hydroquinone (pigmentasa / pigmentasa)

Coenzyme A activates TLR4 and enhances alternative macrophage activation in line with MyD88 agonism.

Jones Anthony E AE, Rios Amy A, Ibrahimovic Neira N, Ball Andréa B AB et al.

Metabolites and metabolic cofactors can shape the innate immune response, though the pathways by which these molecules adjust inflammation remain incompletely understood. Here we show that the metabolic cofactor coenzyme A (CoA) enhances IL-4 driven alternative macrophage activation [M(IL-4)] in vitro and in vivo. Unexpectedly, we find that perturbations in intracellular CoA metabolism do not influence M(IL-4) differentiation. Rather, we discover that exogenous CoA is a weak TLR4 agonist which primes macrophages for increased receptivity to IL-4 signals and resolution of inflammation via MyD88. Mechanistic studies reveal MyD88-linked signals enhance IL-4 responsiveness, in part, by reshaping chromatin accessibility to enhance transcription of IL-4-linked genes. The results identify CoA as a host metabolic co-factor that influences macrophage function through an extrinsic TLR4-dependent mechanism and suggest that damage-associated molecular patterns (DAMPs) can prime macrophages for alternative activation and resolution of inflammation.

Metabolites from blood and formalin-fixed, paraffin-embedded tissue from participants with low- and high-grade prostate cancer: a pilot study.

Graff Rebecca E RE, Bengtsson Henrik L HL, Suh Jung H JH, Olshen Adam B AB et al.

Identifying metabolites associated with prostate cancer (Pca) aggressiveness may elucidate mechanisms underlying disease severity. Doing so in plasma and formalin-fixed, paraffin-embedded (FFPE) tissue may accelerate discovery. In this cross-sectional pilot study, we generated hypotheses for further exploration by assessing the association between plasma metabolites and the Gleason score of individuals with Pca and by evaluating the correlation between plasma and FFPE metabolite levels. We examined plasma and FFPE samples from 10 individuals with Gleason score 7 (6 3 + 4, 4 4 + 3) and 9 individuals with Gleason score 9 (6 4 + 5, 3 5 + 4) tumors from a convenience sample of 19 men with Pca. We measured the relative abundance of polar metabolites at the time of radical prostatectomy. We used linear models of log2 fold changes to examine plasma metabolite levels relative to pathological tumor grade. Relationships among metabolite levels measured in plasma and FFPE tumor tissue within individuals across metabolites were examined using Pearson correlations. Among the 18 selected plasma metabolites, which were chosen a priori because of their prior association with Pca aggressiveness, serine (p = 0.0051) and ornithine (p = 0.036) levels were higher in individuals with Gleason 9 than Gleason 7 Pca. After multiple testing correction, however, no associations were statistically significant. The median correlation between metabolite levels in plasma and FFPE tumor tissue was 0.45 (range: 0.40-0.53) for the 94 metabolites measured in both biospecimens. Plasma serine and ornithine levels demonstrated the largest differences between individuals with Gleason 7 and Gleason 9 Pca. Metabolite levels in FFPE prostate tissue samples were moderately correlated with plasma levels. Future studies with larger sample sizes are needed to further explore the hypotheses generated by this study.

Response: Diagnostic utility of APRI, FIB-4, and FIB-5 in intrahepatic cholestasis of pregnancy.

Cicek Sevil S, Kapudere Bilge B, Kaya Parspancı Yasemin Beyza YB, Tavukcuoglu Zehra Z et al.

Dual acellular subnormothermic machine perfusion for enhanced uterus preservation in a swine model.

Cabanel Lucile L, Oubari Haïzam H, Ellis Bradley W BW, Dion Ludivine L et al.

Machine perfusion has rapidly developed in the last decade and demonstrated improved preservation of conventional and marginal organs by reducing ischemia and hypoxia injuries. The aim of this study was to assess whether subnormothermic machine perfusion improves graft preservation compared with SCS in a porcine uterus model. Swine uteri were procured from circulatory-dead donors and allocated into two groups. In the experimental group, the organs were preserved with 4 h-dual subnormothermic machine perfusion (n = 4) while the control group (n = 4) underwent 4 h-static cold storage. After preservation, all uteri received ex vivo whole blood normothermic reperfusion (NMP) to simulate transplantation. Perfusate samples were analyzed from uterine arteries and veins every 30 min for gas and metabolic analysis, and weight variations were recorded continuously during perfusion. Following simulated transplantation, uterine contraction was assessed after oxytocin injection, and macrovascular perfusion was evaluated using contrast angiography. Several biopsies were procured from different parts of the uterus for histological and immunohistochemistry analysis. In the experimental group, the weight of the uteri and lactate difference between vein and artery decreased during subnormothermic machine perfusion. Weight gain was significantly higher in the control group (p = 0.03), which was consistent with interstitial edema observed on histological sections in this group. Uterine contraction evaluated through semi-quantitative scoring was higher in the experimental group (p = 0.02). In this porcine model, subnormothermic machine perfusion reduces edema and preserves contractility more effectively than static cold storage. We demonstrate its particular interest in recovering organs procured from deceased donors. In addition, subnormothermic machine perfusion may enable other applications, including graft assessment, treatment and tolerance induction.