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Abstract Background Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol. Methods The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a −/− and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers. Results We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells. Conclusions We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.

Abstract Intestinal organoid transplantation is a promising therapy for the treatment of mucosal injury. However, how the transplanted organoids regulate the immune microenvironment of recipient mice and their role in treating intestinal ischemia-reperfusion (I/R) injury remains unclear. Here, we establish a method for transplanting intestinal organoids into intestinal I/R mice. We find that transplantation improve mouse survival, promote self-renewal of intestinal stem cells and regulate the immune microenvironment after intestinal I/R, depending on the enhanced ability of macrophages polarized to an anti-inflammatory M2 phenotype. Specifically, we report that L-Malic acid (MA) is highly expressed and enriched in the organoids-derived conditioned medium and cecal contents of transplanted mice, demonstrating that organoids secrete MA during engraftment. Both in vivo and in vitro experiments demonstrate that MA induces M2 macrophage polarization and restores interleukin-10 levels in a SOCS2-dependent manner. This study provides a therapeutic strategy for intestinal I/R injury.

Abstract Background Lactobacillus has been demonstrated to serve a protective role in intestinal injury. However, the relationship between Lactobacillus murinus (L. murinus)-derived tryptophan metabolites and intestinal ischemia/reperfusion (I/R) injury yet to be investigated. This study aimed to evaluate the role of L. murinus-derived tryptophan metabolites in intestinal I/R injury and the underlying molecular mechanism. Methods Liquid chromatograph mass spectrometry analysis was used to measure the fecal content of tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. Immunofluorescence, quantitative RT-PCR, Western blot, and ELISA were performed to explore the inflammation protective mechanism of tryptophan metabolites in WT and Nrf2-deficient mice undergoing intestinal I/R, hypoxia-reoxygenation (H/R) induced intestinal organoids. Results By comparing the fecal contents of three L. murinus-derived tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. We found that the high abundance of indole-3-lactic acid (ILA) in the preoperative feces was associated with better postoperative intestinal function, as evidenced by the correlation of fecal metabolites with postoperative gastrointestinal function, serum I-FABP and D-Lactate levels. Furthermore, ILA administration improved epithelial cell damage, accelerated the proliferation of intestinal stem cells, and alleviated the oxidative stress of epithelial cells. Mechanistically, ILA improved the expression of Yes Associated Protein (YAP) and Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) after intestinal I/R. The YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of ILA, both in vivo and in vitro. Additionally, we found that ILA failed to protect epithelial cells from oxidative stress in Nrf2 knockout mice under I/R injury. Conclusions The content of tryptophan metabolite ILA in the preoperative feces of patients is negatively correlated with intestinal function damage under CPB surgery. Administration of ILA alleviates intestinal I/R injury via the regulation of YAP and Nrf2. This study revealed a novel therapeutic metabolite and promising candidate targets for intestinal I/R injury treatment.

Abstract Background To evaluate the effect of the single energy metal artifact reduction (SEMAR) algorithm with a multidetector CT (MDCT) for knee tumor prostheses. Methods First, a phantom of knee tumor prosthesis underwent a MDCT scan. The raw data was reconstructed by iterative reconstruction (IR) alone and IR plus SEMAR. The mean value of the CT number and the image noise were measured around the prosthesis at the stem level and articular level. Second, 95 consecutive patients with knee tumor prostheses underwent MDCT scans. The raw data were also reconstructed by the two methods. Periprosthetic structures were selected at the similar two levels. Four radiologists visually graded the image quality on a scale from 0 to 5. Additionally, the readers also assessed the presence of prosthetic complication and tumor recurrence on a same scale. Results In the phantom, when the SEMAR was used, the CT numbers were closer to normal value and the noise of images using soft and sharper kernel were respectively reduced by up to 77.1% and 43.4% at the stem level, and by up to 82.2% and 64.5% at the articular level. The subjective scores increased 1 ~ 3 points and 1 ~ 4 points at the two levels, respectively. Prosthetic complications and tumor recurrence were diagnosed in 66 patients. And the SEMAR increased the diagnostic confidence of prosthetic complications and tumor recurrence (4 ~ 5 vs. 1 ~ 1.5). Conclusions The SEMAR algorithm can significantly reduce the metal artifacts and increase diagnostic confidence of prosthetic complications and tumor recurrence in patients with knee tumor prostheses.

Sepsis is associated with a high risk of death, and the crosstalk between gut microbiota and sepsis is gradually revealed. Indole 3-propionic acid (IPA) is a gut microbiota-derived metabolite that exerts immune regulation and organ protective effects. However, the role of IPA in sepsis is not clear. In this study, the role of IPA in sepsis-related survival, clinical scores, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. Aryl hydrocarbon receptor (AhR) highly specific inhibitor (CH223191) was used to observe the role of AhR in the protection of IPA against sepsis. The effects of IPA on bacterial phagocytosis by macrophages were investigated in vivo and vitro. The levels of IPA in feces were measured and analyzed in human sepsis patients and patient controls. First, we found that gut microbiota-derived IPA was associated with the survival of septic mice. Then, in animal model, IPA administration protected against sepsis-related mortality and alleviated sepsis-induced bacterial burden and organ injury, which was blunted by AhR inhibitor. Next, in vivo and vitro, IPA enhanced the macrophage phagocytosis through AhR. Depletion of macrophages reversed the protective effects of IPA on sepsis. Finally, on the day of ICU admission (day 0), septic patients had significantly lower IPA level in feces than patient controls. Also, septic patients with bacteremia had significantly lower IPA levels in feces compared with those with non-bacteremia. Furthermore, in septic patients, reduced IPA was associated with worse clinical outcomes, and IPA in feces had similar prediction ability of 28-day mortality with SOFA score, and increased the predictive ability of SOFA score. These findings indicate that gut microbiota-derived IPA can protect against sepsis through host control of infection by promoting macrophages phagocytosis and suggest that IPA may be a new strategy for sepsis treatment.

AIM:To evaluate the effect of monocular rectus surgery for adult sensory exotropia. METHODS: Totally 76 cases of adult sensory exotropia of degree -15△ to -160△(-68.36△±30.77△)examined through Krimsky method were included into this study. A total of 16 cases, 37 cases and 23 cases with different degrees of strabismus were treated separately with routine amount monocular lateral rectus recession, routine amount monocular medial rectus resection plus lateral rectus recession, and exceed constant amount monocular medial rectus resection plus lateral rectus recession. Follow-up was performed at 1d, 1wk, 1, 3 and 6mo after operation. The eye position, monocular movement, intraocular pressure(IOP), slit lamp, and fundus of these patients were examined. RESULTS:After surgery, 67 cases(88%)were positive and 9 cases(12%)were undercorrection. The postoperative intraocular pressure of operative eye at 1wk was equal to preoperative(P=0.090), and IOP decreased to a valley value at 1mo(PP=0.092), and no significant difference in intraocular pressure between 6mo and 3mo(P=0.123). And 2 cases(3%)had inflammatory reaction induced by anterior segment ischemia at 1d and 1wk postoperative visits, and they recovered at 1mo follow-up visit; 4 cases(5%)experienced an external dysfunction at the 1, 3 and 6mo follow-up. CONCLUSION:Monocular rectus surgery has a good therapeutic effect on adult patients with sensory exotropia; the decrease in intraocular pressure secondary to the detached rectus is worth the attention of the surgeon; the incidence of complications after detaching monocular of two rectus muscles is comparable low. Exceed constant amount rectus strabismus surgery for sensory exotropia may result in limited function of postoperative ocular hyperextension.

A flexible and efficient carbonylative synthesis of thiochromenones from the commercially available materials by utilizing tert-butyl isocyanide as carbonyl source has been developed. This methodology efficiently constructs thiochromenones in moderate to excellent yields with the advantages of wide range of substrates and being applicable to library synthesis. [ABSTRACT FROM AUTHOR]