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.

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.

Protective effects of fucoidan, a P- and L-selectin inhibitor, in murine acute pancreatitis.

OBJECTIVE: The objective of this study was to investigate the potential protective effects of fucoidan, an L- and P-selectin modulator, in 2 murine models of acute pancreatitis. METHODS: Acute pancreatitis was induced in mice either by the retrograde infusion of taurolithocholic acid sulfate into the pancreatic duct or by intraperitoneal injections of cerulein (50 µg/kg per hour). The experimental groups received fucoidan (25 mg/kg, intravenously) before pancreatitis induction, whereas control groups received only saline. After 24 hours, serum amylase, lipase, interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), and nitrite were measured. In addition, myeloperoxidase (MPO) activity (lung and pancreas) and histological assessment (pancreas) were determined. RESULTS: Serum amylase, lipase, nitrite, TNF-α, and IL-1ß, and pancreatic and lung MPO were increased in both taurolithocholic acid sulfate and cerulein acute pancreatitis compared with the respective control groups. Fucoidan significantly decreased the augmented levels of amylase, lipase, pancreatic and lung MPO, TNF-α, IL-1ß, and nitrite in both models. Pancreas histological changes observed in both acute pancreatitis models were significantly attenuated by fucoidan. CONCLUSIONS: Fucoidan reduced the severity of acute pancreatitis in mice by decreasing neutrophil infiltration and systemic inflammation, suggesting that modulation of selectins may constitute a promising therapeutic approach.

Gastric contractility in experimental gastroschisis.

BACKGROUND/PURPOSE: The mechanism of fetal gastric dilation in gastroschisis is controversial. This study was designed to characterize changes in the contractile profile of strips of stomach from rats following experimental gastroschisis. METHODS: Pregnant Wistar rats were operated on day 18.5. Fetuses were divided into three groups: gastroschisis (G), sham (S), and control (C). On day 21.5, gastric fundus and antrum strips were obtained and suspended to a force transducer connected to a digital data acquisition system. They were submitted to increasing concentrations of carbachol (CCh) and weighed at the end of each procedure. Frequency and amplitude of each contraction were evaluated. RESULTS: Under basal conditions, spontaneous oscillatory contractions of antrum and fundus strips of G, S, and C were similar (P>0.05; ANOVA). However, cumulative concentrations of CCh (0.01-100 µM) produced different effects in all groups and were characterized by a significant increase in amplitude and frequency of spontaneous contractions in antral smooth muscle and a sustained increase in tonus in fundic strips. Upon analysis, no significant difference in frequency or amplitude was noted in antral tissues comparing C to G and to S (P>0.05). No significant contractility difference was noted in fundic smooth muscle (comparing all groups, P>0.05), with the CCh-induced curve following a typical sigmoidal format, dependent on increasing concentrations (P<0.001). CONCLUSIONS: Gastric contractile responses to CCh are preserved in experimental gastroschisis. These results do not support the theory that gastric dilation occurs secondary to intestinal inflammation alone.

Types of pelvic floor dysfunctions in nulliparous, vaginal delivery, and cesarean section female patients with obstructed defecation syndrome identified by echodefecography.

PURPOSE: This study aims to show pelvic floor dysfunctions in women with obstructed defecation syndrome (ODS), comparing nulliparous to those with vaginal delivery or cesarean section using the echodefecography (ECD). MATERIALS AND METHODS: Three hundred seventy female patients with ODS were reviewed retrospectively and were divided in Group I-105 nulliparous, Group II-165 had at least one vaginal delivery, and Group III-comprised of 100 patients delivered only by cesarean section. All patients had been submitted to ECD to identify pelvic floor dysfunctions. RESULTS: No statistical significance was found between the groups with regard to anorectocele grade. Intussusception was identified in 40% from G I, 55.0% from G II, and 30.0% from G III, with statistical significance between Groups I and II. Intussusception was associated with significant anorectocele in 24.8%, 36.3%, and 18% patients from G I, II, and III, respectively. Anismus was identified in 39.0% from G I, 28.5% from G II, and 60% from G III, with statistical significance between Groups I and III. Anismus was associated with significant anorectocele in 22.8%, 15.7%, and 24% patients from G I, II, and III, respectively. Sigmoidocele/enterocele was identified in 7.6% from G I, 10.9% G II, and was associated with significant rectocele in 3.8% and 7.3% patients from G I and II, respectively. CONCLUSION: The distribution of pelvic floor dysfunctions showed no specific pattern across the groups, suggesting the absence of a correlation between these dysfunctions and vaginal delivery.

Amifostine (Wr-2721) prevents indomethacin-induced gastric damage in rats: role of non-protein sulfhydryl groups and leukocyte adherence.

This study was designed to evaluate the protective effect of amifostine on indomethacin-induced gastric damage, and the role of increased gastric non-protein sulfhydryl groups (NP-SH) and decreased leukocyte adherence in this event. Wistar rats were pretreated with amifostine (10, 30, or 90 mg/kg intraperitoneal (i.p.) or subcutaneous (s.c.)) or saline. After 30 min, the rats received indomethacin (20 mg/kg, by gavage) and were then killed 3 hr later. Macroscopic and microscopic gastric damage, concentration of gastric NP-SH, prostaglandin E2 (PGE2), and mesenteric leukocyte adherence (intravital microscopy) were assessed. Amifostine prevented significantly (P < 0.05), macroscopic or microscopic, indomethacin-induced gastric damage, and increased gastric NP-SH, in a dose-dependent manner, with a maximal effect at a dose of 90 mg/kg. Subcutaneous, but not i.p., amifostine administration decreased (P < 0.05) the indomethacin-induced increase in leukocyte adherence. Indomethacin-induced PGE2 depletion was not reversed by amifostine. Amifostine has a protective effect against indomethacin-induced gastropathy by increasing gastric NP-SH and decreasing leukocyte adherence.