Artepillin C as an outstanding phenolic compound of Brazilian green propolis for disease treatment: A review on pharmacological aspects.

Propolis is a viscous resin consisting of plant material (shoots, flowers, and plant exudates), salivary secretions and waxes produced by Apis mellifera bees. Its popular use aroused the interests of scientific research, which proved to be a potential source of various bioactive substances. The chemical composition of propolis depends on several factors, such as the different types of plant sources collected by bees, geographic origin, and the time of year in which they are produced, but it is known that phenolic represent the main bioactive constituents of propolis. Baccharis dracunculifolia DC (Asteraceae) is the most important botanical source of propolis and a native to southeastern Brazil. It is widely known as the green propolis because of its deep green color. One of its major phenolic acids is artepillin C (Art-C), a diprenyl-p-hydroxycinnamic acid derivative. This review aims to provide a comprehensive summary of the pharmacological effects of Art-C. The limited number of publications on this topic over the past two decades have been collected from databases and summarized. Numerous biological activities have been described for the Art-C, such as gastroprotective, anti-inflammatory, antimicrobial, antioxidant, antitumor. This article describes aspects of occurrence, synthesis, biological activities and pharmacokinetic approaches.

Role of the antioxidant properties in the gastroprotective and gastric healing activity promoted by Brazilian green propolis and the healing efficacy of Artepillin C.

Green propolis is a resinous substance used in folk medicine given its anti-inflammatory, antibacterial, and anti-ulcer effects. Our research group has already confirmed the gastroprotective activity of hydroalcoholic extract from green propolis (HEGP), as well as of its main isolated compounds. In continuity, this study evaluated the antioxidant mode of action involved in the preventive effect induced by HEGP, and its therapeutic gastric healing potential on installed ulcers. In addition, the healing effect of its main compound Artepillin C was also investigated. Acute and chronic ulcers were induced in rats by given ethanol or acetic acid, respectively. In acute model, the rats were orally pre-treated with vehicle (water plus 1% Tween, 1 mL/kg), HEGP (30-300 mg/kg), or carbenoxolone (200 mg/kg) 1 h prior the ulcer induction. In the chronic ulcer protocol, the rats received vehicle (water plus 1% Tween, 1 mL/kg), HEGP (300 mg/kg), or omeprazole (20 mg/kg) twice a day by 7 days, whereas groups of mice received vehicle (water plus 1% Tween, 1 mL/kg), Artepillin C (18 mg/kg), or ranitidine (20 mg/kg) twice a day by 4 days. Ulcerated tissue was collected for histological, histochemical, immunostaining, oxidative, and inflammatory analyses. The in vitro scavenger activity of HEGP was also verified using the DPPH assay. The oral pre-treatment with HEGP (100 and 300 mg/kg) prevented the gastric epithelial damage promoted by ethanol. Besides, HEGP (100 and 300 mg/kg) reduced SOD activity about 11% and 26%, respectively, and increased the activity of GST around 20% and CAT in 80%. HEGP (300 mg/kg) also reduced the production of reactive oxygen species, as well as lipoperoxidation levels in the ethanol-ulcerated tissue. In the acetic acid-induced chronic ulcer, the daily treatment with HEGP (300 mg/kg) accelerates the healing process by 71%. In this model, HEGP normalized SOD and CAT activity and increased GST activity by 109% when compared to non-ulcerated rats. In both models, the extract administration increased the mucin PAS staining and reduced the myeloperoxidase activity at the ulcer site. Moreover, the treatment with HEGP enhanced the PCNA immunostaining, but did not alter the concentration of collagen in the acetic acid-ulcerated tissue. The extract had a direct DPPH radical-scavenging ability (LogIC50: 0.56). Besides, as expected, HPLC analysis showed Artepillin C as a major compound and its administration at 18 mg/kg also accelerated the gastric healing ulcer process in mice. Our findings confirm that HEGP displays both gastroprotective and gastric healing properties, contributing to the validation of its popular use as preventive and therapeutic approaches. These actions occur through the increase in mucin production and the reestablishment of the oxidative balance due to a reduction in gastric inflammation.

Ulcer healing and mechanism(s) of action involved in the gastroprotective activity of fractions obtained from Syngonanthus arthrotrichus and Syngonanthus bisulcatus.

BACKGROUND: Syngonanthus arthrotrichus and Syngonanthus bisulcatus, currently known for Comanthera aciphylla (Bong.) L.R.Parra & Giul. and Comanthera bisulcata (Koern.) L.R. Parra & Giul, popularly known in Brazil as "sempre-vivas," are plants from the family Eriocaulaceae. They are found in the states of Minas Gerais and Bahia. The species are known to be rich in flavonoids to which their gastroprotective activity has been attributed. In this research, experimental protocols were performed to elucidate the associated mechanisms of action. METHODS: The activity was evaluated using induced gastric ulcer models (acetic acid and ethanol-induced gastric lesions in NEM or L-NAME pre-treated mice, and by ischemia/reperfusion). Antioxidant enzymes, serum somatostatin, and gastrin were also evaluated. RESULTS: In chronic gastric ulcers, a single daily oral dose of Sa-FRF or Sb-FRF (100 mg/kg body wt.) for 14 consecutive days accelerated ulcer healing to an extent similar to that seen with an equal dose of cimetidine. The pre-treatment of mice with NEM (N-ethylmaleimide) or L-NAME (N-nitro-L-arginine) abolished the protective activity of Sa-FRF, Sa-FDF, Sb-FDF and Sb-FRF or Sa-FRF and Sb-FRF, respectively, which indicates that antioxidant compounds and nitric oxide synthase activity are involved in the gastroprotective. Sa-FRF and Sb-FRF (100 mg/kg p.o) protected the gastric mucosa against ulceration that was induced by ischemia/reperfusion (72 and 76 %, respectively). It also decreased lipid peroxidation and restored total thiols in the gastric wall of mice that had been treated with ethanol. When administered to rats submitted to ethanol-induced gastric lesions, Sa-FRF and Sb-FRF (100 mg/kg, p.o.) increased the somatostatin serum levels, while the gastrin serum levels were proportionally decreased. CONCLUSIONS: The results indicate significant healing effects and gastroprotective activity for the Sa-FRF and Sb-FRF, which probably involves the participation of SH groups, nitric oxide (NO), the antioxidant system, somatostatin, and gastrin. All are integral parts of the gastrointestinal mucosa's cytoprotective mechanisms against aggressive factors.

Evaluation of enteral and parenteral hyaluronic acid in induced ischemic skin flaps in rats: a double-blinded and randomized study.

PURPOSE: To evaluate exogenous hyaluronic acid (HA) derived from bacterial fermentation through enteral and parenteral routes in ischemic skin flaps induced in rats, using clinical and histological exams; and interleukins (IL) as tissue inflammatory biomarkers. METHODS: Sixty-four male adults Wistar rats with ischemic skin flaps on the dorsum were randomized into four groups, based on the treatment protocol: subcutaneous administration of saline solution (0.9%) (GI); oral administration of distilled water (GII); subcutaneous administration of HA (0.3%) (GIII); and oral administration of HA (1%) (GIV). Flaps of all groups were comparable regarding clinical and macroscopic evaluation, histological examination, pro-inflammatory cytokines (IL-1ß, IL-6, and tumor necrosis factor-α) and anti-inflammatory cytokine IL-10. RESULTS: A lower percentage of necrosis was identified in flaps treated with subcutaneous administration of HA (0.3%). The pro- and anti-inflammatory cytokines, epidermis thickness, blood vessels, and inflammatory cells showed statistically significant inter-group and intra-group differences (p < 0.05). CONCLUSIONS: High molecular HA (1,400 ~ 2,000 kDa) administrated by subcutaneous or oral route exhibited beneficial effects in ischemic skin flaps of rats. However, subcutaneous administration of HA (0.3%) showed better results in terms of the percentage of necrosis and epithelialization.

Effects of ozone therapy applied topically, by bagging, or both on the healing of clean wounds induced in rat's skin.

PURPOSE: This study aimed to evaluate the effects of ozone therapy applied topically and/or by bagging on the healing of clean wounds induced in rat's skin. METHODS: One hundred and twenty male rats of about 16 weeks old was divided into five groups: G1) saline solution (0.9%); G2) sunflower oil; G3) ozonated sunflower oil; G4) ozone bagging; G5) association of ozonated sunflower oil and ozone bagging. The wounds were evaluated through macroscopic, morphometric, histopathologic, and tensile strength analyses. RESULTS: Analysis among groups showed a lower percentage of wound contraction in G1 compared to G4 only in M7D. The tensile strength of the wounds showed differences among groups in the seventh (M7D) and the 14th (M14D) postoperative day, and among time points in G1 (M14D > M7D). The elongation of the wounds showed differences in G3 (M7D > M14D). Histological evaluation of the wounds showed significant change in bleeding, mixed to mononuclear infiltrate, congestion, and tissue disorganization for tissue organization between groups and time points. CONCLUSIONS: Ozone therapy applied topically and/or by bagging was not deleterious to the healing of clean wounds induced in rat's skin, but ozone bagging showed the best contribution to the healing process.

Guttiferones: An insight into occurrence, biosynthesis, and their broad spectrum of pharmacological activities.

Guttiferones belong to the polyisoprenylated benzophenone, a class of compounds, a very restricted group of natural plant products, especially in the Clusiaceae family. They are commonly found in bark, stem, leaves, and fruits of plants of the genus Garcinia and Symphonia. Guttiferones have the following classifications according to their chemical structure: A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, and T. All of them have received growing attention due to its multiple biological activities. This review provides a first comprehensive approach to plant sources, phytochemical profile, specific pharmacological effects, and mechanisms of guttiferones already described. Studies indicate a broad spectrum of pharmacological activities, such as: anti-inflammatory, immunomodulatory, antioxidant, antitumor, antiparasitic, antiviral, and antimicrobial. Despite the low toxicity of these compounds in healthy cells, there is a lack of studies in the literature related to toxicity in general. Given their beneficial effects, guttiferones are expected to be great potential drug candidates for treating cancer and infectious and transmissible diseases. However, further studies are needed to elucidate their toxicity, specific molecular mechanisms and targets, and to perform more in-depth pharmacokinetic studies. This review highlights chemical properties, biological characteristics, and mechanisms of action so far, offering a broad view of the subject and perspectives for the future of guttiferones in therapeutics.

Epicatechin used in the treatment of intestinal inflammatory disease: an analysis by experimental models.

Background. This study was pathway of (-)-epicatechin (EC) in the prevention and treatment of intestine inflammation in acute and chronic rat models. Methods. Intestine inflammation was induced in rats using TNBS. The morphological, inflammatory, immunohistochemical, and immunoblotting characteristics of colon samples were examined. The effects of EC were evaluated in an acute model at doses of 5, 10, 25, and 50 mg/kg by gavage for 5 days. The chronic colitis model was induced 1st day, and treated for 21 days. For the colitis relapse model, the induction was repeated on 14th. Results. EC10 and EC50 effectively reduced the lesion size, as assessed macroscopically; and confirmed by microscopy for EC10. The glutathione levels were higher in EC10 group but decreased COX-2 expression and increased cell proliferation (PC) were observed, indicating an anti-inflammatory activity and a proliferation-stimulating effect. In the chronic colitis model, EC10 showed lower macroscopic and microscopic lesion scores and increase in glutathione levels. As in the acute model, a decrease in COX-2 expression and an increase in PC in EC10, the chronic model this increase maybe by the pathway EGF expression. Conclusion. These results confirm the activity of EC as an antioxidant that reduces of the lesion and that has the potential to stimulate tissue healing, indicating useful for preventing and treating intestine inflammation.

Effects of Rhizophora mangle on Experimental Colitis Induced by TNBS in Rats.

Male Unib-WH rats were pretreated for two weeks with butanolic (BuOH) and ethyl acetate (EtOAc) fractions. Colitis was induced by rectal administration of TNBS, the treatment continued, and animals were sacrificed on day 7 after the TNBS administration. Phytochemical studies were performed in order to provide the characterization of the tannins present in the bark of R. mangle. Results showed that EtOAc fraction increased the levels of IL-10 (∗∗P < 0.01) and diminished the levels of TNF-α (∗∗∗P < 0.001) and IL-6 (∗∗P < 0.01). BuOH fraction reduced the MPO activity (∗∗P < 0.01) and levels of TBARS (∗∗∗P < 0.001); it also increased COX-1 expression, diminished the levels of TNF-α (∗∗∗P < 0.001), and increased the levels of IL-12 (∗∗∗P < 0.001). Besides, both treatments augmented the levels of GSH (∗P < 0.05), the activity of GSH-Px (∗∗P < 0.01 for BuOH fraction and ∗∗∗P < 0.001 for EtOAc fraction), and CAT (∗∗P < 0.01). In conclusion, both treatments ameliorated the injury induced by TNBS through different mechanisms, probably by their chemical composition which directed its activity into an antioxidant or anti-inflammatory response, leading to an immune modulation.

Sectorial Analysis of the Fibrous Matrix of Vocal Folds in the Elderly.

OBJECTIVE: to determine the sectorial concentration of fibrous matrix along the vocal folds of the elderly. METHODS: Thirteen fresh vocal folds were removed from 13 cadavers. The subjects were divided into two groups: control group (CG) - age range 25-40 years (n = 5), and elderly group (EG), aged ≥70 years (n-8). The vocal folds were separated according to regions in: anterior macula flava (AMF), posterior macula flava (PMF), medial region (M) and lateral region of the membranous vocal fold (L). The material was examined using a scanning electron microscope and 10 pictures per region were obtained at 1200x magnification. The area of fibrous matrix was quantified in both groups using the AVSOFT Biovew Program. RESULTS: Percentage (%) of fibrous matrix per region (%): AMF (EG = 86.78%; CG = 81.63%); PMF (EG = 88.19%; CG = 81.52%); M (EG = 84.92%; CG = 77.96%); L (EG = 83.93%; CG = 78.91%). Irregular distribution of a dense fibrous matrix was also more evident in the elderly's larynges in a qualitative assessments. CONCLUSION: A higher concentration of fibrous matrix was observed in the vocal folds of the elderly when compared to the control at all the studied regions. The greatest increase in the concentration of fibers in the medial portion of the body of the vocal folds is probably due to the phonatory stimulation. The macula flava remains functional even in the senile larynx.

Histological, Immunohistochemical and Antioxidant Analysis of Skin Wound Healing Influenced by the Topical Application of Brazilian Red Propolis.

Skin wound healing is a complex process that requires the mutual work of cellular and molecular agents to promote tissue restoration. In order to improve such a process, especially in cases of impaired healing (e.g., diabetic ulcer, chronic wounds), there is a search for substances with healing properties and low toxicity: two features that some natural products-such as the bee product named propolis-exhibit. Propolis is a resinous substance obtained from plant resins and exudates with antioxidant, anti-inflammatory, and antitumoral activities, among other biological ones. Based on the previously reported healing actions of different types of propolis, the Brazilian red propolis (BRP) was tested for this matter. A skin wound excision model in male Wistar rats was performed using two topical formulations with 1% red propolis as treatments: hydroalcoholic extract and Paste. Macroscopical, histological and immunohistochemical analysis were performed, revealing that red propolis enhanced wound contraction, epithelialization, reduced crust formation, and modulated the distribution of healing associated factors, mainly collagen I, collagen III, MMP-9, TGF-ß3 and VEGF. Biochemical analysis with the antioxidants SOD, MPO, GSH and GR showed that propolis acts similarly to the positive control, collagenase, increasing these molecules' activity. These results suggest that BRP promotes enhanced wound healing by modulating growth factors and antioxidant molecules related to cutaneous wound healing.

Beta-caryophyllene as an antioxidant, anti-inflammatory and re-epithelialization activities in a rat skin wound excision model.

The skin is a critical organ for the maintenance of the integrity and protection of the organism. When a wound occurs, a sequence of healing mechanisms is triggered to reconstruct the wounded area. ß-caryophyllene is a sesquiterpene in Copaifera langsdorffii oleoresin with antioxidant and anti-inflammatory potential. On the basis of previous studies with C. langsdorffii, ß-caryophyllene was selected to evaluate its wound healing potential and pharmacological mechanisms. The excision wound model was used with male Wistar rats and macroscopic, histological, immunohistochemical and biochemical analyses were performed with skin samples, comparing the ß-caryophyllene-treated group with reference drugs. The results showed macroscopic retraction of the wounds treated with ß-caryophyllene. Biochemical assays revealed the antioxidant and anti-inflammatory mechanisms of the ß-caryophyllene-treated group with increasing levels of IL-10 and GPx and decreasing levels of pro-inflammatory molecules, including TNF-α, IFN-γ, IL-1ß and IL-6. After ß-caryophyllene treatment, immunohistochemical assays showed enhanced re-epithelialization, through the increase in laminin-γ2 and desmoglein-3 immunolabeling. ß-caryophyllene also act in the remodeling mechanism, increasing the collagen content in the Masson's trichrome staining. These findings indicated the wound-healing potential of ß-caryophyllene topical formulation in rat skin wounds, mediated by antioxidant, anti-inflammatory and re-epithelialization mechanisms.

Cutaneous Wound Healing: An Update from Physiopathology to Current Therapies.

The skin is the biggest organ of human body which acts as a protective barrier against deleterious agents. When this barrier is damaged, the organism promotes the healing process with several molecular and cellular mechanisms, in order to restore the physiological structure of the skin. The physiological control of wound healing depends on the correct balance among its different mechanisms. Any disruption in the balance of these mechanisms can lead to problems and delay in wound healing. The impairment of wound healing is linked to underlying factors as well as aging, nutrition, hypoxia, stress, infections, drugs, genetics, and chronic diseases. Over the years, numerous studies have been conducted to discover the correct approach and best therapies for wound healing, including surgical procedures and non-surgical treatments such as topical formulations, dressings, or skin substitutes. Thus, this general approach is necessary to facilitate the direction of further studies. This work provides updated concepts of physiological mechanisms, the factors that can interfere, and updated treatments used in skin wound healing.

The Use of Menthol in Skin Wound Healing-Anti-Inflammatory Potential, Antioxidant Defense System Stimulation and Increased Epithelialization.

Wound healing involves inflammatory, proliferative, and remodeling phases, in which various cells and chemical intermediates are involved. This study aimed to investigate the skin wound healing potential of menthol, as well as the mechanisms involved in its effect, after 3, 7, or 14 days of treatment, according to the phases of wound healing. Skin wound was performed in the back of Wistar rats, which were topically treated with vehicle cream; collagenase-based cream (1.2 U/g); or menthol-based cream at 0.25%, 0.5%, or 1.0% over 3, 7, or 14 days. Menthol cream at 0.5% accelerated the healing right from the inflammatory phase (3 days) by decreasing mRNA expression of inflammatory cytokines TNF-α and Il-6. At the proliferative phase (7 days), menthol 0.5% increased the activity of antioxidant enzymes SOD, GR, and GPx, as well as the level of GSH, in addition to decreasing the levels of inflammatory cytokines TNF-α, IL-6, and IL-1ß and augmenting mRNA expression for Ki-67, a marker of cellular proliferation. At the remodeling phase (14 days), levels of inflammatory cytokines were decreased, and the level of Il-10 and its mRNA expression were increased in the menthol 0.5% group. Menthol presented skin wound healing activity by modulating the antioxidant system of the cells and the inflammatory response, in addition to stimulating epithelialization.

Hyptis suaveolens (L.) Poit protects colon from TNBS-induced inflammation via immunomodulatory, antioxidant and anti-proliferative mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: In folk medicine Hyptis suaveolens (Lamiaceae) has been reported to relieve respiratory and gastrointestinal infections, indigestion, cold, pain, fever, cramps, skin diseases, gastric ulcer and inflammatory disorders. This study investigated the effects and the mechanisms of action of Hyptis suaveolens (L.) Poit (Lamiaceae) ethanol extract (Hs-EtOH) and hexane phase (Hs-HexF) against intestinal inflammation. MATERIAL AND METHODS: Acute and relapse TNBS-induced ulcerative colitis protocols were used to evaluate intestinal anti-inflammatory activity. Damage evaluations, biochemical, histological and immunostaining parameters were determined. RESULTS: Both extracts decreased macroscopic colonic inflammation and the area of lesion induced by TNBS. Nevertheless, only Hs-HexF was able to reduce colonic wall thickness, edema and diffuse inflammatory cell infiltration and to prevent GSH depletion in the acute model of ulcerative colitis. In the chronic phase with relapse of colonic ulceration, yet again only Hs-HexF significantly attenuated inflammatory parameters and presented a decrease in nitrite/nitrate, MDA, MPO, IL-1-ß and TNF-α and increased levels of SOD, CAT, GSH and IL-10. Hs-HexF also significantly reduced positive cells immunostained for PCNA. CONCLUSION: The data indicate intestinal anti-inflammatory activity for H. suaveolens, due to the participation of the antioxidant system, decreased neutrophil infiltration and cytokine modulation, as well as, owing to regulation of cell proliferation.

Mechanisms of the gastric antiulcerogenic activity of Anacardium humile St. Hil on ethanol-induced acute gastric mucosal injury in rats.

Leaves and bark infusions Anacardium humile St. Hil. (Anacardiaceae), known as in Brazil as "cajuzinho do cerrado", have been used in folk medicine as an alternative treatment for ulcers and gastritis. This study evaluated the gastroprotective activity of an ethyl acetate extract of the leaves of A. humile (AcF) and the mechanism involved in this gastroprotection. Pretreatment concentrations (50, 100, 200 mg x kg⁻¹) were administered by gavage. Following a 60 min. period, all the rats were orally administered 1 mL of absolute ethanol. One hour after the administration of ethanol, all groups were sacrificed, and the gastric ulcer index was calculated. Prostaglandin PGE2 concentration, gastric adherent mucous, and the participation of nitric oxide (NO) and sulfhydryl compounds in the gastroprotection process were also analyzed using the most effective tested dose (50 mg x kg⁻¹). A histological study of the glandular stomach for the evaluation of the epithelial damage and mucus content was also performed. AcF significantly reduced the gastric damage produced by ethanol. This effect was statistically significant for the 50 mg x kg⁻¹ group compared to control. Also, it significantly increased the PGE2 (by 10-fold) and mucous production, while pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) or N-ethylmaleimide (NEM) completely abolished the gastroprotection. AcF has a protective effect against ethanol, and this effect, might be due to the augmentation of the protective mechanisms of mucosa.

Corrigendum to "Lupeol, a Dietary Triterpene, Enhances Wound Healing in Streptozotocin-Induced Hyperglycemic Rats with Modulatory Effects on Inflammation, Oxidative Stress, and Angiogenesis".

[This corrects the article DOI: 10.1155/2019/3182627.].

Relationship between mast cells and the colitis with relapse induced by trinitrobenzesulphonic acid in Wistar rats.

The present study aimed to clarify the role of mast cells in colitis with relapse induced in Wistar rats by trinitrobenzenosulphonic acid. Colitis induction increased the histamine concentration in the colon, which peaked on day 26. The number of mast cells, probably immature, was ten times higher on day 8. Different from animals infected with intestinal parasites, after colitis remission, mast cells do not migrate to the spleen, showing that mast cell proliferation presents different characteristics depending on the inflammation stimuli. Treatment with sulfasalazine, doxantrazole, quercetin, or nedocromil did not increase the histamine concentration or the mast cell number in the colon on day 26, thereby showing absence of degranulation of these cells. In conclusion, although mast cell proliferation is associated with colitis, these cells and their mediators appear to play no clear role in the colitis with relapses.

Gastroprotective effect of limonene in rats: Influence on oxidative stress, inflammation and gene expression.

BACKGROUND: In an increasing search for natural products that may heal the ulcers and avoid its recurrence, limonene appears as a promising candidate. HYPOTHESIS/PURPOSE: The present study aimed to investigate the protective effect of limonene in ethanol-induced gastric ulcers, in addition, to investigate the involvement of antioxidant and anti-inflammatory activities, besides the modulation of gene expression. STUDY DESIGN: Male Wistar rats were orally treated with vehicle (8% tween 80), carbenoxolone (100 mg/kg) or limonene (25, 50 or 100 mg/kg) and then orally received ethanol to induce gastric ulcers formation. METHODS: The activity of myeloperoxidase (MPO) was measured. Levels of glutathione (GSH) and activities of glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD) were measured. We investigated the anti-inflammatory effect of limonene measuring the levels of pro-inflammatory cytokines tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and anti-inflammatory cytokine interleukin-10 (IL-10) by ELISA. Additionally, we investigate through real-time PCR (qPCR) the gene expression of nuclear factor-kappa B (Nf-κb), Gpx, Il-1ß, Mpo, and Il-10. RESULTS: Our results showed that limonene 50 mg/kg was the lowest effective dose, offering 93% of reduction in gastric ulcer area compared with the vehicle. There was an increase in mucus production and higher preservation of gastric mucosa integrity after treatment with limonene.There was a reduction in the MPO activity, a biomarker of neutrophils infiltration, and an increase in GPx activity, suggesting an antioxidant effect. Limonene displayed anti-inflammatory activity through decreasing the levels of TNF-a, IL-6, and IL-1ß and increasing the level of IL-10. Limonene could down-regulate the expression of Nf-κb, Il-1ß, and Mpo and up-regulate the expression of Gpx. CONCLUSION: Our results demonstrate that oral treatment with limonene exerts gastroprotection through local mucosal defense mechanisms, such as increasing the mucus production, modulation of the oxidative stress and inflammatory response and inhibition of Nf-κb expression.

Lupeol, a Dietary Triterpene, Enhances Wound Healing in Streptozotocin-Induced Hyperglycemic Rats with Modulatory Effects on Inflammation, Oxidative Stress, and Angiogenesis.

Impaired wound healing is a debilitating complication of diabetes that leads to significant morbidity, particularly foot ulcers. Natural products have shown to be effective in treating skin wounds. Lupeol is known to stimulate angiogenesis, fibroblast proliferation, and expressions of cytokines and growth factors involved in wound healing. The study is performed to evaluate the wound healing activity of lupeol in streptozotocin-induced hyperglycemic rats by macroscopical, histological, immunohistochemical, immunoenzymatic, and molecular methods. Percentage of wound closure and contraction was increased in the lupeol-treated group when compared to the Lanette group. Histopathological observation revealed decreased inflammatory cell infiltration and increased proliferation of fibroblasts, vascularization, and deposition of collagen fibers after lupeol treatment. Immunohistochemical analyses showed decreased intensity of NF-κB and increased intensity of FGF-2, TGF-ß1, and collagen III. ELISA results revealed downregulated IL-6 levels and upregulated IL-10 levels in response to lupeol. The mRNA expression levels of Hif-1α, Sod-2, and Ho-1 were significantly increased in response to lupeol as compared to Lanette whereas Nf-κb and Vegf-A levels were decreased in relation to insulin and lupeol treatment. These findings indicate that lupeol possesses wound healing potential in hyperglycemic conditions and may be useful as a treatment for chronic wounds in diabetic patients.

Evaluation of enteral and parenteral hyaluronic acid in induced ischemic skin flaps in rats: a double-blinded and randomized study

Purpose: To evaluate exogenous hyaluronic acid (HA) derived from bacterial fermentation through enteral and parenteral routes in ischemic skin flaps induced in rats, using clinical and histological exams; and interleukins (IL) as tissue inflammatory biomarkers. Methods: Sixty-four male adults Wistar rats with ischemic skin flaps on the dorsum were randomized into four groups, based on the treatment protocol: subcutaneous administration of saline solution (0.9%) (GI); oral administration of distilled water (GII); subcutaneous administration of HA (0.3%) (GIII); and oral administration of HA (1%) (GIV). Flaps of all groups were comparable regarding clinical and macroscopic evaluation, histological examination, pro-inflammatory cytokines (IL-1ß, IL-6, and tumor necrosis factor-α) and anti-inflammatory cytokine IL-10. Results: A lower percentage of necrosis was identified in flaps treated with subcutaneous administration of HA (0.3%). The pro- and anti-inflammatory cytokines, epidermis thickness, blood vessels, and inflammatory cells showed statistically significant inter-group and intra-group differences (p < 0.05). Conclusions: High molecular HA (1,400 ~ 2,000 kDa) administrated by subcutaneous or oral route exhibited beneficial effects in ischemic skin flaps of rats. However, subcutaneous administration of HA (0.3%) showed better results in terms of the percentage of necrosis and epithelialization.