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Background & aimsClostridium difficile induces intestinal inflammation by releasing toxins A and B. The antimicrobial compound cationic steroid antimicrobial 13 (CSA13) has been developed for treating gastrointestinal infections. The CSA13-Eudragit formulation can be given orally and releases CSA13 in the terminal ileum and colon. We investigated whether this form of CSA13 reduces C difficile infection (CDI) in mice.MethodsC57BL/6J mice were infected with C difficile on day 0, followed by subcutaneous administration of pure CSA13 or oral administration of CSA13-Eudragit (10 mg/kg/d for 10 days). Some mice were given intraperitoneal vancomycin (50 mg/kg daily) on days 0-4 and relapse was measured after antibiotic withdrawal. The mice were monitored until day 20; colon and fecal samples were collected on day 3 for analysis. Blood samples were collected for flow cytometry analyses. Fecal pellets were collected each day from mice injected with CSA13 and analyzed by high-performance liquid chromatography or 16S sequencing; feces were also homogenized in phosphate-buffered saline and fed to mice with CDI via gavage.ResultsCDI of mice caused 60% mortality, significant bodyweight loss, and colonic damage 3 days after infection; these events were prevented by subcutaneous injection of CSA13 or oral administration CSA13-Eudragit. There was reduced relapse of CDI after administration of CSA13 was stopped. Levels of CSA13 in feces from mice given CSA13-Eudragit were significantly higher than those of mice given subcutaneous CSA13. Subcutaneous and oral CSA13 each significantly increased the abundance of Peptostreptococcaceae bacteria and reduced the abundance of C difficile in fecal samples of mice. When feces from mice with CDI and given CSA13 were fed to mice with CDI that had not received CSA13, the recipient mice had significantly increased rates of survival. CSA13 reduced fecal levels of inflammatory metabolites (endocannabinoids) and increased fecal levels of 4 protective metabolites (ie, citrulline, 3-aminoisobutyric acid, retinol, and ursodeoxycholic acid) in mice with CDI. Oral administration of these CSA13-dependent protective metabolites reduced the severity of CDI.ConclusionsIn studies of mice, we found the CSA13-Eudragit formulation to be effective in eradicating CDI by modulating the intestinal microbiota and metabolites.

Many Crohn's disease (CD) patients develop intestinal strictures, which are difficult to prevent and treat. Cationic steroid antimicrobial 13 (CSA13) shares cationic nature and antimicrobial function with antimicrobial peptide cathelicidin. As many functions of cathelicidin are mediated through formyl peptide receptor-like 1 (FPRL1), we hypothesize that CSA13 mediates anti-fibrogenic effects via FPRL1. Human intestinal biopsies were used in clinical data analysis. Chronic trinitrobenzene sulfonic acid (TNBS) colitis-associated intestinal fibrosis mouse model with the administration of CSA13 was used. Colonic FPRL1 mRNA expression was positively correlated with the histology scores of inflammatory bowel disease patients. In CD patients, colonic FPRL1 mRNA was positively correlated with intestinal stricture. CSA13 administration ameliorated intestinal fibrosis without influencing intestinal microbiota. Inhibition of FPRL1, but not suppression of intestinal microbiota, reversed these protective effects of CSA13. Metabolomic analysis indicated increased fecal mevalonate levels in the TNBS-treated mice, which were reduced by the CSA13 administration. CSA13 inhibited colonic HMG-CoA reductase activity in an FPRL1-dependent manner. Mevalonate reversed the anti-fibrogenic effect of CSA13. The increased colonic FPRL1 expression is associated with severe mucosal disease activity and intestinal stricture. CSA13 inhibits intestinal fibrosis via FPRL1-dependent modulation of HMG-CoA reductase pathway.

C. difficile infection (CDI) is a common debilitating nosocomial infection associated with high mortality. Several CDI outbreaks have been attributed to ribotypes 027, 017, and 078. Clinical and experimental evidence indicates that the nonpathogenic yeast Saccharomyces boulardii CNCM I-745 (S.b) is effective for the prevention of CDI. However, there is no current evidence suggesting this probiotic can protect from CDI caused by outbreak-associated strains. We used established hamster models infected with outbreak-associated C. difficile strains to determine whether oral administration of live or heat-inactivated S.b can prevent cecal tissue damage and inflammation. Hamsters infected with C. difficile strain VPI10463 (ribotype 087) and outbreak-associated strains ribotype 017, 027, and 078 developed severe cecal inflammation with mucosal damage, neutrophil infiltration, edema, increased NF-κB phosphorylation, and increased proinflammatory cytokine TNFα protein expression. Oral gavage of live, but not heated, S.b starting 5 days before C. difficile infection significantly reduced cecal tissue damage, NF-κB phosphorylation, and TNFα protein expression caused by infection with all strains. Moreover, S.b-conditioned medium reduced cell rounding caused by filtered supernatants from all C. difficile strains. S.b-conditioned medium also inhibited toxin A- and B-mediated actin cytoskeleton disruption. S.b is effective in preventing C. difficile infection by outbreak-associated via inhibition of the cytotoxic effects of C. difficile toxins.

This study aims to prepare a nanodrug system for insulin delivery and controlled release with Poly(lactic acid-glycolic acid) (PLGA) as the shell and polyethylene glycol-chondroitin sulfate as the core to enhance its oral administration bioavailability. The insulin/CS-PLGA nanoparticles (NPs) with an average size of about 150 nm and regular spherical shape were obtained and showed good biocompatibility and relative high drug loading. Insulin can be controlled release according to the environmental pH and retained its original structure. The oral administration of insulin/CS-PLGA NPs showed a relatively higher hypoglycemic effect than that of insulin, indicating the NPs is a potential oral delivery system to enhance insulin bioavailability. [ABSTRACT FROM AUTHOR]

Deposition of aggregated amyloid beta (Aβ) protein is considered to be a major causative factor that is associated with the development of oxidative stress and neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Selenium nanoparticles (SeNPs) have been experimentally using for treatment of neurological disease due to their low toxicity, high bioavailability, and multiple bioactivities. This study was conducted to investigate the protective effects of biogenic SeNPs by Lactobacillus casei ATCC 393 against Aβ25–35-induced toxicity in PC12 cells and its association with oxidative stress and inflammation. The results showed that SeNPs had no cytotoxicity on PC12 cells. Moreover, SeNPs entered cells through cellular endocytosis, which effectively attenuated Aβ25–35-induced toxicity in PC12 cells. In addition, compared with Aβ25–35 model group, SeNP pretreatment significantly enhanced the antioxidant capacity, inhibited the overproduction of reactive oxygen species (ROS), effectively regulated the inflammatory response, decreased the activity of acetylcholinesterase, significantly reduced the expression level of caspase-1 and the ratio of Bcl-2/Bax, and upregulated the expression level of p53. Furthermore, compared with Aβ25–35 model group, SeNPs effectively promoted the phosphorylation of Akt and cAMP-response element-binding protein (CREB), and upregulated the expression level of brain-derived neurotrophic factor (BDNF). In addition, the Akt inhibitor (AKT inhibitor VIII, AKTi-1/2) could reverse the protective effects of SeNPs on PC12 cells. The Akt agonist (SC79) had a similar effect on PC12 cells as that of SeNPs. Overall, this study demonstrated that biogenic SeNPs can effectively alleviate the Aβ25–35-induced toxicity in PC12 cells via Akt/CREB/BDNF signaling pathway. [ABSTRACT FROM AUTHOR]