Clinical manifestation, lifestyle, and treatment patterns of chronic erosive gastritis: A multicenter real-world study in China.

BACKGROUND: Although chronic erosive gastritis (CEG) is common, its clinical characteristics have not been fully elucidated. The lack of consensus regarding its treatment has resulted in varied treatment regimens. AIM: To explore the clinical characteristics, treatment patterns, and short-term outcomes in CEG patients in China. METHODS: We recruited patients with chronic non-atrophic or mild-to-moderate atrophic gastritis with erosion based on endoscopy and pathology. Patients and treating physicians completed a questionnaire regarding history, endoscopic findings, and treatment plans as well as a follow-up questionnaire to investigate changes in symptoms after 4 wk of treatment. RESULTS: Three thousand five hundred sixty-three patients from 42 centers across 24 cities in China were included. Epigastric pain (68.0%), abdominal distension (62.6%), and postprandial fullness (47.5%) were the most common presenting symptoms. Gastritis was classified as chronic non-atrophic in 69.9% of patients. Among those with erosive lesions, 72.1% of patients had lesions in the antrum, 51.0% had multiple lesions, and 67.3% had superficial flat lesions. In patients with epigastric pain, the combination of a mucosal protective agent (MPA) and proton pump inhibitor was more effective. For those with postprandial fullness, acid regurgitation, early satiety, or nausea, a MPA appeared more promising. CONCLUSION: CEG is a multifactorial disease which is common in Asian patients and has non-specific symptoms. Gastroscopy may play a major role in its detection and diagnosis. Treatment should be individualized based on symptom profile.

Global, regional, and national burden of gallbladder and biliary diseases from 1990 to 2019.

BACKGROUND: Gallbladder and biliary diseases (GABDs) are a major public health issue. AIM: To analysis the cause-specific incidence, prevalence, and years lived with disability (YLDs) and its temporal trends of GABDs at the global, regional, and national level. Data on GABD were available from the Global Burden of Disease study 2019. METHODS: The estimated annual percentage change (EAPC) was used to quantify temporal trend in GABD age-standardized incidence rates (ASIRs), age-standardized prevalence rate (ASPR), and age-standardized YLD rate (ASYR) by region, sex. We analyzed the relationship between the GABD burden and country development level using the human development index (HDI). RESULTS: In 2019, the incident cases of GABD were 52003772, with an ASIR of 63432/100000 population. Globally, the number of incident cases and ASIR of GABD increased 97% and 58.9% between 1990 and 2019. Although, the ASPR and ASYR decreased from 1990 to 2019, the number of prevalent and YLDs cases increased. The highest ASIR was observed in Italy, and the highest ASPR and ASYR was observed in United Kingdom. The highest burden of GABD was found in low-SDI region, and the burden in female was significantly higher than males. A generally negative correlation (ρ = -0.24, P < 0.05) of GABD with the EAPC and human development index (HDI) (in 2021) were observed for ASIR. What's more, no correlation in ASPR (ρ = -0.06, P = 0.39) and ASYR (ρ = -0.07, P = 0.36) of GABD with the EAPC and HDI (in 2021) were observed, respectively. CONCLUSION: GABD remain a major global public health challenge; however, the burden of GABD varies geographically. Globally, the number of incident cases and ASIR of GABD increased between 1990 and 2019. The results of our study provide insight into the global disease burden of GABD and may assist policymakers in formulating effective policies to mitigate modifiable risk factors.

Systematically analysis of decompensated cirrhotic patients with spontaneous bacterial peritonitis to identify diagnostic and prognostic indexes.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a common complication in patients with cirrhosis. The diagnosis of SBP is still mostly based on ascites cultures and absolute ascites polymorphonuclear (PMN) cell count, which restricts the widely application in clinical settings. This study aimed to identify reliable and easy-to-use biomarkers for both diagnosis and prognosis of cirrhotic patients with SBP. METHODS: We conducted a retrospective study including 413 cirrhotic patients from March 2013 to July 2022 in the First Affiliated Hospital of Guangxi Medical University. Patients' clinical characteristics and laboratory indices were collected and analyzed. Two machine learning methods (Xgboost and LASSO algorithms) and a logistic regression analysis were adopted to screen and validate the indices associated with the risk of SBP. A predictive model was constructed and validated using the estimated area under curve (AUC). The indices related to the survival of cirrhotic patients were also analyzed. RESULTS: A total of 413 cirrhotic patients were enrolled in the study, of whom 329 were decompensated and 84 were compensated. 52 patients complicated and patients with SBP had a poorer Child-Pugh score (P < 0.05). Patients with SBP had a greater proportion of malignancies than those without SBP(P < 0.05). The majority of laboratory test indicators differed significantly between patients with and without SBP (P < 0.05). Albumin, neutrophil-to-lymphocyte ratio (NLR), and ferritin-to-neutrophil ratio (FNR) were found to be independently associated with SBP in decompensated cirrhotic patients using LASSO algorithms, and logistic regression analysis. The model established by the three indices showed a high predictive value with an AUC of 0.808. Furthermore, increased neutrophils, ALP, and C-reactive protein-to-albumin ratio (CAR) were associated with the shorter survival time of patients with decompensated cirrhosis, and the combination of these indices showed a greater predictive value for cirrhotic patients. CONCLUSIONS: The present study identified FNR as a novel index in the diagnosis of SBP in decompensated patients with cirrhosis. A model based on neutrophils, ALP and CAR showed high performance in predicting the prognosis of patients with decompensated cirrhosis.

Sleep deprivation leads to further impairment of hippocampal synaptic plasticity by suppressing melatonin secretion in the pineal gland of chronically unpredictable stress rats.

There has been ample research showing that insomnia is a potential trigger of depression as well as a symptom of depression. These two factors contribute to behavioural problems and are closely related to the plasticity of hippocampal synapses. Although depression and insomnia impair hippocampal synaptic plasticity, the mechanism by which this happens remains a mystery. This study aimed to investigate the pathogenesis of insomnia comorbidity in depression and the regulatory effect of venlafaxine combined with melatonin on hippocampal synaptic plasticity in chronic unpredictable mild stress (CUMS) with sleep deprivation (SD) rats. Thus, rats were subjected to 14 days of chronic mild unpredictable stress, gradually acclimated to sleep deprivation on days 12-14. Followed by 21 consecutive days of sleep deprivation, 18 h per day, with daily gavage of venlafaxine (13.5 mg/kg) + melatonin (72 mg/kg) on days 15-36. Venlafaxine + melatonin treatment improves depression-like behaviour, pentobarbital sodium experimental sleep latency, and sleep duration in CUMS +SD rats. In addition to improving depressive-like behaviors, sleep deprivation also upregulates the expression of caspase-specific cysteine protein 3 (Caspase 3) in the pineal glial cells of chronic mild rats, as well as in hippocampal microglia. Expression of ionic calcium-binding adaptor 1 (iba-1), downregulates the secretion of several synaptic plasticity-related proteins, notably cAMP response element binding protein (CREB), glial cell line-derived neurotrophic factor (GDNF), and the synaptic scaffolding protein Spinophiline (Spinophiline). Hematoxylin-eosin staining showed that the structure of the pineal gland and hippocampus was damaged, and Golgi staining showed that the dendrites and spines in the DG area of the hippocampus were destroyed, vaguely aggregated or even disappeared, and the connection network could not be established. Western blot analysis further revealed a positive correlation between low melatonin levels and reduced Spinophiline protein. Interestingly, venlafaxine + melatonin reversed these events by promoting hippocampal synaptic plasticity by regulating melatonin secretion from the pineal gland. Therefore, it exerted an antidepressant effect in sleep deprivation combined with CUMS model rats. Overall, the results of this study suggest that the pathophysiology of depressive insomnia comorbidity is mediated by impaired pineal melatonin secretion and impaired hippocampal synaptic plasticity. In addition, these responses are associated with melatonin secretion from the pineal gland.

Methylated Septin9 has moderate diagnostic value in colorectal cancer detection in Chinese population: a multicenter study.

BACKGROUND: The detection rate of methylated Septin9 (mSEPT9) in colorectal cancer (CRC) is varied greatly across the studies. This study aimed to evaluate the diagnostic ability of mSEPT9 in CRC, and compare the diagnostic efficacy with fecal immunochemical test (FIT). METHODS: 326 subjects from four centers were prospectively recruited, including 179 CRC and 147 non-CRC subjects. The plasma was collected for mSEPT9 and CEA, AFP, CA125, CA153 and CA199 test, and fecal samples for FIT tests. Sensitivity, specificity and area under the curve (AUC) of receiver operating characteristic curve were calculated to evaluate the diagnostic value of each biomarker. RESULTS: The positive rate in mSEPT9 and FIT, and the level of CEA, CA125 and CA199 were significantly higher in CRC compared with non-CRC subjects. The mSEPT9 positive rate was not associated with TNM stage and tumor stage. The sensitivity, specificity and AUC of mSEPT9 in diagnostic CRC were 0.77, 0.88 and 0.82, respectively, while the value in FIT was 0.88, 0.80 and 0.83, respectively. mSEPT9 and FIT have higher AUC value than that of CEA, CA125 and CA199. Combination of both mSEPT9 and FIT positive increased sensitivity and AUC to 0.98 and 0.83, respectively, but the specificity was declined. mSEPT9 has a slightly low sensitivity in diagnosis of colon cancer (0.87) compared with rectal cancer (0.93). CONCLUSION: mSEPT9 demonstrated moderate diagnostic value in CRC detection, which was similar to the FIT but superior to the CEA, CA125 and CA199. Combination of mSEPT9 and FIT further improved diagnostic sensitivity in CRC. TRIAL REGISTRATION: ChiCTR2000038319.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

TLR10: Insights, controversies and potential utility as a therapeutic target.

The Toll-like receptor (TLR) family acts as a bridge connecting innate and acquired immunity. TLR10 remains one of the least understood members of this family. Some studies have examined TLR10 ligands, dimerization of TLR10 with other TLRs, and downstream signalling pathways and functions, but they have often arrived at conflicting conclusions. TLR10 can induce the production of proinflammatory cytokines by forming homodimers with itself or heterodimers with TLR1 or other TLRs, but it can also inhibit proinflammatory responses when co-expressed with TLR2 or potentially other TLRs. Mutations in the Toll/Interleukin 1 receptor (TIR) domain of TLR10 alter its signalling activity. Polymorphisms in the TLR10 gene can change the balance between pro- and anti-inflammatory responses and hence modulate the susceptibility to infection and autoimmune diseases. Understanding the full range of TLR10 ligands and functions may allow the receptor to be exploited as a therapeutic target in inflammation- or immune-related diseases. Here, we summarize recent findings on the pro- and anti-inflammatory roles of TLR10 and the molecular pathways in which it is implicated. Our goal is to pave the way for future studies of the only orphan TLR thought to have strong potential as a target in the treatment of inflammation-related diseases.

The relationship between cardiac muscularis propria and clinical outcomes of peroral endoscopic myotomy in achalasia.

BACKGROUND AND AIM: Achalasia patients usually present lower esophageal sphincter thickening, which can impact the expansibility of cardia. We aimed to investigate the effect of cardiac muscularis propria (MP) on perioperative adverse events (AEs) and treatment outcomes of patients treated with peroral endoscopic myotomy (POEM). METHODS: We retrospectively reviewed 114 patients with achalasia undergoing pre-POEM endoscopic ultrasonography (EUS) between May 2013 and November 2019. Cardiac MP thickness was measured using EUS. POEM failure was defined as Eckardt score >3. Risk factors for perioperative AEs and POEM failure were identified. RESULTS: Patients were divided into the thin (n = 52) and the thick group (n = 62) based on the median of cardiac MP thickness (3.0 mm). Perioperative AEs rate of the thin group seemed to be slightly higher than that of the thick group (11.5% vs. 4.8%, P = 0.30). During a median follow-up of 30 months (range 1-77), 100 patients completed follow-up, 16 (16%) of which occurred clinical failure. The clinical outcomes of patients in the thin group were significantly poorer than those patients in the thick group (P = 0.006). Cardiac MP thickness was an independent risk factor for POEM failure (hazard ratio 3.9, P = 0.02; Cox regression), but not the risk factor for perioperative AEs (odds ratio 2.6, P = 0.2; logistic regression). CONCLUSION: Cardiac MP thickness could be a novel predictive factor for POEM failure in patients with achalasia.

Interleukin-22 regulating Kupffer cell polarization through STAT3/Erk/Akt crosstalk pathways to extenuate liver fibrosis.

AIMS: Interleukin (IL)-22 activates multiple signaling pathways to exert anti-inflammatory effects, but few studies have examined whether and how IL-22 may shift macrophage polarization between M1 (pro-inflammatory) and M2 (anti-inflammatory) states and thereby influence the progression of hepatic fibrosis. MAIN METHODS: Utilized CCl4 to induce liver fibrosis in mice, detected the role of IL-22 in inhibiting liver fibrosis by regulating Kupffer cells (KCs) polarization in vivo and in vitro. U937 cells were used to confirm the mechanism of IL-22 regulating macrophage polarization via the STAT3/Erk/Akt pathways. Human liver specimens were collected to verify the correlation between the levels of IL-22 and KCs during liver fibrogenesis. KEY FINDINGS: During CCl4-induced liver fibrosis progression in mice, adding exogenous IL-22 significantly inhibited pro-fibrogenic and macrophage phenotype-altering factors secreted by M1-KCs, and it increased the number of M2-KCs. In co-cultures of hepatic stellate cells and KCs from mice treated with IL-22, a high M2/M1-KCs ratio inhibited collagen production and stellate cell activation. These results suggest that IL-22 can increase the ratio of M2-KCs to M1-KCs and thereby attenuate the progression of liver fibrosis. Mechanistic studies in vitro showed that IL-22 promoted polarization of lipopolysaccharide-treated U937 macrophages from M1 to M2. The cytokine exerted these effects by activating the STAT3 pathway while suppressing Erk1/2 and Akt pathways. Furthermore, immunofluorescent staining in human liver specimens confirmed that IL-22 levels positively correlated with the number of M2-KCs during liver fibrogenesis. SIGNIFICANCE: IL-22 regulates the STAT3/Erk/Akt to increase the M2/M1-KCs ratio and thereby slow liver fibrogenesis.

Identification of Hub Prognosis-Associated Oxidative Stress Genes in Pancreatic Cancer Using Integrated Bioinformatics Analysis.

BACKGROUND: Intratumoral oxidative stress (OS) has been associated with the progression of various tumors. However, OS has not been considered a candidate therapeutic target for pancreatic cancer (PC) owing to the lack of validated biomarkers. METHODS: We compared gene expression profiles of PC samples and the transcriptome data of normal pancreas tissues from The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) databases to identify differentially expressed OS genes in PC. PC patients' gene profile from the Gene Expression Omnibus (GEO) database was used as a validation cohort. RESULTS: A total of 148 differentially expressed OS-related genes in PC were used to construct a protein-protein interaction network. Univariate Cox regression analysis, least absolute shrinkage, selection operator analysis revealed seven hub prognosis-associated OS genes that served to construct a prognostic risk model. Based on integrated bioinformatics analyses, our prognostic model, whose diagnostic accuracy was validated in both cohorts, reliably predicted the overall survival of patients with PC and cancer progression. Further analysis revealed significant associations between seven hub gene expression levels and patient outcomes, which were validated at the protein level using the Human Protein Atlas database. A nomogram based on the expression of these seven hub genes exhibited prognostic value in PC. CONCLUSION: Our study provides novel insights into PC pathogenesis and provides new genetic markers for prognosis prediction and clinical treatment personalization for PC patients.

Relationship between a 7-mRNA signature of the pancreatic adenocarcinoma microenvironment and patient prognosis (a STROBE-compliant article).

The potential association between the prognosis of the pancreatic adenocarcinoma (PAAD) and its microenvironment is unclear. This study aims to construct a prognostic index (PI) model of the PAAD microenvironment to predict PAAD patient survival outcomes.The mRNA sequencing and the clinical parameters data were obtained from The Cancer Genome Atlas. Immune and stromal scores were computed using the expression data algorithm to capture infiltration of immune and stromal cells in the PAAD tissue, where patients were categorized as high and low score groups according to these scores. Differentially expressed genes were identified using the R package LIMMA. Univariate and multivariate Cox regression analysis were conducted to select candidate survival-correlated gene signatures from the tumor microenvironment for constructing a model. The Kaplan-Meier method was used to access overall survival of the primary and validation cohorts. The immunological features of the PI model was explored using the Tumor Immune Estimation Resource (TIMER) database. Bioinformatic analyses were conducted based on the DAVID database.A total of 1266 overlapping differentially expressed genes and 49 prognosis-associated genes were identified. A 7-mRNA signature (GBP5, BICC1, SLC7A14, CYSLTR1, P2RY6, VENTX, and RAB39B) was screened for the construction of a PI model (area under the curve = 0.791). In both the primary and validation cohorts, Kaplan Meier analysis revealed that the overall survival of the high-risk group was significantly worse compared to the low-risk group (P < .0001, P = .0028 respectively). The TIMER database described that the 7 signature genes were correlated with immune infiltrating cells and tumor purity. Bioinformatic analyses revealed that these prognosis-associated genes were significantly enriched during inflammation, the defense response, would response, calcium ion transport, and plasma membrane part.A list of the prognosis-correlated genes was generated based on the PAAD microenvironment. A 7-mRNA PI model may be used for predicting the prognosis of PAAD patients.

miR-145 Inhibits Th9 Cell Differentiation by Suppressing Activation of the PI3K/Akt/mTOR/p70S6K/HIF-1α Pathway in Malignant Ascites from Liver Cancer.

PURPOSE: Our previous experiments confirmed that T helper type 9 (Th9) cells were involved in the occurrence and development of malignant ascites caused by liver cancer. The current study investigated the mechanism underlying microRNA (miR-145)-mediated inhibition of Th9 cells in an malignant ascites model with liver cancer. MATERIALS AND METHODS: CD4+ T cells were induced to differentiate Th9 cells after transfection with miR-145 mimics or negative control. A malignant ascites mouse model was transfected with miR-145agomir or negative control. Th9 cells were detected by flow cytometry. Enzyme-linked immunosorbent assay was applied to detect the interleukin 9 (IL-9) cytokine and hypoxia-inducible factor 1 alpha (HIF-1α). RT-PCR was used to detect the expression of miR-145 and phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase/HIF-1α (PI3K/Akt/mTOR/p70S6K/HIF-1α) mRNA. Western blotting and immunofluorescence were performed to detect the expression of PI3K/Akt/mTOR/p70S6K/HIF-1α-related proteins. RESULTS: In vitro experiments showed that miR-145 inhibited Th9 cell polarization, HIF-1α expression, and PI3K/Akt/mTOR/p70S6K pathway activation. In the malignant ascites mouse model, miR-145 also demonstrated inhibitory effects on Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. CONCLUSION: miR-145 may inhibit Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. These findings suggest a novel therapeutic target for malignant ascites from liver cancer.

Prognostic value and prospective molecular mechanism of miR-100-5p in hepatocellular carcinoma: A comprehensive study based on 1,258 samples.

The prognostic value and molecular mechanism of microRNA-100-5p (miR-100-5p) in hepatocellular carcinoma (HCC) are still unclear. To explore the prognostic value and the mechanism of miR-100-5p in HCC, the present study analyzed the results of 18 previous studies and bioinformatic datasets. The clinical significance of miR-100-5p and its targets in HCC were investigated using The Cancer Genome Atlas and the Gene Expression Omnibus, as well as relevant literature. In total, 12 online tools were used to predict the target genes of miR-100-5p. Bioinformatics analysis and Spearman correlation analysis were performed, and genomic alterations of the hub genes were evaluated. A meta-analysis with 1,258 samples revealed that miR-100-5p was significantly downregulated in HCC [standard mean difference (SMD), -0.94; 95% confidence interval (CI), -1.14 to -0.74; I2, 35.2%]. Lower miR-100-5p expression was associated with poorer clinical characteristics and a poorer prognosis for patients with HCC. Additionally, bioinformatics analysis revealed that the 'regulation of transcription', 'chromatin remodeling complex', 'transcription regulator activity', 'pathways in cancer' and 'heparan sulfate biosynthesis' were the most enriched terms. Furthermore, expression of histone deacetylase (HDAC)2, HDAC3, SHC-transforming protein 1 (SHC1), Ras-related protein Rac1 (RAC1) and E3 ubiquitin-protein ligase CBL (CBL) was negatively correlated with miR-100-5p expression. Among these, upregulated HDAC2 [hazard ratio (HR), 1.910; 95% CI, 1.309-2.787; P=0.0007], HDAC3 (HR, 1.474; 95% CI, 1.012-2.146; P=0.0435), SHC1 (HR, 1.52; 95% CI, 1.043-2.215; P=0.0281) and RAC1 (HR, 1.817; 95% CI, 1.248-2.645; P=0.0022) were associated with shorter survival. Alterations in HDAC2, SHC1, RAC1 and IGF1R were linked with a poorer outcome for HCC, and alternative splicing of SHC and RAC1 were significantly decreased and increased in HCC, respectively. In summary, the downregulation of miR-100-5p may be involved in the progression and prognosis of HCC. The upregulation of HDAC2, HDAC3, SHC1 and RAC1 may indicate a poorer survival rate for patients with HCC. Thus, miR-100-5p and these 4 potential target genes may provide novel therapeutic targets and prognostic predictors for patients with HCC.

Crosstalk network among multiple inflammatory mediators in liver fibrosis.

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.

Lactulose improves cognition, quality of life, and gut microbiota in minimal hepatic encephalopathy: A multicenter, randomized controlled trial.

OBJECTIVE: Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota. METHODS: This multicenter, open-label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp-L) or no therapy as control (Gp-NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose-responders and non-responders. RESULTS: A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp-NL group and 67 patients in the Gp-L group. At day 60, the MHE reversal rate in Gp-L (64.18%) was significantly higher than that in Gp-NL (22.58%) (P = .0002) with a relative risk of 0.46 (95% confidence interval 0.32-0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp-L (4.62 ± 6.16) than in Gp-NL (1.50 ± 5.34) (P = .0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non-responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. CONCLUSIONS: Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR-TRC-12002342).

Resveratrol improves CCL4-induced liver fibrosis in mouse by upregulating endogenous IL-10 to reprogramme macrophages phenotype from M(LPS) to M(IL-4).

Resveratrol has been suggested to mediate liver fibrosis. The switch from classically M(LPS) to alternatively activated M(IL-4) macrophages shows to protect organs from fibrosis. However, the mechanisms remain unclear. The study aimed to investigate whether resveratrol inhibited liver fibrosis by delivering IL-10 to promote the macrophage polarization in vitro and in vivo. We observed that resveratrol improved CCL4-induced liver fibrosis, upregulated Kupffer cells, increased the expression of IL-10 and M(IL-4) marks including Mrc1, Mrc2, CD163 and Arg1, whereas it slightly suppressed the level of M(LPS) including iNOS, TNF-α and MCP1. In vitro, resveratrol promoted the M(LPS) switch to M(IL-4) macrophage and elevated the expression of CD206 and iNOS as well. Meanwhile, IL-10 increased in both M(IL-4) and M(LPS). We concluded that resveratrol relieved liver fibrosis by producing more IL-10 to promote the polarization of M(LPS) to M(IL-4)-like macrophages.

Recruitment and significance of Th22 cells and Th17 cells in malignant ascites.

T helper (Th)22 and Th17 cells are implicated in the pathogenesis of a number of types of cancer. However, the function of Th22 and Th17 cells in malignant ascites (MA) remains unknown. The present study aimed at examining the distribution, phenotypes, recruitment, and prognostic value of Th22 and Th17 cells in MA from patients with hepatocellular carcinoma (HCC). A total of 26 patients with HCC with MA and 15 healthy controls were included in the present study. The proportion of Th22 cells, Th17 cells, C-C motif chemokine receptor (CCR)4, CCR6 and CCR10 were examined using flow cytometry. Interleukin (IL-)22, IL-17, C-C motif chemokine ligand (CCL)20, CCL22 and CCL27 were investigated using ELISA. In addition, the chemoattractant activity of chemokines for Th22 and Th17 cells in vitro were examined via a chemotaxis assay. The results of the present study demonstrated that Th22 cells, Th17 cells, IL-22 and IL-17 were significantly increased in MA compared with the corresponding blood and peripheral blood from healthy controls. Additionally, Th22 cells expressed increased concentrations of CCR6, CCR4 and CCR10, and Th17 cells expressed increased concentrations of CCR4 and CCR6 in MA compared with the corresponding blood. The chemotaxis assay revealed that CCL20/CCR6, CCL22/CCR4 and CCL27/CCR10 were responsible for the recruitment of Th22 cells into MA, whereas CCL22/CCR4 was responsible for the recruitment of Th17 cells. Furthermore, the patients with an increased number of Th17 cells exhibited an increased survival time compared with patients with a limited number of Th17 cells. Th22 and Th17 cells serve an important function in the development of MA, and the accumulation of Th22 and Th17 cells in MA may be due to a local increase in proinflammatory cytokines and chemokines. Increased Th17 cell numbers in MA may indicate the improvement of patient survival.

Identification of novel therapeutic target genes and pathway in pancreatic cancer by integrative analysis.

BACKGROUND: Gene alterations are crucial to the molecular pathogenesis of pancreatic cancer. The present study was designed to identify the potential candidate genes in the pancreatic carcinogenesis. METHODS: Gene Expression Omnibus database (GEO) datasets of pancreatic cancer tissue were retrieval and the differentially expressed genes (DEGs) from individual microarray data were merged. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) networks, and gene coexpression analysis were performed. RESULTS: Three GEO datasets, including 74 pancreatic cancer samples and 55 controls samples were selected. A total of 2325 DEGs were identified, including 1383 upregulated and 942 downregulated genes. The GO terms for molecular functions, biological processes, and cellular component were protein binding, small molecule metabolic process, and integral to membrane, respectively. The most significant pathway in KEGG analysis was metabolic pathways. PPI network analysis indicated that the significant hub genes including cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1), mitogen-activated protein kinase 3 (MAPK3), and phospholipase C, gamma 1 (PLCG1). Gene coexpression network analysis identified 4 major modules, and the potassium channel tetramerization domain containing 10 (KCTD10), kin of IRRE like (KIRREL), dipeptidyl-peptidase 10 (DPP10), and unc-80 homolog (UNC80) were the hub gene of each modules, respectively. CONCLUSION: Our integrative analysis provides a comprehensive view of gene expression patterns associated with the pancreatic carcinogenesis.

Large numbers of interleukins-22- and -17A-producing T helper cells in cholangiocarcinoma related to liver fluke infection.

Cholangiocarcinoma (CCA) associated with liver fluke infection involves inflammatory and immune processes; however, whether these involve the proinflammatory cytokine IL-17A and proliferative cytokine IL-22 remains unclear. Here, numbers of IL-22- and IL-17A-producing Th cells and cytokine concentrations in 30 patients with CCA and long-term liver fluke infection, 40 patients with liver-fluke infection but not CCA, and 16 healthy controls were compared. Analyses were performed using immunohistochemistry, flow cytometry, ELISA and RT-PCR. Immunohistochemical staining showed weaker expression of IL-22 and IL-17A in patients with CCA with than in those without liver fluke infection (P < 0.01). Flow cytometry revealed significantly greater median proportions of IL-22-producing T helper cells in patients with CCA (2.2%) than in those without it (0.69%) or controls (0.4%, P < 0.001). Similar results were obtained for IL-17A-producing T helper cells. ELISA revealed plasma concentrations of IL-22 were 1.3-fold higher in patients with CCA than in those without it and 4.6-fold higher than in controls (P < 0.001). Plasma concentrations of IL-17A were 2.5-fold higher in patients with CCA than in those without it, and 21-fold higher than in controls (P < 0.001). Amounts of IL-22 and IL-17A mRNAs in blood were significantly higher in patients with CCA than in the other two groups. Proportions of CD4+ CD45RO+ T cells producing IL-22 correlated with proportions producing IL-17A (r = 0.759; P < 0.001), and plasma concentrations of IL-22 correlated with those of IL-17A (r = 0.726; P < 0.001). These results suggest that both IL-17A and IL-22 affect development of CCA related to liver fluke infection.

Interleukin-9 Promotes Pancreatic Cancer Cells Proliferation and Migration via the miR-200a/Beta-Catenin Axis.

Background. Both IL-9 and miR-200a are involved in the pathogenesis of cancers; however, the role of IL-9 in pancreatic cancer and the possible underlying mechanisms remain unknown. The aim of this study was to investigate the effect of IL-9 on pancreatic cancer cells and its interaction with miR-200a. Methods. Pancreatic cancer cells (PANC-1 and AsPC-1) were treated with IL-9 and the expression of miR-200a and ß-catenin in pancreatic cancer cells was measured. ß-Catenin was examined as a target gene of miR-200a in pancreatic cancer cells. The interaction between IL-9 and miR-200a in pancreatic cancer cells was determined by infecting miR-200a mimics prior to IL-9 treatment and then measuring miR-200a and ß-catenin expression. Results. IL-9 significantly promoted the proliferation, invasion, and migration of pancreatic cancer cells; however, the effect on pancreatic cancer cell apoptosis was insignificant. ß-Catenin was verified as a target gene of miR-200a in pancreatic cancer cells. Overexpression of miR-200a in pancreatic cancer cells significantly attenuated proliferation and metastasis and reduced ß-catenin expression. IL-9 treatment of pancreatic cancer cells decreased miR-200a expression and increased ß-catenin expression. The effect of miR-200a on pancreatic cancer cells decreased following IL-9 treatment. Conclusions. IL-9 promotes proliferation and metastasis in pancreatic cancer cells; this effect may partly involve regulation of the miR-200a/ß-catenin axis.