The global burden of alcoholic liver disease: a systematic analysis of the global burden of disease study 2019.

Alcohol use is a major risk factor for the burden of mortality and morbidity. Alcoholic cirrhosis (AC) and alcoholic liver cancer (ALC) are most important and severe liver disease outcomes caused by alcohol use. The objectives of the current study were to investigate the global prevalence and burden of disease in disability-adjusted life years (DALYs) for AC and ALC, based on data from the Global Burden of Disease (GBD). Incidence, prevalence, death, and DALYs for GBDs in different locations, years, sex, and age groups were estimated using DisMod-MR 2.1 and a generic Cause of Death Ensemble Modeling approach. The correlations between the age-standardized incidence rate or age-standardized death rate and gender, sociodemographic index (SDI), and alcohol usage were conducted by Generalized Linear Models. Globally, the changes of age-standardized rates of indicators were not much significant over the 30-year period. However, the changes varied widely across regions. Central Asia and East Europe contributed the highest age-standardized incidence, prevalence, death, and DALYs and increased sharply by past 30 years. Generalized Linear Models (GLMs) showed male gender as a risk factor of AC, with the relative risk of incidence of 1.521 and relative risk of death of 1.503. Globally, there were improvements in overall health with regard to GBDs over the 30 years. However, the prevention of AC and ALC should be promoted in middle and middle-high SDI regions, especially Central Asia and East Europe, whereas more medical resources should be provided to improve treatment levels in low SDI region.

Azonal steatosis correlates with disease severity and poor outcome of nonalcoholic fatty liver disease.

OBJECTIVES: In this study we aimed to assess the clinicopathological characteristics and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) having distinct steatosis distribution patterns. METHODS: Clinicopathological data of 238 individuals with biopsy-confirmed NAFLD were collected. Nonalcoholic steatohepatitis-clinical research network (NASH-CRN) and steatosis, activity and fibrosis (SAF)/fatty liver inhibition of progression (FLIP) algorithm were used. Cumulative incidence of liver-related events (LREs) was compared by Kaplan-Meier analysis. Univariate and multivariate logistic regression analyses were used to identify independent predictors for steatosis distribution. RESULTS: Eligible patients were categorized into three groups based on their steatosis distribution, including azonal steatosis (AS) (62 [26.1%]), perivenular steatosis (PVS) (147 [61.8%]), and the pan-acinar steatosis (PAS) groups (29 [12.1%]). There were significantly higher ballooning grade and disease activity (P < 0.05), more severe fibrosis (P < 0.001), and a higher cumulative incidence of LREs (hazard ratio [HR] 8.0, 95% confidence interval [CI] 2.34-27.35, P < 0.0001) in the AS group than in the PVS and PAS groups after a median of 3.6-year follow-up. Multivariate logistic regression analysis revealed age (odds ratio [OR] 1.11, 95% CI 1.06-1.16, P < 0.001) might be independently associated with AS distribution, and PNPLA3 rs738409 CG/GG genotype (OR 3.36, 95% CI 0.98-11.47, P = 0.053) might also play a role. CONCLUSIONS: AS is associated with more severe disease activity and fibrosis stage in NAFLD, and predisposes toward poor prognosis. Age might be an independent predictor for AS in NAFLD, while PNPLA3 rs738409 CG/GG genotype might also play a role.

Histological assessment based on liver biopsy: the value and challenges in NASH drug development.

Nonalcoholic steatohepatitis (NASH) is increasingly recognized as a serious disease that can lead to cirrhosis, hepatocellular carcinoma (HCC), and death. However, there is no effective drug to thwart the progression of the disease. Development of new drugs for NASH is an urgent clinical need. Liver biopsy plays a key role in the development of new NASH drugs. Histological findings based on liver biopsy are currently used as the main inclusion criteria and the primary therapeutic endpoint in NASH clinical trials. However, there are inherent challenges in the use of liver biopsy in clinical trials, such as evaluation reliability, sampling error, and invasive nature of the procedure. In this article, we review the advantages and value of liver histopathology based on liver biopsy in clinical trials of new NASH drugs. We also discuss the challenges and limitations of liver biopsy and identify future drug development directions.

SRY is a Key Mediator of Sexual Dimorphism in Hepatic Ischemia/Reperfusion Injury.

OBJECTIVES: To identify the role and mechanism of a male specific gene, SRY, in I/R-induced hepatic injury. BACKGROUND: Males are more vulnerable to I/R injury than females. However, the mechanism of these sex-based differences remains poorly defined. METHODS: Clinicopathologic data of patients who underwent hepatic resection were identified from an international multi-institutional database. Liver specific SRY TG mice were generated, and subjected to I/R insult with their littermate WT controls in vivo. In vitro experiments were performed by treating primary hepatocytes from TG and WT mice with hypoxia/reoxygen-ation stimulation. RESULTS: Clinical data showed that postoperative aminotransferase level, incidence of overall morbidity and liver failure were markedly higher among 1267 male versus 508 female patients who underwent hepatic resection. SRY was dramatically upregulated during hepatic I/R injury. Overexpression of SRY in male TG mice and ectopic expression of SRY in female TG mice exacerbated liver I/R injury compared with WTs as manifested by increased inflammatory reaction, oxidative stress and cell death in vivo and in vitro. Mechanistically, SRY interacts with Glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin, and promotes phosphorylation and degradation of ß-catenin, leading to suppression of the downstream FOXOs, and activation of NF-κBand TLR4 signaling. Furthermore, activation of ß-catenin almost completely reversed the SRYoverexpression-mediated exacerbation of hepatic I/R damage. CONCLUSIONS: SRY is a novel hepatic I/R mediator that promotes hepatic inflammatory reaction, oxidative stress and cell necrosis via inhibiting Wnt/ß-catenin signaling, which accounts for the sex-based disparity in hepatic I/R injuries.

Single Large Nodule (>5 cm) Prognosis in Hepatocellular Carcinoma: Kinship with Barcelona Clinic Liver Cancer (BCLC) Stage A or B?

BACKGROUND The aim of the present study was to evaluate the prognosis among patients with a single large hepatocellular carcinoma (HCC) >5 cm compared with other patients in Barcelona Clinic Liver Cancer (BCLC) stage A or stage B. MATERIAL AND METHODS Data on patients with BCLC stage A/B HCC were collected between 2008 and 2012. BCLC stage A was subclassified as A1 (single tumor, 2-5 cm, or 2-3 nodules £3 cm), or A2 (single tumor >5 cm). Overall survival (OS) was evaluated and compared. RESULTS Among 1005 patients with HCC, 455 were stage A1, 188 were stage A2, and 362 were stage B. The OS of stage A2 patients was significantly worse than that of stage A1 patients (median survival, 30.6 vs. 43.2 months, p5 cm had a comparable survival with BCLC stage B. HCC >5 cm should therefore be classified as an intermediate stage.

Isofraxidin ameliorated influenza viral inflammation in rodents via inhibiting platelet aggregation.

Platelets have been proved to exacerbate influenza infection and its complications. Inhibition of platelet activation may be a feasible method for preventing severe infection and secondary acute lung injury (ALI). Isofraxidin (IFD) is a natural coumarin isolated from the plants Sarcandra glabra and Siberian ginseng, and exerts anticancer, antioxidant and antiinflammatory effects. In the present study, we examined the therapeutic effects of IFD in ADP- or arachidonic acid (AA)-induced platelet aggregation model and in influenza A virus (IAV)-induced ALI mouse model. The results showed that IFD significantly inhibited platelet aggregation induced by ADP and AA in vitro in a concentration-dependent manner as well as the release of soluble P-selectin and platelet factor 4. Moreover, IFD significantly relieved IAV-induced lung inflammation, reduced the expressions of platelet activation biomarkers (P-selectin and CD61), decreased the serum levels of TNF-α, IL-1ß, IL-6 and MIP-2, suppressed peripheral platelet aggregation and prolonged the survival time of infected mice. The western blotting results also demonstrated that IFD reduced the phosphorylation levels of PI3K, AKT and p38 in the activated platelets stimulated by ADP and IAV infection. But IFD did not have any effects on IAV replication. It indicated that IFD ameliorated IAV-induced severe lung damage and lethal infection by suppressing platelet aggregation via regulating PI3K/AKT and MAPK pathways.

Robustaflavone-4'-dimethyl ether from Selaginella uncinata attenuated lipopolysaccharide-induced acute lung injury via inhibiting FLT3-mediated neutrophil activation.

Neutrophils act as both messenger and effector which contributed to the pathogenesis of acute lung injury (ALI). Targeting neutrophils could be a novel strategy for prevention and treatment of ALI. Selaginella uncinata is widely used as an antitussive, antipyretic and anti-inflammatory herb to treat various pulmonary diseases, including lung cancer, asthma, pulmonary fibrosis and pneumonia. However, its effective constituents remain unknown. In the present study, the protective effects of flavonoids from S. uncinata (SUF) and its major compound robustaflavone-4'-dimethyl ether (RDE) against lipopolysaccharide (LPS)-induced ALI were investigated in mice and in neutrophils.The results showed that both SUF and RDE had the same inhibition on LPS-induced lung edema and neutrophil infiltration as well as the increased levels of IL-6, TNF-α, P-selectin and ICAM-1 in serum of LPS-challenged mice. Furthermore, RDE significantly inhibited inducible neutrophil activation in a concentration-dependent manner, and also reduced the levels of intracellular calcium as well as the expressions of CCR2. Rescue experiment showed that RDE suppressed FLT3 and its downstream p-p38 and p-AKT, which could be abolished by FLT3 agonist FLT3L but partly by MAPK agonist PDBu or AKT agonist SC79. Therefore, these results indicated that RDE as the main bioactive compound in SUF alleviated LPS-induced acute lung injury and inhibited neutrophil activation via inhibition of FLT3-mediatied AKT and MAPK pathways.

Duodenal neuroendocrine tumors: Impact of tumor size and total number of lymph nodes examined.

BACKGROUND: The current study sought to investigate the impact of tumor size and total number of LN examined (TNLE) on the incidence of lymph node metastasis (LNM) among patients with duodenal neuroendocrine tumor (dNET). METHODS: Patients who underwent curative resection for dNETs between 1997-2016 were identified from 8 high-volume US centers. Risk factors associated with overall survival and LNM were identified and the optimal cut-off of TNLE relative to LNM was determined. RESULTS: Among 162 patients who underwent resection of dNETs, median patient age was 59 (interquartile range [IQR], 51-68) years and median tumor size was 1.2 cm (IQR, 0.7-2.0 cm); a total of 101 (62.3%) patients underwent a concomitant LND at the time of surgery. Utilization of lymphadenectomy (LND) increased relative to tumor size (≤1 cm:52.2% vs 1-2 cm:61.4% vs >2 cm:93.8%; P < .05). Similarly, the incidence of LNM increased with dNET size (≤1 cm: 40.0% vs 1-2 cm:65.7% vs >2 cm:80.0%; P < .05). TNLE ≥ 8 had the highest discriminatory power relative to the incidence of LNM (area under the curve = 0.676). On multivariable analysis, while LNM was not associated with prognosis (hazard ratio [HR] = 0.9; 95% confidence intervals [95%CI], 0.4-2.3), G2/G3 tumor grade was (HR = 1.5; 95%CI, 1.0-2.1). CONCLUSIONS: While the incidence of LNM directly correlated with tumor size, patients with dNETs ≤ 1 cm had a 40% incidence of LNM. Regional lymphadenectomy of a least 8 LN was needed to stage patients accurately.

Serum GP73 predicts posthepatectomy outcomes in patients with hepatocellular carcinoma.

BACKGROUND AND AIMS: Serum GP73 is a useful biomarker in assessing hepatic fibrosis degree. The aim of this study was to evaluate the predictive value of serum GP73 level for posthepatectomy short-term outcomes in hepatocellular carcinoma (HCC) patients. METHODS: A total of 280 patients undergoing liver resection for HCC between October 2015 and April 2018 were included in this study. Detailed preoperative clinicopathological data were collected and GP73 levels in serum obtained the day before hepatectomy were examined. Receiver operating characteristic (ROC) analysis was used to calculate the optimal cutoff of GP73, and independent risk factors for postoperative outcomes was assessed by logistic regression model. RESULTS: The mean GP73 level in patients was 111.8 ± 153.3 ng/mL. Serum GP73 levels were correlated with the METAVIR fibrosis score. Overall complications occurred in 145 patients and major complications developed in 29 patients. ROC analysis demonstrated that the predictive power of serum GP73 for postoperative outcomes was greater than the Child-Pugh score, ALBI score, FIB-4 index and APRI score. The optimal value of serum GP73 to predict overall complications and major complications was 80.9 and 79.2 respectively. Serum GP73 levels were independent factors affecting the incidence of overall complications (odds ratio [OR], 3.996; 95% CI 2.152-7.421; P < 0.001) and major complications (OR, 4.970; 95% CI 1.654-14.934; P = 0.004) by multivariate analysis. CONCLUSION: Serum GP73 is a useful tool to stratify HCC patients and to predict short-term outcomes after hepatectomy.

Mosla scabra flavonoids ameliorate the influenza A virus-induced lung injury and water transport abnormality via the inhibition of PRR and AQP signaling pathways in mice.

ETHNOPHARMACROLOGICAL RELEVANCE: Mosla scabra (Thunb.) C.Y. Wu and H.W. Li has been used as a traditional medicinal herb for centuries in East Asian countries. It has antibacterial, antiviral, antioxidant, anti-inflammatory and immunomodulatory effects. In folk medicine, it is used as a remedy for the treatment of pulmonary diseases, such as fever, cold, cough, pulmonary edema and emphysema. AIM OF THE STUDY: This study was to investigate the protective mechanism of total flavonoids from M. scabra (MF) in influenza A virus (IAV)-infected mice. MATERIALS AND METHODS: The mice were infected with IAV and then were treated daily with MF for five days. At the end of the experiment, the levels of inflammatory-related cytokines (IFN-α, IL-6, TNF-α and IL-1ß) were determined by ELISA. Pathological changes of lung tissue were examined by H&E staining. The protein expressions of AQP5, p-p38, caspase-3 and NF-κB p65 were detected by western blot analysis while the gene expressions of key effectors in AQP5 and PRRs signaling pathways were detected by real-time Fluorescence Quantitative Polymerase Chain Reaction (RFQ-PCR) analysis. RESULTS: The results showed that treatment with MF at doses of 120-360mg/kg for five days to IAV-infected mice significantly attenuated IAV-induced pulmonary injury and decreased the serum levels of IL-6, TNF-α and IL-1ß, but increased IFN-α levels. MF treatment could up-regulate the mRNA expressions of TLR-7, RIG-1, TRAF6, Bcl-2, Bax, VIPR1, PKCα and AQP5 and down-regulate caspase-3 and NF-κB p65 protein expression. CONCLUSION: Treatment with MF could significantly alleviate IAV-induced pulmonary inflammation, apoptosis and water transport abnormality, which was probably through the regulation of TLR7, RIG-1 and AQP5 signaling pathway.

NIM811 downregulates transforming growth factor­ß signal transduction in vivo and in vitro.

Liver fibrosis is the common histological feature of a number of chronic liver diseases, and leads to cirrhosis and hepatocellular carcinoma (HCC). It has been demonstrated that N­methyl­4­isoleucine cyclosporine (NIM811) attenuates CCl4­induced liver fibrosis and inflammation in rats. The present study investigated whether NIM811 downregulated transforming growth factor (TGF)­ß signaling in rats with CCl4­induced liver fibrosis and in HSC­T6 cells. Liver tissues were obtained from rats with CCl4­induced liver fibrosis, with or without NIM811 treatment. HSC­T6 cells were cultured with or without NIM811 for 18 h under serum­free conditions. Expression of collagen I, α­smooth muscle actin (α­SMA), TGF­ß1, TGF­ß receptor I (TßR­I) and TGF­ß pathway downstream signaling molecules were measured by reverse transcription­quantitative polymerase chain reaction and/or western blotting. Collagen I and TGF­ß1 content in the cell supernatant was measured by ELISA. NIM811 profoundly inhibited collagen I, α­SMA, TGF­ß1 and TßR­I expression in the liver of CCl4­treated rats. Phosphorylation of Smad2, 3 and 1/5/8 was decreased in the liver of NIM811­treated groups, accompanied by increased In addition, Smad7 expression compared with the CCl4­treated rats. NIM811 inhibited collagen I, TGF­ß1 and TßR­I expression in HSC­T6 cells. Smad1 mRNA and phospho­Smad1/5/8 protein levels decreased following NIM811 treatment, accompanied by increased Smad7 expression in HSC­T6 cells compared with normal controls. Furthermore, NIM811 also inhibited collagen I mRNA expression in the liver of rats with CCl4­induced liver fibrosis and in HSC­T6 cells. The results suggest that the antifibrotic effect of NIM811 was due to the inhibition of TGF­ß1 and its downstream signaling molecules.

Role of the Toll­like receptor 3 signaling pathway in the neuroprotective effect of sevoflurane pre­conditioning during cardiopulmonary bypass in rats.

The aim of the present study was to explore the roles and possible molecular mechanism of the alleviating effect of sevoflurane pre­treatment on the extracorporeal circulation and to investigate the possible involvement of the Toll­like receptor (TLR3) signaling pathway. A total of 64 male Sprague Dawley rats were randomly divided into three groups: The sham operation group (H group; n=8), cardiopulmonary bypass (CPB) group (C group; n=24) and sevoflurane pre­conditioning group (S group; n=32). The C group was subjected to tracheal intubation and mechanical ventilation, vessel puncture and catheter placement in the right femoral artery and right internal jugular vein, while no CPB was performed in the H group. The S group was pre­treated with 2.4% sevoflurane for 1 h prior to establishing the CPB model. The CPB in the C and S groups was performed for 1 h. Blood of the rats was analyzed and clinical parameters were detected prior to, during and at various time­points after CPB. In addition, eight rats from the C and S groups each were sacrificed at these time­points and brain tissue samples were analyzed. The levels of the brain damage­specific protein S100­ß as well as IL­6 and IFN­ß in the serum were detected by ELISA; furthermore, the expression levels of TLR3 and TIR­domain­containing adapter­inducing interferon­ß (TRIF) in the left hippocampus were assessed by ELISA and/or western blot analysis. The right hippocampus was assessed for neuronal apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The mean arterial pressure, heart rate and hematocrit were significantly decreased following CPB (P<0.05), while there was no significant changes in any other clinical parameters. The serum levels of S100­ß and IL­6 in the C group were significantly increased compared with those in the H group (P<0.05), which was attenuated by sevoflurane­pre­treatment. Compared with the H group, the serum levels of IFN­ß as well as hippocampal protein levels of TLR3 and TRIF were significantly increased in the C group during and after CPB (P<0.05), which was markedly aggravated in the S group (P<0.05). The number of apoptotic hippocampal neurons, although being generally low, was significantly increased in the C group compared with that in the H group (P<0.05), while apoptosis was significantly attenuated by sevoflurane­pre­treatment (P<0.05). The present study therefore concluded that 2.4% sevoflurane pre­treatment has a protective effect on the rat brain against CPB­induced injury, which may be mediated via the TLR3 signaling pathway through upregulating the expression levels of anti­inflammatory and downregulating pro­inflammatory proteins.

MicroRNA-203 accelerates apoptosis in LPS-stimulated alveolar epithelial cells by targeting PIK3CA.

The pathogenesis of endotoxin-induced acute lung injury (ALI) remains obscure and has not been well elucidated hitherto. Recently, microRNAs have distinct expression profiles in innate immunity, inflammation, and infection. However, the functions of microRNAs in ALI remain unknown. In this study, the functions of microRNAs in the development of ALI were investigated to identify potential drug targets. MicroRNA-203 (miR-203) expression in the lung tissues of lipopolysaccharide (LPS)-challenged mice was found to be significantly upregulated and peaked 5d post-LPS injection. MiR-203 overexpression in A549 cells significantly promoted cell apoptosis by inducing S-phase cell-cycle arrest. MiR-203 overexpression also inhibited the protein expression of phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA), a direct target of miR-203 identified by bioinformatics, thereby suppressing the PI3K/Akt pathway. Moreover, repressed miR-203 effectively attenuated LPS-induced interstitial pneumonia. Therefore, regulating or inhibiting miR-203 may be of therapeutic potential in pneumonia and ALI.

Protective effect of a polyphenolic rich extract from Magnolia officinalis bark on influenza virus-induced pneumonia in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Magnolia officinalis bark is used in traditional Chinese medicine for the treatment of cough, colds, fever, chronic bronchitis and stomach ailments. AIM OF THE STUDY: To investigate therapeutic effects of polyphenol rich extract from M. officinalis bark (MPE) in influenza virus A-infected mice, and to provide evidence for the inflammation response and immunomodulatory potential during infection. MATERIALS AND METHODS: Mice were infected with influenza virus A (IVA) and MPE at doses of 10 and 20mg/kg were orally administrated daily for 5 days after challenge. The levels of serum L-6 and TNF-α were determined by ELISA while protein expressions of NF-κB and TLR3 were detected by western blotting analysis. RESULTS: MPE exhibited significant therapeutical effects on reducing levels of serum NO, IL-6 and TNF-α, inhibiting pneumonia, decreasing lung viral titers and sensitizing IVA-induced apoptosis through down-regulation of NF-κB and TLR3 protein expression in the lung tissue of IVA-infected mice. CONCLUSIONS: MPE could exhibit preventive and therapeutical effects on IVA-infected mice as a suppressor of the production of inflammatory mediators, NO and pro-inflammatory cytokines, TNF-α and IL-6. These effects appeared to be mediated, at least in part, by an inhibition of TLR3 and NF-κB activation. Therefore, MPE could provide a safe and effective therapeutic approach for influenza and its subsequent viral pneumonia.

Nodular liver lesions involving multiple myeloma: a case report and literature review.

We report a case of a 62-year old woman admitted to our hospital for multiple nodular metastatic liver lesions found by ultrasonography in a regular medical examination. Routine laboratory tests were normal. PET-CT showed multiple bone lesions and nodular liver lesions. Liver biopsy revealed nodular infiltration of multiple myeloma with positive staining of kappa light chain. Further investigation of bone marrow aspiration, immunofixation and immunoelectrophoresis of serum protein, urine test for Bence-Jones protein, beta(2)-microglobulin in serum and urine confirmed the diagnosis. The patient also coinfected with hepatitis C virus (HCV). With six cycles of chemotherapy with VAD schedule, she achieved complete remission. In this report, a literature review of liver lesions involving multiple myeloma is also provided.

Undifferentiated connective tissue diseases-related hepatic injury.

Hepatic injury is rarely associated with undifferentiated connective tissue diseases (UCTD). We report, here, a case of a middle-aged woman with UCTD-related hepatic injury, including its case history, clinical manifestations, laboratory findings, treatment and its short-term effect. The patient was admitted to the hospital with symptoms of fatigue, anorexia, low-grade fever and skin rashes. She had a past history of left knee joint replacement. Laboratory tests showed elevated levels of serum transaminase, IgG and globulin, accelerated erythrocyte sedimentation rate, eosinophilia and a high titer of antinuclear antibodies (1:320). Imaging studies showed interstitial pneumonitis and hydropericardium. Liver biopsy showed the features which were consistent with those of connective tissue diseases-related polyangitis. After treatment with a low-dose of oral prednisone, both symptoms and laboratory findings were significantly improved. UCTD-related hepatic injury should be considered in the differential diagnosis of connective tissue diseases with abnormal liver function tests. Low-dose prednisone may effectively improve both symptoms and laboratory tests.