Comparative study of the antioxidant and anti-inflammatory effects of the natural coumarins 1,2-benzopyrone, umbelliferone and esculetin: in silico, in vitro and in vivo analyses.

The aim of this work was to compare the anti-inflammatory and antioxidant effects of three natural coumarins: 1,2-benzopyrone, umbelliferone and esculetin. The antioxidant capacity of coumarins was evaluated using both chemical and biological in vitro assays. Chemical assays included DPPH and ABTS∙+ radical scavenging as well as ferric ion reducing ability power (FRAP) assay. Inhibition of mitochondrial ROS generation and lipid peroxidation in brain homogenates were used as biological in vitro assays. The experimental method of carrageenan-induced pleurisy in rats was used for the in vivo investigation of the anti-inflammatory activity. In silico molecular docking analysis was undertaken to predict the affinity of COX-2 to the coumarins. Considering the antioxidant capacity, esculetin was the most efficient one as revealed by all employed assays. Particularly, the mitochondrial ROS generation was totally abolished by the compound at low concentrations (IC50 = 0.57 µM). As for the anti-inflammatory effects, the COX-2 enzyme presented good affinities to the three coumarins, as revealed by the molecular docking analyses. However, considering the in vivo anti-inflammatory effects, 1,2-benzopyrone was the most efficient one in counteracting pleural inflammation and it potentiated the anti-inflammatory actions of dexamethasone. Umbelliferone and esculetin treatments failed to reduce the volume of pleural exudate. Overall, therefore, our results support the notion that this class of plant secondary metabolites displays promising effects in the prevention and/or treatment of inflammation and other diseases associated with oxidative stress, although the singularities regarding the type of the inflammatory process and pharmacokinetics must be taken into account.

Development and characterization of trans-anethole-containing solid lipid microparticles: antiinflammatory and gastroprotective effects in experimental inflammation.

The present study prepared, optimized, and characterized solid lipid microparticles that contained trans-anethole (SLMAN), evaluated their antiinflammatory activity in acute and chronic inflammation models, and investigated their effects on the gastric mucosa in arthritic rats. The microparticles were obtained by a hot homogenization process and characterized by physicochemical analyses. The acute inflammatory response was induced by an intradermal injection of 0.1 ml of carrageenan solution (200 µg) in the hind paw. The rats were treated orally with a single dose of SLMAN 1 h before induction of the inflammatory response. The chronic inflammatory response was induced by the subcutaneous application of 0.1 ml of complete Freund's adjuvant suspension (500 µg) in the hind paw. SLMAN was orally administered, starting on the day of arthritis induction, and continued for 21 days. The results showed that SLMAN was obtained with good encapsulation efficiency. Treatment with SLMAN at doses of 25 and 50 mg/kg was as effective as trans-anethole (AN) at a dose of 250 mg/kg on acute and chronic inflammatory responses. Histological analyses showed that treatment with SLMAN did not aggravate lesions in the gastric mucosa in arthritic rats. These results indicated that treatment with SLMAN at a dose that was 5-10 times lower than non-encapsulated AN exerted an inhibitory effect on acute and chronic inflammatory responses, suggesting the better bioavailability and efficacy of microencapsulated AN without aggravating lesions in the gastric mucosa in arthritic rats.

Moderate intestinal immunopathology after acute oral infection with Toxoplasma gondii oocysts is associated with expressive levels of serotonin.

BACKGROUND: Invasion of the intestinal mucosa by T. gondii elicits a local immune response of variable intensity. These reactions can be lethal in C57BL/6 mice. The tissue damage caused by inflammation and the functional effects depend on the host immunity, strain, and developmental form of the parasite. We investigated the effects of acute oral infection with T. gondii on histoarchitecture, enteric nervous system (ENS), and inflammatory markers in the jejunum and ileum of mice. METHODS: Female C57BL/6 mice were divided into a control group and a group orally infected with 1000 sporulated T. gondii oocysts (ME-49 strain). After 5 days, jejunum and ileum were collected and processed for analyzes (e.g., histological and histopathological examinations, ENS, cytokine dosage, myeloperoxidase, nitric oxide activity). MAIN RESULTS: In infected mice, we observed a significant increase in serotonin-immunoreactive cells (5-HT IR) in the intestinal mucosa, as well as cellular infiltrates in the lamina propria, periganglionitis, and ganglionitis in the myenteric plexus. We also noted decreased neuron density in the jejunum, increased population of enteric glial cells in the ileum, histomorphometric changes in the intestinal wall, villi, and epithelial cells, remodeling of collagen fibers, and increased myeloperoxidase activity, cytokines, and nitric oxide in the intestine. CONCLUSIONS AND INFERENCES: Acute infection of female mice with T. gondii oocysts resulted in changes in ENS and a marked increase in 5-HT. These changes are consistent with its modulatory role in the development of moderate acute inflammation. The use of this experimental model may lend itself to studies aimed at understanding the pathophysiological mechanisms of intestinal inflammation in humans involving ENS.

Hepatoprotective effect of ß-myrcene pretreatment against acetaminophen-induced liver injury.

Objective: In the present study, the hepatoprotective effects of ß-myrcene (MYR) on acetaminophen-induced hepatotoxicity were investigated. Materials and Methods: A total of 40 Balb/c mice were randomly divided into five groups as follows: 1) Normal control group which received only carboxymethylcellulose (CMC), the vehicle used to dissolve acetaminophen (N-acetyl-p-aminophenol, APAP, paracetamol) and MYR; 2) APAP group which received a single dose of acetaminophen (250 mg/kg) orally on day 7; 3) Silymarin group which received 200 mg/kg/day of silymarin; and 4 and 5) pretreatment groups in which, mice were treated with 100 or 200 mg/kg/day of MYR. Liver and blood samples were collected to analyze serum aminotransferases, inflammatory response, oxidative stress markers, and histopathological insults. Results: Our results showed that MYR pretreatment attenuated liver damage and restored liver cells function and integrity as it decreased the leakage of serum aminotransferases (alanine and aspartate aminotransferases (ALT and AST, respectively)) into the blood (p<0.01). MYR treatment also reduced levels of myeloperoxidase (MPO) activity and nitric oxide (NO) (p<0.001). In addition, MYR pretreatment demonstrated significant antioxidant activity by decreasing malondialdehyde (MDA), reactive oxygen species (ROS), and reduced glutathione (GSH) levels (p<0.001). Furthermore, it restored the hepatic level of superoxide dismutase (SOD), catalase (CAT), and oxidized glutathione (GSSG) (p<0.001). Conclusion: For the first time, our results showed that MYR treatment significantly improved liver function by reducing oxidative stress and the inflammatory response induced by APAP.

Exopolysaccharides from Klebsiella oxytoca: anti-inflammatory activity

Abstract Exopolysaccharides (EPS) produced by Klebsiella oxytoca are of environmental, pharmaceutical, and medicinal interest. However, studies about the anti-inflammatory activity of EPS produced by this microorganism still remain limited. The aim of this study was to produce, characterize, and evaluate the anti-inflammatory activity of EPS from K. oxytoca in a pleurisy model. Colorimetric analysis revealed that precipitated crude exopolysaccharides (KEPSC) and deproteinated exopolysaccharides (KEPS) present high levels of total carbohydrates (65.57% and 62.82%, respectively). Analyses of uronic acid (7.90% in KEPSC and 6.21% in KEPS) and pyruvic acid (3.01% in KEPSC and 1.68% in KEPS) confirm that the EPS are acidic. Gas chromatography-mass spectrometry analyses demonstrated that the EPS consisted of rhamnose (29.83%), glucose (11.21%), galactose (52.45%), and mannose (6.50%). The treatment of an experimental pleurisy model in rats through subcutaneous administration of 50, 100, 200, and 400 mg/kg of KEPS decreased both the volume of inflammatory exudate and the number of leukocytes recruited to the pleural cavity. The present data showed that EPS production by K. oxytoca using the method described is easy to perform and results in a good yield. In addition, we show that KEPS exhibit anti-inflammatory activity when administered subcutaneously in rats.

Prostaglandin E1 prevents histopathological changes improving renal function in experimental nephropathy induced by renal microembolism.

This study investigated the effect of prostaglandin E1 (PGE-1) treatment on the biochemical and histopathological changes in a model of nephropathy that was induced using renal microembolism in rats. Wistar rats were assigned to three groups: a control group (C, normal), a renal microembolism (RM) group, and a renal microembolism treated with PGE-1 (RM + PGE-1) group. The renal microembolism was induced by an arterial injection of polymethylmethacrylate microbeads into the remaining kidney of nephrectomized rats. Intramuscular treatment with PGE-1 was initiated on the day of the induction of the renal microembolism and continued once weekly for up to 60 days. At the end of the treatment period, blood samples were taken to assess the serum creatinine and urea concentrations, and 24-h urine samples were collected to determine the total protein levels. The rats' kidneys were removed and processed for histopathological analysis using the hematoxylin and eosin, periodic acid-Schiff, Mallory-Azan, and Picro-Sirius techniques. An immunohistochemical assay with vascular endothelial growth factor receptor-2 (anti-VEGFR-2) was also performed. The results showed that the PGE-1 treatment prevented vascular, glomerular, tubular, and interstitial alterations and reduced the biochemical changes, thus improving the renal function in rats that were subjected to renal microembolism. These effects could be partially attributable to an increase in the PGE-1-induced angiogenesis, because we observed an increase in the tissue expression of VEGFR-2, a specific marker of angiogenesis.

Suplementação com Vitamina D atenua a resposta inflamatória aguda / Vitamin D supplementation attenuates acute inflammatory response

Este estudo avaliou os efeitos da suplementação diária de vitamina D na resposta inflamatória aguda em modelo experimental por diferentes agentes flogísticos: carragenina, prostaglandina e dextrana. Os animais (ratos) receberam por via oral (gavagem), dose única de vitamina D ou suplementação diária durante 7, 15 ou 30 dias antes da indução do edema de pata. A suplementação com vitamina D por 15 e 30 dias reduziu significativamente o processo inflamatório induzido por carragenina, o que poderia ser explicado, pelo menos parcialmente, pela redução dos níveis de fator de necrose tumoral α (TNFα). Os resultados indicam que a suplementação de vitamina D pode ser um útil adjuvante terapêutico para o controle do processo inflamatório agudo.

This study evaluated the effects of daily vitamin D supplementation on the acute inflammatory response in experimental model by different phlogistic agents: carrageenan, prostaglandin and dextran. Animals (rats) orally received (gavage) a single dose of vitamin D or daily supplementation for 7, 15 or 30 days prior to paw edema induced. Vitamin D supplementation for 15 and 30 days significantly reduced the carrageenan-induced inflammatory process, which could be at least partially explained by the reduction of tumor necrosis factor α levels (TNFα). Results indicate that vitamin D supplementation may be a useful therapeutic adjuvant for controlling the acute inflammatory process.

Anti-inflammatory Effect of Low-Dose Anethole and Ibuprofen Combination Is Accompanied by Partial Prevention of Hepatic Metabolic Changes in Arthritic Rats.

Anethole (AN) is a natural compound that has attracted great scientific interest because of its numerous biological activities, including anti-inflammatory effects. However, these effects were obtained with high doses of AN, which may be one limitation of its therapeutic use. This study evaluated the effects of a low-dose AN and ibuprofen (IB) combination on inflammatory parameters in Freund's complete adjuvant-induced arthritis (AIA) and arthritis-induced hepatic metabolic changes. Holtzman rats were used and divided into groups: normal, AIA (control), arthritics treated with IB, arthritics treated with AN, and arthritics treated with AN + IB. The volume of the paws, the appearance of secondary lesions, and the number of synovial leukocytes were evaluated. Gluconeogenesis and ureagenesis from alanine were determined in the rat liver in isolated perfusion. The AN + IB (62.5 + 8.75 mg/kg) treatment exerted an inhibitory effect on inflammatory parameters and partially prevented hepatic metabolic changes that was similar to the effect of high-dose IB (35 mg/kg) and AN (250 mg/kg) treatment. This effect of the treatments on hepatic metabolism can be, partly at least, explained by the preservation of both the alanine aminotransferase (ALT) activity and the cytosolic NADH/NAD+ redox potential in the liver. Taken together, the data obtained provided evidence that the AN + IB combination at lower doses than AN and IB treatment alone had beneficial inhibitory potential for the treatment of AIA and attenuated metabolic changes in the liver. Graphical Abstract.

Biochemical Properties and Effects on Mitochondrial Respiration of Aqueous Extracts of Basidiomycete Mushrooms.

There are different varieties of mushrooms not yet studied spread all over the planet. The objective of this study was to evaluate biochemical properties and effects on mitochondrial respiration of eight Basidiomycete mushrooms: Flaviporus venustus EF30, Hydnopolyporus fimbriatus EF41 and EF44, Inonotus splitgerberi EF46, Oudemansiella canarii EF72, Perenniporia sp. EF79, Phellinus linteus EF81, and Pleurotus albidus EF84. Total phenols, ABTS, TEAC, FRAP, and ORAC were measured in order to determine the antioxidant capacity. Antimicrobial potential was studied by disc-diffusion and microdilution method. Cytotoxicity was determined in murine peritoneal macrophages. The bioenergetic aspects were evaluated by the uncoupling of the oxidative phosphorylation in mitochondrias. The H. fimbriatus mushroom was the one that presented the most significant results for the antioxidant assays. Three mushrooms presented antimicrobial activity, indicating a potential for formulation of drugs. The results suggest that I. spligerberi has an uncoupling activity, even at the lowest concentration tested, dissipating the mitochondrial electrochemical gradient. On the other hand, P. albidus has effect only on succinate-oxidase activity without influencing mitochondrial respiratory efficiency. Therefore, both interfere negatively in mitochondrial respiration. In relation with the cytotoxicity in peritoneal macrophages, O. canarii and F. venustus were cytotoxic in this type of cells.

Effect of (-)-α-Bisabolol on the Inflammatory Response in Systemic Infection Experimental Model in C57BL/6 Mice.

(-)-α-Bisabolol (BISA) is an unsaturated monocyclic sesquiterpenes compound, mainly found in the essential oil of chamomile (Matricaria chamomilla). It has been reported that this compound has several biological activities, but there are few studies evaluating the activity of this compound in the systemic inflammatory response in infectious processes. The aim of this study was to evaluate the effect of BISA on the inflammatory response and survival rate in a systemic infection model, and in vitro neutrophils phagocytic activity. BISA at concentration of 3, 10, 30, and 90 µg/ml did not presented in vitro cytotoxicity in MTT assay, and at concentrations of 1 and 3 µg/ml the BISA treatment increased in vitro phagocytic neutrophil activity. For the inflammatory response study, we verified the BISA treatment effect in a cecal ligation and puncture (CLP)-induced systemic infection model in mice; in this model, we demonstrate that BISA at dose of 100 mg/kg reduced the leukocyte recruitment in peritoneal cavity; at dose of 200 mg/kg, the NO concentration was increased in the peritoneal cavity. The bacteria CFU number was reduced in mice blood in the BISA treatment, at doses of 100 and 200 mg/kg. The BISA treatment at doses of 50 and 100 mg/kg increased the myeloperoxidase activity and reduction NO production in lung tissue of mice in CLP model. At dose of 100 mg/kg, the BISA treatment was able to reduce the mortality rate of mice submitted to CLP-induced sepsis and observed for 7 days. The results suggest an effect of BISA on inflammatory response, with activity on leukocyte chemotactic and NO production, in addition to increasing the survival rate of animals submitted to CLP model.

Rheumatoid arthritis induces enteric neurodegeneration and jejunal inflammation, and quercetin promotes neuroprotective and anti-inflammatory actions.

AIMS: The aim of our study was to study the pathological mechanisms induced by the rheumatoid arthritis (RA) on the Enteric Nervous System (ENS). MAIN METHODS: We evaluated the effect of the chronic arthritis and its treatment with 50 mg/kg quercetin alone (AQ) and combined with 17.5 mg/kg ibuprofen (AIQ) for 60 days on neurons, glial cells and intestinal wall. Other groups were used: control (C), arthritic (A) and arthritic treated with 17.5 mg/kg ibuprofen (AI). After 60 days, the jejunum was removed and processed for immunohistochemical techniques. Immunostainings were performed for HuC/D and S100 (myenteric and submucosal plexuses), and GFAP (only myenteric plexus), while immunolabeling for CD45 and CD20 lymphocytes was performed using cryosections. Western blot was performed for GDNF, S100 and GFAP. KEY FINDINGS: A group yielded a remarkable density decrease of the neurons and glial cells with morphometric changes in the myenteric and submucosal plexuses, reduction of the GDNF expression and GFAP-related parameters (GFAP expression, occupancy area and GFAP-expressing glial cells) and intestinal inflammation and atrophy of the mucosa and intestinal wall. AQ group substantially reversed most of these effects, except for intestinal atrophy of the jejunum. The AI and AIQ groups displayed lower beneficial results than AQ for parameters related to the neurons and glial cells, although AIQ did not prevent the inflammation of the mucosa. SIGNIFICANCE: The severe chronic rheumatoid arthritis induced severe effects on ENS and mucosa, and quercetin treatment continues to be an important antioxidant supplement preventing the progression of the RA severity.

Nephropathy induced by renal microembolism: a characterization of biochemical and histopathological changes in rats.

The aim of this study was to investigate some biochemical parameters of renal function and the vascular, glomerular, tubular, and interstitial manifestations in the progression of nephropathy induced by renal microembolism. Renal microembolism was induced by the arterial injection of polymethacrylate microspheres in the remnant kidney of nephrectomized rats. Animals 110-120 days old were randomly divided into three groups: the control group (C; normal), the nephrectomized group (S; nephrectomized that did not undergo renal microembolism), and the model group (M, nephrectomized animals that underwent renal arterial microembolism). The animals were evaluated 30, 60, and 90 days after the induction of a renal microembolism. Blood and urine samples were collected to determine serum creatinine (Cr) and urea (Ur) concentrations and urine total protein (Pt) concentrations. The kidneys were weighed and processed for histopathological analysis using hematoxylin and eosin (HE), periodic acid-Schiff (PAS), Mallory-Azan, and Picro-Sirius staining. The samples were also subjected to immunohistochemistry with a proliferating cell nuclear antigen (PCNA) and a vascular endothelial growth factor receptor (VEGFR). The data demonstrated evidence of the occurrence of vascular, glomerular, tubular, and interstitial abnormalities in the renal tissue, and changes in the biochemical parameters of renal function (serum Cr and Ur and of 24-h urine Pt) in this experimental model of nephropathy induced by renal microembolism, which may indicate the development of chronic kidney disease (CKD). Additionally, the findings indicate that this is a good reproducibility model that may be useful for studying the pathogenesis of CKD that is caused by atheroembolism and possible treatment alternatives.

Effect of Lavender (Lavandula angustifolia) Essential Oil on Acute Inflammatory Response.

Lavandula angustifolia is a plant of Lamiaceae family, with many therapeutic properties and biological activities, such as anticonvulsant, anxiolytic, antioxidant, anti-inflammatory, and antimicrobial activities. The aim of this study was to evaluate the effect of Lavandula angustifolia Mill. essential oil (LEO) on acute inflammatory response. LEO was analyzed using gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR) methods and showed predominance of 1,8-cineole (39.83%), borneol (22.63%), and camphor (22.12%). LEO at concentrations of 0.5, 1, 3, and 10 µg/ml did not present in vitro cytotoxicity. Additionally, LEO did not stimulate the leukocyte chemotaxis in vitro. The LEO topical application at concentrations of 0.25, 0.5, and 1 mg/ear reduced edema formation, myeloperoxidase (MPO) activity, and nitric oxide (NO) production in croton oil-induced ear edema model. In carrageenan-induced paw edema model, LEO treatment at doses of 75, 100, and 250 mg/kg reduced edema formation, MPO activity, and NO production. In dextran-induced paw edema model, LEO at doses of 75 and 100 mg/kg reduced paw edema and MPO activity. In conclusion, LEO presented anti-inflammatory activity, and the mechanism proposed of LEO seems to be, at least in part, involving the participation of prostanoids, NO, proinflammatory cytokines, and histamine.

Behçet's Disease: Pulmonary Aneurysm Resolution with Oral Therapy and HLA B72 Allele Association.

We report the case of a woman who was diagnosed with a pulmonary artery aneurysm that was caused by Behçet's disease. The patient was initially diagnosed with community-acquired pneumonia and then pulmonary thromboembolism and aneurysm of the right pulmonary artery segmental branch was confirmed. The initial treatment consisted of anticoagulant drugs. After analysis of the family history and a positive pathergy test, the patient was diagnosed with Behçet's disease. Oral pharmacological treatment began with corticosteroids, cyclophosphamide, and anticoagulant suspension. The HLA B72 allele was identified in the patient and her two sisters, demonstrating the familial characteristic of the disease and the presence of this allele in a female patient with Behçet's disease. After 12 months of treatment, the clinical condition completely resolved.

Evaluation of the in vivo acute antiinflammatory response of curcumin-loaded nanoparticles.

Curcumin is the main curcuminoid found in turmeric rhizomes and is a strong candidate to formulate foodstuff with specific properties. Among various bioactive properties of curcumin, its antiinflammatory activity is remarkable; on the other hand, its low water solubility leads to low absorption. Thus, new formulations need to be developed to improve its efficacy, and encapsulation is a promising alternative strategy in this regard. The objective of the present study was to obtain curcumin-loaded polyvinylpyrrolidone (PVP) nanoparticles and evaluate their acute in vivo antiinflammatory activity. Nanoparticles were obtained by complexation using the solid dispersion technique, and the characterization of nanoparticles showed that curcumin and PVP formed an amorphous solid solution. Encapsulated curcumin was colloidally stable in distilled water; this was attributed to the formation of hydrogen bonds between curcumin hydroxyl and PVP carbonyl groups. Rats were treated orally with single doses of curcumin and curcumin-loaded PVP nanoparticles, and antiinflammatory activity was evaluated by an experimental model of carrageenan-induced paw edema, myeloperoxidase (MPO) activity, and microcirculation in situ. Treatment with nanoparticles at 12.5 mg kg-1 significantly reduced the intensity of edema and MPO activity, whereas pure curcumin only presented a significant effect at 400 mg kg-1. Curcumin inhibited cell migration since rolling and adherent leukocytes were significantly reduced using nanoparticles at 50 mg kg-1 and curcumin at 400 mg kg-1. Compared to free curcumin, encapsulated curcumin was effective at lower doses; this might be due to the improved water affinity and colloidal stability of curcumin nanoparticles.

Oral pharmacological treatment for patent ductus arteriosus in premature neonates with hemodynamic repercussions.

OBJECTIVE: To evaluate the efficacy of oral indomethacin, ibuprofen, and paracetamol in oral dosage form on patent ductus arteriosus (PDA) in premature neonates with significant clinical and hemodynamic repercussions (CHRs) and to determine the effect of these respective treatments on renal function. METHODS: A retrospective study of cases of PDA in premature neonates in the Neonatal Intensive Care Unit was conducted. The treatments consisted of indomethacin [0.2 mg/(kg·d), 3-day cycle], ibuprofen [10 mg/(kg·d) followed by 5 mg/(kg·d), 3-day cycle], and paracetamol (15 mg/kg every 6 h, 5-day cycle). The drugs were administered as an oral solution. The following variables were considered: gestational age, newborn weight at birth, Apgar score, diuresis, serum creatinine and urea levels, and serum electrolyte levels (sodium and potassium). RESULTS: Treatment with indomethacin presented efficacy of 87.5% in closure of the ductus with a mean outcome period of 3.5 d. In premature neonates with CHRs and contraindications for indomethacin, the initial treatment with either ibuprofen or paracetamol failed to close the ductus. However, when this treatment was followed by indomethacin, closure occurred in 66.7% of the neonates, with an outcome period of 9.66 d. The initial treatment with one cycle of ibuprofen followed by one or two cycles of paracetamol failed to close the ductus. CONCLUSIONS: Oral indomethacin was effective for closure of the PDA in premature neonates with severe CHRs. Oral paracetamol or ibuprofen for PDA closure in premature neonates with severe CHRs and contraindications for indomethacin was ineffective. However, results in clinical improvements of neonates allowed the subsequent use of indomethacin and successful closure of the ductus. A significant reduction of diuresis occurred in neonates who were treated with indomethacin, either as a first-line treatment or after the failure of ibuprofen or paracetamol.

A single administration of fish oil inhibits the acute inflammatory response in rats.

OBJECTIVE: To investigate the antiinflammatory effects of a single administration of fish oil (FO) on the acute inflammatory response. METHODS: The paw edema and pleurisy models were used to evaluate the effects of FO dissolved in olive oil (FOP) orally administered in a single dose in rats. Nitric oxide (NO) concentrations in the pleural exudate were performed according to the Griess method and the cytokine concentrations were determined by Luminex bead-based multiplex assay. RESULTS: FOP treatment (30 and 300 mg/kg) significantly reduced paw edema. FOP treatment at 18.75, 37.5, 75.0, 150.0, and 300 mg/kg decreased both the volume of pleural exudate and cellular migration into the pleural cavity and each of these doses presented the same effectiveness. Treatment with FOP (300 mg/kg) reduced NO, TNF-α, IL-1ß, and IL-6 concentrations in the pleural exudate. CONCLUSIONS: The present data provide evidence that FO has inhibitory effects on the acute inflammatory response when administered in a single dose in rats. This effect might be attributable to a direct inhibitory effect of FO on the production or release of inflammatory mediators that are involved in the pathological processes evaluated herein.

Insulin complexed with cyclodextrins stimulates epithelialization and neovascularization of skin wound healing in rats.

INTRODUCTION: Skin lesions are a significant public health problem, above all that wounds fail to heal properly and become chronic. Due to its reepithelization action, insulin has the potential to heal skin lesions, by stimulating the proliferation and migration of keratinocytes, angiogenic stimulus, and increasing collagen deposition. In the present study insulin was complexed with 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and its wound healing effect and inclusion complex (HPßCD-I) were evaluated in excisional wounds in the skin of rats. MATERIAL AND METHODS: Three different gel based pharmaceutical forms were created: carbopol 940® base gel, an insulin gel comprising the base gel plus 50 IU of insulin and a gel complex comprising the base gel plus (HPßCD) complexed with insulin (HPßCD-I) were used to verify wound healing in vitro and in vivo assays. RESULTS: The wounds in the skin of rats were treated with gel containing HPßCD-I not cytoxically irritating and cytotoxic. Analysis of cell proliferation and measurement of the length and thickness of the epidermis showed that HPßCD-I prolonged the proliferation and migration of keratinocytes. Revascularization analysis of lesions treated with HPßCD-I compared to those treated with insulin found that angiogenic stimulus was less intense, but more constant and prolonged in the modified release process. There was increased deposition of type I and III collagen fibers in accordance with the treatment time. CONCLUSION: Therefore, the slow release of complexed insulin modulated the reepithelialization process by stimulating cell proliferation and migration of keratinocytes, favoring greater concentration of serum insulin, modulating inflammatory response, matrix remodeling and promoting neovascularization. Angiogenesis extended by the steady release of insulin can be effective in the treatment of chronic wounds.

Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice.

High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP.

Anethole reduces inflammation and joint damage in rats with adjuvant-induced arthritis.

AIM: This study evaluated whether anethole attenuates the inflammatory response and joint damage in a model of adjuvant-induced arthritis (AIA) in rats. METHODS: The animals were treated with 62.5-, 125-, or 250-mg/kg anethole daily for 21 days after AIA and necropsied on days 14 and 21 to evaluate the number of serum and synovial leukocytes (total and differential), serum cytokines (IL-2, IL-6, IL-12, IL-17, and TNF-α), and nitric oxide concentrations. Morphologic changes in the cartilage and bone of the femorotibial articulation in both left paw and right paw were studied in hematoxylin/eosin and Sirius Red-hematoxylin sections. RESULTS: Different doses of anethole suppressed paw swelling and the number of serum and synovial leukocytes. However, 250 mg/kg of anethole more effectively controlled local and systemic inflammation. Histological evaluation revealed significant prevention of cartilage damage and inflammatory infiltrate scores. Morphometric analysis showed pannus formation, the thickness of the articular cartilage, and bone resorption lower in the anethole-treated AIA group compared to untreated AIA group on both days 14 and 21. These significant anti-inflammatory effects in the anethole-treated AIA group were associated with downregulation of cytokines and nitric oxide levels. CONCLUSION: Therefore, anethole may be a useful intervention to treat inflammatory arthritis.