Metabolic-associated fatty liver disease and risk of esophagogastric cancer: a systematic review and meta-analysis.

INTRODUCTION: Metabolic-associated fatty liver disease (MAFLD) has been found to be strongly linked to several diseases. Although previous studies have explored the association between MAFLD and extrahepatic cancers, research on the relationship between MAFLD and gastric carcinoma (GC) and esophageal carcinoma (EC) is relatively scarce and requires updating. Therefore, the objective of this study is to conduct a comprehensive investigation into the association between MAFLD and GC or EC. MATERIAL AND METHODS: We conducted a comprehensive search for relevant studies published up to 5 August 2022, using the PubMed, Embase and Web of Science databases. To estimate the risk ratio (RR) and the 95% confidence interval (CI), we employed a random-effects model. We also conducted subgroup analyses based on study characteristics. The protocol for this systematic review is registered in the Prospero database under the registration number CRD42022351574. RESULTS: Our analysis included eight eligible studies, comprising a total of 8 629 525 participants. We found that the pooled RR values for the risk of GC in patients with MAFLD were 1.49 (95%CI: 1.17-1.91), whereas the pooled RR values for the risk of EC in patients with MAFLD were 1.76 (95%CI: 1.34-2.32). CONCLUSIONS: Based on our meta-analysis, we conclude that there is a significant association between the presence of MAFLD and the development of GC and EC.

DNA Methylation and Resting Brain Function Mediate the Association between Childhood Urbanicity and Better Speed of Processing.

Urbanicity has been suggested to affect cognition, but the underlying mechanism remains unknown. We examined whether epigenetic modification (DNA methylation, DNAm), and brain white matter fiber integrity (fractional anisotropy, FA) or local spontaneous brain function activity (regional homogeneity, ReHo) play roles in the association between childhood urbanicity and cognition based on 497 healthy Chinese adults. We found significant correlation between childhood urbanicity and better cognitive performance. Multiset canonical correlation analysis (mCCA) identified an intercorrelated DNAm-FA-ReHo triplet, which showed significant pairwise correlations (DNAm-FA: Bonferroni-adjusted P, Pbon = 4.99E-03, rho = 0.216; DNAm-ReHo: Pbon = 4.08E-03, rho = 0.239; ReHo-FA: Pbon = 1.68E-06, rho = 0.328). Causal mediation analysis revealed that 1) ReHo mediated 10.86% childhood urbanicity effects on the speed of processing and 2) childhood urbanicity alters ReHo through DNA methylation in the cadherin and Wnt signaling pathways (mediated effect: 48.55%). The mediation effect of increased ReHo in the superior temporal gyrus underlying urbanicity impact on a better speed of processing was further validated in an independent cohort. Our work suggests a mediation role for ReHo, particularly increased brain activity in the superior temporal gyrus, in the urbanicity-associated speed of processing.

A novel cancer-associated fibroblast signature for kidney renal clear cell carcinoma via integrated analysis of single-cell and bulk RNA-sequencing.

Cancer-associated fibroblasts (CAFs), integral components of the tumor microenvironment, play a pivotal role in tumor proliferation, metastasis, and clinical outcomes. However, its specific roles in Kidney Renal Clear Cell Carcinoma (KIRC) remain poorly understood. Employing the established Seurat single-cell analysis pipeline, we identified 21 CAFs marker genes. Subsequently, a prognostic signature consisting of 6 CAFs marker genes (RGS5, PGF, TPM2, GJA4, SEPT4, and PLXDC1) was developed in a cohort through univariate and LASSO Cox regression analyses. The model's efficacy was then validated in an external cohort, with a remarkable predictive performance in 1-, 3-, and 5-year. Patients in the high-risk group exhibited significantly inferior survival outcomes (p < 0.001), and the risk score was an independent prognostic factor (p < 0.05). Distinct differences in immune cell profiles and drug susceptibility were observed between the two risk groups. In KIRC, the PGF-VEGFR1 signaling pathway displayed a notable increase. PGF expression was significantly elevated in tumor tissues, as demonstrated by quantitative real-time polymerase chain reaction. In vitro, transwell assays and CCK8 revealed that recombinant-PGF could enhance the capability of cell proliferation, migration, and invasion in 769P and 786-O cells. This study firstly developed a novel predictive model based on 6 CAFs genes for KIRC. Additionally, PGF may present a potential therapeutic target to enhance KIRC treatment.

PFOS Exposure Promotes Hepatotoxicity in Quails by Exacerbating Oxidative Stress and Inflammation-Induced Apoptosis through Activating TLR4/MyD88/NF-κb Signaling.

PFOS is a ubiquitous pollutant garnering considerable attention due to its deleterious effects on both human and animal health. Given the poultry industry's intimate link with human health, investigating PFOS's impact on quails is crucial. PFOS readily accumulates in the liver, causing hepatotoxicity, yet its molecular mechanisms remain elusive. In our study, we fed quail diets contaminated with varying PFOS concentrations (12.5, 25, and 50 mg/kg) and observed dose-dependent liver damage in quails. The results show that PFOS damages mitochondrial structure, increases ROS levels, and downregulates antioxidants to promote oxidative stress damage in hepatocytes. PFOS also upregulated pro-inflammatory molecules (TNF-α, IL-1ß, and IL-6) while downregulating the anti-inflammatory factor IL-10, activating the TLR4//MyD88/NF-κB signaling pathway, thereby potentiating liver inflammation. Then, oxidative stress and inflammation by PFOS induce apoptosis in quail hepatocytes through the mitochondrial pathway, with severity closely related to hepatotoxicity. In conclusion, PFOS induces mitochondrial apoptosis by exacerbating oxidative stress and inflammation by activating the TLR4/MyD88/NF-κB signaling pathway, ultimately leading to hepatotoxicity in quails.

Generation of Human Endometrial Assembloids with a Luminal Epithelium using Air-Liquid Interface Culture Methods.

The endometrial lining of the uterus is essential for women's reproductive health and consists of several different types of epithelial and stromal cells. Although models such as gland-like structures (GLSs) and endometrial assembloids (EnAos) are successfully established, they lack an intact luminal epithelium, which makes it difficult to recapitulate endometrial receptivity. Here, a novel EnAo model (ALI-EnAo) is developed by combining endometrial epithelial cells (EnECs) and stromal cells (EnSCs) and using an improved matrix and air-liquid interface (ALI) culture method. ALI-EnAos exhibit intact EnSCs and glandular and luminal epithelia, which recapitulates human endometrium anatomy, cell composition, hormone-induced menstrual cycle changes, gene expression profiles, and dynamic ciliogenesis. The model suggests that EnSCs, together with the extracellular matrix and ALI culture conditions, contribute to EnAo phenotypes and characteristics reflective of the endometrial menstrual cycle. This enables to transcriptionally define endometrial cell subpopulations. It anticipates that ALI-EnAos will facilitate studies on embryo implantation, and endometrial growth, differentiation, and disease.

Chlorogenic Acid Alleviates Chronic Stress-Induced Intestinal Damage by Inhibiting the P38MAPK/NF-κB Pathway.

Chronic stress can cause intestinal barrier damage. MAPK and NF-κB are closely related to it. Chlorogenic acid (CGA), a dietary polyphenol, has been shown to have intestinal protective effects, but whether by regulating MAPK and NF-κB is not known. Therefore, in this experiment, 24 Wistar rats were randomly divided into 4 groups (C group, CS group, CS + SB203580, and CS + CGA group). Rats in the CS group were restrained stress for 6 h per day for 21 days. Rats in the CS + SB203580 group were given SB203582 (0.5 mg/kg, intraperitoneal injection) 1 h before restraint stress every other day. Rats in the CS + CGA group were given CGA (100 mg/kg, gavage) 1 h before restraint stress. In chronic stress, intestinal barrier damage was evident, while being restored after CGA treatment. After chronic stress, the levels of p-P38 were increased (P < 0.01), while the levels of p-JNK and p-ERK were not changed. The levels of p-p38 were elevated after CGA treatment (P < 0.01). These results suggested that p38MAPK played an important role in chronic stress-induced intestinal injury, and CGA could inhibit p38MAPK activity. Therefore, we chose SB203582 (P38MAPK inhibitor) to elucidate the role of p38. After chronic stress, intestinal tight junction key proteins Occludin, ZO-1, and Claudin3 protein and gene expression were reduced (P < 0.01), while being elevated after CGA or SB203582 intervention (P < 0.05). After CGA treatment, the levels of p-IκB, p-p65, p-p38, and TNF-α were reduced (P < 0.01). SB203582 intervention reduced p-p65 and TNF-α levels significantly (P < 0.01). These results suggested that CGA could inhibit the NF-κB pathway by suppressing p38MAPK, thereby alleviating chronic stress-induced intestinal damage.

Predicting response to immunotherapy in gastric cancer via assessing perineural invasion-mediated inflammation in tumor microenvironment.

BACKGROUND: The perineural invasion (PNI)-mediated inflammation of the tumor microenvironment (TME) varies among gastric cancer (GC) patients and exhibits a close relationship with prognosis and immunotherapy. Assessing the neuroinflammation of TME is important in predicting the response to immunotherapy in GC patients. METHODS: Fifteen independent cohorts were enrolled in this study. An inflammatory score was developed and validated in GC. Based on PNI-related prognostic inflammatory signatures, patients were divided into Clusters A and B using unsupervised clustering. The characteristics of clusters and the potential regulatory mechanism of key genes were verified by RT-PCR, western-blot, immunohistochemistry and immunofluorescence in cell and tumor tissue samples.The neuroinflammation infiltration (NII) scoring system was developed based on principal component analysis (PCA) and visualized in a nomogram together with other clinical characteristics. RESULTS: Inflammatory scores were higher in GC patients with PNI compared with those without PNI (P < 0.001). NII.clusterB patients with PNI had abundant immune cell infiltration in the TME but worse prognosis compared with patients in the NII.clusterA patients with PNI and non-PNI subgroups. Higher immune checkpoint expression was noted in NII.clusterB-PNI. VCAM1 is a specific signature of NII.clusterB-PNI, which regulates PD-L1 expression by affecting the phosphorylation of STAT3 in GC cells. Patients with PNI and high NII scores may benefit from immunotherapy. Patients with low nomogram scores had a better prognosis than those with high nomogram scores. CONCLUSIONS: Inflammation mediated by PNI is one of the results of tumor-nerve crosstalk, but its impact on the tumor immune microenvironment is complex. Assessing the inflammation features of PNI is a potential method in predicting the response of immunotherapy effectively.

Unsuppressed Striatal Activity and Genetic Risk for Schizophrenia Associated With Individual Cognitive Performance Under Social Competition.

BACKGROUND AND HYPOTHESIS: Social competition affects human behaviors by inducing psychosocial stress. The neural and genetic mechanisms of individual differences of cognitive-behavioral response to stressful situations in a competitive context remain unknown. We hypothesized that variation in stress-related brain activation and genetic heterogeneity associated with psychiatric disorders may play roles towards individually differential responses under stress. STUDY DESIGN: A total of 419 healthy subjects and 66 patients with schizophrenia were examined functional magnetic resonance imaging during working memory task including social competition stressors. We explored the correlation between stress-induced brain activity and individual working memory performance. The partial least squares regression was performed to examine the genetic correlates between stress-related activity and gene expression data from Allen Human Brain Atlas. Polygenic risk score (PRS) was used to assess individual genetic risk for schizophrenia. STUDY RESULTS: Greater suppression of bilateral striatal activity was associated with better behavioral improvement in working memory manipulation under social competition (left: rPearson = -0.245, P = 4.0 × 10-6, right: rPearson = -0.234, P = 1.0 × 10-5). Genes transcriptionally related to stress-induced activation were linked to genetic risk for schizophrenia (PFDR < 0.005). Participants with decreased accuracy under social competition exhibited higher PRS of schizophrenia (t = 2.328, P = .021). Patients with schizophrenia showed less suppressed striatal activity under social stress (F = 13.493, P = 3.5 × 10-4). CONCLUSIONS: Striatal activity change and genetic risk for schizophrenia might play a role in the individually behavioral difference in working memory manipulation under stress.

The Systemic Immune-Inflammation Index May Be a Novel and Strong Marker for the Accurate Early Prediction of Acute Kidney Injury in Severe Acute Pancreatitis Patients.

OBJECTIVE: This research was performed to investigate the correlation between acute kidney injury (AKI) and systemic immune-inflammation index (SII) in severe acute pancreatitis (SAP) patients. METHODS: The study included 218 SAP patients from Chongqing Jiangjin Center Hospital during January 2016 to October 2020. The SII was defined as platelet × neutrophil/lymphocyte ratio. After univariate analysis, logistic regression analysis was used for analyzing independent risk factors of AKI in SAP patients. Receiver operating characteristic (ROC) curve was used for analyzing the prognostic value of the SII. RESULTS: AKI occurred in 74 cases and its incidence rate was 33.9%. The median SII value of AKI patients was higher than that of patients without AKI. After multivariate analysis, SII, age, triglyceride (TG), neutrophil ratio (NEU-R), C-reactive protein (CRP), aspartate aminotransferase (AST), and serum albumin (ALB) were independent predictors of AKI. Serum ALB was an independent protective factor. The optimum threshold truncation value of SII was 2880.1*10^9/L. Compared with other inflammatory factors, SII had a better prediction efficiency. CONCLUSION: The SII, TG, NEU-R, CRP, and ALB were significant independent predictors of AKI in SAP patients. Serum TG, NEU-R, CRP, and SII were risk factors. Serum ALB was a protective factor. The SII may be a novel, simple, and strong marker for the accurate early prediction of AKI in SAP patients.

Effect of Chlorogenic Acid via Upregulating Resolvin D1 Inhibiting the NF-κB Pathway on Chronic Restraint Stress-Induced Liver Inflammation.

Chronic stress can cause chronic inflammatory injury to the liver. Chlorogenic acid (CGA) is known to have a wide range of biological activities and anti-inflammatory effects. Resolvin D1 (RvD1) is a polyunsaturated fatty acid derivative that has inhibitory effects on a variety of inflammatory diseases. However, whether CGA can inhibit liver inflammation in chronic stress through RvD1 remains unclear. In this work, male rats were subjected to restraint stress for 6 h every day and built a chronic stress model for 21 days. CGA (100 mg/kg) was administered intragastrically 1 h before restraint, with intraperitoneal injection of RvD1 inhibitor WRW4 (antagonist of FPR2, 0.1 mg/kg) or WRW4 solution every 2 days for 30 min before CGA administration. CGA reduced hepatic hemorrhage and inflammatory cell infiltration, alleviated hepatic injury, decreased the activation of the NF-κB pathway and the expression of interleukin 1ß, interleukin 6, and tumor necrosis factor α in the liver, and increased RvD1 in the serum and liver. The therapeutic effect of CGA was blocked after WRW4 intervention. These results suggest that the protective effects of CGA mediate the NF-κB pathway by upregulating the generation of RvD1. Above all, this research demonstrates the liver protective effect of CGA and provides a potential treatment strategy for chronic inflammatory disease.

Lycopene Alleviates Chronic Stress-Induced Liver Injury by Inhibiting Oxidative Stress-Mediated Endoplasmic Reticulum Stress Pathway Apoptosis in Rats.

The liver is the major organ of metabolism and is extremely vulnerable to chronic stress. Lycopene (LYC) is a natural carotenoid with potent antioxidant and chronic disease potential. However, whether LYC protects against chronic restraint stress (CRS)-induced liver injury and the underlying mechanisms remain unclear. In this study, rats were restrained for 21 days for 6 h per day, with or without gavage of LYC (10 mg/kg). Serum ALT (85.99 ± 4.07 U/L) and AST (181.78 ± 7.35 U/L) and scores of liver injury were significantly increased in the CRS group. LYC significantly promoted the nuclear translocation of Nrf2, elevated the expression of antioxidant genes, and attenuated reactive oxygen radicals (ROS) levels within the liver. Cellular thermal shift assay (CETSA) and molecular docking results indicated that LYC competitively binds to Keap1 with the lowest molecule affinity of -9.0 kcal/mol. Moreover, LYC significantly relieved the hepatic endoplasmic reticulum swelling and decreased the expression of endoplasmic reticulum stress (ERS) hallmarks like GRP78, CHOP, and cleaved caspase-12. Meanwhile, LYC also mitigated CRS-induced hepatocyte apoptosis. Interestingly, every other day, the intraperitoneal injection of the Nrf2 inhibitor brusatol (0.4 mg/kg) significantly counteracted the protective effect of LYC. In conclusion, LYC protects against CRS-induced liver injury by activating the Nrf2 signaling pathway, scavenging ROS, and further attenuating ERS-associated apoptosis pathways.

Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans.

AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis.

A Scoring System for Surgical Site Infection after Pancreaticoduodenectomy Using Clinical Data.

Object: To analyze the factors influencing surgical site infection (SSI) after pancreaticoduodenectomy and to establish a scoring system for predicting such infections. Methods: Patients who underwent pancreaticoduodenectomy in the Department of Hepatobiliary Surgery of the Second Affiliated Hospital of Chongqing Medical University from January 2015 to March 2019 were divided randomly into a model group and a test group in a proportion of 3:1. According to whether an SSI occurred after operation, the model group was divided into an incision-infection group and a non-infection group. Univariable analysis and multivariable regression analysis were used to analyze factors related to post-operative incision infection and to establish a clinical predictive scoring system. The scoring system was evaluated for the test group. Results: A total of 236 patients, 177 in the model group and 59 in the test group, were included. In the model group, univariable and logistic regression analysis showed that tumor nature (benign versus malignant), post-operative albumin concentration, pancreatic fistula formation, post-operative cough, and peri-operative blood transfusion were the independent risk factors for incision infection. Then we established a clinical predictive scoring system. In the test group, the area under the receiver operator characteristic curve of the system was 0.768 (p < 0.001, with sensitivity = 59.1% and specificity = 94.6%). Conclusion: The scoring system had good clinical prediction ability and high specificity, so it was worth using in the clinic.

Childhood Maltreatment Was Correlated With the Decreased Cortical Function in Depressed Patients Under Social Stress in a Working Memory Task: A Pilot Study.

Background: Major depressive disorder (MDD) is a common psychiatric disorder associated with working memory (WM) impairment. Neuroimaging studies showed divergent results of the WM process in MDD patients. Stress could affect the occurrence and development of depression, in which childhood maltreatment played an important role. Methods: Thirty-seven MDD patients and 54 healthy control subjects were enrolled and completed a WM functional magnetic resonance imaging task with maintenance and manipulation conditions under stress and non-stress settings. We collected demographical and clinical data, using 17-item Hamilton Depression Scale (HAMD-17) and Childhood Trauma Questionnaire (CTQ) in MDD patients. In the WM task, we analyzed the main diagnosis effect and explored the correlation of impaired brain regions in MDD patients with CTQ and HAMD-17. Results: No group differences were found in the accuracy rate and reaction time between the two groups. MDD patients had lower brain activation in following regions (P FWE < 0.05). The left fusiform gyrus showed less activation in all conditions. The right supplementary motor area (SMA) exhibited decreased activation under non-stress. The anterior prefrontal cortex showed reduced activation during manipulation under stress, with the ß estimations of the peak voxel showing significant group difference negatively correlated with childhood sex abuse (P Bonferroni < 0.05). Conclusions: In our pilot study, MDD patients had reduced brain activation, affecting emotional stimuli processing function, executive function, and cognitive control function. Childhood maltreatment might affect brain function in MDD. This work might provide some information for future studies on MDD.

Prefrontal cognitive systems in schizophrenia: towards human genetic brain mechanisms.

Schizophrenia has complex genetic heritability. It is also genetically heterogeneous. To the extent that genes are associated with symptom constellations in schizophrenia, they do so by affecting the development and function of neural systems that mediate the expression of such diverse behavioral, cognitive and perceptual phenomena. The genetic mechanisms of human brain dysfunction remain to be well understood. "Imaging genetics" is an emerging field that attempts to integrate the basic biology of putative disease mechanisms with physiological correlates from the live human brain. Here, we review recent imaging genetics work on prefrontal brain systems associated with working memory and executive function - heritable traits relevant to schizophrenia. Starting with genetic variation in dopaminergic systems (e.g., COMT), we examined the modulation of prefrontal brain networks during active cognitive processing; there is also evidence that variation in the expression of dopamine-related downstream intra-cellular signaling molecules (e.g., AKT1) are implicated. Moreover, these genetic variants evidence epistasis on neuroimaging measures, lending further support to the conceptualization that non-additive combinations of multiple genes modulate active human cognitive brain mechanisms. The imaging genetics platform therefore could extend understanding of genetic mechanisms of human cognitive brain processes relevant to neuropsychiatric disease.

Long-Term Efficacy of Laparoscopic Radiofrequency Ablation in Early Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Objective: The aim of this study was to investigate the long-term efficacy of laparoscopic radiofrequency ablation (LRFA) in early hepatocellular carcinoma (HCC) compared with other surgical procedures. Methods: A literature search of Cochrane library, PubMed, and Embase through October 2018 was conducted by two investigators (J.-F.G. and F.Y.) independently. The quality of included studies was estimated by the Newcastle-Ottawa Scale. Review Manager 5.3 software was used for meta-analysis, and either fixed- or random-effects model was used according to the heterogeneity of included studies. The chi-square test was used for heterogeneity analysis of included studies, and subgroup analysis was conducted to estimate the heterogeneity between each study and also to estimate the efficacy of different studies. Results: A total of 11 studies involving 1691 patients were included in this analysis. Patients undergoing hepatic resection (HR) had higher 3-, 5-year overall survival rate, 3-year disease-free survival rate, and lower local recurrence rate than those undergoing LRFA. However, patients undergoing LRFA had higher 3-, 5-year overall survival rate than those undergoing other minimally invasive ablation, although there was no statistical difference in local recurrence rate or disease-free survival rate. Conclusion: HR is still an ideal choice for early HCC. If minimally invasive ablation is an alternative treatment, LRFA will be better than other minimally invasive options.

Risk Assessment of Laparoscopic Cholecystectomy in Liver Cirrhotic Patients with Clinically Significant Portal Hypertension: A Retrospective Cohort Study.

Objective: This study was aimed to evaluate the correlation between clinically significant portal hypertension (CSPH) and postoperative complications and risk predictors of postoperative complications. Methods: The retrospective study was conducted to identify the effect. The cirrhotic patients were divided into two groups, those with or without CSPH. The intraoperative and postoperative conditions were evaluated. Multivariate logistic regression analysis was performed to identify potential risk predictors for postoperative complications in cirrhotic patients with CSPH. Results: The cirrhotic patients with CSPH who underwent laparoscopic cholecystectomy (LC) had postoperative hospitalization than the patients without CSPH. However, the incidence of postoperative complications between two groups showed no significant difference. The results of multivariate analysis showed that male, gallbladder wall >3 mm, size of stones ≥1 cm, scores of Model for end-stage liver disease (MELD) ≥10, and operation time >60 minutes were the potential risk predictors for postoperative complications. Conclusions: CSPH did not increase the incidence of postoperative complications in cirrhotic patients who underwent LC, but increased conversion rate and prolonged postoperative hospitalization. Furthermore, our study showed that gender, sizes of gallbladder wall and stones, scores of MELD, and operation time were the important postoperative risk predictors for cirrhotic patients with CSPH.

Shenfu Injection Attenuates Bile Duct Injury in Rats with Acute Obstructive Cholangitis.

Background: We investigated the effect of Shenfu injection (SFI) in Wistar rats with acute obstructive cholangitis (AOC) and considered the possible molecular mechanisms of the effects. Methods: The 96 rats were divided randomly into three groups. In one group, the common bile duct was subjected to ligation (BDL), and 0.2 mL of saline was injected into the proximal bile ducts. To create AOC, again, the common bile duct was ligated, and 0.2 mL of lipopolysaccharide (LPS)) (2 mg/mL) was injected into the proximal ducts. In the Shenfu injection (SFI) group, the material (10 mg/kg) was injected into the tail vein 2 hours before induction of AOC. The hepatic histopathologic changes were observed under a light microscope. The endotoxin, tumor necrosis factor-α (TNF-α), alanine transaminase (ALT), and total bilirubin (TB) concentrations in the serum were measured at different time points (0, 4, 8, and 16 hours) after ligation. The expression of nuclear transcription factor-κB (NF-κB) and CD14 in Kupffer cells also was analyzed at different times by Western blotting. Results: The TNF-α, ALT, and TB concentrations in the serum and the expression of CD14 and NF-κB in Kupffer cells were significantly higher in the SFI group than in the BDL group, but all were significantly lower than in the AOC group. Compared with the AOC group, the edema of cholangiocytes was alleviated in the SFI group, and the infiltration of inflammatory cells around cholangiocytes was reduced. Conclusion: Shenfu injection significantly alleviated bile duct injury. The potential mechanism may be associated with inhibition of CD14 expression and prevention of NF-κB activation in Kupffer cells.

Nonalcoholic fatty liver disease and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis.

Whether nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of mortality remains controversial. The present study aimed to clarify this issue. A systematic search of PubMed and Embase was conducted through October 2018. Studies providing risk estimates of NAFLD and mortality were included. A random-effects model was employed to calculate summary risk estimates. Subgroup analyses were performed to identify potential effect modifiers. Fourteen studies, involving 498501 subjects and 24234 deaths, were included. Patients with NAFLD were found to be at an elevated risk of all-cause mortality compared with those without [hazard ratio (HR) = 1.34; 95% confidence interval (CI) 1.17-1.54)]. The significantly positive association between NAFLD and all-cause mortality could not be modified by age, sex, follow-up duration, and adjustment for body mass index, diabetes, smoking or hypertension (all Pinteraction > 0.05), and remained in sensitivity analyses. No significant associations of NAFLD with CVD (HR = 1.13; 95% CI 0.92-1.38) and cancer (HR = 1.05; 95% CI 0.89-1.25) mortality were found. In conclusion, NAFLD is a predictor of increased all-cause mortality but not CVD and cancer mortality. These findings have important implications for decision making in public health and clinical practice, and highlight the urgency of developing effective treatments for NAFLD.

Catechol-O-methyltransferase Val158Met modulation of prefrontal-parietal-striatal brain systems during arithmetic and temporal transformations in working memory.

Working memory (WM) is critically mediated by dopaminergic tuning of signal-to-noise in cortical neural assemblies. However, little is known about the distributed neuronal networks impacted by dopaminergic modulation in the component processes of WM. Here, we used the genotype of the Val158Met polymorphism in catechol-O-methyltransferase (COMT) as an index of relative cortical dopamine bioavailability and tuning efficiency, to examine the spatial and subprocess specificity by which dopaminergic modulation occurs within the prefrontal-parietal-striatal network during WM, thus empirically showing that dopamine plays key roles in updating and stabilizing new information at the neural systems level. In an event-related fMRI task dissociating component numerical WM subprocesses, baseline numerical size comparison engaged ventrolateral prefrontal cortical activation that correlated with COMT Val-allele load (COMT Val>Met), while performing arithmetic transformations further engaged this genotype effect in dorsolateral prefrontal cortex (DLPFC), as well as in parietal and striatal regions. Critically, additional temporal integration of information in WM disproportionately engaged greater COMT Val>Met effects only at DLPFC. COMT Val>Met effects were also observed in DLPFC during encoding of new information into WM, but not at its subsequent retrieval. Thus, temporal updating operations, but less so the retrieval of already encoded representations, engaged relatively specific dopaminergic tuning at the DLPFC. Manipulating and rapidly updating representations were sensitive to dopaminergic modulation of neural signaling in a larger prefrontal-parietal-striatal network. These findings add to the integration of dopaminergic signaling in basic cortical assemblies with their roles in specific human brain networks during the orchestration of information processing in WM.