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Seaweed lectins are very promising biotechnological tools that also gain prominence when applied to the pharmacology field. The purpose of the present work was to isolate and characterize lectin from the red algae Amansia multifida and subsequently test it in general inflammation models. The lectin was purified by ion exchange chromatography, characterized with two-dimensional electrophoresis, automated analysis of amino acid sequences and circular dichroism spectroscopy. The pharmacological tests performed were paw edema induced by carrageenan or rapid inflammatory mediators, peritonitis induced by carrageenan and myeloperoxidase leukocyte count assays, glutathione and cytokine concentration. Our results have identified a 30 KDa molecular weight protein that presents a major secondary structure arranged in β-strand elements (~43%). A fragment of 20 amino acid residues was sequenced and presented low identity to the known classes of lectins from marine alga. This lectin was able to modulate inflammatory parameters such as paw edema, leukocyte migration, oxidative stress and proinflammatory cytokines. Thus, the lectin from the seaweed Amansia multifida has evident anti-inflammatory properties because it acts by reducing the formation of edema by modulating the effect of vascular mediators, migration of neutrophils, proinflammatory cytokines and oxidative stress control.

Peripheral neuropathies (PN) and primary headaches (PH) are common comorbidities in inflammatory bowel disease (IBD) patients. We aimed to evaluate whether PN and PH affect the same subgroups of IBD patients. Since 2004, we established a cohort study to evaluate neurological diseases in IBD patients. Over 2 years, all consecutive (N = 155) IBD patients (either Crohn’s disease (CD) or ulcerative colitis (UC) were evaluated for the presence of PN and PH. PH were also evaluated in dyspeptic patients (N = 84) and IBD relatives (controls, N = 101). After neurological evaluation, symptomatic patients underwent skin wrinkling test to evaluate small fiber function and/or electromyography. Headaches and migraine were more prevalent in IBD than control patients: 52.3 and 34.2% vs. 40.6 and 20.8% (P 0.05). Multivariate regression analysis disclosed that headaches were more prevalent in women, co-existing psychiatric disease, IBD, CD, and UC. After age, gender distribution, and prevalence of hypertension and psychiatric diseases were matched among the groups, there were still differences in the prevalence of headaches and migraine among IBD, CD, and UC versus control patients. In summary, PH and PN are common in IBD and do not affect the same subgroups of patients.

Sulfated polysaccharides derived from seaweeds have important biological activities. The aim of this work was to demonstrate the anti-inflammatory effect of a sulfated polysaccharide extracted from the seaweed Digenea simplex (Wulfen) C. Agardh 1822 on 2,4,6-trinitrobenzene sulfonic acid–induced colitis in rats. After inducing colitis, rats were euthanized, and the colon was excised to determine macroscopic lesion scores and wet weight and to histologically evaluate and quantify glutathione, malondialdehyde, myeloperoxidase, nitrate/nitrite, and cytokines. The polysaccharide, composed of β-d-galactose and 3,6-α-l-anhydrogalactose residues, reduced wet weight as well as macroscopic and microscopic lesion scores. It also reduced myeloperoxidase activity; reduced proinflammatory cytokines, malondialdehyde, and nitrate/nitrite levels; and preserved glutathione consumption in the colon. According to these results, we can infer that the sulfated polysaccharide derived from D. simplex has an anti-inflammatory effect on induced colitis in vivo.

Choledocholithiasis is the most frequent cause of biliary obstruction commonly seen in gastroenterological practice. Objective: evaluate the rate and factors related to success and complications in patients with choledocholithiasis, referred or ERCP in HUWC- UFC. Methodology: Retrospective study of 56 patients submitted to 67 examinations for choledocholithiasis from 01/2017 to 04/2018. The information was taken from the Endoscopy unit medical records database. Success rates (complete withdrawal of calculus), complications (pancreatitis, hemorrhage and perforation), and factors related to these outcomes were analyzed. CEP: 43321014.6.0000.5045. Results: There was a predominance of women (80%), in their early 50 years old. The success rate was 89%. With surgical therapeutic complementation in 9%. 2% of the cases are still under follow-up. The most frequent complication was pancreatitis (7%), being (1) patient with evolution to death (1.8%) without perforations or bleeding. There was an association between the presence of large stones (p = 0.05) and bile duct disproportion (p = 0.01) with ERCP failure. There was no association of the factors evaluated, with the presence of complications. Conclusion: The study shows that there was a high success rate, as described in the literature. The presence of large stones and disproportion, factors related to ERCP failure. A coledocolitíase é a causa mais frequente de obstrução biliar comumente vista na prática gastroenterológica. Objetivo: avaliar taxa e fatores relacionados ao sucesso assim como complicações nos pacientes com coledocolitíase, encaminhados para CPRE no HUWC-UFC. Metodologia: Estudo retrospectivo de 56 pacientes submetidos a 67 CPREs por coledocolitíase de 01/2017 a 04/2018. As informações foram retiradas do banco de dados da unidade de Endoscopia e prontuários. Analisadas as taxas de sucesso (retirada completa dos cálculos), complicações (pancreatite, hemorragia e perfuração) e fatores relacionados a estes desfechos. CEP: 43321014.6.0000.5045. Resultados: Houve predominância de mulheres (80%), com idade média de 51 anos. A taxa sucesso foi 89%. Com complementação terapêutica cirúrgica em 9%. 2% dos casos, estão ainda em seguimento ambulatorial. A complicação mais frequente foi pancreatite (7%), sendo (1) paciente com evolução ao óbito (1,8%). Sem a existência de perfurações ou hemorragias. Houve associação entre a presença de cálculos grandes (p= 0.05) e desproporção da via biliar (p=0.01) com insucesso da CPRE. Não houve nenhuma associação dos fatores avaliados com a presença de complicações. Conclusão: O estudo demonstra que houve alta taxa de sucesso, como descrito na literatura, sendo a presença de cálculos grandes e desproporção fatores relacionados ao insucesso da CPRE.

Significance Carbon monoxide (CO) is an endogenous gaseous mediator that plays an important role in maintaining gastrointestinal (GI) tract homeostasis, acting in mucosal defence, and providing negative modulation of pathophysiological markers of clinical conditions. Recent Advances: Preclinical studies using animal models and/or cell culture show that CO can modulate the inflammatory response and oxidative stress in GI mucosal injuries and pathological conditions, reducing pro-inflammatory cytokines and reactive oxygen species, while increasing antioxidant defence mechanisms. Critical issues CO has potent anti-inflammatory and antioxidant effects. The defence mechanisms of the GI tract are subject to aggression by different chemical agents (e.g., drugs and ethanol) as well as complex and multifactorial diseases, with inflammation and oxidative stress as strong triggers for the deleterious effects. Thus, it is possible that CO acts on a variety of molecules involved in the inflammatory and oxidative signalling cascades, as well as reinforcing several defence mechanisms that maintain GI homeostasis. Future directions CO-based therapies are promising tools for the treatment of GI disorders, such as gastric and intestinal injuries, inflammatory bowel disease, and pancreatitis. Therefore, it is necessary to develop safe and selective CO-releasing agents and/or donor drugs to facilitate effective treatments and methods for analysis of CO levels that are simple and inexpensive.

Lactobacillus spp. and Bifidobacterium spp. was used to protect against gastrointestinal disorders. The present study evaluated the effects of probiotic mixture (PM) containing Lactobacillus spp. a...

Background: Inflammatory bowel disease (IBD) is associated with delay in gastric emptying, increase in ghrelin, and decrease in leptin. The aim was to investigate the correlation between gastroduodenal (GD) symptoms, gastric emptying, and serum levels of active ghrelin and leptin in IBD. Twenty-seven IBD patients and 26 healthy volunteers were asked to complete the Porto Alegre Dyspeptic Symptoms Questionnaire. A gastric emptying test for solids was performed using a C13 octanoic acid breath test. During this test, serum samples were collected for measuring active ghrelin and leptin concentrations by radioimmunoassay. Summary: Patients with IBD demonstrated delayed gastric emptying compared with healthy volunteers. In patients with GD symptoms, the delay in gastric emptying was more pronounced, and there were significant correlations of satiety and vomiting with gastric emptying. Basal leptin, but not active ghrelin, increased in patients with GD symptoms compared with patients without these symptoms. There were negative correlations between basal active ghrelin with total Porto Alegre score and epigastric pain in IBD patients with GD symptoms. Key Messages: In IBD, satiety and vomiting were associated with delay in gastric emptying. Conversely, epigastric pain had a negative correlation with active ghrelin. Our results suggest that different pathophysiological mechanisms contribute to GD symptoms in IBD.

The angiotensin (Ang) II converting enzyme (ACE II) pathway has recently been shown to be associated with several beneficial effects on the body, especially on the cardiac system and gastrointestinal tract. ACE II is responsible for converting Ang II into the active peptide Ang-(1-7), which in turn binds to a metabotropic receptor, the Mas receptor (MasR). Recent studies have demonstrated that Diminazene Aceturate (DIZE), a trypanosomicide used in animals, activates the ACE II pathway. In this study, we aimed to evaluate the antidiarrheal effects promoted by the administration of DIZE to activate the ACE II/Ang-(1-7)/MasR axis in induced diarrhea mice models. The results show that activation of the ACE II pathway exerts antidiarrheal effects that reduce total diarrheal stools and enteropooling. In addition, it increases Na+/K+-ATPase activity and reduces gastrointestinal transit and thus inhibits contractions of intestinal smooth muscle; decreases transepithelial electrical resistance, epithelial permeability, PGE2-induced diarrhea, and proinflammatory cytokines; and increases anti-inflammatory cytokines. Enzyme-linked immunosorbent assay (ELISA) demonstrated that DIZE, when activating the ACE II/Ang-(1-7)/MasR axis, can still interact with GM1 receptors, which reduces cholera toxin-induced diarrhea. Therefore, activation of the ACE II/Ang-(1-7)/MasR axis can be an important pharmacological target for the treatment of diarrheal diseases.

In this study, a polysaccharide from marine alga Acanthophora spicifera (PAs) was isolated and structurally characterized. Its protective potential against chemically-induced gastric mucosa injury was evaluated. The gel permeation chromatography experiments and spectroscopy spectrum showed that PAs is a sulfated polysaccharide with a high molecular mass (6.98 × 105g/mol) and degree of sulfation of 1.23, exhibiting structural characteristic typical of an agar-type polysaccharide. Experimental results demonstrated that PAs reduced the hemorrhagic gastric injury, in a dose-dependent manner. Additionally, PAs reduced the intense gastric oxidative stress, measured by glutathione (GSH) and malondialdehyde (MDA) levels. PAs also prevented the reduction of mucus levels adhered to the gastric mucosa, promoted by the aggressive effect of ethanol. In summary, the sulfated polysaccharide from A. spicifera protected the gastric mucosa through the prevention of lipid peroxidation and enhanced the defense mechanisms of the gastric mucosa, suggesting as a promising functional food as gastroprotective agent.

The present work aimed at carrying out the isolation and biochemical characterization of a sulfated polysaccharide fraction (PLS) from the marine algae Gracilaria intermedia and investigating its anti-inflammatory and antinociceptive potential. PLS was obtained through enzymatic digestion with papain and analyzed by means of gel permeation chromatography and Nuclear Magnetic Resonance to 1H and 13C. In order to evaluate the potential of anti-inflammatory action of PLS, we performed paw edema induced by carrageenan, dextran, compound 48/80, histamine and serotonin. In addition, we also measured the concentration of myeloperoxidase, cytokines, the count of inflammatory cells and performed tests of the nociception. The PLS isolated was of high purity and free of contaminants such as proteins, and had molecular weight of 410 kDa. The same macromolecule was able to decrease the paw edema induced by all inflammatory agents (P

Polysaccharide from marine alga Gracilaria caudata has potential health benefits, such as anti-inflammatory, gastroprotective and antidiarrheal effects. Here, we investigated the effect of a sulfated polysaccharide from G. caudata (SP-GC) on hypernociception and inflammatory response in arthritis models. The animals received SP-GC (3, 10 or 30 mg/kg) 1 h before tibio-tarsal injection of zymosan. Hypernociception, histopathology, edema, vascular permeability, myeloperoxidase (MPO) activity, cell influx, interleukin (IL)-1β and nitric oxide (NO) levels were evaluated in acute phase. In another protocol, animals received SP-GC (30 mg/kg) 2 h post-complete Freund's adjuvant (CFA). Hypernociception, edema and arthritis index were determined in acute, sub-chronic and chronic phases. Rota-rod test measured the motor performance. SP-GC significantly reduced, in a dose-dependent manner, the zymosan-induced hypernociception with maximal effect at 30 mg/kg. The microscopic inflammation, joint edema, MPO activity, cell influx, IL-1β and NO levels were also reduced by SP-GC. In the CFA-induced arthritis, SP-GC inhibits the hypernociception, edema and arthritic index in acute, sub-chronic and chronic phases. SP-GC did not alter the motor performance of animals. In conclusion, SP-GC exerts protective effect in models of arthritis due to the modulation of cell influx, IL-1β and NO levels, culminating in the reduction of hypernociception and edema.

Anadenanthera colubrina var. cebil (Griseb.) Altschul (Fabaceae family), commonly known as the red angico tree, is a medicinal plant found throughout Brazil&rsquo, s semi-arid area. In this study, a chemical analysis was performed to investigate the antidiarrheal activity and safety profile of red angico gum (RAG), a biopolymer extracted from the trunk exudate of A. colubrina. Upon FT-IR spectroscopy, RAG showed bands in the regions of 1608 cm&minus, 1, 1368 cm&minus, 1, and 1029 cm&minus, 1, which relate to the vibration of O&ndash, H water molecules, deformation vibration of C-O bands, and vibration of the polysaccharide C-O band, respectively, all of which are relevant to glycosidic bonds. The peak molar mass of RAG was 1.89 &times, 105 g/mol, with the zeta potential indicating electronegativity. RAG demonstrated high yield and solubility with a low degree of impurity. Pre-treatment with RAG reduced the total diarrheal stool and enteropooling. RAG also enhanced Na+/K+-ATPase activity and reduced gastrointestinal transit, and thereby inhibited intestinal smooth muscle contractions. Enzyme-Linked Immunosorbent Assay (ELISA) demonstrated that RAG can interact with GM1 receptors and can also reduce E. coli-induced diarrhea in vivo. Moreover, RAG did not induce any signs of toxicity in mice. These results suggest that RAG is a possible candidate for the treatment of diarrheal diseases.

Activation of 5' adenosine monophosphate-activated protein kinase (AMPK) stimulates production of the gaseous mediators nitric oxide (NO) and carbon monoxide (CO), which are involved in mucosal defense and gastroprotection. As AMPK itself has gastroprotective effects against several gastric ulcer etiologies, in the present study, we aimed to elucidate whether AMPK may also prevent ethanol-induced injury and play a key role in the associated gastroprotection mediated by hydrogen sulfide (H2S), NO, and CO. Mice were pretreated with AICAR (20 mg/kg, an AMPK activator) alone or with 50% ethanol. Other groups were pretreated with respective gaseous mediator inhibitors PAG, l-NAME, or ZnPP IX 30 min prior to AICAR, or with gaseous mediator donors NaHS, Lawesson's reagent and l-cysteine (H2S), SNP, l-Arginine (NO), Hemin, or CORM-2 (CO) 30 min prior to ethanol with or without compound C (10 mg/kg, a non-selective AMPK inhibitor). H2S, nitrate/nitrite (NO3-/NO2-), bilirubin levels, GSH and MDA concentration were evaluated in the gastric mucosa. The gastric mucosa was also collected for histopathological analysis and AMPK expression assessment by immunohistochemistry. Pretreatment with AICAR attenuated the ethanol-induced injury and increased H2S and bilirubin levels but not NO3-/NO2- levels in the gastric mucosa. In addition, inhibition of H2S, NO, or CO synthesis exacerbated the ethanol-induced gastric damage and inhibited the gastroprotection by AICAR. Pretreatment with compound C reversed the gastroprotective effect of NaHS, Lawesson's reagent, l-cysteine, SNP, l-Arginine, CORM-2, or Hemin. Compound C also reversed the effect of NaHS on H2S production, SNP on NO3-/NO2- levels, and Hemin on bilirubin levels. Immunohistochemistry revealed that AMPK is present at basal levels mainly in the gastric mucosa cells, and was increased by pretreatment with NaHS, SNP, and CORM-2. In conclusion, our findings indicate that AMPK activation exerts gastroprotection against ethanol-induced gastric damage and mutually interacts with H2S, NO, or CO to facilitate this process.

Hydrogen sulphide (H2S) is a gasotransmitter that participates in various physiological and pathophysiological processes within the gastrointestinal tract. We studied the effects and possible mechanism of action of H2S in secretory diarrhoea caused by cholera toxin (CT). The possible mechanisms of action of H2S were investigated using an intestinal fluid secretion model in isolated intestinal loops on anaesthetized mice treated with CT. NaHS and Lawesson's reagent and l-cysteine showed antisecretory activity through reduction of intestinal fluid secretion and loss of Cl- induced by CT. Pretreatment with an inhibitor of cystathionine-γ-lyase (CSE), dl-propargylglycine (PAG), reversed the effect of l-cysteine and caused severe intestinal secretion. Co-treatment with PAG and a submaximal dose of CT increased intestinal fluid secretion, thus supporting the role of H2S in the pathophysiology of cholera. CT increased the expression of CSE and the production of H2S. Pretreatment with PAG did not reverse the effect of SQ 22536 (an AC inhibitor), bupivacaine (inhibitor of cAMP production), KT-5720 (a PKA inhibitor), and AICAR (an AMPK activator). The treatment with Forskolin does not reverse the effects of the H2S donors. Co-treatment with either NaHS or Lawesson's reagent and dorsomorphin (an AMPK inhibitor) did not reverse the effect of the H2S donors. H2S has antisecretory activity and is an essential molecule for protection against the intestinal secretion induced by CT. Thus, H2S donor drugs are promising candidates for cholera therapy. However, more studies are needed to elucidate the possible mechanism of action.

Seaweeds are sources of biomolecules with biological activities and pharmacological potential - for example, lectins, a group of proteins that can bind reversibly to carbohydrates or compounds containing them. The aim of this study was to elucidate the structural properties of a lectin extracted from the red seaweed Bryothamnion triquetrum (BtL) and to investigate its anti-inflammatory activity in mice. The lectin was purified by precipitation with ammonium sulfate and ion-exchange chromatography. Its secondary structure and tryptophan (Trp) microenvironment were analyzed by circular dichroism spectroscopy and steady-state fluorescence spectroscopy, respectively. The anti-inflammatory effect was evaluated by means of paw edema induced by carrageenan or dextran, myeloperoxidase activity in paw tissue, and by measurement of leukocyte and neutrophil migration and cytokine quantification in a peritonitis model. The secondary structure of BtL is mostly composed of β-strands and unordered conformation, and it is quite resistant to extremes of pH and temperature, preserving the exposure of Trp residues under these conditions. In an assessment of biological activities, groups of mice were subjected to pretreatment with BtL before the inflammatory stimulus. BtL had anti-inflammatory effects in the models tested, and hence may be considered a molecule with potential to be used in the pharmaceutical industry.

Intestinal mucositis (IM) is a common side effect of irinotecan-based chemotherapy. The involvement of inflammatory mediators, such as TNF-α, IL1-β, IL-18 and IL-33, has been demonstrated. However, the role of adaptive immune system cells, whose activation is partially regulated by these cytokines, is yet unknown. Thus, we investigated the role of regulatory T cells (Tregs) in irinotecan-induced IM. C57BL/6 mice were injected with saline or irinotecan (75 mg kg− 1, i.p.), once a day for 4 days, and euthanized at day 1, 3, 5 or 7 following the first dose of irinotecan. For Treg depletion, the mice were pretreated with a low single dose of cyclophosphamide (100 mg kg− 1, i.p). Intestinal lamina propria lymphocytes were harvested and purified by Percoll gradient. Treg and Th17 cells were identified by flow cytometry. Blood leukocyte count was obtained and ileum samples were collected for histopathological analysis and myeloperoxidase assay. IM caused an accumulation of Tregs and Th17 cells over time. Treg depletion exacerbated intestinal damage, diarrhea, neutrophil infiltration and animal mortality, despite a reduction in Th17 cell number. The frequency of other Th cells increased and was positively correlated with neutrophil infiltration. Tregs showed a negative correlation with neutrophils and the frequency of non-regulatory Th cells. In conclusion, Tregs are important in the control of intestinal damage induced by irinotecan, and their depletion showed a deleterious effect on IM. Activation of these cells appears to be a compensatory mechanism for intestinal inflammation.

Objectives/hypothesis Evaluate the effect of in vitro exposure of mice laryngeal mucosa to solutions that simulated human gastric juice and to assess the topical protective effect of cashew gum on mice laryngeal mucosal integrity in vitro. Study design Animal study. Methods Murine (Swiss) laryngeal samples were mounted in Ussing chambers. The luminal side of biopsies was exposed to solutions of different acidity with or without pepsin and/or taurodeoxycholic acid (TDC). Transepithelial electrical resistance (TER) was continuously recorded. The topical protective effect of cashew gum solution was evaluated by precoating the biopsies before the exposure with a solution at pH 5 containing 5 mM TDC. Changes in TER and mucosal permeability to fluorescein were measured. Results Exposure of laryngeal mucosa to acidic solutions containing pepsin and TDC provoked a pH-dependent drop in TER with the maximal effect at pH 1, but still present at pH 5 (weakly acidic). The exposure of the laryngeal mucosa to a solution of pH 5 with TDC, but not with pepsin, produced a dose-dependent decrease in TER. Precoating the mucosa with cashew gum prevented the reduction of TER and increased transepithelial permeability by exposure to a solution at pH5 containing TDC. Conclusions Weakly acidic solutions containing bile acids can produce impairment of laryngeal epithelial barrier, which may be protected by topical treatment with cashew gum. Level of evidence NA. Laryngoscope, 128:1157-1162, 2018.

Irinotecan-based regimens are commonly used for treatment of colorectal cancer, which is limited by mucositis and non-alcoholic steatohepatitis (NASH). Silymarin (SIL) prevents fatty liver disease in the clinical setting and in models of liver damage induced chemically. This study investigated the possible effect of SIL on irinotecan (IRI)-induced NASH. Swiss female mice were injected with saline (SAL 5 ml/kg i.p.), IRI (50 mg/kg i.p.), SIL (150 mg/kg p.o.) or IRI (50 mg/kg i.p.) + (SIL 1.5, 15 or 150 mg/kg p.o.) thrice/week/7 weeks. On the seventh week, blood samples were collected for transaminases assay and livers were collected for histopathology, measurement of the total lipids, malondyadehyde (MDA), non-protein sulfhydryl groups (NPSH), cytokines (IL-1β, IL 6 and IL-10), 3-nitrotyrosine (N-Tyr) and toll-like receptor 4 (TLR4) immunoexpression, quantification of NF-kB, α-smooth muscle actin (α-SMA), and Escherichia coli 16S rRNA gene (RRS) expression. IRI increased liver transaminases, neutrophil infiltration, lipid accumulation, MDA, IL-1β and IL-6 levels, N-Tyr and TLR4 immunostaining, NF-kB, α-SMA expression and RRS versus the SAL group (p < 0.05). Additionally, SIL (1.5 mg/kg) improved these parameters (p < 0.05), except neutrophil infiltration and RSS versus the IRI group. Furthermore, the SIL (15 mg/kg) only improved the inflammatory parameters, the expression of α-SMA and RRS versus the IRI group (p < 0.05). The higher dose of SIL (150 mg/kg) was even more deleterious than the intermediate dose. Therefore, silymarin showed a dual effect on liver damage induced by IRI. Hepatoprotection seems to involve the inhibition of oxidative stress and protein nitrosylation, preventing activation of hepatic fibrosis mechanisms.

Nonerosive reflux disease (NERD) is a highly prevalent phenotype of the gastroesophageal reflux disease. In this study, we developed a novel murine model of NERD in mice with microscopic inflammation and impairment in the epithelial esophageal barrier. Female Swiss mice were subjected to the following surgical procedure: the transitional region between the forestomach and the glandular portion of the stomach was ligated, and a nontoxic ring was placed around the duodenum near the pylorus. The control group underwent sham surgery. The animals were euthanized at 1, 3, 7, and 14 days after surgery. Survival and body weight were monitored daily. Esophageal wet weight, macroscopic lesion, histopathological alterations, myeloperoxidase (MPO) activity, cytokine levels, transepithelial electrical resistance (TEER), and mucosal permeability were evaluated. The survival rate was 78% at 14 days, with mild loss in body weight. Surgery did not induce erosive esophagitis but instead induced microscopic inflammation and increased esophageal wet weight, IL-6, keratinocyte-derived cytokine (KC) levels, and MPO activity with maximal peak between 3 and 7 days and resolution at 14 days postsurgery. Epithelial esophageal barrier was evaluated in operated mice at 7 and 14 days postsurgery; a decrease in TEER and increase in the esophageal epithelial permeability were observed compared with the sham-operated group. In addition, the inhibition of acid secretion with omeprazole significantly prevented the esophageal inflammation and impairment of barrier function at 7 days postsurgery. Thus we established a novel experimental model of NERD in mice, which can contribute to understanding the pathophysiological events associated with NERD.NEW & NOTEWORTHY In this study, we standardized an experimental model of nonerosive reflux disease (NERD) in mice. This model involves an acute inflammatory response followed by impaired esophageal mucosal integrity, even in the absence of inflammation. Thus this model can serve for evaluation of pathophysiological aspects of NERD and open new perspectives for therapeutic strategies for patients with this disorder.

Objective This study aimed to investigate the protective effect of epiisopiloturine hydrochloride (EPI), an imidazole alkaloid, on NAP-induced gastrointestinal damage in rats. Methods Initially, rats were pretreated with 0.5% carboxymethylcellulose (vehicle) or EPI (3, 10 and 30 mg/kg, p.o. or i.p. , groups 3–5, respectively) twice daily, for 2 days. After 1 h, NAP (80 mg/kg, p.o. ) was given. The control group received only vehicle (group 1) or vehicle + naproxen (group 2). Rats were euthanized on 2nd day, 4 h after NAP treatment. Stomachs lesions were measured. Samples were collected for histological evaluation and glutathione (GSH), malonyldialdehyde (MDA), myeloperoxidase (MPO), and cytokines levels. Moreover, gastric mucosal blood flow (GMBF) was evaluated. Results EPI pretreatment prevented NAP-induced macro and microscopic gastric damage with a maximal effect at 10 mg/kg. Histological analysis revealed that EPI decreased scores of damage caused by NAP. EPI reduced MPO (3.4 ± 0.3 U/mg of gastric tissue) and inhibited changes in MDA (70.4 ± 8.3 mg/g of gastric tissue) and GSH (246.2 ± 26.4 mg/g of gastric tissue). NAP increased TNF-α levels, and this effect was reduced by EPI pretreatment. Furthermore, EPI increased GMBF by 15% compared with the control group. Conclusion Our data show that EPI protects against NAP-induced gastric and intestinal damage by reducing pro-inflammatory cytokines, reducing oxidative stress, and increasing GMBF.

Objectives/hypothesis The objectives of this study were to evaluate laryngeal inflammation and mucosal integrity in a murine model of reflux disease and to assess the protective effects of topical agents including alginate, hyaluronic acid, and cashew gum. Study design Animal study. Methods A surgical murine model of reflux disease was evaluated at 3 or 7 days postsurgery, and laryngeal samples were collected to measure inflammation (wet weight and myeloperoxidase [MPO]) and mucosal integrity (transepithelial resistance [TER] and mucosal permeability to fluorescein). Additional groups of animals were administered one of several topical agents (alginate, hyaluronic acid, or cashew gum) daily, and laryngeal inflammation and mucosal integrity were evaluated at 3 days postsurgery. Results At 3 days, and not 7 days postsurgery, we observed increased laryngeal wet weight and MPO, decreased laryngeal TER, and increased laryngeal mucosa permeability. Alginate partially decreased laryngeal inflammation (wet weight and not MPO) and dramatically improved laryngeal mucosal integrity. Conversely, hyaluronic acid eliminated the inflammation; however, it had no effect on laryngeal mucosal integrity impairment. Cashew gum eliminated laryngeal inflammation as well as the impairment in laryngeal mucosal integrity. Conclusions This study shows that a surgical model of reflux disease induced laryngeal inflammation and impairment in laryngeal barrier function. These observed alterations were partially attenuated by alginate and hyaluronic acid and completely reversed by cashew gum. Level of evidence NA Laryngoscope, 2020.

Gabapentin is an anticonvulsant drug that is also used for post-herpetic neuralgia and neuropathic pain. Recently, gabapentin showed anti-inflammatory effect. Nuclear factor kappa B (NFκB) is a regulator of the inflammatory process, and Peroxisome Proliferator-activated Receptor gamma (PPAR-gamma) is an important receptor involved in NFκB regulation. The aim of the present work was to study the potential role of PPAR-gamma receptor in gabapentin-mediated anti-inflammatory effects in a colitis experimental model. We induced colitis in rats using trinitrobenzenosulfonic acid and treated them with gabapentin and bisphenol A dicyldidyl ether (PPAR-gamma inhibitor). Macroscopic lesion scores, wet weight, histopathological analysis, mast cell count, myeloperoxidase, malondialdehyde acid, glutathione, nitrate/nitrite, and interleukin levels in the intestinal mucosa were determined. In addition, western blots were performed to determine the expression of Cyclooxygenase-2 (COX-2) and NFκB; Nitric Oxide Inducible Synthase (iNOS) and Interleukin 1 beta (IL-1β) levels were also determined. Gabapentin was able to decrease all inflammatory parameters macroscopic and microscopic in addition to reducing markers of oxidative stress and cytokines such as IL-1β and Tumor Necrosis Factor alpha (TNF-α) as well as enzymes inducible nitric oxide synthase and cyclooxygenase 2 and inflammatory genic regulator (NFκB). These effect attributed to gabapentin was observed to be lost in the presence of the specific inhibitor of PPAR-gamma. Gabapentin inhibits bowel inflammation by regulating mast cell signaling. Furthermore, it activates the PPAR-gamma receptor, which in turn inhibits the activation of NFκB, and consequently results in reduced activation of inflammatory genes involved in inflammatory bowel diseases.

LASSBio-596 (2-[4-(1,4-thiazinan-4-ylsulfonyl) phenylcarbamoyl] benzoic acid) is a molecular hybrid of anti-tumor necrosis factor α (TNF-α) and phosphodiesterase 5 inhibitors, and its anti-inflammatory effects have been demonstrated in experimental models of inflammation. The aim of this study was to evaluate the gastroprotective effect of LASSBio-596 in an ethanol-induced acute gastritis model. Before induction of gastric damage, mice were pretreated with LASSBio-596 (20 mg per os (p.o.), Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 3 mg/kg, intraperitoneally [i.p.]) or with 1400W (10 mg/kg, i.p.) given alone or in their combinations. Thirty minutes later, gastric damage was induced by intragastric instillation of 50% ethanol (0.5 ml/25 g, by gavage). After 1 h, gastric damage (hemorrhagic or ulcerative lesions) was measured by planimetry. Samples of the stomach were also taken for histopathological assessment and for assays of tissue myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), and inflammatory cytokines. Ethanol administration induced the development of gastric lesions in mice. LASSBio-596 reduced gastric damage, epithelial cell loss and hemorrhage, and restored the antioxidant defense system by decreasing the levels of MDA and the consumption of GSH in gastric mucosa. LASSBio-596 also decreased gastric TNF-α and interleukin-1β (IL-1β) protein levels, MPO enzymatic activity, and hemoglobin levels. Treatment with the nitric oxide synthase inhibitors L-NAME and 1400W reversed the effects of LASSBio-596 on ethanol-induced gastric lesions. LASSBio-596 did not alter mucus content and pH of gastric secretions. In summary, LASSBio-596 exerts protective effects against ethanol-induced gastric injury. The gastroprotective effects of LASSBio seem to be NO-dependent.

This study aimed to evaluate the in vitro protective effect of topical treatment with a native sulfated polysaccharide of G. caudata (SP-Gc), hydrolyzed (H-SP-Gc), or desulfated (D-SP-Gc) polysaccharide of Gracilaria caudata in esophageal biopsies obtained from GERD patients. Biopsies were obtained from nonerosive reflux disease (NERD) patients and from erosive esophagitis patients. Then, the biopsies were mounted in an Ussing chamber to measure the basal transepithelial electrical resistance (TEER). The effect of mucosal exposure to an acid solution on TEER was analyzed with or without different concentrations (1, 0.3 or 1%) of SP-Gc, H-SP-Gc, or D-SP-Gc, precoated on the mucosa. Basal esophageal mucosal electrical resistance was significantly lower in erosive esophagitis than from NERD. Mucosal samples precoated with native SP-Gc (1%) significantly prevented TEER drop induced by an acidic solution in NERD, but this effect was not observed in erosive esophagitis. Topical application of D-SP-Gc showed no difference compared to native SP-Gc. However, when treated with chemically-modified SP-Gc, the protective effect observed with native SP-Gc was lost. The present study indicated that SP-Gc protects the human esophageal mucosal barrier in NERD patients. This effect is dependent on the structure but is independent of the presence of sulfate.

The gastroprotective effects of N-acylarylhydrazone derivatives on ethanol-induced gastric lesions in mice were investigated with respect to the NO/cGMP/KATP pathway. To investigate our hypothesis, the mice were intraperitoneally pretreated with glibenclamide, L-NAME, or ODQ 30 min before treatment with DMSO, LASSBio-294 (1, 2, and 4 mg/kg, p.o.), LASSBio-897 (0.5, 1, and 2 mg/kg, p.o.), or omeprazole. After 1 h, the mice received absolute ethanol (4 ml/kg) by gavage to induce gastric mucosal lesions, and the microscopic and macroscopic parameters were evaluated. GSH (non-protein sulfhydryl groups) and MDA (malondialdehyde) concentrations, hemoglobin levels, nitric oxide production, myeloperoxidase (MPO) activity, and TNF-α and IL-1β levels were also analyzed in the stomach after absolute ethanol administration. Pretreatment with LASSBio-294 or LASSBio-897 significantly reduced the microscopic and macroscopic lesion area. The compounds restored the GSH, MDA, and hemoglobin levels and reduced MPO activity. Moreover, the compounds significantly reduced nitrate and nitrite concentrations in the stomach samples after ethanol administration. Molecular docking studies revealed that LASSBio-294 and LASSBio-897 interact with active sites of the eNOS (endothelial nitric oxide synthase) enzymes through hydrogen bonds. LASSBio-294 and LASSBio-897 also reduced TNF-α and IL-1β levels. It was observed that a NO synthase inhibitor, an ATP-sensitive potassium channel blocker, and a guanylate cyclase inhibitor significantly reversed the gastroprotective effects of these compounds. Thus, the gastroprotective effect of LASSBio-294 and LASSBio-897 against gastric lesions is mediated through the NO/cGMP cascade, followed by blocking of the KATP channels.

Inflammation is the response of the body to noxious stimuli such as infections, trauma, or injury. Experimental studies have shown that vanillic acid has anti-inflammatory effects. The objective of this study was to investigate the anti-inflammatory and antipyretic properties of the derivative of vanillic acid, isopropyl vanillate (ISP-VT), in mice. The results of this study indicated that ISP-VT reduced paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin, bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, ISP-VT reduced recruitment of leukocytes and neutrophils and reduced its adhesion and rolling, and decreased myeloperoxidase enzyme activity (MPO), cytokine levels (tumor necrosis factor-α and interleukin-6), and vascular permeability. ISP-VT also significantly reduced the expression of cyclooxygenase-2 (COX-2) in subplantar tissue of mice. ISP-VT inhibited COX-2 selectively compared to the standard drug. Our results showed that although ISP-VT binds to COX-1, it is less toxic than indomethacin, as evidenced by MPO analysis of gastric tissue. Treatment with the ISP-VT significantly reduced rectal temperature in yeast-induced hyperthermia in mice. Our results showed that the main mechanism ISP-VT-induced anti-inflammatory activity is by inhibition of COX-2. In conclusion, our results indicate that ISP-VT has potential as an anti-inflammatory and antipyretic therapeutic compound.

Galactomannans are neutral polysaccharides isolated from the endosperm of some Leguminosae seeds. They consist of a (1 → 4) linked β-mannopyranosyl backbone partially substituted at O-6 with α- d -galactopyranosyl side groups. C. pulcherrima have anti-inflammatory and muco-adhesive proprieties. Acute gastritis is an inflammatory disease triggered by use of non-steroidal anti-inflammatory drugs. We investigated the gastroprotective effect of galactomannan obtained from the seeds of Caesalpinia pulcherrima L. (GM-CP) in acute gastritis model induced by indomethacin. Gastritis was induced with indomethacin (30 mg/kg, P.·O.) in female Swiss mice. Animal groups (n = 7) were pretreated with saline-dissolved GM-CP (3 mg/kg, 10 mg/kg, 30 mg/kg, P.O.) or vehicle 1 h before gastritis induction. Mice were euthanized seven hours after the induction. The stomach and blood samples were collected for analysis. At 10 mg/kg, GP-CP reduced the extension of macroscopic lesion and the loss of superficial cells by alleviating inflammatory symptoms (neutrophil infiltration, migration and adhesion of mesenteric leukocytes, production of TNF-α and thiobarbituric acid reactive species (TBARS) and helping to maintain mucin labeling of the tissue. Thus, the findings of the study suggest that GM-CP exhibits gastroprotective effects.

Background and aim Chemotherapy drugs that act via Toll-like receptors (TLRs) can exacerbate mucosal injury through the production of cytokines. Intestinal mucositis can activate TLR2 and TLR4, resulting in the activation of NF-κB. Intestinal mucositis characterized by intense inflammation is the main side effect associated with 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii CNCM I-745 (S.b) is a probiotic yeast used in the treatment of gastrointestinal disorders. The main objective of the study was to evaluate the effect of S.b treatment on the Toll-like/MyD88/NF-κB/MAPK pathway activated during intestinal mucositis and in Caco-2 cells treated with 5-FU. Methods The mice were divided into three groups: saline (control), saline + 5-FU, and 5-FU + S.b (1.6 × 1010 colony forming units/kg). After 3 days of S.b administration by gavage, the mice were euthanized and the jejunum and ileum were removed. In vitro, Caco2 cells were treated with 5-FU (1 mM) alone or in the presence of lipopolysaccharide (1 ng/ml). When indicated, cells were exposed to S.b. The jejunum/ileum samples and Caco2 cells were examined for the expression or concentration of the inflammatory components. Results Treatment with S.b modulated the expressions of TLR2, TLR4, MyD88, NF-κB, ERK1/2, phospho-p38, phospho-JNK, TNF-α, IL-1β, and CXCL-1 in the jejunum/ileum and Caco2 cells following treatment with 5-FU. Conclusion Toll-like/MyD88/NF-κB/MAPK pathway are activated during intestinal mucositis and their modulation by S.b suggests a novel and valuable therapeutic strategy for intestinal inflammation.

This study aimed to evaluate the effect of Lactobacillus reuteri DSM 17938 (DSM) on ethanol-induced gastric injury, and if its possible mechanism of action is related to inhibiting the transient receptor potential vanilloid type 1 (TRPV1). We evaluated the effect of supplementing 108 CFU•g body wt−1•day−1 of DSM on ethanol-induced gastric injury. DSM significantly reduced the ulcer area (1.940 ± 1.121 mm2) with 3 days of pretreatment. The effects of DSM supplementation were reversed by Resiniferatoxin (RTX), TRPV1 agonist (3 nmol/kg p.o.). Substance P (SP) (1 μmol/L per 20 g) plus 50% ethanol resulted in hemorrhagic lesions, and DSM supplementation did not reverse the lesion area induced by administering SP. TRPV1 staining intensity was lower, SP, malondialdehyde (MDA) and nitrite levels were reduced, and restored normal levels of antioxidant parameters (glutathione and superoxide dismutase) in the gastric mucosa in mice treated with DSM. In conclusion, DSM exhibited gastroprotective activity through decreased expression of TRPV1 receptor and decreasing SP levels, with a consequent reduction of oxidative stress.

Simple Summary The detection of early-stage colorectal cancer increases the chance to prevent tumor progression and death by the disease. Colonoscopy is one sensitive screening test to detect malignant or potentially malignant lesions in the intestines. However, it has some disadvantages, including sedation requirements, increased risk of colon perforation, and bleeding. Circulating microRNAs (miRNAs) in plasma or serum from cancer patients have been investigated and described as potential diagnostic or prognostic markers. We conducted an miRNAs screening test in plasma samples from colorectal cancer patients and subjects without cancer, aiming to identify markers for the early detection of the disease. We identified and validated four miRNAs capable of distinguishing cancer from non-cancer cases. Our non-invasive diagnostic biomarkers presented high performance and are easily applicable to clinical practice. Abstract Colorectal cancer (CRC) is a disease with high incidence and mortality. Colonoscopy is a gold standard among tests used for CRC traceability. However, serious complications, such as colon perforation, may occur. Non-invasive diagnostic procedures are an unmet need. We aimed to identify a plasma microRNA (miRNA) signature for CRC detection. Plasma samples were obtained from subjects (n = 109) at different stages of colorectal carcinogenesis. The patients were stratified into a non-cancer (27 healthy volunteers, 17 patients with hyperplastic polyps, 24 with adenomas), and a cancer group (20 CRC and 21 metastatic CRC). miRNAs (381) were screened by TaqMan Low-Density Array. A classifier based on four differentially expressed miRNAs (miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p) was able to discriminate cancer versus non-cancer cases. The overexpression of these miRNAs was confirmed by RT-qPCR, and a cross-study validation step was implemented using eight data series retrieved from Gene Expression Omnibus (GEO). In addition, another external data validation using CRC surgical specimens from The Cancer Genome Atlas (TCGA) was carried out. The predictive model’s performance in the validation set was 76.5% accuracy, 59.4% sensitivity, and 86.8% specificity (area under the curve, AUC = 0.716). The employment of our model in the independent publicly available datasets confirmed a good discrimination performance in five of eight datasets (median AUC = 0.823). Applying this algorithm to the TCGA cohort, we found 99.5% accuracy, 99.7% sensitivity, and 90.9% specificity (AUC = 0.998) when the model was applied to solid colorectal tissues. Overall, we suggest a novel signature of four circulating miRNAs, i.e., miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p, as a predictive tool for the detection of CRC.

A sulfated polysaccharide (SFP) fraction from the marine alga Solieria filiformis was extracted and submitted to microanalysis, molar mass estimation and spectroscopic analysis. We evaluated its gastroprotective potential in vivo in an ethanol-induced gastric damage model and its in vitro antioxidant properties (DPPH, chelating ferrous ability and total antioxidant capacity). Its chemical composition revealed to be essentially an iota-carrageenan with a molar mass of 210.9kDa and high degree of substitution for sulfate groups (1.08). In vivo, SFP significantly (P

Sulfated polysaccharides extracted from seaweed have important pharmacological properties. Thus, the aim of this study was to characterize the sulfated polysaccharide (PLS) from the algae Hypnea musciformis and evaluate its protective effect in colitis induced by trinitrobenzene sulfonic acid in rats. The sulfated polysaccharide possess a high molecular mass (1.24×10(5)gmol(-1)) and is composed of a κ-carrageenan, as depicted by FT-IR and NMR spectroscopic data. PLS was administered orally (10, 30, and 60mg/kg, p.o.) for three days, starting before TNBS (trinitrobenzene sulfonic acid) instillation (day 1). The rats were killed on day three, the portion of distal colon (5cm) was excised and evaluated macroscopic scores and wet weight. Then, samples of the intestinal were used for histological evaluation and quantification of glutathione, malonyldialdehyde acid, myeloperoxidase, nitrate/nitrite and cytokines. Our results demonstrate that PLS reduced the colitis and all analyzed biochemical parameters. Thus, we concluded that the PLS extracted from the marine algae H. musciformis reduced the colitis in animal model and may have an important promising application in the inflammatory bowel diseases.

Parotoid glands of amphibians are known for the production of several biologically active compounds having pharmacological and toxic effects in mammals. In the present work, a protein fraction obtained from Rhinella schneideri parotoid gland (RsPP) was characterized to study its biological and toxic effects. Rhinella schneideri parotoid secretion is composed of up to 30% (w/w) of soluble proteins. Tandem mass spectrometric analysis of the RsPP identified 104 proteins, including actin, beta-actin, ribosomal proteins, catalase, galectin, and uncharacterized proteins; however, no peptidases were found, and this result was reinforced by the absence of proteolytic activity. In addition, RsPP did not exhibit pro-coagulant or antibacterial effects. However, pretreatment of mice with different doses of RsPP intraperitoneally inhibited carrageenan-induced paw edema and increased tissue myeloperoxidase activity. RsPP also reduced interleukin 1β levels in the peritoneal cavities and cell migration in the peritoneal cavities of an animal model of carrageenan-induced peritonitis. Subchronic treatment of animals with RsPP for 7 consecutive days did not alter the serum biochemical, renal, or liver parameters. However, a significant reduction in blood leukocyte count was observed. Our results showed that R. schneideri parotoid secretion contains proteins with anti-inflammatory and slight toxic effects.

Background This study aimed to investigate and characterize the anti-inflammatory and anti-hypernociceptive effects of the total polysaccharides of X. americana (TPL-Xa) bark in a mouse model of acute pancreatitis-induced by caerulein and the potential involvement of cannabinoid receptors. Methods TPL-Xa was characterized by1H and 13C NMR spectroscopy. Animals received TPL-Xa (10 mg/kg, i.v.) 30 min before and after caerulein (50 μg/kg, 10×, i.p.) administration. To evaluate the involvement of cannabinoid receptors, AM281 (3 mg/kg, s.c.) and AM630 (1 mg/kg, s.c.) were administered 30 min before TPL-Xa. Plasma levels of amylase and lipase, pancreatic myeloperoxidase (MPO), histology, visceral hypernociception and motor coordination were evaluated 11 and 24 h after acute pancreatitis (AP) induction. Results TPL-Xa, containing a heteropolysaccharide composed of glucose, galactose, arabinose, rhamnose, fucose and galacturonic acid, reduced amylase and lipase levels, MPO activity, acinar cell necrosis, edema and neutrophil infiltration. TPL-Xa increased the threshold of visceral hypernociception, an effect reversed by AM630, an antagonist of cannabinoid receptor type 2 (CB2). In addition, TPL-Xa did not alter the animals’ motor coordination. Conclusions TPL-Xa contains heteropolysaccharides that inhibit inflammation and hypernociception in the experimental model of caerulein-induced AP, by a mechanism involving type CB2 receptors.

Introdução: pacientes com doença do refluxo gastroesofágico (DRGE) têm de 10 a 15% de chance de desenvolver esôfago de Barrett. Este pode evoluir para displasia e adenocarcinoma esofágico. Objetivo: avaliar fatores relacionados à detecção de displasia em pacientes com esôfago de Barrett longo. Metodologia: estudo retrospectivo com análise de informações de 18 pacientes com diagnóstico de esôfago de Barrett longo, colhidas de bancos de dados dos serviços de Endoscopia e Patologia e prontuários do Hospital Universitário Walter Cantídio (HUWC-UFC), no período de 2010 a 2015. Os pacientes foram divididos em dois grupos para comparação, grupo sem displasia (N=11) e grupo com displasia/adenocarcinoma (N=7). Resultados: do total de 18 pacientes com esôfago de Barrett longo no HUWC, 72% eram do sexo masculino, 47% tinham mais de 50 anos, 64% apresentavam sintomas típicos de DRGE, 23% eram tabagistas, 77% tinha hérnia hiatal, 50% realizaram fundoplicatura. Não houve diferenças estatísticas destas características entre o grupo com e sem displasia. Entretanto, o grupo com displasia teve uma média de 5 endoscopias/paciente, enquanto o grupo sem displasia teve apenas 2 endoscopias/paciente(p

CHAVES, Hellíada Vasconcelos Objective and design To investigate the role of heme oxygenase-1 (HO-1), carbon monoxide (CO), and biliverdin (BVD) in the zymosan-induced TMJ arthritis in rats. Materials and Methods Mechanical threshold was assessed before and 4 h after TMJ arthritis induction in rats. Cell influx, myeloperoxidase activity, and histological changes were measured in the TMJ lavages and tissues. Trigeminal ganglion and periarticular tissues were used for HO-1, TNF-α, and IL-1β mRNA time course expression and immunohistochemical analyses. Hemin (0.1, 0.3, or 1 mg kg−1), DMDC (0.025, 0.25, or 2.5 µmol kg−1), biliverdin (1, 3, or 10 mg kg−1), or ZnPP-IX (1, 3 or 9 mg kg−1) were injected (s.c.) 60 min before zymosan. ODQ (12.5 µmol kg−1; s.c.) or glibenclamide (10 mg kg−1; i.p.) was administered 1 h and 30 min prior to DMDC (2.5 µmol kg−1; s.c), respectively. Results Hemin (1 mg kg−1), DMDC (2.5 µmol kg−1), and BVD (10 mg kg−1) reduced hypernociception and leukocyte migration, which ZnPP (3 mg kg−1) enhanced. The effects of DMDC were counteracted by ODQ and glibenclamide. The HO-1, TNF-α, and IL-1β mRNA expression and immunolabelling increased. Conclusions HO-1/BVD/CO pathway activation provides anti-nociceptive and anti-inflammatory effects on the zymosan-induced TMJ hypernociception in rats.

Ifosfamide (IFO) is an antineoplastic drug that is commonly used to treat gynecological and breast cancers. Hemorrhagic cystitis (HC) is a common side effect associated with IFO injection, which courses with neutrophil accumulation and affects 6-50% of patients depending on dose intensity. Here, we investigated the role of neutrophils in this inflammatory process. Female Swiss mice (n = 8/group) were injected with saline, IFO (400 mg/kg, i.p.), fucoidan (a P- and L-selectins inhibitor, 100 mg/kg, i.v.) or IFO + fucoidan (1-100 mg/kg) alone or combined with mesna (80 mg/kg i.p.). Another group of mice received anti-Ly6G antibody (500 μg/mouse, once daily for 2 days) for neutrophil depletion before IFO injection. In another experimental setting, animals received granulocyte colony-stimulating factor (G-CSF, 400 μg/kg), IFO (200 mg/kg), G-CSF (25-400 μg/kg, for 5 days) + IFO (200 mg/kg, i.p.) or fucoidan + G-CSF + IFO. Bladder injury was evaluated 12 h after IFO injection. IFO 400 mg/kg significantly increased visceral hyperalgesia, bladder edema, hemorrhage, vascular permeability, MPO, IL-1β and IL-6 tissue levels, and COX-2 immunostaining and expression versus the saline group (P < 0.05). Conversely, fucoidan (100 mg/kg) significantly attenuated these parameters compared to IFO-injected mice (P < 0.05). Additionally, fucoidan potentiated mesna protective effect when compared with IFO + mesna group (P < 0.05). Accordingly, neutrophil depletion with anti-Ly6G reduced inflammatory parameters and bladder injury compared to IFO (P < 0.05). In contrast, G-CSF enhanced IFO (200 mg/kg)-induced HC, which was significantly attenuated by treatment with fucoidan (P < 0.05). Therefore, neutrophils contribute to the pathogenesis of HC.

The aim of our study was to evaluate the anti-inflammatory, anti-nociceptive, and anti-oxidant action of Riparin B in vivo. We performed experiments in which we induced paw edema by carrageenan and other mediators, carrageenan-induced peritonitis and the level of myeloperoxidase (MPO) activity, pro-inflammatory cytokines (TNF-α and IL-1β), malondialdehyde (MDA) acid, and glutathione (GSH) from the peritoneal fluid. We also performed behavior tests such as acetic acid-induced writhing, formalin-induced linking, and the hot plate test. Among the doses tested of the Riparin B (1, 3, and 10 mg/kg), the dose of 10 mg/kg showed the strongest effect, and this dose was able to reduce the paw edema induced by carrageenan, dextran, histamine serotonin, bradykinin, 48/80, and PGE2. Similarly, the Riparin B in the same dose reduced cell migration and significantly decreased the nociception induced by formalin and acetic acid and reversed the parameters of the oxidative stress. Thus, we can infer that Riparin B exhibits anti-inflammatory, anti-nociceptive, and anti-oxidant actions in vivo.

Objectives The aim of the study was to investigate the anti-inflammatory, antioxidant and antinociceptive actions of PFPe, a polysaccharide fraction isolated from the dried fruit of the Passiflora edulis. Methods Animals were pretreated with PFPe (0.3, 1 or 3 mg/kg, i.p.) 1 h before induction of paw oedema by carrageenan, histamine, serotonin, compound 48/80 or prostaglandin E2 (PGE2). Neutrophil migration and vascular permeability were measured after carrageenan injection into the peritoneum, and the action of the PFPe on the tumour necrosis factor-alpha, interleukin-1 beta (IL-1β), myeloperoxidase (MPO), glutathione (GSH) and malondialdehyde (MDA) levels was also evaluated. To assay nociception, we examined acetic acid-induced writhing, formalin-induced paw licking and response latency in the hot plate test. Key findings Pretreatment with PFPe significantly inhibited carrageenan-induced paw oedema. PFPe also reduced paw oedema induced by compound 48/80, histamine, serotonin, and PGE2 and compound 48/80-induced vascular permeability. In addition, PFPe significantly reduced the MPO activity, MDA and GSH concentrations, and IL-1β level. In the nociception tests, PFPe reduced acetic acid-induced writhing and formalin-induced paw licking and did not increase the response latency time. Conclusions Our results suggest that PFPe administration reduces the inflammatory response by modulation of the liberation or synthesis of histamine and serotonin, by reduction of neutrophil migration, IL-1β levels, and oxidative stress and nociception.

Here, we have evaluated the protective effect of the NO donor cis-[Ru(bpy) 2 (SO 3 )NO](PF 6 ) (FOR0810) in experimental models of gastric damage induced by naproxen or ethanol in mice, and the involvement of soluble guanylate cyclase (sGC) and ATP-sensitive K + channels (K ATP ) in these events. Swiss mice were pre-treated with saline, ODQ (a soluble guanylate cyclase inhibitor; 10 mg kg −1 ) or glibenclamide (a K ATP channels blocker; 10 mg kg −1 ). After either 30 min or 1 h, FOR0810 (3 mg kg −1 ) was administered. At the end of 30 min, the animals received naproxen (300 mg kg −1 ) by gavage. After 6 h, the animals were sacrificed and gastric damage, myeloperoxidase (MPO) activity, and TNF-α and IL-1β gastric concentrations were evaluated. In addition, the effects of FOR0810 on naproxen-induced mesenteric leukocyte adherence were determined by intravital microscopy. Other groups, were pre-treated with saline, ODQ or glibenclamide. After either 30 min or 1 h, FOR0810 was administered. At the end of 30 min, the animals received 50% ethanol by gavage. After 1 h, the animals were sacrificed, and gastric damage, gastric reduced glutathione (GSH) concentration and malondialdehyde (MDA) levels were determined. In naproxen-induced gastric damage, FOR0810 prevented gastric injury, decreased gastric MPO activity and leukocyte adherence, associated with a decrease in TNFα and IL-1β gastric concentrations. FOR0810 also prevented ethanol-induced gastric damage by increase in GSH levels and decrease in MDA levels. ODQ and glibenclamide completely reversed FOR0810's ability to prevent gastric damage by either naproxen or ethanol. We infer that FOR0810 prevented gastric damage through the activation of both sGC and K ATP channels, which triggered a decrease in both free radical and cytokine production via the blocking of neutrophil adhesion and infiltration.

Lactobacillus acidophilus is widely used for gastrointestinal disorders, but its role in inflammatory conditions like in chemotherapy-induced mucositis is unclear. Here, we report the effect of L. acidophilus on 5-fluorouracil-induced (5-FU) intestinal mucositis in mice.Mice weighing 25-30 g (n = 8) were separated into three groups, saline, 5-FU, and 5-FU + L. acidophilus (5-FU-La) (16 × 10(9) CFU/kg). In the 5-FU-La group, L. acidophilus was administered concomitantly with 5-FU on the first day and alone for two additional days. Three days after the last administration of L. acidophilus, the animals were euthanized and the jejunum and ileum were removed for histopathological assessment and for evaluation of levels of myeloperoxidase activity, sulfhydryl groups, nitrite, and cytokines (TNF-α, IL-1β, CXCL-1, and IL-10). In addition, we investigated gastric emptying using spectrophotometry after feeding a 1.5-ml test meal by gavage and euthanasia. Data were submitted to ANOVA and Bonferroni's test, with the level of significance at p 0.05.Intestinal mucositis induced by 5-FU significantly (p 0.05) reduced the villus height-crypt depth ratio and GSH concentration and increased myeloperoxidase activity and the nitrite concentrations compared with the control group. Furthermore, 5-FU significantly (p 0.05) increased cytokine (TNF-α, IL-1β, and CXCL-1) concentrations and decreased IL-10 concentrations compared with the control group. 5-FU also significantly (p 0.05) delayed gastric emptying and gastrointestinal transit compared with the control group. All of these changes were significantly (p 0.05) reversed by treatment with L. acidophilus.Lactobacillus acidophilus improves the inflammatory and functional aspects of intestinal mucositis induced by 5-FU.

Background Microscopic inflammation and impairment of the esophageal epithelial barrier are considered relevant for perception of symptoms in patients with nonerosive reflux disease (NERD). In these patients, the receptor transient receptor potential vanilloid 1 (TRPV1) is overexpressed in the esophageal mucosa, but its role is not yet fully understood. We evaluated the role of TRPV1 in esophageal inflammation and mucosal barrier impairment in a murine model of NERD. Methods Nonerosive reflux disease was surgically induced in Swiss mice by pyloric substenosis and ligature of the gastric fundus, and the mice were killed 7 days post surgery. The experimental groups were: I, sham surgery (negative control); II, NERD untreated; III and IV, NERD + SB366791 or capsazepine (TRPV1 antagonists); and V, NERD + resiniferatoxin (for long-term desensitization of TRPV1). The esophagus was collected for western blotting and histopathology and for evaluation of wet weight, myeloperoxidase (MPO), keratinocyte-derived chemokine (KC), transepithelial electrical resistance (TEER), and basal permeability to fluorescein. Key results Compared to sham, NERD mice had increased esophageal wet weight and MPO and KC levels. The mucosa had no ulcers but exhibited inflammation. NERD mice showed mucosal TRPV1 overexpression, a more pronounced decrease in TEER at pH 0.5 (containing pepsin and taurodeoxycholic acid), and increased basal permeability. Pharmacological modulation of TRPV1 prevented esophageal inflammation development, TEER changes by acidic exposure, and increase in esophageal permeability. Conclusions & inferences The TRPV1 receptor has a critical role in esophageal inflammation and mucosal barrier impairment in NERD mice, suggesting that TRPV1 might be a pharmacological target in patients with NERD.

Co-morbid auto-immune disorders may affect 0.2% of the population. We present the clinical and electrodiagnostic findings of 2 patients with inflammatory bowel disease and myasthenia gravis from a Brazilian cohort of 218 inflammatory bowel disease patients. Patient 1: A 40 year-old man was diagnosed with ulcerative colitis at age 37 and underwent total colectomy 3 years later. After prednisone was tapered, he experienced a clinical relapse and was diagnosed with Crohn’s disease. He then developed quadriparesis, bilateral ptosis, dysphagia and dysarthria. Patient 2: A 41 year-old woman (diagnosed with ulcerative colitis and primary sclerosing cholangitis at age 35) developed speech impairment and ptosis. On both patients, symptoms quickly progressed over few weeks. Myasthenia gravis was diagnosed and confirmed by abnormal repetitive nerve stimulation and elevated anti-acetylcholine receptor antibody titers. Pyridostigmine and prednisone successfully treated both patients. Myasthenia gravis prevalence over 9 years was 0.9%. Myasthenia gravis clinical course was not significantly modified by inflammatory bowel disease relapses and should be suspected with new onset weakness.

Polysaccharides (PLS) have notably diverse pharmacological properties. In the present study, we investigated the previously unexplored anti-inflammatory and antinociceptive activities of the PLS fraction isolated from the marine red alga Digenea simplex. We found that the PLS fraction reduced carrageenan-induced edema in a dose-dependent manner, and inhibited inflammation induced by dextran, histamine, serotonin, and bradykinin. The fraction also inhibited neutrophil migration into both mouse paw and peritoneal cavity. This effect was accompanied by decreases in IL1-β and TNF-α levels in the peritoneal fluid. Pre-treatment of mice with PLS (60 mg/kg) significantly reduced acetic acid-induced abdominal writhing. This same dose of PLS also reduced total licking time in both phases of a formalin test, and increased latency in a hot plate test. Therefore, we conclude that PLS extracted from D. simplex possess anti-inflammatory and antinociceptive activities and can be useful as therapeutic agents against inflammatory diseases.