prepared from Trifolium repens hydroethanolic extract (T repens) concerning excisional wounds in a rat model. MATERIALS AND METHODS: Seventy-two adult Wistar rats were divided into 4 groups: a control group and 3 groups of animals treated with 1.5% T repens, 3% T repens, and 6% T repens. A full-thickness wound with an area of 314 mm2 was created in each rat. To investigate the effect of T repens on wound healing, the wound area, histological analyses (eg, angiogenesis, fibroblast, fibrocyte, mast-cell distribution), intracytoplasmic carbohydrate storage, and B-cell lymphoma 2-like protein 4 (BAX), B-cell lymphoma 2 (Bcl-2), and p53 gene expression in the wound tissue were evaluated for 21 days. Antioxidant activity was further measured by 2,20-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and 2,2-Di(4-tert-octylphenyl)-1-picrylhydrazyl (DPPH) assays. RESULTS: The animals in the treated groups showed higher wound contraction ratios (P ⟨ .05), angiogenesis, fibroblast, fibrocyte, and mast-cell distribution and intracytoplasmic carbohydrate storage compared with the control group (P ⟨ .05). Moreover, the topical administration of T repens increased the messenger ribonucleic acid (mRNA) level of Bcl-2 and reduced the BAX and p53 mRNA levels (P ⟨ .05). These findings further revealed the strong antioxidant activity of T repens. CONCLUSIONS: The topical administration of T repens accelerated wound healing by increasing angiogenesis; fibroblast, fibrocyte, and mast-cell distribution; intracytoplasmic carbohydrate storage; and modulation in genes involved in apoptosis in a rat model.

Topical co-administration of Teucrium polium hydroethanolic extract and Aloe vera gel triggered wound healing by accelerating cell proliferation in diabetic mouse model.

Diabetic wounds are major issues in patients with diabetes. Medicinal plants of Teucrium polium and Aloe vera have antioxidant and anti-inflammatory properties that may be profitable for diabetic patients. This study was conducted to evaluate the effect of co-administration of ointments prepared from Teucrium polium hydroethanolic extract (TPEO) and Aloe vera gel (AVGO) on excisional wound healing in a diabetic mouse model. Following the induction of diabetes and circular excisional wound (7 mm), the mice were divided into six groups, namely (Ⅰ) control mice treated with mupirocin (as a standard drug), (Ⅱ and Ⅲ) the mice treated with 5 and 10 % TPEO, (Ⅳ and Ⅴ) the mice treated with 5 and 10 % AVGO, and (Ⅵ) the mice treated with a combination of 5% TPEO and 5% AVGO (TPEO+AVGO). To investigate the wound area, we further evaluated the wound area ratio, histological analysis and the serum levels of tissue antioxidant capacity (TAC) and malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß), immunohistochemistry staining for vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1), glucose transporter-1(GLUT-1) and collagen type 1 and mRNA expression levels for VEGF, IGF-1, GLUT-1 and fibroblast growth factor-2 (FGF-2). The results showed that administration of the ointments, especially in combination form, shortened the inflammatory phase and reduced the levels of tissue MDA, TNF-α and IL-1ß compared to mupirocin group (P < 0.05). Moreover, fibroblasts proliferation, collagen deposition, VEGF, IGF-1, GLUT-1-positive cells and level of TAC, and expressions of VEGF, IGF-1, GLUT-1 and FGF-2 were significantly (P < 0.05) increased in TPEO and AVGO, and especially in the mice treated with the mixed form. Therefore, topical co-administration of TPEO + AVGO accelerated open diabetic wound healing through shortening the inflammatory phase and increasing cell proliferation and collagen deposition.

Accelerated healing by topical administration of Salvia officinalis essential oil on Pseudomonas aeruginosa and Staphylococcus aureus infected wound model.

BACKGROUND: Salvia officinalis L. (Lamiaceae) is known to have antibacterial properties possibly conducive to the healing process of infected wounds. PURPOSE: The present study aimed to evaluate the effects of an ointment containing Salvia officinalis essential oil (SOO) on an infected wound model. METHODS: Essential oil hydrodistillated from the dried leaves of the plant was analyzed by GC-FID and GC-MS. After creating two full-thickness cutaneous wounds, mice were classified into four groups, control, and animals treated with 2 % mupirocin® (standard positive drug), and 2 % and 4 % (w/w) of SOO. In order to evaluate the effects of SOO on the wound healing phases, the expression levels of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), cyclin-D1, Bcl-2, fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factors (VEGF) were analyzed using qRT-PCR. Immunohistochemistry analysis, tissue total antioxidant capacity (TAC) and malondialdehyde (MDA) were further assessed in all groups. RESULTS: Concerning essential oil, the main compounds were found to be cis-thujone (26.8 %), camphor (16.4 %), trans-thujone (14.1 %) and 1,8-cineole (10.8 %). Our findings showed that the topical application of SOO was able to shorten the inflammatory phase and accelerate the cellular proliferation, re-vascularization, collagen deposition and re-epithelialization in comparison to the control group (p < 0.05). Moreover, increased mRNA levels of FGF-2 and VEGF, and up-regulation of cyclin-D1 and Bcl-2 were observed following the topical application of SOO compared to the control group (p < 0.05). The expression levels of IL-6, IL-1ß and TNF-α were reduced in animals treated with SOO on days 3, 7 and 14 (p < 0.05). CONCLUSIONS: Administration of SOO increased the TAC level and reduced the MDA content and levels of IL-1ß and TNF-α. It is concluded that SOO is able to accelerate the wound healing process by regulating the expression of pro-inflammatory cytokines, growth factors, and antioxidant properties.

Topical application of Cinnamomum hydroethanolic extract improves wound healing by enhancing re-epithelialization and keratin biosynthesis in streptozotocin-induced diabetic mice.

Context: Cinnamomum verum J. Presl. (Lauraceae) has a high number of polyphenols with insulin-like activity, increases glucose utilization in animal muscle, and might be beneficial for diabetic patients.Objective: This study evaluated the effectiveness of an ointment prepared from Cinnamomum verum hydroethanolic extract on wound healing in diabetic mice.Materials and methods: A total of 54 male BALB/c mice were divided into three groups: (1) diabetic non-treated group mice that were treated with soft yellow paraffin, (2 and 3) mice that were treated with 5 and 10% C. verum. Two circular full-thickness excisional wounds were created in each mouse, and the trial lasted for 16 d following induction of the wound. Further evaluation was made on the wound contraction ratio, histopathology parameters and mRNA levels of cyclin D1, insulin-like growth factor 1 (IGF-1), glucose transporter-1 (GLUT-1), total antioxidant capacity, and malondialdehyde of granulation tissue contents. HPLC apparatus was utilized to identify the compounds.Results: The HPLC data for cinnamon hydroethanolic extract identified cinnamaldehyde (11.26%) and 2-hydroxyl cinnamaldehyde (6.7%) as the major components. A significant increase was observed in wound contraction ratio, fibroblast proliferation, collagen deposition, re-epithelialization and keratin biosynthesis in the C. verum-treated groups in comparison to the diabetic non-treated group (p < 0.05). The expression level of cyclin D1, IGF1, GLUT 1 and antioxidant capacity increased in the C. verum-treated groups in comparison to the diabetic non-treated group (p < 0.05).Conclusions: Topical administration of C. verum accelerated wound healing and can possibly be employed in treating the wounds of diabetic patients.

Topical application of Mentha piperita essential oil accelerates wound healing in infected mice model.

This study was conducted to evaluate the effects of the prepared ointments from Mentha piperita essential oil (M. piperita) on wound healing in the infected mice models. Each circular full-thickness wound was inoculated with 25 × 107 units of Staphylococcus aureus and Pseudomonas aeruginosa bacteria strains. The tissue bacterial count, histological analyses and expression levels of IL-10, TNF-α, TGF-ß1, IL-1ß, CCL2, CXCL1, VEGF and FGF-2 were assessed to identify the different doses of M. piperita on wound healing. Total tissue bacterial count, edema and inflammation level were declined, but the migration of fibroblasts, collagen synthesis and re-epithelization were increased in treated animals with M. piperita. The expression levels of CCL2, CXCL1, IL-1ß, TGF-ß1 and IL-10 genes were up-regulated in the M. piperita-treated animals compared to the control group. While the expression of TNF-α, VEGF and FGF-2 was down-regulated in comparison to the control group. This study indicated that M. piperita can be used for treatment of the infected wound.

Effectiveness of topical administration of Anethum graveolens essential oil on MRSA-infected wounds.

Medicinal plants are conventionally used for wound healing, but their action mechanisms are still unknown. The present study evaluated the effect of topical administration of ointment containing dill (Anethum graveolens) essential oil (DEO) in the management of apoptosis and cell proliferation during MRSA-infected experimentally induced wound healing process in BALB/c mice model. The GC-FID and GC-MS techniques were used to analyze chemical composition of the essential oil. The mice were randomly divided into four treatment groups including negative control (sham), 2% and 4% DEO and mupirocin®-treated animals. The full-thickness excisional wounds were inoculated by 5 × 107 colony-forming units of MRSA. In order to assess the effect of different concentrations of DEO on wounds infection, wound area, bacterial count, histopathological, immunohistochemical and RT-PCR analysis were evaluated. The GC-MS analysis identified α-phellandrene (47.3%), p-cymene (18.5%) and carvone (14.1%) as the main compounds of the essential oil tested here. Administration of DEO prevented bacterial growth and also reduced wound area in comparison to the control group. Topical administration of DEO significantly reduced the inflammatory phase and accelerated re-epithelialization, angiogenesis, fibroblast and collagen deposition. Moreover, the DEO-treated animals exhibited higher expressions of Bcl-2, p53 caspase-3, VEGF and FGF-2 in comparison to the control and mupirocin®-treated groups (P < 0.05). Topical administration of DEO decreases the inflammatory phase by increasing p53 and caspases-3 expression. It triggers the proliferative phase by up-regulation of the Bcl-2, VEGF and FGF-2 expression and also up-regulates the collagen biosynthesis by enhancing the ERα expression level. Thus, ointment prepared from dill essential oil, in Iran, with its major compounds such as α-phellandrene, p-cymene and carvone can be used as an agent for accelerating the infected wound healing.

Effectiveness of topical application of ostrich oil on the healing of Staphylococcus aureus- and Pseudomonas aeruginosa-infected wounds.

BACKGROUND/AIMS: Management of infected wounds is one of the major challenges that surgeons and nurses face. Several antimicrobial agents have been used, but the toxicity, drug resistance, and their effect on the healing process remain a matter of concern. The present study was designed to analyze the accelerative impact of topical application of ostrich oil on infected wounds in a mouse model. MATERIALS AND METHODS: 72 BALB/c mice were divided into four main groups of control-sham, mupirocin, and two treatment groups receiving 2% and 4% (w/w) concentrations of ostrich oil, topically. The mice were routinely anesthetized and wounds were created by excising the skin with a 5-mm biopsy punch. Immediately after wounding, an aliquot of 25 × 107 Staphylococcus aureus and Pseudomonas aeruginosa was suspended in 50-µL phosphate-buffered saline and applied on the wound and the wound was left open. The healing rate in the infected wound was assessed using wound area, histopathological characteristics, and expression of growth factors including vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF-ß1), and fibroblast growth factor 2 (FGF-2). RESULTS: The wound area significantly decreased (p < 0.05) in the treated animals. There was a significant increase (p < 0.05) in new vessels, fibroblasts count, and collagen deposition in the ostrich oil-treated animals. Expression of VEGF, TGF-ß1, and FGF-2 revealed the immunomodulation and angiogenesis effects of the ostrich oil on wound healing. CONCLUSIONS: Our study demonstrated that ostrich oil may be a useful treatment in infected cutaneous wounds.

Topical application of Salvia officinalis hydroethanolic leaf extract improves wound healing process.

Salvia officinalis L. (common sage) is a popular herb in the mint family, Lamiaceae. To our knowledge, literature regarding the wound healing properties hydroethanolic extract of Salvia officinalis is scarce. Here, we tried to evaluate the in vitro antioxidant properties and in vivo wound healing activity of the hydroethanolic extract of S. officinalis. About 105 healthy Wistar rats were inflicted with wound by excision and incisionand were randomly divided into five experimental groups: Group I, as control; Group II, received placebo; groups III-V treated with 1, 3 and 5% S. officinalis hydroethanolic leaf extract, respectively. Thehydroethanolic leaf extract of Salvia officinalis showed the highest total flavonoid and phenolic content and antioxidant capacity. Topical application of S. officinalis extract, especially higher dose,significantly (P <0.05) increased the percentage of wound contraction, a period of re-epithelialization, breaking strength ratio and upregulated hydroxyproline content versus control group. Additionally, S. officinalis significantly (P <0.05) increased the new vessel formation and Fibroblast distribution. Our results showed that S. officinalis,especially S. officinalis 5%,were significantly promoting wound healing effect and can be considered as an appropriate compound for clinical application in wound care.

Hydroethanolic Allium sativum extract accelerates excision wound healing: evidence for roles of mast-cell infiltration and intracytoplasmic carbohydrate ratio

ABSTRACT The present study was designed to evaluate the in vivo effect of Allium sativum (garlic) hydroalcoholic extract on wound healing in rats. For this purpose, 72 mature Wistar rats were divided into four groups (n=18/each) to receive no treatment, placebo, Cicalfate(r), or 2% Allium sativum (AS) extract, administered topically to the wound area, for 21 days. Following the experimental period, tissue samples were dissected out and underwent to histopathological analyses. Fibroblasts, fibrocytes, mast cells, intra-cytoplasmic carbohydrate ratio, neovascularization, collagen deposition, and re-epithelialization were analyzed in all groups. Animals in the treated groups showed significant enhancement in fibroblast, fibrocyte, and mast-cell distribution. Significantly higher neovascularization was observed on day 3 after wound induction in AS-treated animals versus those in the placebo, Cicalfate, and untreated groups (P<0.05). A dose-dependent, significantly higher intra-cytoplasmic carbohydrate storage was observed in treated animals. Our data show that AS promotes wound healing due to its preliminary impact on mast-cell distribution, which enhanced collagen synthesis and upregulated angiogenesis, and shortened the healing process by enhancing the intra-cytoplasmic carbohydrate ratio.

Topical Moltkia coerulea hydroethanolic extract accelerates the repair of excision wound in a rat model.

PURPOSE: To evaluate the effect of a hydroethanolic extract of Moltkia coerulea ointment (MCO) on the healing of excision wound in a rat model. METHODS: Circular surgical full thickness excision wound, with 314 mm² size, was induced in the anterior-dorsal side of each rat. Three different doses of MCO (1%, 3% and 6%) were administrated. On Day 3, 7, 14 and 21, the tissue was sampled and immune cells, fibroblasts and fibrocytes distribution per one mm² of wound area, collagen density and re-epithelialization were analyzed. Moreover, the total flavnoid, phenols and anti-oxidant potential of the MCO were evaluated. Ultimately, the percentage of wound contraction in different groups was compared with each other. RESULTS: Hydroethanolic extract of MCO significantly (p < 0.05) increased wound contraction percentage. The animals in medium and high dose MCO-treated groups exhibited remarkably (p<0.05) higher fibroblast and fibrocyte distribution and significantly (p < 0.05) lower immune cells infiltration. On Day 7 after injury, MCO up-regulated neovascularization in a dose-dependent way. CONCLUSION: Our data showed that MCO shortened the inflammation phase by provoking the fibroblast proliferation. Moreover, MCO promoted the healing process by up-regulating the angiogenesis and provoking the structural cells proliferation as well as increasing the collagen synthesis, cross-linking, and deposition.

Hydroethanolic Pistacia atlantica hulls extract improved wound healing process; evidence for mast cells infiltration, angiogenesis and RNA stability.

In Iranian traditional therapy folk, the Pistacia is used for treatment of wound inflammation. Here in the present study, the In vivo effect of Pistacia atlantica hulls ointment (PAO) on the wound healing process was assessed. Excision and incision wounds were induced in rats. Three different doses of PAO were administrated. Following 3, 7, 14 and 21 days, the tissue samples were obtained and skin irritation ratio, hydroxyproline content, as well as immune cells, fibroblasts, fibrocytes distribution and collagen density were analyzed. Moreover, the cellular RNA damage examined using epi-fluorescent microscope. Hydroethanolic extract of PAO significantly (P < 0.05) increased wound contraction percentage and up-regulated hydroxyproline content. The animals in medium and high dose PAO-treated groups exhibited remarkably (P < 0.05) higher fibroblast distribution and significantly (P < 0.05) lower immune cells infiltration. PAO up-regulated mast cells distribution on day 7 and elevated neovascularization in a dose dependent manner. Significantly lower RNA damage was revealed in PAO-treated animals. Our data showed that, PAO shortened the inflammation phase by provoking the fibroblast proliferation. Moreover, PAO enhanced mast cells distribution and infiltration, which in turn promoted the neovascularization. Ultimately, promoted angiogenesis increased RNA stability in different cell types. Thus, Hydroethanolic extract of PAO can be considered as an appropriate compound for wound healing medicine.