Neuropathy and primary headaches affect different subgroups of inflammatory bowel disease patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). Migraine was 2.6 times more common in CD patients than controls (CI = 1.34-5.129) and 8.6 times (13.3 times in the CD group) more common in men with IBD (P < 0.05). Headache and migraine were also more common in dyspeptic patients (P < 0.05). Chi-square, univariate, and multivariate regression analysis did not disclose any association between PN, headache, or PH (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. CONCLUSION: In summary, PH and PN are common in IBD and do not affect the same subgroups of patients.

Modulation of 5-fluorouracil activation of toll-like/MyD88/NF-κB/MAPK pathway by Saccharomyces boulardii CNCM I-745 probiotic.

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-1ß, 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.

Efficacy of a phenol derivative, isopropyl vanillate, as an anti-inflammatory agent: A new small molecule inhibitor of COX and neutrophil migration.

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.

AMPK activation promotes gastroprotection through mutual interaction with the gaseous mediators H2S, NO, and CO.

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.

H2S is a key antisecretory molecule against cholera toxin-induced diarrhoea in mice: Evidence for non-involvement of the AC/cAMP/PKA pathway and AMPK.

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.

A novel murine model of esophageal nonerosive reflux disease: from inflammation to impairment in mucosal integrity.

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.

The nitric oxide donor cis-[Ru(bpy)2(SO3)NO](PF6) increases gastric mucosa protection in mice--involvement of the soluble guanylate cyclase/K(ATP) pathway.

Here, we have evaluated the protective effect of the NO donor cis-[Ru(bpy)2(SO3)NO](PF6) (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 (KATP) in these events. Swiss mice were pre-treated with saline, ODQ (a soluble guanylate cyclase inhibitor; 10 mg kg(-1)) or glibenclamide (a KATP 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-1ß 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-1ß 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 KATP channels, which triggered a decrease in both free radical and cytokine production via the blocking of neutrophil adhesion and infiltration.

Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/K(ATP) signaling pathway.

Chronic use of alendronate has been linked to gastrointestinal tract problems. Our objective was to evaluate the role of the NO/cGMP/KATP signaling pathway and nitric oxide synthase expression in alendronate-induced gastric damage. Rats were either treated with the NO donor, sodium nitroprusside (SNP; 1, 3, and 10 mg/kg), or the NO synthase (NOS) substrate, L-arginine (L-Arg; 50, 100, and 200 mg/kg). Some rats were pretreated with either ODQ (a guanylate cyclase inhibitor; 10 mg/kg) or glibenclamide (KATP channels blocker; 10 mg/kg). In other experiments, rats were pretreated with L-NAME (non-selective NOS inhibitor; 10 mg/kg), 1400 W (selective inducible NOS [iNOS] inhibitor; 10 mg/kg), or L-NIO (a selective endothelial NOS [eNOS] inhibitor; 30 mg/kg). After 1 h, the rats were treated with alendronate (30 mg/kg) by gavage for 4 days. SNP and L-Arg prevented alendronate-induced gastric damage in a dose-dependent manner. Alendronate reduced nitrite/nitrate levels, an effect that was reversed with SNP or L-Arg treatment. Pretreatment with ODQ or glibenclamide reversed the protective effects of SNP and L-Arg. L-NAME, 1400 W, or L-NIO aggravated the severity of alendronate-induced lesions. In addition, alendronate reduced the expression of iNOS and eNOS in the gastric mucosa. Gastric ulcerogenic responses induced by alendronate were mediated by a decrease in NO derived from both eNOS and iNOS. In addition, our findings support the hypothesis that activation of the NO/cGMP/KATP pathway is of primary importance for protection against alendronate-induced gastric damage.

Treatment with Saccharomyces boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in 5-fluorouracil-induced intestinal mucositis in mice.

Intestinal mucositis is an important toxic side effect of 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii is known to protect from intestinal injury via an effect on the gastrointestinal microbiota. The objective of the present study was to evaluate the effect of S. boulardii on intestinal mucositis induced by 5-FU in a murine model. Mice were divided into saline, saline (control)+5-FU or 5-FU+S. boulardii (16 × 109 colony-forming units/kg) treatment groups, and the jejunum and ileum were removed after killing of mice for the evaluation of histopathology, myeloperoxidase (MPO) activity, and non-protein sulfhydryl group (mainly reduced glutathione; GSH), nitrite and cytokine concentrations. To determine gastric emptying, phenol red was administered orally, mice were killed 20 min after administration, and the absorbance of samples collected from the mice was measured by spectrophotometry. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following oral administration. S. boulardii significantly reversed the histopathological changes in intestinal mucositis induced by 5-FU and reduced the inflammatory parameters: neutrophil infiltration (control 1·73 (SEM 0·37) ultrastructural MPO (UMPO)/mg, 5-FU 7·37 (SEM 1·77) UMPO/mg and 5-FU+S. boulardii 4·15 (SEM 0·73) UMPO/mg); nitrite concentration (control 37·00 (SEM 2·39) µm, 5-FU 59·04 (SEM 11·41) µm and 5-FU+S. boulardii 37·90 (SEM 5·78) µm); GSH concentration (control 477·60 (SEM 25·25) µg/mg, 5-FU 270·90 (SEM 38·50) µg/mg and 5-FU+S. boulardii 514·00 (SEM 38·64) µg/mg). Treatment with S. Boulardii significantly reduced the concentrations of TNF-α and IL-1ß by 48·92 and 32·21 % in the jejunum and 38·92 and 61·79 % in the ileum. In addition, S. boulardii decreased the concentrations of chemokine (C-X-C motif) ligand 1 by 5-fold in the jejunum and 3-fold in the ileum. Interestingly, S. boulardii reduced the delay in gastric emptying (control 25·21 (SEM 2·55) %, 5-FU 54·91 (SEM 3·43) % and 5-FU+S. boulardii 31·38 (SEM 2·80) %) and induced the recovery of intestinal permeability (lactulose:mannitol ratio: control 0·52 (SEM 0·03), 5-FU 1·38 (SEM 0·24) and 5-FU+S. boulardii 0·62 (SEM 0·03)). In conclusion, S. boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in intestinal mucositis induced by 5-FU.

Pepsin Inhibitors Prevent Inflammation and Loss of Laryngeal Barrier Function in Mice with Gastroesophageal Reflux.

OBJECTIVE: This study aimed to evaluate the role of pepsin inhibitors in the inflammatory response and their effects on laryngeal mucosal integrity during gastroesophageal reflux (GERD) under in vivo conditions. METHODS: A surgical model of GERD was used, in which mice were treated with pepstatin (0.3 mg/kg) or darunavir (8.6 mg/kg) for 3 days. On the third day after the experimental protocol, the laryngeal samples were collected to assess the severity of inflammation (wet weight and myeloperoxidase activity) and mucosal integrity (transepithelial electrical resistance and paracellular epithelial permeability to fluorescein). RESULTS: The surgical GERD model was reproduced. It showed features of inflammation and loss of barrier function in the laryngeal mucosa. Pepstatin and darunavir administration suppressed laryngeal inflammation and preserved laryngeal mucosal integrity. CONCLUSION: Pepsin inhibition by the administration of pepstatin and darunavir improved inflammation and protected the laryngeal mucosa in a mouse experimental model of GERD. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3080-3085, 2024.

Diminazene aceturate inhibits the SARS-CoV-2 spike protein-induced inflammation involving leukocyte migration and DNA extracellular traps formation.

AIMS: To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE). MATERIALS AND METHODS: Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction. KEY FINDINGS: Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as ß2 integrin, PI3K, and PAD2 due to its intermolecular coupling. SIGNIFICANCE: Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.

Inflammatory intestinal damage induced by 5-fluorouracil requires IL-4.

BACKGROUND: 5-Fluorouracil (5-FU) induces intestinal mucositis, which is characterized by epithelial ulcerations in the mucosa and clinical manifestations, such as pain and dyspeptic symptoms. Cytokines participate in the inflammatory and functional events of intestinal mucositis. IL-4 is an important mediator of intestinal inflammation, with either anti-inflammatory or pro-inflammatory functions, depending on the model of intestinal inflammation. This study aimed to evaluate the role of IL-4 in 5-FU-induced intestinal mucositis. METHODS: IL-4+/+ or IL-4-/- mice (25-30 g) were intraperitoneally injected with 5-FU (450 mg/Kg) or saline (C). After 3 days, the mice were sacrificed and the duodenum was evaluated for epithelial damage, MPO activity and cytokine concentration. RESULTS: 5-FU induced significant damage in the intestinal epithelium of IL-4+/+ mice (reduction in the villus/crypt ratio: control=3.31±0.21 µm, 5-FU=0.99±0.10 µm). However, the same treatment did not induce significant damage in IL-4-/- mice (5-FU=2.87±0.19 µm) compared to wild-type mice. 5-FU-induced epithelial damage increased the MPO activity (neutrophil number) and the level of pro-inflammatory cytokines (IL-4, TNF-α, IL-1ß and CXCL-8) in the duodenum. These results were not observed in IL-4-/- mice treated with 5-FU. CONCLUSION: Our data suggest that IL-4 participates as a pro-inflammatory cytokine in a 5-FU-induced intestinal damage model and suggests that IL-4 antagonists may be novel therapeutics for this condition.

A sulfated-polysaccharide fraction from seaweed Gracilaria birdiae prevents naproxen-induced gastrointestinal damage in rats.

Red seaweeds synthesize a great variety of sulfated galactans. Sulfated polysaccharides (PLSs) from seaweed are comprised of substances with pharmaceutical and biomedical potential. The aim of the present study was to evaluate the protective effect of the PLS fraction extracted from the seaweed Gracilaria birdiae in rats with naproxen-induced gastrointestinal damage. Male Wistar rats were pretreated with 0.5% carboxymethylcellulose (control group-vehicle) or PLS (10, 30, and 90 mg/kg, p.o.) twice daily (at 09:00 and 21:00) for 2 days. After 1 h, naproxen (80 mg/kg, p.o.) was administered. The rats were killed on day two, 4 h after naproxen treatment. The stomachs were promptly excised, opened along the greater curvature, and measured using digital calipers. Furthermore, the guts of the animals were removed, and a 5-cm portion of the small intestine (jejunum and ileum) was used for the evaluation of macroscopic scores. Samples of the stomach and the small intestine were used for histological evaluation, morphometric analysis and in assays for glutathione (GSH) levels, malonyldialdehyde (MDA) concentration, and myeloperoxidase (MPO) activity. PLS treatment reduced the macroscopic and microscopic naproxen-induced gastrointestinal damage in a dose-dependent manner. Our results suggest that the PLS fraction has a protective effect against gastrointestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration and lipid peroxidation.

Role of capsaicin-sensitive primary afferent neurons and non-protein sulphydryl groups on gastroprotective effect of amifostine against ethanol-induced gastric damage in rats.

BACKGROUND: Amifostine has been widely tested as a cytoprotective agent against a number of aggressors in different organs. Recently, a gastroprotective effect was observed for this drug in a model of indomethacin-induced gastric injury. Our objective was to investigate the effect of amifostine on ethanol-induced gastric injury and the role played in this mechanism by afferent sensory neurons, non-protein sulfhydryl groups, nitric oxide, ATP-sensitive potassium channels, and cyclooxygenase-2. METHODS: Rats were treated with amifostine (22.5, 45, 90, or 180 mg/kg, PO or SC). After 30 min, the rats received absolute ethanol (5 ml kg(-1), PO). One hour later, gastric damage was quantified with a planimeter. Samples from the stomach were also taken for histopathological assessment and for assays of non-protein sulfhydryl groups. The other groups were pretreated with L-NAME (10 mg kg(-1), IP), glibenclamide (10 mg kg(-1), PO), or celecoxib (10 mg kg(-1), PO). After 30 min, the animals were given amifostine (90 mg kg(-1), PO or SC), followed 30 min later by gavage with absolute ethanol (5 ml kg(-1)). Other rats were desensitized with capsaicin (125 mg kg(-1), SC) 8 days prior to amifostine treatment. RESULTS: Amifostine administration PO and SC significantly and dose-dependently reduced ethanol-induced macroscopic and microscopic gastric damage by restoring glutathione levels in the stomach mucosa. Amifostine-promoted gastroprotection against ethanol-induced stomach injury was reversed by pretreatment with neurotoxic doses of capsaicin, but not by L-NAME, glibenclamide, or celecoxib. CONCLUSIONS: Amifostine protects against ethanol-induced gastric injury by increasing glutathione levels and stimulating the afferent sensory neurons in the stomach.

Anti-diarrheal therapeutic potential of diminazene aceturate stimulation of the ACE II/Ang-(1-7)/Mas receptor axis in mice: A trial study.

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.

Protective effect against gastric mucosa injury of a sulfated agaran from Acanthophora spicifera.

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.

Chemical structure, anti-inflammatory and antinociceptive activities of a sulfated polysaccharide from Gracilaria intermedia algae.

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 < 0.05), myeloperoxidase (MPO) activity, neutrophil migration and IL-1ß levels. It also decreased acetic acid-induced writhing (P < 0.05) and formalin-induced paw licking time (P < 0.05), but no in hot plate test. In summary, the PLS decreased the inflammatory response by reducing neutrophil migration and modulating IL-1ß production and antinociceptive effects by a peripheral mechanism dependent on the down-modulation of the inflammatory mediators.

Laryngeal Mucosa Alterations in Mice Model of Gastroesophageal Reflux: Effects of Topical Protection.

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.

Biopolymer Extracted from Anadenanthera colubrina (Red Angico Gum) Exerts Therapeutic Potential in Mice: Antidiarrheal Activity and Safety Assessment.

Anadenanthera colubrina var. cebil (Griseb.) Altschul (Fabaceae family), commonly known as the red angico tree, is a medicinal plant found throughout Brazil'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-1, 1368 cm-1, and 1029 cm-1, which relate to the vibration of O-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 × 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.