Effect of endovascular treatment on patients with basilar artery occlusion presenting with different pathologic mechanisms: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to summarize the clinical outcomes of endovascular treatment in patients with basilar artery occlusion (BAO) with different pathologic mechanisms. METHODS: Two independent reviewers searched PubMed/MEDLINE, Embase and Cochrane Library database up to December 2022, patients with different BAO pathological mechanisms (BAO with in situ atherosclerosis vs. embolism alone without vertebral artery steno-occlusion vs. embolism from tandem vertebral artery steno-occlusion) were collected and analyzed. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) to assess the associations between clinical outcomes and BAO pathological mechanisms. RESULTS: A total of 1163 participants from 12 studies were identified. Compared with embolism alone, patients with in situ atherosclerotic BAO had a lower favorable outcome rate (modified Rankin score [mRS] 0-2: 34.5% vs. 41.2%; OR 0.83, 95% CI 0.70-0.98; P = 0.03) and moderate outcome rate (mRS 0-3: 45.8% vs. 55.4%; OR 0.65, 95% CI 0.47-0.90; P = 0.01) at 3 months and a higher risk of mortality (29.9% vs. 27.2%; OR 1.31, 95% CI 0.96-1.79, P = 0.09; adjusted OR 1.46, 95% CI 1.08-1.96). Tandem BAO had a comparable mortality risk to that of in situ atherosclerotic BAO (OR 1.37, 95% CI 0.84-2.22; P = 0.48) or embolism alone (OR 1.44, 95% CI 0.65-3.21; P = 0.43), and there were no significant differences in favorable or moderate outcomes between tandem BAO and each of the other two BAO mechanisms. CONCLUSION: Among BAO patients with endovascular treatment, embolism mechanism had better clinical outcomes than in situ atherosclerosis, and atherosclerotic mechanism was associated with a higher mortality at 3 months. RCTs are needed to further confirm clinical outcomes of BAO by different mechanisms.

Endovascular treatment in patients with middle cerebral artery occlusion of different aetiologies.

PURPOSE: The purpose of this study was to evaluate differences in endovascular treatment (EVT) outcomes in M1 segment middle cerebral artery occlusion (MCAO) patients with different pathologic subtypes. METHODS: Patients with MCAO who received EVT from July 2014 to December 2020 were categorized into three groups: embolism without internal carotid artery steno-occlusion (MCAO-E), in situ atherosclerotic thrombosis (MCAO-AS) and embolism from tandem ICA steno-occlusion (MCAO-T). Baseline characteristics, EVT-related factors and clinical outcomes were compared between groups. Multivariable regression analyses were performed to evaluate the relationship between aetiologic classification and outcomes at 90 days after stroke. RESULTS: Among eligible patients (n = 220), MCAO-E (n = 129, 58.6%) was the most common aetiology, followed by MCAO-AS (n = 47, 21.4%) and MCAO-T (n = 44, 20.0%). Patients with MCAO-E were significantly older but had a lower rate of dyslipidaemia and smoking history than those with MCAO-AS. Although patients with MCAO-AS and MCAO-T more often required rescue balloon angioplasty and stenting (p < 0.001), no significant difference in the rate of final recanalization was found. Patients in the MCAO-AS group obtained better functional outcomes (90-day modified Rankin Scale score, 0-2) (p = 0.002) and lower mortality than in the MCAO-E group (p = 0.009). On multivariable logistic regression, we failed to find that stroke subtype was an independent predictor of functional outcomes and mortality. CONCLUSIONS: Patients with acute MCA M1 occlusion stroke due to different pathogeneses had comparable successful recanalization rates and functional independence at 90 days. The optimal management for MCAO patients with different aetiologies requires further research.

Reliability and validity of the Chinese version of chronic liver disease questionnaire-nonalcoholic fatty liver disease in patients with nonalcoholic fatty liver disease: a multicenter cross-sectional survey in China.

PURPOSE: The Chronic Liver Disease Questionnaire (CLDQ)-Nonalcoholic Fatty Liver Disease (NAFLD) is a disease-specific instrument to assess the health-related quality of life (HRQL) of patients with NAFLD. In order to provide further evidence for the cross-cultural utility of this instrument in the Chinese population, we translated the CLDQ-NAFLD into Chinese and examined its reliability and validity. METHODS: Patients with NAFLD in 90 hospitals across China were enrolled in this multicenter cross-sectional survey. Eligible patients completed the Chinese version of CLDQ-NAFLD at enrollment to assess HRQL. Internal consistency of the questionnaire was assessed using Cronbach's alpha coefficient and split-half reliability. Convergent and discriminant validity were assessed using Spearman correlation coefficient. Factor analysis was used to test the construct validity. RESULTS: Between March and August 2019, 5181 patients with a mean age of 43.8 ± 13.3 years were enrolled. All domains exhibited good internal consistency, with Cronbach's alpha and split-half reliability greater than 0.70. The scaling success rate of all domains was 100% for convergent validity and 99.4% (179/180) for discriminant validity. The inter-scale correlations indicated a significant correlation between all CLDQ-NAFLD domains (r = 0.608 to 0.832, all p < 0.001). Factor analysis of 36 items extracted 6 factors, which explained 69.14% of the total variance. CONCLUSION: The Chinese version of CLDQ-NAFLD is a reliable and valid instrument for assessing the HRQL of Chinese patients with NAFLD.

The protective effect of puerarin-loaded mesoporous silicon nanoparticles on alcoholic hepatitis through mTOR-mediated autophagy pathway.

Puerarin, a bioactive flavone compound isolated from Pueraria (Wild.), provides hepatoprotection by anti-inflammatory, anti-alcoholism, and regulating mechanistic target of rapamycin (mTOR). Building evidence suggests that the activation of mTOR reduces liver injuries associated with alcohol consumption and metabolism. However, the poor water solubility, low bioavailability, and short half-life of puerarin hinder its clinical application. The utility of mesoporous silicon nanoparticles (MSNs) can improve traditional Chinese medicine limitations. Stober methods were used to fabricate MSNs@Pue, and the size, zeta potentials and drug encapsulation efficiency were characterized by a series of analytical methods. IVIS Imaging System demonstrated liver-targeted bio-distribution, and then high-throughput sequencing, immunoproteomics and ultrastructure methods indicated autophagy related protective mechanism, followed by curative effect evaluation for the treatment efficacy. An acute-on chronic ethanol-drinking according to Gao-binge model induced alcoholic hepatitis (AH) pathology and resulted in hepatic hyper-autophagy, which was improved with MSNs@Pue administration (puerarin: 30 mM, 42 mg/kg; intravenously [i.v.]). Ethanol-fed mice were found to have increased expression of autophagy-related proteins (Atg3, Atg7, LC3 and p62). In contrast, MSNs@Pue administration significantly decreased the expression of these proteins and alleviated fatty droplets infiltration in damaged liver. Furthermore, acute-on-chronic ethanol feeding also resulted in the activiation of ERK activation and mTOR expression, which were reversed with MSNs@Pue administration and better than the usage of puerarin alone. Results point to MSNs@Pue mediated ERK/mTOR signaling pathway activation as a possible protective strategy to improve AH, which provides a strategy and evidence for treating liver disease using an MSN delivery system.

The mitophagosome, a novel ultrastructure of mitophagy in the alcoholic steatohepatitis mouse model: a transmission electron microscope study.

Acute alcohol feeding can activate autophagy and promotes the selection of autophagic vacuoles in the mitochondria, which is a key process regulating the occurrence and progression of alcohol steatohepatitis (ASH). In this study, ASH mice expressed more autophagy-associated proteins than healthy controls, as revealed by immunohistochemistry. In addition, transmission electron microscopy (TEM) detected a unique autophagy ultrastructure in ASH mouse liver cells, consisting of a large vesicle fused directly with mitochondria, which differed from the classical pattern. This novel type of mitophagy may provide a new avenue for a protective mechanism targeting mitophagy, which would benefit patients with ASH.Abbreviations: ASH: alcoholic steatohepatitis; ALD: Alcoholic liver disease; ALT: alanine aminotransferase; AST: aspartate aminotransferase; HE: hematoxylin and eosin; TEM: transmission electron microscope; LC3: microtubule-associated protein 1 light chain 3; SQSTM1/p62: sequestosome 1; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; PINK1: PTEN induced kinase 1; AMPK: AMP-activated protein kinase.

Polypeptides Isolated from Lactococcus lactis Alleviates Lipopolysaccharide (LPS)-Induced Inflammation in Ctenopharyngodon idella.

The main purpose of the present study was to evaluate the anti-inflammatory activity of Lactococcus lactis BL52 and isolate active substances responsible for anti-inflammatory activity. Head-kidney (HK) macrophages were used for in vitro bioassay-guided isolation, and the structure of the two peptides was identified by mass spectrometry analysis. Lipopolysaccharide (LPS)-induced inflammatory responses in Ctenopharyngodon idella were also examined to evaluate the in vivo anti-inflammatory activity of active substances. Two active peptides were isolated by HPLC from L. lactis BL52, and an in vitro anti-inflammatory assay demonstrated that peptide ALBL1 and ALBL2 dose-dependently inhibited LPS-induced inflammatory cytokines TNF-α, IL-6, and IL-1ß and inflammatory factors NO and PGE 2 production in macrophages (p < 0.05). After being treated with 20 mg/Kg peptide ALBL1 and ALBL2, the expression levels of TNF-α, IL-6, IL-1ß, NO, and PGE 2 were significantly inhibited (p < 0.05). Results from the in vivo test showed that when the concentration of peptide ALBL1 and ALBL2 reached 30 mg/Kg, the LPS-induced upregulations of TNF-α, IL-6, IL-1ß, NO, and PGE 2 were prevented. In addition, peptide ALBL1 and ALBL2 blocked the expression of Toll-like receptor 2 (TLR2) and then suppressed the phosphorylation of nuclear transcription factor-kappa B (NF-κB) p65 and degradation inhibitor of IκBα. Moreover, C. idella treated with peptide ALBL1 and ALBL2 can relieve pathological inflammatory responses caused by LPS. These results suggest that the anti-inflammatory properties of peptide ALBL1 and ALBL2 might be a result from the inhibition of IL-6, IL-1ß, and TNF-α expressions through the downregulation of Toll2/NF-κB signaling pathways.

Impact of the COVID-19 pandemic and post-epidemic periods on the process of endovascular treatment for acute anterior circulation ischaemic stroke.

BACKGROUND AND PURPOSE: The purpose of our study was to analyse endovascular treatment (EVT) in patients presenting acute anterior circulation ischemic stroke with large-vessel occlusion (AIS-LVO) during the pandemic and post-epidemic periods. METHODS: Patients with AIS-LVO of the anterior circulation who underwent EVT were enrolled. According to the times of Wuhan closure and reopening, patients were divided into a pre-pandemic group (from November 8, 2019, to January 22, 2020), pandemic group (from January 23, 2020, to April 8, 2020) and post-epidemic group (from April 9, 2020, to June 24, 2020). The primary endpoints were the time delay among symptom onset to arriving hospital door, to groining puncture and to vascular reperfusion. Secondary endpoints were the functional outcomes evaluated by 90-day modified Rankin scale (mRS) score. RESULTS: In total, the times from onset to reperfusion (OTR, median 356 min vs. 310 min, p = 0.041) and onset to door (OTD, median 238 min vs. 167 min, p = 0.017) were prolonged in the pandemic group compared to the pre-pandemic group, and the delay continue in the post-epidemic period. In the subgroup analysis, the time from door to imaging (DTI) was significantly prolonged during the pandemic period. Interestingly, the prolonged DTI was corrected in the directly admitted subgroup during post-epidemic period. In addition, the functional outcomes showed no significant differences across the three periods. CONCLUSIONS: Total time and prehospital time were prolonged during the pandemic and post-epidemic periods. Urgent public education and improved in-hospital screening processes are necessary to decrease time delays.

Health-related quality of life in Chinese population with non-alcoholic fatty liver disease: a national multicenter survey.

BACKGROUND: Health Related Quality of Life (HRQL) is a multi-dimensional construct that can comprehensively evaluate the patient's health status, including physical, emotional, mental and social well-being. In this study, we aimed to evaluate the impact of non-alcoholic fatty liver disease (NAFLD) on HRQL in a Chinese population. METHODS: In this national multicenter cross-sectional survey, patients with NAFLD were enrolled. Chronic Liver Disease Questionnaire (CLDQ)-NAFLD was used to qualify HRQL. Univariate and multivariate analysis were used to identify independent risk factors of HRQL. RESULTS: A total of 5181 patients with NAFLD from 90 centers were enrolled in this study (mean age, 43.8 ± 13.3 years; male, 65.8%). The overall CLDQ score was 5.66 ± 0.89. Multivariate logistic regression analysis showed that body mass index (BMI: HR, 1.642; 95% CI, 1.330-2.026), alanine transaminase (ALT: HR, 1.006; 95% CI, 1.001-1.011), triglyceride (HR, 1.184; 95% CI, 1.074-1.305), disease severity (HR, 3.203; 95% CI, 1.418-7.232) and cardiovascular disease (HR, 4.305; 95% CI, 2.074-8.939) were independent risk factors for overall CLDQ score. In the logistic analyses of individual domain, BMI and triglyceride were independent risk factors of all domains. ALT, disease severity, diabetes, depression and cardiovascular disease were influencing factors for the CLDQ score of several domains. CONCLUSIONS: This national multicenter cross-sectional survey in China indicated that the HRQL in patients with NAFLD was impaired. HRQL was found to be significantly associated with sociodemographic and clinical factors. Attention should be paid to the optimally managing care of patients with NAFLD to improve their HRQL.

The impaired anti-tumoral effect of immune surveillance cells in the immune microenvironment of gastric cancer.

Immune surveillance cells in the tumor microenvironment play an important role in inhibiting tumorigenesis and metastasis, but their anti-tumoral effects are impaired. The anti-tumoral effects of innate immune cells and adaptive immune cells in the immune microenvironment of gastric cancer are also impaired. Their degree of functional impairment is closely related to the prognosis of gastric cancer. Multiple factors inhibit the anti-tumoral effects of immune surveillance cells, such as decreased numbers of immune surveillance cells, reduced activating receptors, decreased secretion of pro-inflammatory cytokines, increased apoptosis, elevated expression of coinhibitory molecules on cancer cells or immunosuppressive cells, increased secretion of inhibitory cytokines, impaired antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by antigen-presenting cells (APCs) and pro-tumoral polarization of cells with functional plasticity. These factors can potentially combine to suppress the immune surveillance cells' functions. However, there are conflicting conclusions on the effects of immune surveillance cells on gastric cancer cells. These contradictions are partly due to the heterogeneity of the tumor microenvironment.

Early steep decline of liver stiffness predicts histological reversal of fibrosis in chronic hepatitis B patients treated with entecavir.

It is unknown whether dynamic changes of liver stiffness measurement (LSM) can predict the reversibility of fibrosis. Therefore, we evaluated the utility of LSM changes in predicting histological changes of fibrosis in patients with chronic hepatitis B (CHB) on antiviral therapy. In a prospective cohort of CHB patients treated with entecavir, virological measurement and biochemical measurement along with LSM were measured at baseline and every 6 months. Liver biopsies were conducted at baseline and month 18 of treatment. Fibrosis regression was defined by the following two criteria: (a) Ishak score decrease ≥1 stage, (b) Ishak score decrease ≥1 stage or predominantly regressive by post-treatment PIR classification. The dynamic changes of LSM and its predictive value for histological reversibility were evaluated with piecewise linear mixed-effects model and ROC analysis. We found that at month 18 of antiviral therapy, liver fibrosis was reserved in 86 of 212 (40.6%) CHB patients by Ishak reversal criterion. Overall, a decline in LSM was associated with attenuation of Ishak score. The rate of LSM decline in the first 6 months was significantly faster in patients with fibrosis reversal (ΔLSM%Ishak  = -2.19%/month, P = 0.0025; ΔLSM%Ishak/PIR  = -2.56%/month, P = 0.0004). The predictive model based on baseline FIB-4 and Ishak score as well as baseline LSM, PLT, albumin and their changes during the first 6 months could predict histological reversal (AUROCIshak  = 0.74, 95% CI: 0.67-0.80; AUROCIshak/PIR  = 0.81, 95% CI: 0.74-0.87). We conclude that in CHB patients, changes in LSM during the first 6 months of entecavir therapy can predict histological reversibility of liver fibrosis at month 18 of antiviral therapy.

On-treatment changes of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein are associated with the regression of liver fibrosis in chronic hepatitis B patients on interferon α add-on therapy.

Wisteria floribunda agglutinin-positive Mac-2-binding protein (M2BP) has been identified as a predictor for the response of interferon α (IFN-α) in patients with viral hepatitis. However, whether serum glycosylation isomer of M2BP (M2BPGi) was associated with the regression of liver fibrosis in patients with chronic hepatitis B (CHB) during IFN-α add-on therapy is still unknown. CHB patients were treated with entecavir for 26 weeks followed by entecavir plus pegylated IFN-α for 52 weeks. Liver biopsies were taken at baseline and treatment week 78. The regression of fibrosis was identified according to Ishak standard or Ishak plus Progressive-Indeterminate-Regressive (P-I-R) standard. Serum M2BPGi and liver function tests were measured at baseline and every 26 weeks of treatment. A total of 72 CHB patients were included in the present study. Serum M2BPGi was correlated with fibrosis and necroinflammation both at baseline and week 78. If Ishak standard was used as the reference, only the percent change of M2BPGi at week 52 from week 26 (Δ%M2BPGi26w-52W ) was independently associated with fibrosis regression at treatment week 78, the area under the ROC curve (AUROC) of Δ%M2BPGi26w-52W for predicting fibrosis regression was 0.705. As for Ishak plus P-I-R standard, the AUROC of the predictive model for fibrosis regression (0.896*M2BPGi52W + 0.363*necroinflammation score0w + 2.051*Ishak score0w - 4.489) was 0.888. These data indicated that dynamic changes of serum M2BPGi were associated with fibrosis regression in CHB patients on IFN-α add-on therapy.

New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment.

Liver fibrosis is the net result of dynamic changes between fibrogenesis and fibrolysis. Evidence has shown that antiviral therapy can reverse liver fibrosis or even early cirrhosis caused by hepatitis B virus. However, current evaluation systems mainly focus on the severity of, but not the dynamic changes in, fibrosis. Here, we propose a new classification to evaluate the dynamic changes in the quality of fibrosis, namely: predominantly progressive (thick/broad/loose/pale septa with inflammation); predominately regressive (delicate/thin/dense/splitting septa); and indeterminate, which displayed an overall balance between progressive and regressive scarring. Then, we used this classification to evaluate 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir-based therapy for 78 weeks. Progressive, indeterminate, and regressive were observed in 58%, 29%, and 13% of patients before treatment versus in 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 29 cases (53%) had fibrosis improvement of at least one Ishak stage, and, more interestingly, 25 cases (45%) had significant improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. CONCLUSION: This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of antiviral therapy.(Hepatology 2017;65:1438-1450).

A study on relationship between metabolic syndrome and colorectal cancer.

PURPOSE: To investigate the effects of metabolic syndrome (MS) and its components on the pathological manifestations and metastasis of colorectal cancer (CRC). METHODS: Clinical and pathological data of inpatients with CRC admitted to our hospital from January 1st 2010 to December 31st 2017 were collected, including the patients' general information, initial symptoms, previous history, family history, whether MS or related components were complicated, endoscopic description, imaging diagnosis, pathological diagnosis and metastasis. According to the diagnostic criteria of MS, the patients were divided into MS group and non-MS group, and then patients in non-MS group were further grouped based on whether they met MS single component. The clinical and pathological characteristics in each group were analyzed by SPSS 20.0 statistical software. RESULTS: Among 1528 CRC patients, 76 (4.9%) were complicated with MS. CRC patients complicated with MS and those complicated with hypertension alone or diabetes alone were diagnosed at higher age, and most of them were elderly (p<0.05). CRC patients with body mass index (BMI) ≥25 kg/m2 were diagnosed at lower age (p<0.05). The infiltration depth of CRC patients with diabetes was higher than that in the non-diabetic group, and it was more likely to invade the whole layer (p<0.05). The locations of CRC lesions in different BMI subgroups, fatty liver and nonfatty liver subgroups had statistically significant differences (p<0.05). In BMI ≥25 kg/m2 group, CRC was mostly located in the left colon and rectum, while it was mostly located in the rectum in CRC patients with fatty liver. CONCLUSION: Reducing the occurrence of MS and its components can reduce the incidence of CRC, and reduce its pathological manifestations and affect its metastasis at the same time.

MicroRNA-140 Inhibits Cell Proliferation in Gastric Cancer Cell Line HGC-27 by Suppressing SOX4.

BACKGROUND Gastric cancer is a malignant tumor with a high morbidity and mortality. MicroRNAs are important regulators of gene expression, influencing the progression of gastric cancer. This study aimed to reveal the role of microRNA-140 (miR-140) in gastric cancer cell proliferation and its potential mechanisms. MATERIAL AND METHODS Gastric cancer tissues and cell lines BGC-823, SGC-7901, and HGC-27 were used to analyze miR-140 levels compared to normal tissues and cell line GES-1. In HGC-27 cells transfected with miR-140 mimic, we performed MTT, colony formation assay, and cell cycle assay by flow cytometry. SOX4, a predicted target of miR-140, was mutated to verify its regulation by miR-140, and was overexpressed to analyze its function in cell proliferation. Doxorubicin treatment was performed to investigate the effect of miR-140 on drug resistance. RESULTS miR-140 was down-regulated in gastric cancer tissues and cell lines, with the lowest expression level in HGC-27. miR-140 overexpression inhibited HGC-27 cell viability and colony formation and resulted in G0/G1 arrest. miR-140 suppressed SOX4 expression via binding to the 3' untranslated region, while the mutant SOX4 could not be regulated. Overexpressing SOX4 led to promoted cell viability, colony formation, and cell cycle progress. miR-140 overexpression also improved the anti-viability effects of doxorubicin, suggesting its potential in reducing the drug resistance of gastric cells. CONCLUSIONS These findings suggest that miR-140 directly inhibits SOX4, which might be one of its mechanisms in suppressing gastric cancer cell proliferation. This study provides a promising therapeutic strategy for treating gastric cancer and facilitates microRNA research in various diseases.

Notch1-nuclear factor κB involves in oxidative stress-induced alcoholic steatohepatitis.

AIMS: The Notch1 signaling pathway is implicated in multiple inflammatory diseases. However, the role of Notch1 signaling in alcoholic steatohepatitis (ASH) has not been fully investigated. We aimed to determine whether Notch1-Nuclear factor-κB (NF-κB) signaling mediates oxidative stress-induced ASH. METHODS: In vitro, three cell lines were used: the HepG2 cells, HepG2 cells transfected with a control vector (Neo cells) and HepG2 cells transfected with a cytochrome P4502E1-expression vector (2E1 cells), which allows the cells to undergo oxidative stress in response to ethanol. All three cell lines were incubated with ethanol with/without Notch1 inhibitor treatment, oxidative stress marker, steatohepatitis marker and Notch1-NF-κB signaling were assessed. To further test Notch1-NF-κB signaling in vivo, rats were fed with ethanol, ethanol plus Notch1 inhibitor or an isocaloric diet for 8 weeks. Hepatitis, oxidative stress and Notch1-NF-κB activity in the liver were assessed to further verify the in vitro results. RESULTS: Ethanol was shown to induce oxidative stress and steatohepatitis with remarkably elevated Notch1-NF-κB expression in 2E1 cells rather than HepG2 and Neo cells. Notch1 inhibitor was non-toxic in the three cell lines and had a protective effect against markers of ASH. Similarly, chronic alcohol administration in vivo induced alcoholic hepatitis, oxidative stress and elevated Notch1-NF-κB expression in rats, while Notch1 inhibitor attenuated alcoholic liver injury. CONCLUSION: These findings provide direct in vitro and in vivo evidence that the oxidative stress-induced ASH is mediated by the Notch1-NF-κB signaling pathway, which can be effectively reversed by Notch1 inhibitor.

[TLR4 contributes to intestinal hyperpermeability in alcoholic liver disease].

OBJECTIVE: To determine whether Toll-like receptor 4 (TLR4) is involved in development of gut leakiness in alcoholic steatohepatitis using an in vivo animal model and an in vitro cell culture system. METHODS: Mice were fed an alcohol (ethanol group, EtOH) or isocaloric liquid diet (control group, Ctrl). Successful establishment of the alcoholic steatohepatitis model was assessed at week 6 by measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and evaluating the liver pathology using hematoxylin and eosin (HandE) staining of liver tissues. Gut permeability was assessed by measuring serum endotoxin and urine lactulose/mannitol (L/M) levels and evaluating HandE-stained colon tissues. Intestinal and colon tissue expression levels of TLR4 were assessed by immunohistochemistry. Cultured Caco-2 cells were exposed to 25 - 400 mmol/L EtOH and changes in TLR4 were assessed by enzyme-linked immunoassay and in permeability were assessed by intracellular uptake of FD4. RESULTS: The mice in the EtOH group had significantly higher levels of serum ALT (46.5 +/- 6.9 U/L vs. Ctrl: 30.9 +/- 4.4 U/L, P less than 0.01), serum AST (53.3 +/- 7.9 U/L vs. Ctrl: 29.3 +/- 3.8 U/L, P less than 0.01), serum endotoxin (0.33 +/- 0.05 Eu/L vs. Ctrl: 0.27 +/- 0.04 Eu/L, P less than 0.01), and urine L/M (2.59 +/- 0.44% vs. Ctrl: 2.17 +/- 0.31%, P less than 0.05). The mice in the EtOH group also had significantly higher expression levels of TLR4 in intestinal tissues (13.1 +/- 2.0 ng/ml vs. Ctrl: 7.4 +/- 1.2 ng/L, P less than 0.01) and in colonic tissues (18.5 +/- 2.7 ng/ml vs. Ctrl: 9.1 +/- 1.6 ng/ml, P less than 0.01). The intestinal histopathology of the two groups was not different. Immunohistochemical staining of colonic tissues showed brown particles distributed in the endochylema and membrane of the EtOH group, which was almost completely absent in the Ctrl group. EtOH treatment of Caco-2 cells led to a dose-dependent increase in TLR4 expression and in cellular permeability. CONCLUSION: Chronic alcohol exposure induced TLR4 expression and cellular permeability in gut tissues. Activation of TLR4 may be involved in development of gut leakiness in alcoholic liver disease.

Stages of psychological change among patients with non-alcoholic fatty liver disease in China: a national cross-sectional study.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease worldwide. However, treatment of NAFLD is potentially influenced by psychological conditions. Using the simplified version of the University of Rhode Island Change Assessment (URICA-SV) scale, this study aimed to evaluate the stage of psychological change as a prerequisite to refining implementation strategies for psychological change. DESIGN: A multicentre cross-sectional survey. SETTING: Ninety hospitals in China. PARTICIPANTS: 5181 patients with NAFLD were included in this study. OUTCOME MEASURES: All patients completed the URICA-SV questionnaire and were assigned to one of the three stages of change (precontemplation, contemplation or action) according to their readiness scores. A stepwise multivariate logistic regression analysis was used to identify independent factors associated with the stage of psychological change. RESULTS: A total of 4832 (93.3%) patients were included in the precontemplation stage and only 349 (6.7%) considered making a change or preparing to make one. There were significant differences in gender (Cohen's d=0.039, p=0.005), age (Cohen's d=-0.327, p<0.001), waist circumference (Cohen's d=0.143, p=0.003), alanine transaminase (Cohen's d=0.347, p=0.001), triglyceride (Cohen's d=0.351, p=0.002), body mass index (BMI; Cohen's d=0.056, p<0.001), proportion of hyperlipidaemia (Cohen's d=0.068, p<0.001) and cardiovascular disease (Cohen's d=0.032, p=0.029), therapeutic regimen (Cohen's d=0.136, p<0.001), and Chronic Liver Disease Questionnaire-Non-Alcoholic Fatty Liver Disease overall score (Cohen's d=-0.420, p<0.001) between patients with NAFLD in the precontemplation stage and those in the contemplation/action stage. Logistic regression identified BMI (HR 0.659, 95% CI 0.469 to 0.928, p=0.017), cardiovascular disease (HR 2.161, 95% CI 1.089 to 4.287, p=0.027) and triglyceride (HR 0.751, 95% CI 0.591 to 0.955, p=0.020) as independent factors predicting psychological change. CONCLUSIONS: The results demonstrated that very few patients with NAFLD presented psychological condition in the stage of action. Psychological condition was found to be significantly related to BMI, cardiovascular disease and triglyceride factors. Integrated diversity considerations for evaluating psychological change are necessary.

The amelioration of AH by abstinence and the attenuation of oxidative stress.

BACKGROUND/AIMS: Alcohol abstinence is considered the cornerstone in the management of alcoholic hepatitis (AH), but the degree of improvement and how abstinence ameliorates alcoholic liver injury remains unclear. The purpose of the study was to investigate the amelioration of AH after 3 and 6 months of alcohol abstinence, and its possible mechanism. METHODOLOGY: Thirty-six AH patients who strictly abstained from alcohol and 20 AH patients who did not abstain from alcohol, were followed-up for 6 months. The control group consisted of 15 healthy individuals with no history of alcohol abuse. The testing of serum biomarkers and abdominal CT scans were performed. RESULTS: Alcohol abstinence ameliorated the AH by decreasing the liver enzyme and fibrotic markers, and improving the hepatic steatosis. Comparing between AH patients with and without alcohol abstinence, the ratio between hepatic and splenic CT value were 1.01 ± 0.13 and 0.75 ± 0.25, respectively (p<0.01). GSH and SOD levels were significantly higher, while the MDA level was significantly lower, in patients with abstinence compared to those without abstinence. CONCLUSIONS: Alcohol abstinence is useful in the clinical management of AH. The attenuation of AH was associated with the decrease of oxidative stress.

Melatonin inhibits the expression of vascular endothelial growth factor in pancreatic cancer cells.

OBJECTIVE: To investigate the effects of melatonin on cellular proliferation and endogenous vascular endothelial growth factor (VEGF) expression in pancreatic carcinoma cells (PANC-1). METHODS: PANC-1 cells were cultured for this study. The secreted VEGF concentration in the culture medium was determined using ELISA method, VEGF production in the tumor cells was detected by immunocytochemistry, and VEGF mRNA expression was determined by RT-PCR. RESULTS: Higher melatonin concentrations significantly inhibited cellular proliferation, with 1 mmol/L concentration exhibiting the highest inhibitory effect (P<0.01). VEGF concentrations in the cell culture supernatants and intra-cellules were all significantly reduced after melatonin (1 mmol/L) incubation (P<0.05). VEGF mRNA expression decreased markedly in a time-dependent manner during the observation period (P<0.05). CONCLUSIONS: High melatonin concentrations markedly inhibited the proliferation of pancreatic carcinoma cells. The endogenous VEGF expression was also suppressed by melatonin incubation.

Serum level of free thyroxine is an independent risk factor for non-alcoholic fatty liver disease in euthyroid people.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem concern in recent decades. The specific mechanism of NAFLD is still not clear. Previous studies had shown the correlation between NAFLD and thyroid dysfunction. The correlation between thyroid hormones within the euthyroid range and NAFLD has not yet been clarified. This study sought to investigate the association between NAFLD and thyroid hormones in euthyroid patients. METHODS: A retrospective cross-sectional study was conducted at Beijing Tiantan Hospital from January 1, 2019, to October 1, 2021. Eighty-one NAFLD patients with normal thyroid function and 34 healthy individuals were enrolled. Participants' demographic information, biochemical parameters, and thyroid hormone levels were collected. The severity of NAFLD was assessed by abdominal computed tomography (CT). The association between NAFLD and thyroid hormones was analyzed. RESULTS: Patients in the NAFLD group were older and more likely to be female than those in the healthy control group (P<0.05). Compared to the healthy control group, the serum levels of fasting plasma glucose (FPG), alanine transaminase (ALT), plasma aspartate transaminase (AST), triglyceride, gamma-glutamyl transferase (γ-GT), and uric acid (UA) were higher, but the levels of high-density lipoprotein cholesterol (HDL-C), and free thyroxine (FT4) were lower in the NAFLD group (P<0.05). NAFLD is more severe in females than males (P<0.05). ALT, AST, low-density lipoprotein cholesterol (LDL-C), γ-GT, tetraiodothyronine, and free triiodothyronine (FT3) levels increased significantly as the severity of NAFLD increased (P<0.05). The results of the Spearman correlation analysis indicated that the severity of NAFLD was positively correlated with ALT (r=0.376, P=0.001), AST (r=0.275, P=0.015), and LDL (r=0.313, P=0.007). The multiple logistic regression analysis showed that age [odds ratio (OR) =1.071; 95% confidence interval (CI): 1.010-1.136, P=0.021], ALT (OR =1.091; 95% CI: 1.034-1.150, P=0.001), HDL-C (OR =0.085; 95% CI: 0.010-0.690, P=0.021), and FT4 (OR =0.738; 95% CI: 0.545-1.001, P=0.046) were independently related to the risk of NAFLD in patients with normal thyroid function. CONCLUSIONS: FT4 within the normal range was lower in the NAFLD group compared to the healthy control group. The serum level of FT4 is an independent risk factor of NAFLD in euthyroid people.