Verteporfin mitigates sepsis-induced liver injury by blocking macrophage-derived inflammation

Purpose: To study the role of yes-associated protein (YAP) inhibition by verteporfin (VTF) in LPSinduced acute liver injury (ALI) after sepsis.Methods: In vitro, VTF was used to treat LPS-stimulated RAW 267.4 cells. In vivo, LPS was injected to induce sepsis in mice, followed by treatment with VTF. The inflammatory mediators were determined using quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence spectroscopy (IF) and immunohistochemical staining (IHC), and the levels of YAP, P53 and ERK were measured by qRT-PCR, WB and IHC. Moreover, liver histology and liver function were examined using HE staining and ELISA respectively.Results: The results showed that VTF reduced YAP expression and inhibited LPS-induced cell activation and inflammatory cytokine production such as IL-6 and IL-1β, by attenuating the expressions of p53 and ERK pathway in macrophages. The levels of AST, AIL and TBiL remarkably decreased in ALI mice after VTF treatment (p < 0.05). Moreover, it was observed that inflammatory mediators, including inducible nitric oxide synthase (iNOS), IL-6 and IL-1β, decreased significantly in VTF treated mice (P < 0.05).Conclusion: VTF plays an antagonistic role in LPS-induced inflammatory response after ALI. Therefore, VTF is a potential medicinal agent for preventing infectious acute liver injury

Eag1 K +

Ether-à-go-go1 (Eag1, Kv10.1, KCNH1) K+ channel is a member of the voltage-gated K+ channel family mainly distributed in the central nervous system and cancer cells. Like other types of voltage-gated K+ channels, the EAG1 channels are regulated by a variety of endogenous signals including reactive oxygen species, rendering the EAG1 to be in the redox-regulated ion channel family. The role of EAG1 channels in tumor development and its therapeutic significance have been well established. Meanwhile, the importance of hEAG1 channels in the nervous system is now increasingly appreciated. The present review will focus on the recent progress on the channel regulation by endogenous signals and the potential functions of EAG1 channels in normal neuronal signaling as well as neurological diseases

Comparison of efficacy of anti-diabetics on non-diabetic NAFLD: a network meta-analysis

Objective: This study aimed to assess the efficacy of currently used anti-diabetic medications in the treatment of non-alcoholic fatty liver disease (NAFLD) without diabetes. DESIGN: The efficacy of various anti-diabetic medicines on non-alcoholic fatty liver disease in the absence of diabetes was evaluated by searching Pubmed, Embase, Cochrane Library, and Web of Science for randomized controlled trials (RCT) only. The methodological quality was evaluated using the Revised Cochrane risk-of-bias tool for randomized trials (RoB2), and the data were analyzed using Stata software (version 15.1). Results: All papers published between the time of the pooling and September 2022 were searched. There were a total of 18 randomized controlled studies with a total sample size of 1141 cases. The outcomes of interest included variations in alanine transaminase (ALT) and aspartate transaminase (AST). Rosiglitazone (SUCRA: 100%) and vildagliptin (SUCRA: 99.9%) were the best anti-diabetic medicines to improve ALT and AST, respectively, in patients with NAFLD without diabetes, according to the findings of this network meta-analysis. Conclusion: In accordance with the Network Ranking plot, Rosiglitazone was the best anti-diabetic medicine for improving ALT, and vildagliptin was the best for improving AST in patients with non-diabetic NAFLD

Impacts of geomechanical damage on waterflood-induced fracture propagation in deeply deposited tight oil reservoirs

Waterflood-induced fractures can enhance the production of deep tight oil reservoirs. However, if waterflood-induced fractures propagate fast, they connect injection wells to production wells earlier, inhibiting the production of tight oil reservoirs. In the present research, the fast propagation mechanism of waterflood-induced fractures was mainly investigated. The changes in sandstone mechanical properties by water were investigated by laboratory experiments, and the relationship of the geomechanical damage of sandstones with water saturation was quantified. Flow-geomechanics-coupled numerical simulations were performed to analyze the impacts of water flooding on stress distribution in a deeply deposited tight oil reservoir. Based on the fracture mechanics theory, the propagation length of the waterflood-induced fracture was calculated and the characteristics of waterflood-induced fracture propagation were analyzed. Experimental results revealed that water changed the mineral composition and microscopic structure of sandstones. This phenomenon decreased the Young’s modulus and tensile strength of sandstones and increased the Poisson’s ratio. The changing magnitude of these properties increased with the rise of water saturation, and the maximum changing magnitude reached 70%. The water saturation distribution became heterogeneous after waterflooding, causing a heterogeneous distribution of mechanical properties. The stress around the fracture tip and the fracture propagation length were significantly affected by these property changes. After the geomechanical damage, the fracture propagation pressure decreased by about 20%. Moreover, the initial fracture length enhanced the propagation length of the waterflood-induced fracture. These results suggest that the propagation of waterflood-induced fractures becomes more significant during waterflooding; thus, the injection pressure should be reduced to avoid fast fracture propagation

Discovery of Digenic Mutation, KCNH2 c.1898A >C and JUP c.916dupA, in a Chinese Family with Long QT Syndrome via Whole-Exome Sequencing

Long QT syndrome (LQTS), which is caused by an ion channel–related gene mutation, is a malignant heart disease with a clinical course of a high incidence of ventricular fibrillation and sudden cardiac death in the young. Mutations in KCNH2 (which encodes potassium voltage-gated channel subfamily H member 2) are responsible for LQTS in many patients. Here we report the novel mutation c.1898A>C in KCNH2 in a Chinese family with LQTS through whole-exome sequencing. The c.916dupA mutation in JUP (which encodes junction plakoglobin) is also discovered. Mutations in JUP were found to be associated with arrhythmogenic right ventricular cardiomyopathy. The double mutation in the proband may help explain his severe clinical manifestations, such as sudden cardiac death at an early age. Sequencing for the proband’s family members revealed that the KCNH2 mutation descends from his paternal line, while the mutation in JUP came from his maternal line. The data provided in this study may help expand the spectrum of LQTS-related KCNH2 mutations and add support to the genetic diagnosis and counseling of families affected by malignant arrhythmias