The dual effects of dexmedetomidine on intestinal barrier and intestinal motility during sepsis.

BACKGROUND: Sepsis, characterized by dysregulated host responses to infection, remains a critical global health concern, with high morbidity and mortality rates. The gastrointestinal tract assumes a pivotal role in sepsis due to its dual functionality as a protective barrier against injurious agents and as a regulator of motility. Dexmedetomidine, an α2-adrenergic agonist commonly employed in critical care settings, exhibits promise in influencing the maintenance of intestinal barrier integrity during sepsis. However, its impact on intestinal motility, a crucial component of intestinal function, remains incompletely understood. METHODS: In this study, we investigated dexmedetomidine's multifaceted effects on intestinal barrier function and motility during sepsis using both in vitro and in vivo models. Sepsis was induced in Sprague-Dawley rats via cecal ligation and puncture. Rats were treated with dexmedetomidine post-cecal ligation and puncture, and various parameters were assessed to elucidate dexmedetomidine's impact. RESULTS: Our findings revealed a dichotomous influence of dexmedetomidine on intestinal physiology. In septic rats, dexmedetomidine administration resulted in improved intestinal barrier integrity, as evidenced by reduced mucosal hyper-permeability and morphological alterations. However, a contrasting effect was observed on intestinal motility, as dexmedetomidine treatment inhibited both the frequency and amplitude of contractions in isolated intestinal strips and decreased the distance of ink migration in vivo. Additionally, dexmedetomidine suppressed the secretion of pro-motility hormones while having no influence on hormones that inhibit intestinal peristalsis. CONCLUSION: The study revealed that during sepsis, dexmedetomidine exhibited protective effects on barrier integrity, although concurrently it hindered intestinal motility, partly attributed to its modulation of pro-motility hormone secretion. These findings underscore the necessity of a comprehensive understanding of dexmedetomidine's impact on multiple facets of gastrointestinal physiology in sepsis management, offering potential implications for therapeutic strategies and patient care.

SOV sensitizes gastric cancer cells to radiation by suppressing radiation-induced autophagy in vitro and in vivo.

Vanadium is a transition metal that naturally occurs in the environment and has a variety of biological and physiological impacts on humans. Sodium orthovanadate (SOV), a well-known chemical compound of vanadium, has shown notable anti-cancer activity in various types of human malignancies. However, the effect of SOV on stomach cancer is yet undetermined. Furthermore, only a few studies have investigated the association of SOV and radiosensitivity with stomach cancer. Our study has investigated the ability of SOV to increase the sensitivity of gastric cancer cells to radiation. To detect autophagy triggered by ionizing radiation and the influence of SOV on cell radiosensitivity, the Cell Counting Kit-8 (CCK8) test, EDU staining experiment, colony formation assay, and immunofluorescence were performed. The possible synergistic effects of SOV and irradiation were examined in vivo using a xenograft mouse model of stomach cancer cells. Both in vitro and in vivo studies showed that SOV markedly reduced the growth of stomach cancer cells and improved their radiosensitivity. Our results showed that SOV increased gastric cancer cells' radiosensitivity, thereby blocking the radiation-induced autophagy-related protein, ATG10. Thus, SOV can be considered a potential agent for radiosensitizing gastric cancer.

Inhibition of miR-155 alleviates sepsis-induced inflammation and intestinal barrier dysfunction by inactivating NF-κB signaling.

MicroRNA-155 (miR-155) is implicated in the pathological processes of sepsis. However, the function and regulatory mechanism of miR-155 in sepsis-induced inflammation and intestinal barrier dysfunction remain unknown. In this study, mouse models of sepsis were established by caecal ligation and puncture (CLP). To reduce miR-155 expression, the mice were injected for three consecutive days with an miR-155 inhibitor (80 mg/kg) before CLP. The serum DAO concentration was measured by ELISA, and histological changes in the intestine were identified by H&E staining 24 h after CLP. FITC-dextran assays were used to evaluate intestinal permeability. MiR-155 gene expression was evaluated with RT-PCR, and relative protein expression was assessed by Western blotting. NCM460 cells were transfected with an miR-155 mimic/miR-155 inhibitor or pretreated with an NF-κB inhibitor before LPS treatment, and the cytokines levels, miR-155 gene expression and relative protein expression were measured. Sepsis increased miR-155, DAO and FITC-dextran levels and reduced Occludin and ZO-1 expression. Mice injected with the miR-155 inhibitor recovered from the damages. Transfection of NCM460 cells with the miR-155 mimic elevated the NF-κB (P65) and p-NF-κB (p-P65) localization and expression in the nucleus, which was reversed by the miR-155 inhibitor. Pretreatment with an NF-κB inhibitor suppressed inflammation, improved cell permeability to FITC-dextran and increased Occludin and ZO-1 levels. Transfection with the miR-155 inhibitor decreased TNF-α and IL-6 levels, reduced cell permeability to FITC-dextran and increased ZO-1 and Occludin expression. The effects induced by transfection with the miR-155 mimic, including elevated TNF-α and IL-6 levels, hyperpermeability to FITC-dextran and reduced ZO-1 and Occludin expression, were partly rescued by pretreatment with the NF-κB inhibitor. These findings reveal that the miR-155 inhibitor alleviates inflammation and intestinal barrier dysfunction by inactivating NF-κB signaling during sepsis.

Resuscitation with hydroxyethyl starch 130/0.4 attenuates intestinal injury in a rabbit model of sepsis.

OBJECTIVE: Improvement of mucosal barrier function and reduction of bacterial translocation are important in the management of sepsis. The mechanisms that underlie the protective effects of colloids on the intestinal mucosal barrier are unclear. The study aims to investigate the effect of fluid resuscitation with hydroxyethyl starch (HES) 130/0.4 against intestinal mucosal barrier dysfunction in a rabbit model of sepsis. MATERIALS AND METHODS: Thirty healthy rabbits were randomly and equally divided into a sham-operated control, a sepsis model, or a sepsis + HES treatment group. The sepsis model and sepsis + HES treatment groups were subjected to a modified colon ascendens stent peritonitis (CASP) procedure to induce sepsis. Four hours after the CASP procedure, fluid resuscitation was performed with 6% HES 130/0.4. Arterial and superior mesenteric vein blood samples were collected 4 and 8 h after the CASP procedure for blood gas analysis and measuring tumor necrosis factor-α, interleukin-10, and D-lactate levels. The rabbits were euthanized 8 h after CASP, and sections of the small intestine were stained to evaluate histopathological changes. RESULTS: Respiratory rate and blood pressure were stable during the resuscitation period. Fluid resuscitation with 6% HES 130/0.4 alleviated pathological changes in the abdominal cavity, improved blood gas parameters and inflammatory mediator levels, decreased plasma D-lactate levels, and reduced intestinal mucosal injury compared with the non-treated sepsis model. CONCLUSIONS: Fluid resuscitation with 6% HES 130/0.4 protects against intestinal mucosal barrier dysfunction in rabbits with sepsis, possibly via mechanisms associated with improving intestinal oxygen metabolism and reducing the release of inflammatory mediators.