Regulation of hepatocyte phospholipid peroxidation signaling by a Chinese patent medicine against psychological stress-induced liver injury.

BACKGROUND: Psychological stress is associated with various diseases including liver dysfunction, yet effective intervention strategies remain lacking due to the unrevealed pathogenesis mechanism. PURPOSE: This study aims to explore the relevance between BMAL1-controlled circadian rhythms and lipoxygenase 15 (ALOX15)-mediated phospholipids peroxidation in psychological stress-induced liver injury, and to investigate whether hepatocyte phospholipid peroxidation signaling is involved in the hepatoprotective effects of a Chinese patent medicine, Pien Tze Huang (PZH). METHODS: Restraint stress models were established to investigate the underlying molecular mechanisms of psychological stress-induced liver injury and the hepatoprotective effects of PZH. Redox lipidomics based on liquid chromatography-tandem mass spectrometry was applied for lipid profiling. RESULTS: The present study discovered that acute restraint stress could induce liver injury. Notably, lipidomic analysis confirmed that phospholipid peroxidation was accumulated in the livers of stressed mice. Additionally, the essential core circadian clock gene Brain and Muscle Arnt-like Protein-1 (Bmal1) was altered in stressed mice. Circadian disruption in mice, as well as BMAL1-overexpression in human HepaRG cells, also appeared to have a significant increase in phospholipid peroxidation, suggesting that stress-induced liver injury is closely related to circadian rhythm and phospholipid peroxidation. Subsequently, arachidonate 15-lipoxygenase (ALOX15), a critical enzyme that contributed to phospholipid peroxidation, was screened as a potential regulatory target of BMAL1. Mechanistically, BMAL1 promoted ALOX15 expression via direct binding to an E-box-like motif in the promoter. Finally, this study revealed that PZH treatment significantly relieved pathological symptoms of psychological stress-induced liver injury with a potential mechanism of alleviating ALOX15-mediated phospholipid peroxidation. CONCLUSION: Our findings illustrate the critical role of BMAL1-triggered phospholipid peroxidation in psychological stress-induced liver injury and provide new insight into treating psychological stress-associated liver diseases by TCM intervention.

Fufang Luohanguo Qingfei granules reduces influenza virus susceptibility via MAVS-dependent type I interferon antiviral signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Luohanguo Qingfei granules (LQG) is a Chinese patent medicine, clinically used to treat flu-like symptoms including cough with yellow phlegm, impeded phlegm, dry throat and tongue. However, the protective activity of LQG against influenza infection is indeterminate. AIM OF THE STUDY: This study is to investigate the therapeutic effect of LQG on influenza infection and elucidate its underlying mechanism. MATERIALS AND METHODS: In vivo: A viral susceptible mouse model induced by restraint stress was established to investigate LQG's beneficial effects on influenza susceptibility. MAVS knockout (Mavs-/-) mice were used to verify the potential mechanism of LQG. In vitro: Corticosteroid (CORT)-treated A549 cells were employed to identify the active ingredients in LQG. Mice morbidity and mortality were monitored daily for 21 days. Histopathologic changes and inflammatory cytokines in lung tissues were examined by H&E staining and ELISA. RNA-seq was used to explore the signaling pathway influenced by LQG and further confirmed by qPCR. Immunoblotting and immunohistochemistry (IHC) were used to determine the protein levels. CO-IP and DARTS were applied to detect protein-protein interaction and compound-protein interaction, respectively. RESULTS: LQG effectively attenuated the susceptibility of restrained mice to H1N1 infection. LQG significantly boosted the production of IFN-ß transduced by mitochondrial antiviral-signaling protein (MAVS), while MAVS deficiency abrogated its protective effects on restrained mice infected with H1N1. Moreover, in vitro studies further revealed that mogroside Ⅱ B, amygdalin, and luteolin are potentially active components of LQG. CONCLUSION: These results suggested that LQG inhibited the mitofusin 2 (Mfn2)-mediated ubiquitination of MAVS by impeding the E3 ligase synoviolin 1 (SYVN1) recruitment, thereby enhancing IFN-ß antiviral response. Overall, our work elaborates a potential regimen for influenza treatment through reduction of stress-induced susceptibility.

Novel insights into stress-induced susceptibility to influenza: corticosterone impacts interferon-ß responses by Mfn2-mediated ubiquitin degradation of MAVS.

Although stress has been known to increase the susceptibility of pathogen infection, the underlying mechanism remains elusive. In this study, we reported that restraint stress dramatically enhanced the morbidity and mortality of mice infected with the influenza virus (H1N1) and obviously aggravated lung inflammation. Corticosterone (CORT), a main type of glucocorticoids in rodents, was secreted in the plasma of stressed mice. We further found that this stress hormone significantly boosted virus replication by restricting mitochondrial antiviral signaling (MAVS) protein-transduced IFN-ß production without affecting its mRNA level, while the deficiency of MAVS abrogated stress/CORT-induced viral susceptibility in mice. Mechanistically, the effect of CORT was mediated by proteasome-dependent degradation of MAVS, thereby resulting in the impediment of MAVS-transduced IFN-ß generation in vivo and in vitro. Furthermore, RNA-seq assay results indicated the involvement of Mitofusin 2 (Mfn2) in this process. Gain- and loss-of-function experiments indicated that Mfn2 interacted with MAVS and recruited E3 ligase SYVN1 to promote the polyubiquitination of MAVS. Co-immunoprecipitation experiments clarified an interaction between any two regions of Mfn2 (HR1), MAVS (C-terminal/TM) and SYVN1 (TM). Collectively, our findings define the Mfn2-SYVN1 axis as a new signaling cascade for proteasome-dependent degradation of MAVS and a 'fine tuning' of antiviral innate immunity in response to influenza infection under stress.

Síndrome de la bolsa de orina morada / Purple urine bag síndrome

No disponible

Unscheduled return visits with and without admission post emergency department discharge.

BACKGROUND: Monitoring unscheduled return visits to the Emergency Department (ED) is useful to identify medical errors. OBJECTIVE: To investigate the differences between unscheduled return visit admissions (URVA) and unscheduled return visit no admissions (URVNA) after ED discharge. METHODS: From January 1, 2008 to March 31, 2008, URVA and URVNA patients who returned within 3 days after ED discharge were enrolled in the study. We compared the clinical characteristics, underlying diseases, ED crowding indicators, staff experience at the patient's first visit, and several other risk factors. We used multivariate logistic regression to evaluate differences between the two groups and to identify predictors of admission from unscheduled return visits. RESULTS: The unscheduled return visit rate was 3.1%. Of the 413 patients included, 147 patients (36%) were admitted, and had a mortality rate of 4.1%. The most common reason for the return visit was an illness-based factor (47.9%). Compared to URVNA patients, unscheduled return visit admissions had higher prevalence rates for old age, non-ambulatory status, high-grade triage, and underlying diseases (e.g., malignancy, diabetes mellitus, hypertension, coronary artery disease, heart failure, and chronic obstructive pulmonary disease). The independent predictors for URVA were: age≥65 years (adjusted odds ratio [OR] 2.2, 95% confidence interval [CI] 1.4-3.5); high-grade triage (adjusted OR 2.1, 95% CI 1.3-3.2); and doctor-based factors (adjusted OR 3.5, 95% CI 2.0-6.1). More advanced staff experience (p=0.490) and ED crowding were not significant predictors (p=0.498 for whole-day number of patients, p=0.095 for whole-shift number of patients). CONCLUSION: Old age, high-grade triage, and doctor-based factors were found to be significant predictors for URVA, whereas advanced staff experience and ED crowding were not.

Does CT evidence of a flat inferior vena cava indicate hypovolemia in blunt trauma patients with solid organ injuries?

BACKGROUND: Nonoperative management for selective patients with solid organ injuries from blunt trauma has gained wide acceptance. However, for trauma surgeons, it is often difficult to estimate a patient's circulatory volume. Some authors have proposed that the presence of a collapsed inferior vena cava (IVC) on computed tomography (CT) scan correlates with inadequate circulatory volume. Our aim was to verify whether CT evidence of a flat IVC (FI) is an indicator of hypovolemia in blunt trauma patients with solid organ injuries. METHODS: We conducted a retrospective chart review of all blunt trauma patients with solid organ injuries admitted to our Medical Center from July 2003 to September 2006. Of the 226 patients reviewed, 29 had CT evidence of FI. We compared Injury Severity Scores, hemodynamic parameters, fluid and blood transfusion requirements, mortality rate, and hospital course between patients with (FI group) and without FI (non-FI [NFI] group). RESULTS: The FI group had higher rates of intensive care unit admission and mortality, in addition to longer intensive care unit stays, when compared with the NFI group. In addition, the patients in the FI group needed larger amounts of fluid and blood transfusions and presented lower hemoglobin levels during the first week of admission; furthermore, the majority deteriorated to a state of shock in the emergency department. CONCLUSIONS: CT evidence of FI is a good indicator of hypovolemia and an accurate predictor for prognosis in trauma patients with blunt solid organ injuries.