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.

COVID-19 IN INFLAMMATORY BOWEL DISEASE: SHOULD WE BE MORE CAREFUL WITH THE USE OF SALICYLATES?

BACKGROUNDS: Fortunately, much has been studied about COVID-19 in patients with inflammatory bowel diseases (IBD). Evidence suggests that these patients do not appear to be at increased risk of severe COVID-19. However, there are still some uncertainties regarding the clinical manifestations of COVID-19 in patients with immune-mediated diseases. OBJECTIVE: This study aimed to describe the main symptoms of COVID-19 and their frequency in IBD patients and evaluate the impact of the IBD therapeutic drugs on clinical presentation of COVID-19 and to determine factors associated with COVID-19 in this population. METHODS: Adult patients with IBD from three tertiary-care public, teaching hospitals in Ceará, Northeastern Brazil, were evaluated during one scheduled appointment from March to December 2020. Patients with possible or confirmed COVID-19 were compared with patients without COVID-19. Furthermore, incidences of each symptom were evaluated based on the use of IBD therapeutic drugs. RESULTS: A total of 515 patients with IBD were included in the study: 234 with CD, and 281 with UC. Of these, 174 patients (34%) had possible/confirmed COVID-19 of whom 156 (90%) were symptomatic. Main symptoms were fever (65%) and headache (65%); gastrointestinal symptoms occurred in one third of patients and were higher than COVID-19 in general population. The factors associated with having COVID-19 were female gender (OR 1.71, 95%CI: 1.17-2.50); contact at home (OR 5.07, 95%CI: 3.31-7.78) and outside the home (OR 3.14, 95%CI: 2.10-4.71) with a case of COVID-19; work outside of the home (OR 1.87, 95%CI: 1.26-2.78); family history of COVID-19 (OR 2.29, 95%CI 1.58-3.33) use of salicylate (OR 1.71, 95%CI: 1.17-4.28); and asthma (OR 7.10, 95%CI: 1.46-34.57). CONCLUSION: IBD patients at high risk of COVID-19 infection may need to avoid salicylate therapy but further studies are necessary to confirm this association.

Comprehensive analysis of gastrointestinal side effects in COVID-19 patients undergoing combined pharmacological treatment with azithromycin and hydroxychloroquine: a systematic review and network meta-analysis.

During the COVID-19 pandemic, several drugs were repositioned and combined to quickly find a way to mitigate the effects of the infection. However, the adverse effects of these combinations on the gastrointestinal tract are unknown. We aimed investigate whether Hydroxychloroquine (HD), Azithromycin (AZ), and Ivermectin (IV) used in combination for the treatment of COVID-19, can lead to the development of gastrointestinal disorders. This is a systematic review and network meta-analysis conducted using Stata and Revman software, respectively. The protocol was registered with PROSPERO (CRD42023372802). A search of clinical trials in Cochrane Library databases, Embase, Web of Science, Lilacs, PubMed, Scopus and Clinicaltrials.gov conducted on November 26, 2023. The eligibility of the studies was assessed based on PICO criteria, including trials that compared different treatments and control group. The analysis of the quality of the evidence was carried out according to the GRADE. Six trials involving 1,686 COVID-19 patients were included. No trials on the association of HD or AZ with IV met the inclusion criteria, only studies on the association between HD and AZ were included. Nausea, vomiting, diarrhea, abdominal pain and increased transaminases were related. The symptoms of vomiting and nausea were evaluated through a network meta-analysis, while the symptom of abdominal pain was evaluated through a meta-analysis. No significant associations with these symptoms were observed for HD, AZ, or their combination, compared to control. Low heterogeneity and absence of inconsistency in indirect and direct comparisons were noted. Limitations included small sample sizes, varied drug dosages, and potential publication bias during the pandemic peak. This review unveils that there are no associations between gastrointestinal adverse effects and the combined treatment of HD with AZ in the management of COVID-19, as compared to either the use of a control group or the administration of the drugs individually, on the other hand, highlighting the very low or low certainty of evidence for the evaluated outcomes. To accurately conclude the absence of side effects, further high-quality randomized studies are needed.

Vaccine adherence and adverse events of the SARS-COV vaccine in patients with inflammatory bowel disease.

OBJECTIVE: To assess adherence to and the adverse effects of the SARS-COV vaccine in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: This is an observational, analytical, cross-sectional study. Sociodemographic and clinical data, SARS-COV vaccine data, medications for IBD with use during the vaccination period, and adverse events during the vaccination period were collected. Carried out logistic regressions with robust variance estimation to estimate the odds ratio with the respective 95% confidence intervals (95%CI) to assess the factors associated with non-serious adverse effects following vaccine doses as outcome variables. RESULTS: 194 patients participated, with vaccine compliance of 78.3% for three doses of any vaccine (n=152). Local symptoms and mild systemic symptoms predominated, regardless of the type of vaccine. The first dose of the SARS-COV vaccine with AstraZeneca had a higher percentage of patients with vaccine symptoms. AstraZeneca vaccine increased the chance of non-serious adverse effects in IBD patients by 2.65 times (95% CI: 1.38-5.08; p=0.003), regardless of age, gender, physical activity, excess weight, use of disease-modifying drugs, immunobiological and corticosteroids. CoronaVac vaccine was associated with asymptomatic patients at the first dose and reduced the chance of adverse effects by 0.28 times (OR: 0.284; 95%CI: 0.13-0.62; p=0.002). CONCLUSION: Local symptoms and mild systemic symptoms predominated, regardless of the type of vaccine. Using CoronaVac in the first dose reduced the chances of adverse effects, while AstraZeneca increased the risk of adverse effects.

A polyphenol-rich açaí seed extract protects against 5-fluorouracil-induced intestinal mucositis in mice through the TLR-4/MyD88/PI3K/mTOR/NF-κBp65 signaling pathway.

Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1ß; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway.

Exploring the clinical relevance of "Angico Gum": an effective biopolymer for topical protection of oesophageal mucosa in gastroesophageal reflux disease patients.

OBJECTIVES: Angico gum (AG) (Anadenanthera colubrina var. Cebil [Griseb.] Altschul) is utilized by some Brazilian communities to alleviate symptoms from gastroesophageal reflux disease. Here, we aimed to investigate the "in vitro" topical protective capacity of AG on human esophageal mucosa. METHODS: Biopsies of the distal esophageal mucosa were collected from 35 patients with heartburn (24 non-erosive and 11 with erosive oesophagitis (EE)) and mounted in Üssing chambers. AG was applied topically, followed by exposure with acid solution (pH 2.0 or pH 1.0), where transepithelial electrical resistance (TER) and The transepithelial permeability for fluorescein was assessed. The incubation of the AG labeled with FITC in the esophageal mucosa was localized by fluorescence microscopy. KEY FINDINGS: Pretreatment with AG prevented the drop in TER induced by acid solution, as well as significantly decreases the fluorescein permeability in non-erosive patients. The protective effect of AG was sustained for up to 120 min both in biopsies of non-erosive and erosive esophagitis. Confocal microscope images showed mucosal luminal adherence of FITC-labeled AG. CONCLUSION: AG had a prolonged topical protective effect against acid solution in mucosal biopsies of patients with non-erosive and erosive esophagitis.

A MEDICAL AND NEUROPSYCHIATRIC MANAGEMENT SURVEY IN A BRAZILIAN COHORT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD).

BACKGROUND: Inflammatory bowel disease (IBD) can be accompanied by several neurological disorders. Since 2004, we started a Brazilian cohort to assess neuropsychiatric complications in IBD patients. Changes in therapeutic strategy and differences in the prevalence and relevance of neuropsychiatric disorders have been reported in the literature. We conducted a short patient-reported survey about the medical management of IBD (with a special focus on neuropsychiatric management) and its complications. During the enrollment period (9/1/2021 to 8/31/2022), 279 patients with IBD answered the survey (128 patients with ulcerative colitis and 151 with Crohn's disease). This is the first medical management survey aimed to verify the level of perception of IBD patients about their neuropsychiatric conditions. We found a high prevalence of neurologic (59%), psychiatric (32%), and neuropsychiatric co-morbidities (69%). There is a marked discrepancy between the findings of neurological disorders reported in our studies over the first 10 years of the cohort in comparison with the current perception/knowledge among the patients registered in the present management survey. Patients tend to have a better understanding of central rather than peripheral nerve conditions. BACKGROUND: • What is already known? BACKGROUND: • The prevalence and spectrum of neuropsychiatric co-morbidities varies among different epidemiologic studies. BACKGROUND: • What is new here? BACKGROUND: • Patients self report a high percentage of neuropsychiatric diseases but tend to better recognize central rather than peripheral nervous system disorders. BACKGROUND: • How can this study help patient care? BACKGROUND: • This study may guide practioners to educate IBD patients about their neuropsychiatric co-morbidities.

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.

COVID-19 na doença inflamatória intestinal: devemos ser mais cautelosos com o uso dos salicilatos? / Covid-19 in inflammatory bowel disease: should we be more careful with the use of salicylates?

ABSTRACT Backgrounds: Fortunately, much has been studied about COVID-19 in patients with inflammatory bowel diseases (IBD). Evidence suggests that these patients do not appear to be at increased risk of severe COVID-19. However, there are still some uncertainties regarding the clinical manifestations of COVID-19 in patients with immune-mediated diseases. Objective: This study aimed to describe the main symptoms of COVID-19 and their frequency in IBD patients and evaluate the impact of the IBD therapeutic drugs on clinical presentation of COVID-19 and to determine factors associated with COVID-19 in this population. Methods: Adult patients with IBD from three tertiary-care public, teaching hospitals in Ceará, Northeastern Brazil, were evaluated during one scheduled appointment from March to December 2020. Patients with possible or confirmed COVID-19 were compared with patients without COVID-19. Furthermore, incidences of each symptom were evaluated based on the use of IBD therapeutic drugs. Results: A total of 515 patients with IBD were included in the study: 234 with CD, and 281 with UC. Of these, 174 patients (34%) had possible/confirmed COVID-19 of whom 156 (90%) were symptomatic. Main symptoms were fever (65%) and headache (65%); gastrointestinal symptoms occurred in one third of patients and were higher than COVID-19 in general population. The factors associated with having COVID-19 were female gender (OR 1.71, 95%CI: 1.17-2.50); contact at home (OR 5.07, 95%CI: 3.31-7.78) and outside the home (OR 3.14, 95%CI: 2.10-4.71) with a case of COVID-19; work outside of the home (OR 1.87, 95%CI: 1.26-2.78); family history of COVID-19 (OR 2.29, 95%CI 1.58-3.33) use of salicylate (OR 1.71, 95%CI: 1.17-4.28); and asthma (OR 7.10, 95%CI: 1.46-34.57). Conclusion: IBD patients at high risk of COVID-19 infection may need to avoid salicylate therapy but further studies are necessary to confirm this association.

RESUMO Contexto: Felizmente, muito se tem estudado sobre a COVID-19 em pacientes com doenças inflamatórias intestinais (DII). As evidências sugerem que esses pacientes não parecem ter risco aumentado de COVID-19 grave. Mas ainda se tem algumas incertezas com relação às manifestações clínicas da COVID-19 em portadores de doenças imunomediadas. Objetivo: Este estudo teve como objetivo descrever os principais sintomas da COVID-19 e sua frequência em pacientes com DII e avaliar o impacto dos medicamentos utilizados no tratamento das DII na apresentação clínica da COVID-19. Métodos: Pacientes adultos com DII de três hospitais públicos terciários de ensino do Ceará, Nordeste do Brasil, foram avaliados em consulta ambulatorial no período de março a dezembro de 2020. Pacientes com COVID-19 possível ou confirmada foram comparados com pacientes sem COVID-19. Além disso, as incidências de cada sintoma foram avaliadas com base no uso de medicamentos utilizados para tratamento da DII. Resultados: Foram incluídos no estudo 515 pacientes com DII: 234 com DC e 281 com RCU. Destes, 174 pacientes (34%) tinham COVID-19 possível/confirmado, dos quais 156 (90%) eram sintomáticos. Os principais sintomas foram febre (65%) e dor de cabeça (65%); sintomas gastrointestinais ocorreram em um terço dos pacientes, sendo mais frequentes do que na população geral com COVID-19. Os fatores associados a ter COVID-19 foram sexo feminino (OR 1,71, IC95%: 1,17-2,50); ter contato com caso de COVID-19, tanto intradomiciliar (OR 5,07; IC95%: 3,31-7,78) como fora do domicílio (OR 3,14; IC95%: 2,10-4,71); trabalhar fora de casa (OR 1,87; IC95%: 1,26-2,78); história familiar de COVID-19 (OR 2,29, IC95% 1,58-3,33), uso de salicilato (OR 1,71, IC95%: 1,17-4,28) e asma (OR 7,10; IC95%: 1,46-34,57). Conclusão: Pacientes com DII com alto risco de infecção por COVID-19 podem precisar evitar a terapia com salicilatos, mas mais estudos são necessários para confirmar esta associação.

Uma pesquisa de manejo médico e neuropsiquiátrico em uma coorte brasileira de pacientes com doença inflamatória intestinal (DII) / A medical and neuropsychiatric management survey in a brazilian cohort of patients with inflammatory bowel disease (ibd)

ABSTRACT Inflammatory bowel disease (IBD) can be accompanied by several neurological disorders. Since 2004, we started a Brazilian cohort to assess neuropsychiatric complications in IBD patients. Changes in therapeutic strategy and differences in the prevalence and relevance of neuropsychiatric disorders have been reported in the literature. We conducted a short patient-reported survey about the medical management of IBD (with a special focus on neuropsychiatric management) and its complications. During the enrollment period (9/1/2021 to 8/31/2022), 279 patients with IBD answered the survey (128 patients with ulcerative colitis and 151 with Crohn's disease). This is the first medical management survey aimed to verify the level of perception of IBD patients about their neuropsychiatric conditions. We found a high prevalence of neurologic (59%), psychiatric (32%), and neuropsychiatric co-morbidities (69%). There is a marked discrepancy between the findings of neurological disorders reported in our studies over the first 10 years of the cohort in comparison with the current perception/knowledge among the patients registered in the present management survey. Patients tend to have a better understanding of central rather than peripheral nerve conditions.

RESUMO A doença inflamatória intestinal (DII) pode ser acompanhada por vários distúrbios neurológicos. Desde 2004, iniciamos uma coorte brasileira para avaliar complicações neuropsiquiátricas em pacientes com DII. Mudanças na estratégia terapêutica e diferenças na prevalência e relevância dos transtornos neuropsiquiátricos têm sido relatadas na literatura. Realizamos uma breve pesquisa relatada pelos pacientes sobre o manejo médico da DII (com foco especial no manejo neuropsiquiátrico) e suas complicações. Durante o período de 01/09/2021 a 31/08/2022, 279 pacientes com DII responderam à pesquisa (128 pacientes com retocolite ulcerativa e 151 com doença de Crohn). Esta é a primeira pesquisa de gestão médica que visa verificar o nível de percepção dos pacientes com DII acerca de suas condições neuropsiquiátricas. Encontramos uma alta prevalência de comorbidades neurológicas (59%), psiquiátricas (32%) e neuropsiquiátricas (69%). Há uma discrepância marcante entre os achados de distúrbios neurológicos relatados em nossos estudos durante os primeiros 10 anos da coorte em comparação com a percepção/conhecimento atual entre os pacientes da presente pesquisa de manejo. Os pacientes tendem a ter uma melhor compreensão das condições que afetam o sistema nervoso central do que as que afetam o sistema nervoso periférico.

Crucial role of carbon monoxide as a regulator of diarrhea caused by cholera toxin: Evidence of direct interaction with toxin.

The present study evaluated the role of heme oxygenase 1 (HO-1)/carbon monoxide (CO) pathway in the cholera toxin-induced diarrhea and its possible action mechanism. The pharmacological modulation with CORM-2 (a CO donor) or Hemin (a HO-1 inducer) decreased the intestinal fluid secretion and Cl- efflux, altered by cholera toxin. In contrast, ZnPP (a HO-1 inhibitor) reversed the antisecretory effect of Hemin and potentiated cholera toxin-induced intestinal secretion. Moreover, CORM-2 also prevented the alteration of intestinal epithelial architecture and local vascular permeability promoted by cholera toxin. The intestinal absorption was not altered by any of the pharmacological modulators. Cholera toxin inoculation also increased HO-1 immunoreactivity and bilirubin levels, a possible protective physiological response. Finally, using fluorometric technique, ELISA assay and molecular docking simulations, we show evidence that CO directly interacts with cholera toxin, forming a complex that affects its binding to GM1 receptor, which help explain the antisecretory effect. Thus, CO is an essential molecule for protection against choleric diarrhea and suggests its use as a possible therapeutic tool.

Laryngeal and Esophageal Mucosal Protection Using the Angico Gum Biopolymer in a Mouse Model of Reflux.

OBJECTIVE: This study aimed to evaluate the in vivo protective effect of the angico gum biopolymer in reducing the inflammatory response and preserving the integrity of the laryngeal and esophageal mucosa. STUDY DESIGN: Animal study. METHODS: A murine surgical model of gastroesophageal reflux disease was accomplished and subsequently treated with angico gum or omeprazole. On days 3 and 7 post surgery, samples of the larynx and esophagus, respectively, were collected to measure the level of inflammation (wet weight and myeloperoxidase activity) and mucosal integrity (transepithelial electrical resistance and mucosal permeability to fluorescein). RESULTS: Angico gum and omeprazole decreased laryngeal inflammation (wet weight and myeloperoxidase activity) and dramatically improved the integrity of the laryngeal mucosa. It also reduced inflammation (decreased wet weight and myeloperoxidase activity) of the esophagus and preserved the barrier function (inferred by assessing the integrity of the mucosa). CONCLUSION: This study demonstrates the protective effect of angico gum in an experimental gastroesophageal reflux disease model. Angico gum attenuates inflammation and impairment of the mucosal barrier function not only in the larynx but also in the esophagus. LEVEL OF EVIDENCE: NA Laryngoscope, 133:162-168, 2023.

BILIARY FISTULAS ASSOCIATED WITH LIVER TRANSPLANTATION VERSUS OTHER ETIOLOGIES: WHAT IS THE SUCCESS RATE OF THE ENDOSCOPIC TREATMENT?

BACKGROUND: Biliary fistulas typically occur as surgical complications after laparoscopic cholecystectomy, liver transplantation, or partial liver resection. AIMS: This study aimed to evaluate the efficacy of the endoscopic treatment of biliary fistulae secondary to liver transplantation compared to that of other etiologies. METHODS: A retrospective study of 25 patients undergoing endoscopic retrograde cholangiopancreatography for biliary fistula from 2015 to 2021 was conducted at the Endoscospy Unit of Walter Cantídio University Hospital. Clinical characteristics and endoscopic success rates of the post-liver transplantation group were analyzed in comparison with those of other etiologies. RESULTS: The main causes of biliary fistula were liver transplantation (44%) and cholecystectomy complications (44%). The post-liver transplantation group had a significantly higher proportion of male sex (liver transplantation=81.8%, others=28.6%) and older age (liver transplantation=54.1 years, others=42.0 years) and a higher incidence of biliary stenosis (liver transplantation=90.9%, others=14.3%) than those of the group with other etiologies (p<0.05). The two groups received similar treatment types, among which sphincterotomy associated with biliary stent placement was most commonly used. Endoscopic therapeutic success rates showed no significant difference between the post-liver transplantation group (63.6%) and the group with other etiologies (71.4%). CONCLUSIONS: The endoscopic treatment of biliary fistulae secondary to liver transplantation presented a recovery rate similar to that of other etiologies despite the patients older age and the presence of biliary stenosis.

Dietary polysaccharides from guavira pomace, a co-product from the fruit pulp industry, display therapeutic application in gut disorders.

Inflammatory bowel disease (IBD) includes two distinct diseases: Crohn's disease (CD) and ulcerative colitis (UC). IBD is a chronic systemic disease of the gastrointestinal tract, characterized by an inflammatory process. The mechanisms by which diseases develop are still unknown, but it is known that it results from a complex interaction between genetic variability, the host's immune system, and environmental factors. One of the main complaints of patients is abdominal pain, which may be associated with the release of inflammatory mediators, changes in the normal motility of the digestive tract, and increased intestinal permeability. Currently available drugs for abdominal pain are not satisfactory, therefore, it is extremely necessary to seek new therapeutic options for the treatment of abdominal pain. Polysaccharides extracted from fruits have attracted interest, as these molecules protect the intestinal mucosa and promote wound healing, attenuating inflammation, pain, and altered intestinal motility. In this study, we investigated the ability of pectic polysaccharides obtained from guavira pomace, named CPW to reduce visceral hypersensitivity, regulate intestinal motility, and control diarrhea in mice. Acetic acid, capsaicin, or mustard oil were used to assess visceral pain in normal mice. CPW reduced abdominal writhing, cell migration, and capsaicin-induced visceral nociception. Furthermore, it regulated intestinal motility and all measured parameters of castor oil-induced diarrhea. CPW treatment reversed the increase in mucosal permeability, TEER, and tissue weight caused by acetic acid. In addition, molecular docking analysis showed that specific the CPW units binds to the 3N8V, 5COX, 2J67 and 6RBF proteins. Thus, the results suggest that CPW has attractive therapeutic characteristics for the treatment of abdominal pain and ulcerative colitis.

Anti-inflammatory and anti-necrotic effects of lectins from Canavalia ensiformis and Canavalia brasiliensis in experimental acute pancreatitis.

Lectins isolated from Canavalia ensiformis (ConA) and Canavalia brasiliensis (ConBr) are promising molecules to prevent cell death. Acute pancreatitis, characterized by acinar cell necrosis and inflammation, presents significant morbidity and mortality. This study has investigated the effects of ConA and ConBr in experimental acute pancreatitis and pancreatic acinar cell death induced by bile acid. Pancreatitis was induced by retrograde pancreatic ductal injection of 3% sodium taurocholate (Na-TC) in male Swiss mice. ConA or ConBr (0.1, 1 or 10 mg/kg) were intravenously applied to mice 1 h and 12 h after induction. After 24 h, the severity of pancreatitis was evaluated by serum amylase and lipase, histopathological changes and myeloperoxidase assay. Pancreatic acinar cells were incubated with ConA (200 µg/ml) or ConBr (200 µg/ml) and taurolithocholic acid 3-sulfate (TLCS; 500 µM). Necrosis and changes in mitochondrial membrane potential (ΔÑ°m) were detected by fluorescence confocal microscopy. Treatment (post-insult) with ConA and ConBr decreased pancreatic damage caused by retrograde injection of Na-TC in mice, reducing pancreatic neutrophil infiltration, edema and necrosis. In addition, ConA and ConBr decreased pancreatic acinar cell necrosis and depolarization of ΔÑ°m caused by TLCS. The inhibition of necrosis was prevented by the lectin domain blockade. In conclusion, ConA and ConBr markedly inhibited in vitro and in vivo damage, effects partly dependent on the interaction with mannose residues on acinar cells. These data support the potential application of these proteins for treatment of acute pancreatitis.

Modulatory Role of Carbon Monoxide on the Inflammatory Response and Oxidative Stress Linked to Gastrointestinal Disorders.

Significance: Carbon monoxide (CO) is an endogenous gaseous mediator that plays an important role in maintaining gastrointestinal (GI) tract homeostasis, acting in mucosal defense, 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 proinflammatory cytokines and reactive oxygen species, while increasing antioxidant defense mechanisms. Critical Issues: CO has potent anti-inflammatory and antioxidant effects. The defense 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 signaling cascades, as well as reinforcing several defense 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. Antioxid. Redox Signal. 37, 98-114.

Biliary fistulas associated with liver transplantation versus other etiologies: what is the success rate of the endoscopic treatment? / Fístulas biliares associadas com transplante hepático versus outras etiologias: qual a taxa de sucesso do tratamento endoscópico?

ABSTRACT - BACKGROUND: Biliary fistulas typically occur as surgical complications after laparoscopic cholecystectomy, liver transplantation, or partial liver resection. AIMS: This study aimed to evaluate the efficacy of the endoscopic treatment of biliary fistulae secondary to liver transplantation compared to that of other etiologies. METHODS: A retrospective study of 25 patients undergoing endoscopic retrograde cholangiopancreatography for biliary fistula from 2015 to 2021 was conducted at the Endoscospy Unit of Walter Cantídio University Hospital. Clinical characteristics and endoscopic success rates of the post-liver transplantation group were analyzed in comparison with those of other etiologies. RESULTS: The main causes of biliary fistula were liver transplantation (44%) and cholecystectomy complications (44%). The post-liver transplantation group had a significantly higher proportion of male sex (liver transplantation=81.8%, others=28.6%) and older age (liver transplantation=54.1 years, others=42.0 years) and a higher incidence of biliary stenosis (liver transplantation=90.9%, others=14.3%) than those of the group with other etiologies (p<0.05). The two groups received similar treatment types, among which sphincterotomy associated with biliary stent placement was most commonly used. Endoscopic therapeutic success rates showed no significant difference between the post-liver transplantation group (63.6%) and the group with other etiologies (71.4%). CONCLUSIONS: The endoscopic treatment of biliary fistulae secondary to liver transplantation presented a recovery rate similar to that of other etiologies despite the patients older age and the presence of biliary stenosis

RESUMO - RACIONAL: As fístulas biliares geralmente ocorrem como complicações cirúrgicas, especialmente após colecistectomia laparoscópica, transplante hepático ou ressecção hepática parcial. OBJETIVOS: Avaliar a eficácia do tratamento endoscópico das fístulas biliares secundária ao transplante hepático em comparação com outras etiologias. MÉTODOS: Estudo retrospectivo de 25 pacientes submetidos a Colangiopancreatografia Retrógada Endoscópica por fístula biliar entre 2015 e 2021 no Serviço de Endoscopia do Hospital Universitário Walter Cantídeo. As características clínicas e as taxas de sucesso endoscópico do grupo pós-transplante hepático foram analisadas em comparação com as de outras etiologias. RESULTADOS: As principais causas de fístula biliar foram pós-transplante hepático (44%) e complicações da pós-colecistectomia (44%). O grupo pós-transplante hepático apresentou proporção significativamente maior de sexo masculino (pós-transplante hepático=81,8%, outros=28,6%) e idade mais avançada (pós-transplante hepático=54,1 anos, outros=42,0 anos) e maior incidência de estenose biliar (pós-transplante hepático=90,9%, outros=14,3%) do que o grupo com outras etiologias (p<0,05). Os dois grupos receberam tipos de tratamento semelhantes, dentre os quais a esfincterotomia associada à aposição de prótese biliar foi a mais utilizada. As taxas de sucesso terapêutico endoscópico não mostraram diferença significativa entre o grupo pós-transplante hepático (63,6%) e o grupo com outras etiologias (71,4%). CONCLUSÕES: O tratamento endoscópico das fístulas biliares secundária ao transplante hepático apresentou taxa de recuperação semelhante à de outras etiologias, apesar da idade avançada dos pacientes e da presença de estenose biliar.

Circulating let-7e-5p, miR-106a-5p, miR-28-3p, and miR-542-5p as a Promising microRNA Signature for the Detection of Colorectal Cancer.

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.

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.