C. Alarcón de la Lastra

Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions.

This study was designed to determine the ulcer-protecting effects of rutin, a natural flavone, against gastric lesions induced by 50% ethanol, the experimental model related to lesion pathogenesis with production of reactive species. The possible involvement of sulphydryl compounds (SH), neutrophil infiltration, and the capacity of this flavone to restrain the oxidative process produced in the gastric tissue were also investigated. The levels of thiobarbituric acid (TBA, as index of lipid peroxidation), the myeloperoxidase activity (MPO, as a marker of neutrophil infiltration), the content of mucosal sulphydryls (SH) groups and the activity of glutathione peroxidase (GSH-Px, an important antioxidant enzyme) were determined. Pretreatment with the highest dose of rutin (200 mg/kg), 120 min before 50% ethanol, resulted in the most effective necrosis prevention. TBA reactive substances in the gastric mucosa, were increased by ethanol injury, and this increase was inhibited by the administration of 200 mg/kg of rutin. However, the flavonoid was not able to modify the ethanol-induced neutrophil infiltrate expressed as myeloperoxidase activity. Exposure of the gastric mucosa to 50% ethanol induced a significant diminution in gastric non-protein SH content; this parameter also was not modified by the treatment with rutin. GSH-Px activity decreased in the gastric mucosa after ethanol-treatment. In contrast, rutin at all tested doses induced a significant increase in this enzymatic activity, higher than in control group. These results suggest that the gastroprotective effect of rutin in this experimental model appears through an anti-lipoperoxidant effect, and also by enhancement of the anti-oxidant enzymatic (GSH-Px) activity.

Olive oil and health: Summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008

Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory properties, prevent lipoperoxidation, induce favorable changes of lipid profile, improve endothelial function, and disclose antithrombotic properties. Observational studies from Mediterranean cohorts have suggested that dietary MUFA may be protective against age-related cognitive decline and Alzheimers disease. Recent studies consistently support the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity. In countries where the population adheres to the MedDiet, such as Spain, Greece and Italy, and OO is the principal source of fat, rates of cancer incidence are lower than in northern European countries. Experimental and human cellular studies have provided new evidence on the potential protective effect of OO on cancer. Furthermore, results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk (mainly breast, colorectal and prostate cancers).

Mediterranean Diet and Health: Biological Importance of Olive Oil

Olive oil, the main fatty component of the Mediterranean diet, is characterized by consisting of monounsaturated fatty acids as well as by its elevated content in antioxidant agents. This oil exhibits numerous biological functions which are beneficial for the state of health. A diet rich in monounsaturated fatty acids provides an adequate fluidity to the biological membranes, diminishing the hazard of lipid peroxidation which affects polyunsaturated fatty acids. Moreover, the antioxidants present in olive oil are able to scavenge free radicals and afford an adequate protection against peroxidation. Regarding the heart, olive oil decreases the plasmatic levels of LDL-cholesterol and increases those of HDL-cholesterol, hence diminishing the risk of suffering from heart complaints. In this context, it has been suggested that increased consumption of monounsaturated fatty acids in place of polyunsaturated fatty acids will render circulating lipoproteins less sensitive to peroxidation and thereby diminish the development of atherosclerosis. Olive oil has also been proven to contribute to a better control of the hypertriglyceridemia accompanying diabetes and may reduce the risk of breast cancer and colorectum. On the other hand, several investigations have suggested that olive oil can be beneficial in inflammatory and autoimmune diseases, such as rheumatoid arthritis. In this sense, some reports have indicated that olive oil modifies inflammatory cytokines production. As for the digestive system, olive oil enhances gallbladder emptying consequently reducing cholelithiasis risk, decreases the pancreatic exocrine secretion and gastric secretory function in response to food. Finally, it has been demonstrated that a diet rich in olive oil is associated with a high percentage of gastric ulcer healing and affords a higher resistance against non steroidal antiinflammatory drugs-induced gastric ulcerogenesis.

Antiulcer and Gastroprotective Effects of Quercetin: A Gross and Histologic Study

This study was designed to determine the cytoprotective properties of quercetin and the involvement of endogenous prostaglandins in mucosal injury produced by absolute ethanol. Gastric glands were also analyzed histologically. Oral pretreatment with the highest dose of quercetin (200 mg/kg), 120 min before absolute ethanol, was most effective in necrosis prevention. Subcutaneous administration of indomethacin (10 mg/kg) to the animals treated with quercetin (200 mg/kg) partially inhibited gastric protection. All treated groups showed a marked increase in the amount of gastric mucus although this increase was less in animals pretreated with indomethacin. Total proteins and the hexosamine content decreased in the groups receiving indomethacin. The histomorphometric evaluation of the gastric damage confirmed a significant increase in mucus production accompanied by a parallel reduction of gastric lesions with the highest dose of quercetin tested.

ROLE OF ENDOGENOUS SULPHYDRYLS AND NEUTROPHIL INFILTRATION IN THE PATHOGENESIS OF GASTRIC MUCOSAL INJURY INDUCED BY PIROXICAM IN RATS

In the present report we studied the formation of severe gastric erosions produced in fasted rats by intragastric administration of piroxicam (PRX), an enolic acid-derived NSAID. The time course of gastric damage and the possible role of mucus secretion, endogenous sulphydryl compounds, changes of gastric vascular permeability and neutrophil infiltration in the development of PRX-induced gastric lesions were also investigated. PRX dose-dependently (1.25–20 mg/kg) caused acute gastric haemorrhagic erosion in the rat. The lesions increased with time until 9 hr after dosing. Mucus secretion did not change significantly with respect to the control group with 5, 10 and 20 mg/kg of PRX at different times (3 and 6 hours) of treatment. There was also no increase in the concentration of its components. In addition, oral pretreatment of the animals with PRX did not significantly change the amount of dye trapped in the stomach. In contrast, non-protein SH fraction was decreased after administration of PRX and MPO activity as an index of neutrophil infiltration was significantly increased. These results suggest that independently of the PRX dose, depletion of endogenous non-protein SH and neutrophil infiltration could play an important part in the pathogenesis of gastric mucosal injury induced by PRX.

Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease.

Current epidemiological and experimental studies support a beneficial role of dietary polyphenols in several gastrointestinal diseases, including inflammatory bowel disease. The aim of this study was to gain a better understanding of the effects of a naturally occurring polyphenol, ellagic acid, present in some fruits such as pomegranate, raspberries and nuts among others, in an experimental murine model of Crohns disease by intra-colonic administration of TNBS in rats. Analysis of the lesions were carried out by macroscopic and histological technics. Inflammation response was assessed by histology and myeloperoxidase activity. iNOS and COX-2 are upregulated by MAPKs and NF-κB nuclear transcription factor in intestinal epithelial cells thus, we determined the expression of iNOS, COX-2 and the involvement of the p38, JNK, ERK1/2 MAPKs and NF-κB signalling in the protective effect of EA by western blotting. Oral administration of EA (10-20 mg/kg) diminished the severity and extension of the intestinal injuries induced by TNBS although there was no observed a significant dose-response. In addition, EA increased mucus production in goblet cells in colon mucosa, decreased neutrophil infiltration and pro-inflammatory proteins COX-2 and iNOS overexpression. Also EA was capable of reducing the activation of p38, JNK and ERK1/2 MAPKs, preventing the inhibitory protein IκB-degradation and inducing an inhibition of the nuclear translocation level of p65 in colonic mucosa. In conclusion, EA reduces the damage in a rat model of Crohns disease, alleviates the oxidative events and returns pro-inflammatory proteins expression to basal levels probably through MAPKs and NF-κB signalling pathways.

Poly(ADP-Ribose) Polymerase Inhibitors: New Pharmacological Functions and Potential Clinical Implications

Poly(ADP-ribose) polymerase (PARP) comprise of a family of enzymes which catalyses poly(ADP-ribosyl)ation of DNA-binding proteins. To date, seven isoforms have been identified: PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), PARP-5 (Tankyrases), PARP-7 and PARP-10 with structural domains and different functions. PARP-1, the best characterised member, works as a DNA damage nick-sensor protein that uses beta-NAD(+) to form polymers of ADP-ribose and has been implicated in DNA repair, maintenance of genomic integrity and mammalian longevity. The generation of free radicals, reactive oxygen species, and peroxynitrite causes overactivation of PARP resulting in the depletion of NAD(+) and ATP and consequently in necrotic cell death and organ dysfunction. PARP has also been involved in the up-regulation of numerous pro-inflammatory genes through the activation of several transcription nuclear factors. Thus, PARP plays an important role in the pathogenesis of several diseases, such as, stroke, myocardial infarction, circulatory shock, diabetes, neurodegenerative disorders, including Parkinson and Alzheimer diseases, allergy, colitis and other inflammatory disorders. Pharmacological modulation of PARP activity may constitute a suitable target to enhance the cytotoxicity of certain DNA-damaging anticancer drugs. Also, PARP inhibition may be a viable strategy to control viral infections. This review is intended to provide an appreciation of new pharmacological perspectives of these remarkable drugs, summarize novel underlying mechanisms and discuss their potential clinical implications.

Acute and chronic responses associated with adrenomedullin administration in experimental colitis.

Adrenomedullin (AM) is a 52 amino acid peptide and member of the calcitonin gene-related peptide (CGRP) super family. Given that AM has emerged as a potential immuno-regulatory and anti-inflammatory agent in various experimental models, this study has deepened into its possible therapeutic effect in intestinal inflammation analyzing the responses in both acute and chronic (14 and 21 days) phases of TNBS-induced colitis in rats. In the acute model, AM treatment reduced the incidence of diarrhea and the severity of colonic damage, and improved the survival rate at the three doses assayed (50, 100, and 200ng/kg animal). AM administration was able to reduce the early production of TNF-alpha and collaborated to maintaining basal levels of IFN-gamma and IL-10. In the chronic studies the peptide attenuated the extent of the damage with lesser incidence of weight loss and diarrhea (50 and 100ng/kg animal). Cellular neutrophil infiltration, with the subsequent increase in myeloperoxidase (MPO) levels caused by TNBS, was reduced after chronic AM administration. The peptide played a role in the evolution of Th1/Th2 cytokines balance and chronic disease recuperation: levels of proinflammatory TNF-alpha and IFN-gamma decreased and anti-inflammatory IL-10 increased significantly. Cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) protein expression were not modified by AM administration, although a reduction of nitric oxide (NO) production could be detected in the chronic model. These results support a role of AM as an anti-inflammatory factor with beneficial effects in intestinal inflammatory colitis.

Ulcer-protecting Effects of Naringenin on Gastric Lesions Induced by Ethanol in Rat: Role of Endogenous Prostaglandins

Abstract— This study was designed to determine the cytoprotective properties of naringenin and the involvement of endogenous prostaglandins on mucosal injury produced by absolute ethanol. Gastric glands were also histologically analysed. Oral pretreatment with the highest dose of naringenin (200 mg kg−1), 240 min before absolute ethanol, was the most effective in ulcer prevention. Subcutaneous administration of indomethacin (10 mg kg−1) to the animals treated with naringenin (200 mg kg−1) partially inhibited the gastric protection but there was no increase in prostaglandin E2. All treated groups showed a marked increase in gastric mucus, although this increase was less in animals pretreated with indomethacin. Total proteins and hexosamine content decreased in the groups receiving indomethacin. Histomorphometric evaluation of the gastric damage, with the highest dose of naringenin (200 mg kg−1), confirmed a significant increase of mucus production accompanied by a parallel reduction of gastric lesion.

New Pharmacological Perspectives and Therapeutic Potential of PPAR-γ Agonists

The peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear hormone receptor superfamily has classically been characterized for its implications in adipocyte differentiation and fat metabolism. Recently, PPARg has been implicated in the pathophysiology of inflammatory and immune responses possibly through inhibition of the mitogen-activated protein kinase (MAPK) pathways or the activation of the transcription nuclear factor kappa B (NF-κB). Thus, these agents might also have therapeutic potential in the treatment of gastrointestinal inflammatory disorders, such as ulcerative colitis and Crohns disease. The synthetic thiazolidinediones (TZDs), a novel class of insulin-sensitizing drugs, were the first class of compounds identified as PPARγ ligands, and represent a significant advance in anti-diabetic therapy. However, there is less information about endogenous ligands, although the prostaglandin (PG)J2 and the oxidized phosphatidylcholine have been suggested. Furthermore, PPARg ligands have been shown to be potent inhibitors of angiogenesis, a process necessary for tumor growth and metastasis, and protect against cellular transformation. Further work is needed to establish in detail the anti-proliferative and pro-differentiation mechanisms of PPARγ activators and their efficacy in certain cancers.