Gut Microbiota Plays Essential Roles in Soyasaponin's Preventive Bioactivities against Steatohepatitis in the Methionine and Choline Deficient (MCD) Diet-Induced Non-Alcoholic Steatohepatitis (NASH) Mice.

SCOPE: Gut microbiota (GM) is involved in nonalcoholic steatohepatitis (NASH) development. Phytochemicals soyasaponins can prevent NASH possibly by modulating GM. This study aims to investigate the preventive bioactivities of soyasaponin monomers (SS-A1 and SS-Bb) against NASH and explores the mechanisms by targeting GM. METHODS AND RESULTS: Male C57BL/6 mice are fed with methionine and choline deficient (MCD) diet containing SS-A1 , SS-Bb, or not for 16 weeks. Antibiotics-treated pseudo germ-free (PGF) mice are fed with MCD diet containing SS-A1 , SS-Bb, or not for 8 weeks. GM is determined by 16S rRNA amplicon sequencing. Bile acids (BAs) are measured by UPLC-MS/MS. In NASH mice, SS-A1 and SS-Bb alleviate steatohepatitis and fibrosis, reduce ALT, AST, and LPS in serum, decrease TNF-α, IL-6, α-SMA, triglycerides, and cholesterol in liver. SS-A1 and SS-Bb decrease Firmicutes, Erysipelotrichaceae, unidentified-Clostridiales, Eggerthellaceae, Atopobiaceae, Aerococcus, Jeotgalicoccus, Gemella, Rikenella, increase Proteobacteria, Verrucomicrobia, Akkermansiaceae, Romboutsia, and Roseburia. SS-A1 and SS-Bb alter BAs composition in liver, serum, and feces, activate farnesoid X receptor (FXR) in liver and ileum, increase occludin and ZO-1 in intestine. However, GM clearance abrogates the preventive bioactivities of SS-A1 and SS-Bb against NASH. CONCLUSION: GM plays essential roles in soyasaponin's preventive bioactivities against steatohepatitis in MCD diet-induced NASH mice.

Postinterventional Petechial Hemorrhage Associated With Poor Functional Outcome After Successful Recanalization Following Endovascular Therapy.

BACKGROUND AND OBJECTIVES: Endovascular therapy (EVT) has emerged as the standard for treating patients with acute ischemic stroke due to large vessel occlusion. The aim of this study was to investigate the relationship between early petechial hemorrhage and patient outcomes after successful EVT of anterior circulation. METHODS: We retrospectively analyzed multicenter data from 316 patients who underwent EVT for acute occlusion of anterior circulation. Patients were divided into petechial hemorrhage group and without hemorrhage group based on post-EVT head imaging. Logistical regression analysis was performed to determine independent predictors for petechial hemorrhage, and for petechial hemorrhage as a predictor of early neurological improvement, favorable outcome at 90 days (modified Rankin Scale 0-2), and 90-day mortality, with adjustment for all factors significantly associated with these endpoints in univariate regression to P < .10. RESULTS: Of 316 included patients with successful EVT, 49 (15.50%) had petechial hemorrhage. The petechial hemorrhage group showed less early neurological improvement (36.73% compared with 53.56%, P = .030), less favorable outcomes at 90 days (32.65% compared with 61.80%, P < .001, absolute risk difference 29.15%), and higher mortality at 90 days (28.57% compared with 10.49%, P = .001) then the group without hemorrhage. Petechial hemorrhage was inversely associated with favorable 90-day outcome (odds ratio = 0.415, 95% CI 0.206-0.835) and higher mortality rate at 90 days (odds ratio = 2.537, 95% CI 1.142-5.635) in multivariable regression but was not independently associated with early neurological improvement. CONCLUSION: In patients with anterior large vessel occlusion who underwent successful EVT, petechial hemorrhage was associated with poor functional outcome and 90-day mortality when adjusted for complete recanalization, pre-EVT National Institute of Health Stroke Scale/Score, and Alberta Stroke Program Early Computed Tomography Score. Despite the relatively lower rate of a favorable 90-day outcome with petechial hemorrhage compared with no petechial hemorrhage, the absolute rate of a favorable outcome exceeds the natural history of medical management for this condition.

Macrophage exosomes mediate palmitic acid-induced metainflammation by transferring miR-3064-5p to target IκBα and activate NF-κB signaling.

INTRODUCTION: High palmitic acid (PA) levels trigger metainflammation, facilitating the onset and progression of chronic metabolic diseases. Recently, exosomes were identified as new inflammation mediators. However, the mechanism by which macrophage exosomes mediate PA-induced inflammation remains unclear. OBJECTIVES: To explore how PA induces metainflammation through macrophage exosomes. METHODS: Exosomes secreted by RAW264.7 mouse macrophages stimulated with PA (ExosPA) or not (Exos) were prepared by ultracentrifugation. The differential miRNAs between ExosPA and Exos were identified by high-throughput sequencing, and their targeted mRNAs and proteins were bioinformatically analyzed and verified by qPCR and western blot. Mouse macrophages and metabolic cells (AML-12 hepatocytes, C2C12 myocytes or 3T3-L1 adipocytes) were treated with ExosPA or Exos. The verified miRNAs and its targeted molecules related to inflammation were analyzed in recipient cells. Furthers, exosomes were prepared from primary peritoneal macrophages isolated from AIN93G diet-fed (Control PM-Exos) or HPD-fed (PA PM-Exos) mice. Control or PA PM-Exos were then tail vein injected (30 µg) into mice (n = 10), once a week for 2 weeks. The verified miRNA and its targets in blood, blood exosomes, and metabolic tissues were detected. Finally, measured the levels of miRNA, inflammatory factors, and fatty acids in the blood of 20 obese/overweight individuals and 20 healthy individuals. RESULTS: ExoPA activate NF-κB signaling and enhance inflammatory enzyme/cytokine production in macrophages and metabolic cells. ExoPA enrich miR-3064-5p and target to inhibit IκBα as verified by exosome inhibitors and miR-3064-5p mimics and inhibitors. HPD elevates exosomal miR-3064-5p, macrophage exosomal miR-3064-5p, and inflammatory cytokine levels in mice circulation. PA PM-Exos from HPD-fed mice triggered inflammation in the circulation and metabolic tissues/organs of chow diet-fed mice. Overweight/obese individuals exhibit increased levels of circulating palmitoleic acid, exosomal miR-3064-5p, and high-sensitivity C-reactive proteins. CONCLUSIONS: Macrophage exosomes transferring miR-3064-5p to target IκBα and activate NF-κB signaling in metabolic cells is a mechanism of PA-induced metainflammation.