Erratum: Author correction to 'FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis' [Acta Pharm Sin B 14 (2024) 1605-1623].

[This corrects the article DOI: 10.1016/j.apsb.2023.12.012.].

FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis.

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinasekinase 2 (CaMKKß) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

Image quality of coronary CT angiography at ultra low tube voltage reconstructed with a deep-learning image reconstruction algorithm in patients of different weight.

Background: GE Healthcare's new generation of deep-learning image reconstruction (DLIR), the Revolution Apex CT is the first CT image reconstruction engine based on a deep neural network to be approved by the US Food and Drug Administration (FDA). It can generate high-quality CT images that restore the true texture with a low radiation dose. The aim of the present study was to assess the image quality of coronary CT angiography (CCTA) at 70 kVp with the DLIR algorithm as compared to the adaptive statistical iterative reconstruction-Veo (ASiR-V) algorithm in patients of different weight. Methods: The study group comprised 96 patients who underwent CCTA examination at 70 kVp and were subdivided by body mass index (BMI) into normal-weight patients [48] and overweight patients [48]. ASiR-V40%, ASiR-V80%, DLIR-low, DLIR-medium, and DLIR-high images were obtained. The objective image quality, radiation dose, and subjective score of the two groups of images with different reconstruction algorithms were compared and statistically analyzed. Results: In the overweight group, the noise of the DLIR image was lower than that of the routinely used ASiR-40%, and the contrast-to-noise ratio (CNR) of DLIR (H: 19.15±4.31; M: 12.68±2.91; L: 10.59±2.32) was higher than that of the ASiR-40% reconstructed image (8.39±1.46), with statistically significant differences (all P values <0.05). The subjective image quality evaluation of DLIR was significantly higher than that of ASiR-V reconstructed images (all P values <0.05), with the DLIR-H being the best. In a comparison of the normal-weight and overweight groups, the objective score of the ASiR-V-reconstructed image increased with increasing strength, but the subjective image evaluation decreased, and both differences (i.e., objective and subjective) were statistically significant (P<0.05). In general, the objective score of the DLIR reconstruction image between the two groups increased with increased noise reduction, and the DLIR-L image was the best. The difference between the two groups was statistically significant (P<0.05), but there was no significant difference in subjective image evaluation between the two groups. The effective dose (ED) of the normal-weight group and the overweight group was 1.36±0.42 and 1.59±0.46 mSv, respectively, and was significantly higher in the overweight group (P<0.05). Conclusions: As the strength of the ASiR-V reconstruction algorithm increased, the objective image quality increased accordingly, but the high-strength ASiR-V changed the noise texture of the image, resulting in a decrease in the subjective score, which affected disease diagnosis. Compared with the ASiR-V reconstruction algorithm, the DLIR reconstruction algorithm improved the image quality and diagnostic reliability for CCTA in patients with different weights, especially in heavier patients.

FGF4 improves hepatocytes ferroptosis in autoimmune hepatitis mice via activation of CISD3.

Autoimmune hepatitis (AIH) is increasingly affecting human health but pharmacotherapies remain to be identified. Growing evidence reveals that ferroptosis, a newly recognized form of programmed cell death, is critical for AIH. However, the exact mechanisms of the ferroptotic cascade remain elusive. Data in this study showed that ferroptosis aggravation was associated with protectively-elevated fibroblast growth factor 4 (FGF4) expression in Concanavalin A (ConA)-induced AIH liver injury, with these effects being effectively reversed by Ferrostatin-1 (Fer-1). Moreover, hepatic Fgf4 depletion was more susceptible to lipid peroxidation and iron accumulation, as well as hepatic lesion and inflammation caused by ConA administration. Conversely, treatment with non-mitogenic recombinant FGF4 (rFGF4) mitigated liver damage and hepatocellular ferroptosis while being accompanied by the upregulation of CDGSH iron-sulfur domain-containing protein 3 (CISD3) in vivo and in vitro. Furthermore, CISD3 overexpression exhibited stronger resistance to ferroptosis while CISD3 knockdown reduced ferroptotic biomarkers cystine/glutamate transporter (xCT) and glutathione peroxidase 4（GPX4) in rFGF4-treated Erastin-induced AML12 cells. In addition, rFGF4 significantly enhanced the levels of heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in ConA-induced AIH mice. Overall, this study showed that FGF4 can act as a phylactic role in AIH progression, with rFGF4 treatment inhibiting ferroptosis of hepatocytes by increasing CISD3 levels and activating Nrf2/HO-1 signaling.

Cryptococcal Meningitis in HIV-Negative Patients: A 12-Year Single-Center Experience in China.

OBJECTIVE: Cryptococcal meningitis (CM) is a not rare condition in HIV-negative patients. Here, we describe the clinical characteristics, possible risk factors, and outcomes of HIV-negative patients with CM. METHODS: Medical records from 99 HIV-negative patients with CM admitted to our hospital from 2010 to 2021 were reviewed systematically. We compared the clinical features and outcomes between patients with underlying diseases and otherwise healthy hosts. RESULTS: The 99 HIV-negative CM patients had a mean age at presentation of 56.2 ± 16.2 years, and the female-to-male ratio was 77:22. A total of 52 (52.5%) CM patients had underlying conditions, and 47 patients (47.5%) had no underlying conditions. Kidney transplant represented the most frequent underlying condition (11.1%), followed by rheumatic disease (10.1%) and hematological diseases (9.1%). Compared to patients without underlying conditions, those with underlying conditions had significantly more fever, more steroid therapy, higher serum creatinine, and lower albumin, IgG, hemoglobin, and platelets (p < 0.05 for each). CM patients without underlying conditions had significantly more alcohol abuse than those with underlying conditions (31.9% vs. 9.6%, p = 0.011). By logistic regression analysis, male gender (OR = 3.16, p = 0.001), higher CSF WBC (OR = 2.88, p = 0.005), and protein (OR = 2.82, p = 0.002) were significantly associated with mortality. CONCLUSION: Patients with underlying conditions had a similar mortality to patients without underlying conditions. Alcohol abuse was a probable risk factor for CM for previously healthy patients. Male gender, higher CSF WBC, and protein were significantly associated with mortality.

Polymeric immunoglobulin receptor deficiency exacerbates autoimmune hepatitis by inducing intestinal dysbiosis and barrier dysfunction.

Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease with unclear pathogenesis. The gut microbiota and intestinal barrier play an essential role in AIH. Polymeric immunoglobulin receptor (pIgR) is a central component of mucosal immunity. Herein, we aimed to test the hypothesis that pIgR plays a pivotal role in maintaining gut microbiota homeostasis and gut barrier integrity in an AIH mouse model. The expression of intestinal pIgR shows the variation tendency of falling after rising with the aggravation of experimental AIH (EAH). The deletion of Pigr exacerbates liver damage in EAH. Furthermore, we identified a distinct microbiota profile of Pigr-deficient EAH mice, with a significant increased aboundance in the Oscillospiraceae family, particularly the Anaeromassilibacillus genus. Such a situation occurs because the loss of Pigr inhibits MEK/ERK, a key signal pathway whereby pIgR transports immunoglobulin A (IgA), resulting in reduced IgA secretion, which leads to the destruction of intestinal epithelial tight junction proteins and intestinal flora disturbance. Increased intestinal leakage causes increased translocation of bacteria to the liver, thus aggravating liver inflammation in EAH. Treatment with the Lactobacillus rhamnosus GG supernatant reverses liver damage in EAH mice but loses its protective effect without pIgR. Our study identifies that intestinal pIgR is a critical regulator of the adaptive response to S100-induced alterations in gut flora and the gut barrier function, which closely correlates with liver injury. Intestinal upregulation of pIgR could be a novel approach for treating AIH.

Polyguanine alleviated autoimmune hepatitis through regulation of macrophage receptor with collagenous structure and TLR4-TRIF-NF-κB signalling.

Autoimmune hepatitis (AIH) is a progressive and chronic inflammatory disease in the liver. MARCO is a surface receptor of macrophage involving in tissue inflammation and immune disorders. Moreover, polyguanine (PolyG) is considered to bind to macrophage receptor with collagenous structure (MARCO). However, the role of MARCO and PolyG in the development and treatment of AIH still remains unclear. Therefore, this study explores the expression of MARCO and therapeutic activity of PolyG in both S100-induced AIH in mouse and Lipopolysaccharide (LPS)-treated macrophage (RAW264.7 cells). Moreover, there were significant increases in inflammatory factors and MARCO, as well as decrease in I-kappa-B-alpha (Ik-B) in the liver of AIH mice and LPS-induced cells. However, PolyG treatment significantly reversed the elevation of inflammatory cytokins, MARCO and reduction of Ik-B. In addition, PolyG treatment could downregulate the expression of Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor inducing interferon-ß (TRIF), decrease macrophage M1 polarization and increase macrophage M2 polarization. When hepatocytes were co-cultured with different treatment of macrophages, similar expression profile of inflammatory cytokines was observed in hepatocytes. The research revealed that MARCO expression was elevated in AIH mice. PolyG treatment and inhibition of MARCO significantly reduced inflammatory cytokines expression in the liver as well as hepatocytes and macrophages. Therefore, MARCO could be a target for the treatment of AIH.

An Experimental and Analytical Study on a Damage Constitutive Model of Engineered Cementitious Composites under Uniaxial Tension.

Engineered cementitious composites (ECC) exhibit ultra-high ductility and post-cracking resistance, which makes it an attractive material in civil engineering. First, a monotonic uniaxial tensile test was performed, considering the effects of polyvinyl alcohol (PVA) fiber volume content and water-binder ratio. Then, the effects of the above variables on the tensile characteristics including the tensile stress-strain relationship, deformation capacity, and fracture energy were investigated based on test results; and when the water-binder ratio is 0.28 and the fiber volume content is 2%, the deformation performance of ECC is improved most significantly. Next, combined with damage mechanics theory, the damage evolution mechanism of ECC in monotonic uniaxial tension was revealed, based on which the damage factor and damage evolution equation of ECC were developed and the expressions of model parameters were proposed. Moreover, the comparison between the proposed model and test results demonstrated the accuracy of the proposed model. Finally, to further verify the feasibility of the proposed model, a finite element (FE) simulation analysis of the tensile performance of high-strength stainless steel wire rope (HSSWR) reinforced ECC by adopting the proposed model was compared with test results and the simulation analysis results by using anther existing model, the "trilinear model of ECC". The comparison shows that the proposed model in this paper can predict more accurately.

miRNA-432 and SLC38A1 as Predictors of Hepatocellular Carcinoma Complicated with Alcoholic Steatohepatitis.

Alcoholic steatohepatitis (ASH) is asymptomatic in the early stages and is typically advanced at the time of diagnosis. With the global rise in alcohol abuse, ASH is currently among the most detrimental diseases around the world. Hepatocellular carcinoma (HCC) is one of the final outcomes of numerous liver diseases. However, at present, HCC screening is mostly focused on liver cancer development. Moreover, there is no effective biomarker to predict the prognosis and recurrence of liver cancer. Meanwhile, there are limited studies on the prognosis and recurrence of HCC patients complicated with ASH. In this study, using bioinformatic analysis as well as cellular and animal models, we screened the differentially expressed (DE) miRNA-432 and SLC38A1 gene in ASH. Based on our analysis, miRNA-432 targeted SLC38A1, and the levels of miRNA-432 and SLC38A1 could accurately predict the overall survival (OS) and relapse free survival (RFS) in patients with liver cancer. Hence, these two genetic elements have the potential to synergistically predict the prognosis and recurrence of HCC complicated with ASH.

Nimbolide attenuated the inflammation in the liver of autoimmune hepatitis's mice through regulation of HDAC3.

A chronic liver disease named autoimmune hepatitis (AIH) will carry elevated levels of inflammatory cytokines, but there is currently no effective treatment to cure it. Histone deacetylase 3 (HDAC3) takes an important position in regulating the expression of inflammatory genes. Nimbolide (NIB) is a limonoid extracted from the neem tree (Azadirachta indica) that has been found to be effective against many diseases, including cancer, scleroderma, and acute respiratory distress syndrome. Here, we investigated the protective effect of nimbolide on AIH liver. Mice and AML12 cells were employed to establish AIH model with liver antigen S100 and cell injury model of LPS, and then treated with different concentrations of nimbolide. After the successful establishment of the animal model and cell model, inflammatory cytokines of IL-1ß, IL-6 and TNF-α as well as cellular signaling related to inflammation such as STAT3, IκB-α and NF-κB were examined. We observed for the first time about nimbolide can effectively inhibit inflammation in AIH mice's liver and AML12 cells by inhibiting HDAC3 expression. HDAC3 knocked down by siRNA in cells can also effectively alleviate the inflammation in AML12 cells, further confirming that HDAC3 plays an important role in the inflammation of liver cells. These results suggest nimbolide could be a potential new treatment for autoimmune hepatitis, and HDAC3 may become a new target for autoimmune hepatitis.

Vitexin attenuates autoimmune hepatitis in mouse induced by syngeneic liver cytosolic proteins via activation of AMPK/AKT/GSK-3ß/Nrf2 pathway.

Autoimmune hepatitis (AIH) is a chronic progressive liver disease that currently does not have a successful therapeutic option. Vitexin, a bioflavonoid isolated from various medicinal plants, possesses a variety of activities; however, whether vitexin protects against AIH remains unclear. Therefore, the current study aims to investigate the hepatoprotective effects and mechanism of action of vitexin in both an experimental autoimmune hepatitis (EAH) mouse model and in D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced hepatocyte injury. Syngeneic liver antigen S100 was used to establish EAH. Vitexin treatment significantly decreased the infiltration of inflammatory and CD4+ T cells in the liver, reduced ALT and AST levels in the serum and attenuated hepatic injury due to oxidative stress. Moreover, vitexin mitigated the upregulation of Bax and cleaved caspase-3 and the downregulation of Bcl-2 in the livers of AIH mice. These regulations were accompanied by not only increased phosphorylation of AMPK, AKT and GSK-3ß but also activation of Nrf2. Furthermore, vitexin inhibited apoptosis and the overexpression of inflammatory cytokines in D-GalN/LPS-treated AML12 cells. In addition, vitexin enhanced the phosphorylation of AMPK, AKT and GSK-3ß. When AML12 cells were treated with an inhibitor of AMPK/AKT or specific siRNA targeting Nrf2, vitexin did not further induce the activation of Nrf2/HO-1. A molecular docking study confirmed that vitexin could interact with AMPK through hydrogen bonding interactions. In conclusion, vitexin ameliorated hepatic injury in EAH mice through activation of the AMPK/AKT/GSK-3ß pathway and upregulation of the Nrf2 gene.

GPX4-Regulated Ferroptosis Mediates S100-Induced Experimental Autoimmune Hepatitis Associated with the Nrf2/HO-1 Signaling Pathway.

Autoimmune hepatitis (AIH) is an inflammatory autoimmune disease of the liver. Oxidative stress triggered by reactive oxygen radicals is a common pathophysiological basis for the pathogenesis of many liver diseases, and ferroptosis is associated with the toxic accumulation of reactive oxygen species. The signaling transduction pathways responsible for iron processing and lipid-peroxidation mechanisms are believed to drive ferroptosis. However, the specific mechanisms regulating ferroptosis remain unclear. The aims of this investigation were to identify the possible effector functions of ferroptosis, based on glutathione peroxidase 4 (GPX4) regulation in an S100-induced autoimmune hepatitis mouse model and hepatocyte injury models. The S100 liver antigen-induced AIH mouse model was used to detect ferroptotic biomarkers using western blotting. Upregulated levels of cyclooxygenase2 (COX2) and Acyl-Coenzyme A synthase long-chain family member 4 (ACSL4) were observed in the S100-induced AIH model group, while levels of GPX4 and ferritin heavy chain 1 (FTH1) were downregulated (P < 0.05). The expression profiles of COX2, ACSL4, GPX4, and FTH1 were restored following the administration of ferrostatin-1. In addition, Nrf2 and HO-1 levels in the S100-induced AIH model mice after treatment with ferrostatin-1 were downregulated compared to the nonferrostatin-1-treated S100-induced AIH model mice (P < 0.05). Moreover, COX2 and ACSL4 levels were significantly upregulated, with significant FTH1 downregulation, in the AIH model mice when liver-specific GPX4 was silenced using AAV8 constructs. These data indicate that inhibition of ferroptosis significantly ameliorated the influence of AIH on the Nuclear factor E2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, and that ferroptosis may act as an initiator or intermediate mediator leading to AIH.

Model to predict cause-specific mortality in patients with olfactory neuroblastoma: a competing risk analysis.

PURPOSE: The main objective of this study was to evaluate the cumulative incidence of cause-specific mortality and other causes of mortality for patients with olfactory neuroblastoma (ONB). The secondary aim was to model the probability of cause-specific death and build a competing risk nomogram to predict cause-specific mortality for this disease. METHODS: Patients with ONB from 1975 to 2016 were identified from the Surveillance, Epidemiology, and End Results database. We estimated the cumulative incidence function (CIF) for cause-specific mortality and other causes of mortality, and constructed the Fine and Gray's proportional subdistribution hazard model, as well as a competing-risk nomogram based on Fine and Gray's model, to predict the probability of cause-specific mortality for patients with ONB. RESULTS: After data selection, 826 cases were included for analysis. Five-year cumulative incidence of cause-specific mortality was 19.5% and cumulative incidence of other causes of mortality was 11.3%. Predictors of cause-specific mortality for ONB included tumor stage, surgery and chemotherapy. Age was most strongly predictive of other causes of mortality: patients aged > 60 years exhibited subdistribution hazard ratios of 1.063 (95 % confidence interval [CI] 1.05-1.08; p = 0.001). The competing risk nomogram for cause-specific mortality was well-calibrated, and had good discriminative ability (concordance index = 0.79). CONCLUSIONS: We calculated the CIF of cause-specific mortality and other causes of mortality in patients with the rare malignancy ONB. We also built the first competing risk nomogram to provide useful individualized predictive information for patients with ONB.

Inhibition of miR-431-5p attenuated liver apoptosis through KLF15/p53 signal pathway in S100 induced autoimmune hepatitis mice.

AIMS: The purpose of this study was to investigate the effects of miR-431-5p on hepatocyte apoptosis in AIH. MATERIALS AND METHODS: We used intraperitoneal injection of S100 to establish AIH mouse model and injected AAV into tail vein on day 14 of modeling to regulate miR-431-5p expression. The expression of ALT, AST, IgG and apoptosis-related proteins Bax, Bcl-2 and cleaved caspase 3 were measured in each group. Cellular experiments were performed using miR-431-5p mimics or inhibitors to transfect LPS-stimulated AML12 cells, and apoptosis was verified using Western blot and Hoechst 33342/PI Double Staining. The target of miR-431-5p, KLF15, was screened using databases and verified by the luciferase reporter assay. The relationship between KLF15 and p53 was verified by si-KLF15 and PFTß (a p53-specific inhibitor). KEY FINDINGS: Here, we observed that the increase in the level of miR-431-5p was accompanied by a decrease in the expression of Krüppel-like zinc finger transcription factor 15 (KLF15). In addition, the deletion of miR-431-5p significantly reduced hepatocyte apoptosis in AIH mice induced by liver S100 and apoptosis of AML12 cells induced by LPS stimulation, accompanied by decreased expression of Bax and cleaved caspase-3 as well as increased expression of Bcl-2. Moreover, KLF15 was the direct and functional target of miR-431-5p. Furthermore, miR-431-5p negatively regulated the expression of KLF15, and KLF15 deletion partially abolished the inhibitory effect of miR-431-5p deletion on apoptosis by activating p53 signaling. SIGNIFICANCE: In summary, miR-431-5p may be a potential therapeutic target for AIH.

MicroRNA-29c Acting on FOS Plays a Significant Role in Nonalcoholic Steatohepatitis Through the Interleukin-17 Signaling Pathway.

Nonalcoholic fatty liver disease is the most common hepatic disease in western countries and is even more ubiquitous in Asian countries. Our study determined that TH17/Treg cells were imbalanced in animal models. Based on our interest in the mechanism underlying TH17/Treg cell imbalance in nonalcoholic fatty liver mice, we conducted a joint bioinformatics analysis to further investigate this process. Common gene sequencing analysis was based on one trial from one sequencing platform, where gene expression analysis and enrichment analysis were the only analyses performed. We compared different sequencing results from different trials performed using different sequencing platforms, and we utilized the intersection of these analytical results to perform joint analysis. We used a bioinformatics analysis method to perform enrichment analysis and map interaction network analysis and predict potential microRNA sites. Animal experiments were also designed to validate the results of the data analysis based on quantitative polymerase chain reaction (qPCR) and western blotting. Our results revealed 8 coexisting differentially expressed genes (DEGs) and 7 hinge genes. The identified DEGs may influence nonalcoholic steatosis hepatitis through the interleukin-17 pathway. We found that microRNA-29c interacts with FOS and IGFBP1. Polymerase chain reaction analyses revealed both FOS and microRNA-29c expression in NASH mice, and western blot analyses indicated the same trend with regard to FOS protein levels. Based on these results, we suggest that microRNA-29c acts on FOS via the interleukin-17 signaling pathway to regulate TH17/Treg cells in NASH patients.

Menstrual blood-derived mesenchymal stem cells attenuate inflammation and improve the mortality of acute liver failure combining with A2AR agonist in mice.

BACKGROUND AND AIM: Acute liver failure (ALF) poses a serious public health issue. The menstrual blood-derived mesenchymal stem cells (MenSCs) have been applied to cure various liver-related diseases. However, the efficacy and mechanism are far from clear. This study aims to explore the efficacy and potential mechanism of MenSCs to cure ALF. METHODS: We investigate the potential mechanism of MenSCs on the ALF in vitro and in vivo. A2A adenosine receptor (A2AR) activation was investigated as the potential reinforcer for MenSCs treatment. Lipid polysaccharide/d-galactosamine (d-GalN) was employed to induce ALF. Diverse techniques were used to measure the inflammatory cytokines and key signaling molecules. Hematoxylin-eosin stain and aminotransaminases were applied to evaluate the liver injury. Flow cytometry was employed to assess the T cells. RESULTS: The MenSCs can decrease the lipid polysaccharide-induced inflammatory cytokine elevation and related signaling molecules in ALF, including TLR4, phosphorylated-NF-kBp65 (p-NF-kBp65), PI3K, and p-AKT, p-mTOR and p-IKK in vitro. Moreover, MenSCs also can significantly reverse the liver injury, inflammatory cytokines elevation and related signaling molecules increase, and Treg/Th17 ratio decrease in vivo. In addition, MenSCs plus A2AR agonist can enhance the above changes. CONCLUSIONS: The MenSCs can attenuate the ALF-induced liver injury via inhibition of TLR4-mediated PI3K/Akt/mTOR/IKK signaling. Then, this inhibits the p-NF-κBp65 translocate into nuclear, which causes a decrease of inflammatory cytokines release. Moreover, A2AR agonist can play a synergic role with MenSCs and enhance the above-mentioned effects.

Role of modern neoadjuvant chemoradiotherapy in locally advanced thymic epithelial neoplasms.

PURPOSE: To improve resectability in patients with stage III-IVA thymic epithelial neoplasms, neoadjuvant chemotherapy and radiotherapy are considered. This retrospective study aimed to investigate the efficacy and safety of neoadjuvant therapies using modern techniques in thymic epithelial neoplasms. METHODS: We included 32 patients with Masaoka stage III-IV disease treated at our institution from January 2010 to December 2017. Data regarding clinicopathologic characteristics, treatment protocols, toxicities, and survival were collected. Response was evaluated according to the Response Evaluation Criteria in Solid Tumours 1.1. Survival was assessed using the Kaplan-Meier method. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Neoadjuvant radiotherapy alone, chemotherapy alone, sequence chemoradiotherapy, and concurrent chemoradiotherapy were administered to 10 (31.3%), 9 (28.1%), 3 (9.4%), and 10 (31.3%) patients, respectively. Twenty-nine patients (90.6%) underwent R0 resection. The median follow-up time was 38.0 months (3.3-109.5 months). After neoadjuvant therapy, 18 patients (56.3%) achieved partial response and 14 (43.8%) had stable disease. Pathologic complete response was achieved in 6 patients (18.8%), all of whom had thymic carcinoma. The 5-year overall and progression-free survival rates were 90.9% and 67.5%, respectively. For patients with thymic carcinoma, the 5-year overall and progression-free survival rates were 80.0% and 66.2%, respectively. Grade 3 toxicities were observed in only 1 patient (leukopenia). CONCLUSIONS: For patients with primary unresectable thymic neoplasms, neoadjuvant chemoradiotherapy is an efficient and safe choice, with favorable response and survival and moderate toxicities. Patients with thymic carcinoma might benefit more from neoadjuvant therapies.

Ubiquitously specific protease 4 inhibitor-Vialinin A attenuates inflammation and fibrosis in S100-induced hepatitis mice through Rheb/mTOR signalling.

Inflammation and fibrosis are major consequences of autoimmune hepatitis, however, the therapeutic mechanism remains to be investigated. USP4 is a deubiquitinating enzyme and plays an important role in tissue fibrosis and immune disease. Vialinin A is an extract from mushroom and is a specific USP4 inhibitor. However, there is lack of evidences that Vialinin A plays a role in autoimmune hepatitis. By employing S100-induced autoimmune hepatitis in mice and AML12 cell line, therapeutic mechanism of Vialinin A was examined. Inflammation was documented by liver histological staining and inflammatory cytokines. Fibrosis was demonstrated by Masson, Sirius red staining and fibrotic cytokines with western blot and real-time RT-PCR. In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR. Moreover, in LPS-treated AML12 cells, LPS-induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb. Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above. In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver. The mechanism may be related to regulation of Rheb/mTOR signalling.

Hydrogen Sulfide Protects Against Ammonia-Induced Neurotoxicity Through Activation of Nrf2/ARE Signaling in Astrocytic Model of Hepatic Encephalopathy.

Objective: Hepatic encephalopathy (HE) characterized by neuropsychiatric abnormalities is a major complication of cirrhosis with high mortality. However, the pathogenesis of HE has not been fully elucidated. This study aimed to determine endogenous hydrogen sulfide (H2S) in the blood of HE patients and investigate the role of H2S in an astrocytic model of HE. Methods: Patients with and without HE were recruited to determine plasma H2S levels and blood microbial 16S rRNA gene. Rat astrocytes were employed as a model of HE by treatment of NH4Cl. Exogenous H2S was preadded. Cell viability was measured by Cell Counting Kit-8 (CCK-8) assay, and cell death was evaluated by lactate dehydrogenase (LDH) release. Apoptosis was determined by Hoechst 33342/Propidium Iodide (PI) Double Staining and Western blot analysis of apoptosis-related protein expression. Intracellular reactive oxygen species (ROS) levels were assessed by flow cytometer. Expressions of Nrf2 and its downstream regulated genes were examined by immunofluorescence staining and Western blot, respectively. Nrf2 gene knockdown was performed by antisense shRNA of Nrf2 gene. Results: There was a significant decrease in H2S levels in cirrhotic patients with HE compared with without HE. Blood microbiota analyses revealed that certain strains associated with H2S production were negatively correlated with HE. In vitro, H2S markedly attenuated NH4Cl-induced cytotoxicity, oxidative stress, and apoptosis. This effect was mediated by Nrf2/ARE signaling, and knockdown of Nrf2 expression abolished the antagonistic effect of H2S on NH4Cl-induced neurotoxicity in astrocytes. Conclusion: Levels of H2S and bacteria associated with H2S production are decreased in HE, and H2S functions as the neuroprotector against NH4Cl-induced HE by activating Nrf2/ARE signaling of astrocytes.