Publications by authors named "Yuanjie Yu"

22 Publications

  • Page 1 of 1

Effect of a deep learning-based system on the miss rate of gastric neoplasms during upper gastrointestinal endoscopy: a single-centre, tandem, randomised controlled trial.

Lancet Gastroenterol Hepatol 2021 09 21;6(9):700-708. Epub 2021 Jul 21.

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China; Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address:

Background: White light endoscopy is a pivotal first-line tool for the detection of gastric neoplasms. However, gastric neoplasms can be missed during upper gastrointestinal endoscopy due to the subtle nature of these lesions and varying skill among endoscopists. Here, we aimed to evaluate the effect of an artificial intelligence (AI) system designed to detect focal lesions and diagnose gastric neoplasms on reducing the miss rate of gastric neoplasms in clinical practice.

Methods: This single-centre, randomised controlled, tandem trial was done at Renmin Hospital of Wuhan University, China. We recruited consecutive patients (≥18 years old) undergoing routine upper gastrointestinal endoscopy for screening, surveillance, or investigation of symptoms. Same-day tandem upper gastrointestinal endoscopy was done where patients first underwent either AI-assisted (AI-first) or routine (routine-first) white light endoscopy, followed immediately by the other procedure, with targeted biopsies for all detected lesions taken at the end of the second examination. Patients were randomly assigned (1:1) to the AI-first or routine-first group using a computer-generated random numerical series and block randomisation (block size of four). Endoscopists were not blinded to randomisation status, whereas patients and pathologists were. The primary endpoint was the miss rate of gastric neoplasms and the analysis was done per protocol. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR2000034453, and has been completed.

Findings: Between July 6, 2020, and Dec 11, 2020, 907 patients were randomly assigned to the AI-first group and 905 to the routine-first group. The gastric neoplasm miss rate was significantly lower in the AI-first group than in the routine-first group (6·1%, 95% CI 1·6-17·9 [3/49] vs 27·3%, 15·5-43·0 [12/44]; relative risk 0·224, 95% CI 0·068-0·744; p=0·015). The only reported adverse event was bleeding from a target lesion after biopsy.

Interpretation: The use of an AI system during upper gastrointestinal endoscopy significantly reduced the gastric neoplasm miss rate. AI-assisted endoscopy has the potential to improve the yield of gastric neoplasms by endoscopists.

Funding: The Project of Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision and the Hubei Province Major Science and Technology Innovation Project.
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http://dx.doi.org/10.1016/S2468-1253(21)00216-8DOI Listing
September 2021

IRE1α-JNK pathway-mediated autophagy promotes cell survival in response to endoplasmic reticulum stress during the initial phase of hepatic steatosis.

Life Sci 2021 Jan 26;264:118668. Epub 2020 Oct 26.

Medical Examination Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China. Electronic address:

Aims: It has been widely reported that autophagy and inositol-requiring enzyme-1α (IRE1α)-c-Jun N-terminal kinase (JNK) pathway was involved in cell survival under endoplasmic reticulum (ER) stress, but their specific roles in hepatic steatosis remain unclear. This study aimed to determine the interaction between autophagy and IRE1α-JNK pathway on cell survival in response to ER stress during the initial phase of hepatic steatosis.

Methods: Hepatic steatosis was induced in HepG2 cells by supplementing oleic acid (OA). Lipid accumulation was evaluated by BODIPY493/503 staining. ER stress and IRE1α-JNK signaling were investigated by western blot. Autophagy was monitored by western blot, GFP-LC3 plasmid and immunofluorescence staining, while apoptosis was determined by western blotting, Annexin-V-FITC/PI staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.

Key Findings: Aggravated lipid accumulation was found under increased ER stress during the initial phase of hepatic steatosis. Meanwhile, an increase of autophagy and no alteration of apoptosis were observed under increased ER stress. Interestingly, autophagy was induced by ER stress, while autophagy suppression led to an increase of apoptosis in response to ER stress Moreover, further study showed that IRE1α-JNK pathway was activated after ER stress and consequently induced autophagy, which promoted cell survival in the initial phase of hepatic steatosis.

Significance: We conclude that IRE1α-JNK pathway was activated during ER stress in the initial phase of hepatic steatosis and promoted cell survival by enhancing autophagy. Targeting IRE1α-JNK-autophagy signaling may provide new insight into preventive strategies for hepatic steatosis.
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http://dx.doi.org/10.1016/j.lfs.2020.118668DOI Listing
January 2021

Ursodeoxycholic acid alleviates nonalcoholic fatty liver disease by inhibiting apoptosis and improving autophagy via activating AMPK.

Biochem Biophys Res Commun 2020 08 25;529(3):834-838. Epub 2020 Jun 25.

Medical examination center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430061, China. Electronic address:

Ursodeoxycholic acid (UDCA), first identified in bear bile, was widely used in cholestatic liver diseases. Our previous studies have suggested UDCA may exert favorable influence on hepatic steatosis. However, the molecular mechanism remains elusive. Given the role of autophagy and apoptosis dysregulation in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and pharmacological effects of UDCA on modulating autophagy, apoptosis. we sought to investigate whether UDCA had therapeutic effect on NAFLD and its mechanism of modulating autophagy, apoptosis. Our finding revealed that UDCA exerted obviously favorable influence on hepatic steatosis in NAFLD rats by activating AMP-activated protein kinase (AMPK). Mechanistic studies indicated UDCA inhibited apoptosis and improved autophagy by influencing Bcl-2/Beclin-1 and Bcl-2/Bax complex interaction. Importantly, above-mentioned influence of UDCA on autophagy, apoptosis and Bcl-2/Beclin-1, Bcl-2/Bax complex interaction in NAFLD were partly counteracted by AMPK inhibitor compound C(CC). In conclusion, UDCA exerts favorable influence on hepatic steatosis in NAFLD rats, which is attributable to apoptosis inhibition and autophagy induction by influencing Bcl-2/Beclin-1 complex and Bcl-2/Bax complex interaction via activating AMPK, indicating that UDCA may be a promising therapeutic target for NAFLD.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.128DOI Listing
August 2020

The role of the miR-21-5p-mediated inflammatory pathway in ulcerative colitis.

Exp Ther Med 2020 Feb 4;19(2):981-989. Epub 2019 Dec 4.

Department of Gastroenterology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei 430060, P.R. China.

Ulcerative colitis (UC), a major type of inflammatory bowel disease, is also a chronic non-specific intestinal inflammation condition of unknown etiology. The pathogenesis of UC is closely associated with immune abnormalities, inflammatory damage and genetics. The present study aimed to explore the effects of microRNA (miR)-21-5p on the interleukin-6 (IL-6) receptor (IL6R)/signal transducer and activator of transcription (STAT3) signal pathway in UC, in order to identify a highly effective treatment for UC. A total of 45 patients with UC and 45 healthy controls were recruited for the present study. The expression levels of miR-21-5p and STAT3 in the sera of patients with UC and healthy controls were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A UC rat model was established using dextran sulfate sodium. Following lipopolysaccharide (LPS) treatment, RAW264.7 cells were transfected with a miR-21-5p inhibitor. The levels of morphological damage and apoptosis of the colonic mucosal epithelial tissue were investigated using hematoxylin and eosin staining and a TUNEL staining assay, and then the colon macroscopic damage index and disease activity index were measured in rats. Western blot analysis was used to detect the protein expression levels of IL6R, STAT3, intracellular adhesion molecule 1 (ICAM-1), NF-κB, cleaved caspase-3, cleaved caspase-9 and Fas ligand (FasL). RT-qPCR detected the mRNA expression levels of miR-21-5p, IL6R, STAT3, ICAM-1, NF-κB, caspase-3, caspase-9 and FasL. An ELISA was performed to measure the levels of inflammatory cytokines. The viability and apoptosis levels of RAW264.7 cells were examined using MTT and flow cytometry assays. Additionally, STAT3 was investigated as a direct target of miR-21-5p in RAW264.7 cells using a dual-luciferase reporter assay. The results of the present study demonstrated that inflammation and apoptotic markers were revealed to be significantly downregulated following transfection with miR-21-5p inhibitors in RAW264.7 cells induced by LPS, and that cell viability was increased. Furthermore, STAT3 was confirmed to be a target of miR-21-5p in RAW264.7 cells. Collectively, these data demonstrated that miR-21-5p inhibition mediated the IL-6/STAT3 pathway in UC rats to decrease the levels of inflammation and apoptosis in RAW264.7 cells, and suggested that miR-21-5p may be an important therapy target in human UC.
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http://dx.doi.org/10.3892/etm.2019.8277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966149PMC
February 2020

Homo Sapiens Circular RNA 0079993 (hsa_circ_0079993) of the POLR2J4 Gene Acts as an Oncogene in Colorectal Cancer Through the microRNA-203a-3p.1 and CREB1 Axis.

Med Sci Monit 2019 Sep 13;25:6872-6883. Epub 2019 Sep 13.

Department of Gastroenterology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China (mainland).

BACKGROUND Worldwide, dietary changes have resulted in an increased incidence of colorectal cancer (CRC). Circular RNAs (circRNAs) are involved in tumorigenesis of several human tumors, but their role in CRC remains unknown. This study aimed to investigate the expression and effects of Homo sapiens (hsa)_circ_0079993 of POLR2J4 and its impact on CRC. MATERIAL AND METHODS Paired CRC tissue and adjacent normal colorectal tissue samples (N=41), and HCT116 and SW620 human CRC cells were studied. The expression of circ_0079993 and its parental gene, POLR2J4, were examined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Two small-interfering RNAs (siRNAs) against circ_0079993 were used to silence circ_0079993 expression in HCT116 and SW620 CRC cells. Cell proliferation was evaluated using the cell counting kit-8 (CCK-8) assay, colony formation, and in vivo tumor growth assays. The target miRNAs of circ_0079993 was predicted using TargetScan, and the interaction between circ_0079993 and its target miRNAs were verified by the dual-luciferase reporter (DLR) assay. RESULTS In CRC tissue POLR2J4 expression was reduced, and circ_0079993 expression was increased compared with normal tissue. Knockdown of circ_0079993 significantly inhibited the proliferation of CRC cells in vitro. Also, circ_0079993 was predicted to sponge multiple miRNAs, miR-203a-3p.1 was verified as a target of circ_0079993, and circ_0079993 indirectly regulated mRNA expression of the CREB1 gene by sponging miR-203a-3p.1 in CRC cells. The use of anti-miR-203a-3p.1 reversed the inhibitory effects of circ_0079993 knockdown on CRC cell proliferation. CONCLUSIONS The findings supported that hsa_circ_0079993 acts as an oncogene in CRC through the miRNA-203a-3p.1/CREB1 axis.
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http://dx.doi.org/10.12659/MSM.916064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755939PMC
September 2019

Long non-coding XIAP-AS1 regulates cell proliferation, invasion and cell cycle in colon cancer.

Artif Cells Nanomed Biotechnol 2019 Dec;47(1):767-775

a Department of Gastroenterology , Renmin Hospital of Wuhan University, Hubei Key Laboratory of Digestive System Disease , Wuhan , Hubei , China.

Colon cancer is one of the most commonly diagnosed and deadly cancers worldwide. Further understanding of the biological mechanisms is important for exploring the molecular biomarkers and therapeutic targets of this disease. Dysregulation of long non-coding RNAs (lncRNAs) has been reported to be associated with the development and progression of various cancers. XIAP-AS1 is a novel lncRNA, which can regulate apoptosis in gastric cancer cells. However, the role of XIAP-AS1 in colorectal cancer (CRC) remains unclear. In this study, we found that XIAP-AS1 expression was significantly increased in CRC tissues and its expression showed a positive correlation with TNM stage and cumulative survival rate of CRC. To investigate whether XIAP-AS1 regulates the progression of CRC, we knocked down its expression in several CRC cell lines. CCK-8 assays showed that XIAP-AS1 knockdown remarkably suppressed CRC cell growth and arrested the cell cycle at the G0/G1 phase (flow cytometric analysis). Furthermore, XIAP-AS1 knockdown also remarkably blocked cell invasion of colon cancer cells by regulating the expression of EMT markers, such as E-cadherin, ZO-1, vimentin, and N-cadherin. Importantly, we found that XIAP-AS1 knockdown significantly reduced STAT3 phosphorylation. Overall, this study suggests that lncRNA XIAP-AS1 might serve as a potential oncogene for colon cancer.
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http://dx.doi.org/10.1080/21691401.2019.1577880DOI Listing
December 2019

Identification of 8-miRNAs as biomarkers for nonalcoholic fatty liver disease.

J Cell Physiol 2019 08 20;234(10):17361-17369. Epub 2019 Feb 20.

Department of Medical Ultrasonics, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China.

Nonalcoholic fatty liver disease (NAFLD) poses serious threats to humans. Several studies have studied the biomarkers associated with NAFLD; however, the results vary because of the differences in the sequencing platform, sample selection, and filter conditions. This study aimed to explore the key microRNAs (miRNAs) of NAFLD by a systematic bioinformatics analysis. A total of 10 qualified NAFLD miRNA data sets were selected through a literature review. Signature miRNAs were identified by overlap comparison. The target genes of miRNAs were predicted by TargetScan software and functional enrichment, and transcription factor (TF) binding analysis of target genes was carried out by the database for annotation, visualization, and integrated discovery and Tfacts database, respectively. A total of three upregulated miRNAs and five downregulated miRNAs were identified in the NAFLD tissue. The target genes of upregulated miRNAs mainly enriched in the RNA polymerase II promoter transcriptional regulation, chromatin remodeling process, and O-glycan synthesis, circadian rhythm, and endocytosis; the target genes of downregulated miRNAs mainly enriched in the transcriptional regulation of DNA as a template, negative regulation process of protein phosphorylation, and Fc epsilon RI signaling pathways, Ras signaling pathways and the interaction between cytokines and cytokines. Besides, 136 interactions were formed between 62 TFs and 45 target genes of upregulated miRNA, whereas 157 interactions were formed between 72 TFs and 45 target genes of downregulated miRNA. Both contained 102 TFs, and 32 TFs were present in both target genes. To summarize, we identified an eight-miRNA set as a signature for NAFLD, which will benefit the clinical treatment of NAFLD.
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http://dx.doi.org/10.1002/jcp.28356DOI Listing
August 2019

Alcohol-Related Liver Disease Is Rarely Detected at Early Stages Compared With Liver Diseases of Other Etiologies Worldwide.

Clin Gastroenterol Hepatol 2019 10 29;17(11):2320-2329.e12. Epub 2019 Jan 29.

Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil.

Background & Aims: Despite recent advances in treatment of viral hepatitis, liver-related mortality is high, possibly owing to the large burden of advanced alcohol-related liver disease (ALD). We investigated whether patients with ALD are initially seen at later stages of disease development than patients with hepatitis C virus (HCV) infection or other etiologies.

Methods: We performed a cross-sectional study of 3453 consecutive patients with either early or advanced liver disease (1699 patients with early and 1754 with advanced liver disease) seen at 17 tertiary care liver or gastrointestinal units worldwide, from August 2015 through March 2017. We collected anthropometric, etiology, and clinical information, as well as and model for end-stage liver disease scores. We used unconditional logistic regression to estimate the odds ratios for evaluation at late stages of the disease progression.

Results: Of the patients analyzed, 81% had 1 etiology of liver disease and 17% had 2 etiologies of liver disease. Of patients seen at early stages for a single etiology, 31% had HCV infection, 21% had hepatitis B virus infection, and 17% had nonalcoholic fatty liver disease, whereas only 3.8% had ALD. In contrast, 29% of patients seen for advanced disease had ALD. Patients with ALD were more likely to be seen at specialized centers, with advanced-stage disease, compared with patients with HCV-associated liver disease (odds ratio, 14.1; 95% CI, 10.5-18.9; P < .001). Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. These patients had significantly more visits to health care providers, with more advanced disease, compared with patients without excess alcohol use. The mean model for end-stage liver disease score for patients with advanced ALD (score, 16) was higher than for patients with advanced liver disease not associated with excess alcohol use (score, 13) (P < .01).

Conclusions: In a cross-sectional analysis of patients with liver disease worldwide, we found that patients with ALD are seen with more advanced-stage disease than patients with HCV-associated liver disease. Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. Early detection and referral programs are needed for patients with ALD worldwide.
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http://dx.doi.org/10.1016/j.cgh.2019.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682466PMC
October 2019

MiR-490-5p inhibits the stemness of hepatocellular carcinoma cells by targeting ECT2.

J Cell Biochem 2019 01 11;120(1):967-976. Epub 2018 Sep 11.

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

To explore the targeting relationship between miR-490-5p and ECT2 in hepatocellular carcinoma (HCC) and the influences of miR-490-5p and ECT2 on the stemness of HCC cells. The expressions of miR-490-5p and ECT2 in HCC tissues and adjacent tissues were identified by quantitative real-time polymerase chain reaction (qRT-PCR). The relationships between the expression levels of miR-490-5p/ ECT2 and the overall/disease-free survival (OS/DFS) of patients with HCC were evaluated using correlative curves. In addition, the targeting relationship between miR-490-5p and ECT2 was predicted by TargetScan and verified by dual-luciferase reporter assay. Plasmid transfection was used for overexpression of ECT2 in HepG2 cells, and transfection efficiency was verified by qRT-PCR. Cell Counting Kit-8 assay and cell sphere-formation assay were conducted to detect the proliferation and sphere-formation ability of HCC cells, respectively. Cell populations with different cell transfections were sorted using flow cytometry. The expression levels of proteins in the stem cell signaling pathway were determined using Western blot analysis. MiR-490-5p was remarkably downregulated, yet ECT2 was upregulated in HCC tissues compared with adjacent tissues. MiR-490-5p expression was positively correlated with OS and DFS of patients with HCC, which were otherwise negatively correlated with ECT2 expression. ECT2 was validated to be the downstream target of miR-490-5p. Overexpression of miR-490-5p restrained the sphere formation ability, stemness, and proliferation of HCC cells. MiR-490-5p repressed the stemness of HCC cells through inhibiting the expression of ECT2. MiR-490-5p may be an underlying therapeutic target in HCC treatment.
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http://dx.doi.org/10.1002/jcb.27459DOI Listing
January 2019

Tissue Factor Coagulant Activity is Regulated by the Plasma Membrane Microenvironment.

Thromb Haemost 2018 06 21;118(6):990-1000. Epub 2018 Apr 21.

Laboratory of Clinical Chemistry, and Vesicle Observation Centre, Academic Medical Centre of the University of Amsterdam, Amsterdam, The Netherlands.

Background: Tissue factor (TF) can be present in a non-coagulant and coagulant form. Whether the coagulant activity is affected by the plasma membrane microenvironment is unexplored.

Objective: This article studies the presence and coagulant activity of human TF in plasma membrane micro-domains.

Methods: Plasma membranes were isolated from human MIA PaCa2 cells, MDA-MB-231 cells and human vascular smooth muscle cells by Percoll gradient ultracentrifugation after cell disruption. Plasma membranes were fractionated by OptiPrep gradient ultracentrifugation, and the presence of TF, flotillin, caveolin, clathrin, protein disulphide isomerase (PDI), TF pathway inhibitor (TFPI) and phosphatidylserine (PS) were determined.

Results: Plasma membranes contain two detergent-resistant membrane (DRM) compartments differing in density and biochemical composition. High-density DRMs (DRM-H) have a density () of 1.15 to 1.20 g/mL and contain clathrin, whereas low-density DRMs (DRM-L) have a density between 1.09 and 1.13 g/mL and do not contain clathrin. Both DRMs contain TF, flotillin and caveolin. PDI is detectable in DRM-H, TFPI is not detectable in either DMR-H or DRM-L and PS is detectable in DRM-L. The DRM-H-associated TF (> 95% of the TF antigen) lacks detectable coagulant activity, whereas the DRM-L-associated TF triggers coagulation. This coagulant activity is inhibited by lactadherin and thus PS-dependent, but seemed insensitive to 16F16, an inhibitor of PDI.

Conclusion: Non-coagulant and coagulant TF are present within different types of DRMs in the plasma membrane, and the composition of these DRMs may affect the TF coagulant activity.
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http://dx.doi.org/10.1055/s-0038-1642031DOI Listing
June 2018

p53 expression in patients with ulcerative colitis - associated with dysplasia and carcinoma: a systematic meta-analysis.

BMC Gastroenterol 2017 Oct 25;17(1):111. Epub 2017 Oct 25.

Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China.

Background: Tumor suppressor gene p53 expression has been reported in patients with ulcerative colitis (UC). However, the correlation between p53 expression and UC remains controversial. The aim of this meta-analysis was to investigate the association between p53 expression and different pathological types of UC.

Methods: Publications were searched in the PubMed, Embase, EBSCO, Wangfang, and CNKI databases. The overall odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were summarized in this study.

Results: Final 19 papers were identified in this meta-analysis, including 1068 patients with UC and 130 normal tissue samples. Immunohistochemical p53 expression was significantly higher in UC without dysplasia and carcinoma (UC group) compared to normal tissue samples (OR = 3.14, P = 0.001), higher in UC with dysplasia than in UC group (OR = 10.76, P < 0.001), and higher in UC with colorectal cancer (CRC) than in UC with dysplasia (OR = 1.69, P = 0.035). Subgroup analysis of ethnicity (UC group vs. normal tissues) showed that p53 expression was correlated with UC in Asians, but not in Caucasians. When UC with dysplasia was compared to UC group, p53 expression was linked to UC with dysplasia among both Asians and Caucasians. When UC-CRC was compared to UC with dysplasia, p53 expression was not associated with UC-CRC in both Caucasians and Asians.

Conclusions: p53 expression was closely associated with UC-CRC development. p53 expression showed different ethnic characteristics among different pathological types of UC.
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http://dx.doi.org/10.1186/s12876-017-0665-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655860PMC
October 2017

Intraluminal pressure patterns in the human colon assessed by high-resolution manometry.

Sci Rep 2017 02 20;7:41436. Epub 2017 Feb 20.

McMaster University, Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Hamilton, Ontario, Canada.

Assessment of colonic motor dysfunction is rarely done because of inadequate methodology and lack of knowledge about normal motor patterns. Here we report on elucidation of intraluminal pressure patterns using High Resolution Colonic Manometry during a baseline period and in response to a meal, in 15 patients with constipation, chronically dependent on laxatives, 5 healthy volunteers and 9 patients with minor, transient, IBS-like symptoms but no sign of constipation. Simultaneous pressure waves (SPWs) were the most prominent propulsive motor pattern, associated with gas expulsion and anal sphincter relaxation, inferred to be associated with fast propagating contractions. Isolated pressure transients occurred in most sensors, ranging in amplitude from 5-230 mmHg. Rhythmic haustral boundary pressure transients occurred at sensors about 4-5 cm apart. Synchronized haustral pressure waves, covering 3-5 cm of the colon occurred to create a characteristic intrahaustral cyclic motor pattern at 3-6 cycles/min, propagating in mixed direction. This activity abruptly alternated with erratic patterns resembling the segmentation motor pattern of the small intestine. High amplitude propagating pressure waves (HAPWs) were too rare to contribute to function assessment in most subjects. Most patients, dependent on laxatives for defecation, were able to generate normal motor patterns in response to a meal.
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http://dx.doi.org/10.1038/srep41436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316981PMC
February 2017

Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol.

Gastroenterology 2016 10 21;151(4):733-746.e12. Epub 2016 Jun 21.

Division of Digestive Diseases, Department of Medicine, Yerkes National Primate Center, Emory University, Atlanta, Georgia; Atlanta VA Medical Center, Decatur, Georgia. Electronic address:

Background & Aims: There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH.

Methods: Male C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy.

Results: F11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation.

Conclusions: Mice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH.
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http://dx.doi.org/10.1053/j.gastro.2016.06.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037035PMC
October 2016

Cytochrome bd Displays Significant Quinol Peroxidase Activity.

Sci Rep 2016 06 9;6:27631. Epub 2016 Jun 9.

Department of Biotechnology, Delft University of Technology, The Netherlands.

Cytochrome bd is a prokaryotic terminal oxidase that catalyses the electrogenic reduction of oxygen to water using ubiquinol as electron donor. Cytochrome bd is a tri-haem integral membrane enzyme carrying a low-spin haem b558, and two high-spin haems: b595 and d. Here we show that besides its oxidase activity, cytochrome bd from Escherichia coli is a genuine quinol peroxidase (QPO) that reduces hydrogen peroxide to water. The highly active and pure enzyme preparation used in this study did not display the catalase activity recently reported for E. coli cytochrome bd. To our knowledge, cytochrome bd is the first membrane-bound quinol peroxidase detected in E. coli. The observation that cytochrome bd is a quinol peroxidase, can provide a biochemical basis for its role in detoxification of hydrogen peroxide and may explain the frequent findings reported in the literature that indicate increased sensitivity to hydrogen peroxide and decreased virulence in mutants that lack the enzyme.
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http://dx.doi.org/10.1038/srep27631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899803PMC
June 2016

Neurotensin Changes Propulsive Activity into a Segmental Motor Pattern in the Rat Colon.

J Neurogastroenterol Motil 2016 Jul;22(3):517-28

Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China.

Background/aims: Neurotensin is a gut-brain peptide with both inhibitory and excitatory actions on the colonic musculature; our objective was to understand the implications of this for motor patterns occurring in the intact colon of the rat.

Methods: The effects of neurotensin with concentrations ranging from 0.1-100 nM were studied in the intact rat colon in vitro, by investigating spatio-temporal maps created from video recordings of colonic motility before and after neurotensin.

Results: Low concentration of neurotensin (0.1-1 nM) inhibited propagating long distance contractions and rhythmic propagating motor complexes; in its place a slow propagating rhythmic segmental motor pattern developed. The neurotensin receptor 1 antagonist SR-48692 prevented the development of the segmental motor pattern. Higher concentrations of neurotensin (10 nM and 100 nM) were capable of restoring long distance contraction activity and inhibiting the segmental activity. The slow propagating segmental contraction showed a rhythmic contraction-- relaxation cycle at the slow wave frequency originating from the interstitial cells of Cajal associated with the myenteric plexus pacemaker. High concentrations given without prior additions of low concentrations did not evoke the segmental motor pattern. These actions occurred when neurotensin was given in the bath solution or intraluminally. The segmental motor pattern evoked by neurotensin was inhibited by the neural conduction blocker lidocaine.

Conclusions: Neurotensin (0.1-1 nM) inhibits the dominant propulsive motor patterns of the colon and a distinct motor pattern of rhythmic slow propagating segmental contractions develops. This motor pattern has the hallmarks of haustral boundary contractions.
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http://dx.doi.org/10.5056/jnm15181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930308PMC
July 2016

Haustral boundary contractions in the proximal 3-taeniated rabbit colon.

Am J Physiol Gastrointest Liver Physiol 2016 Feb 3;310(3):G181-92. Epub 2015 Dec 3.

Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China; and Farncombe Family Digestive Health Research Institute, McMaster University Department of Medicine, Hamilton, Ontario, Canada.

The rabbit proximal colon is similar in structure to the human colon. Our objective was to study interactions of different rhythmic motor patterns focusing on haustral boundary contractions, which create the haustra, using spatiotemporal mapping of video recordings. Haustral boundary contractions were seen as highly rhythmic circumferential ring contractions that propagated slowly across the proximal colon, preferentially but not exclusively in the anal direction, at ∼0.5 cycles per minute; they were abolished by nerve conduction blockers. When multiple haustral boundary contractions propagated in the opposite direction, they annihilated each other upon encounter. Ripples, myogenic propagating ring contractions at ∼9 cycles per min, induced folding and unfolding of haustral muscle folds, creating an anarchic appearance of contractile activity, with different patterns in the three intertaenial regions. Two features of ripple activity were prominent: frequent changes in propagation direction and the occurrence of dislocations showing a frequency gradient with the highest intrinsic frequency in the distal colon. The haustral boundary contractions showed an on/off/on/off pattern at the ripple frequency, and the contraction amplitude at any point of the colon showed waxing and waning. The haustral boundary contractions are therefore shaped by interaction of two pacemaker activities hypothesized to occur through phase-amplitude coupling of pacemaker activities from interstitial cells of Cajal of the myenteric plexus and of the submuscular plexus. Video evidence shows the unique role haustral folds play in shaping contractile activity within the haustra. Muscarinic agents not only enhance the force of contraction, they can eliminate one and at the same time induce another neurally dependent motor pattern.
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http://dx.doi.org/10.1152/ajpgi.00171.2015DOI Listing
February 2016

Motor patterns of the small intestine explained by phase-amplitude coupling of two pacemaker activities: the critical importance of propagation velocity.

Am J Physiol Cell Physiol 2015 Sep 1;309(6):C403-14. Epub 2015 Jul 1.

Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan University Institute of Digestive and Liver Diseases, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, China.

Phase-amplitude coupling of two pacemaker activities of the small intestine, the omnipresent slow wave activity generated by interstitial cells of Cajal of the myenteric plexus (ICC-MP) and the stimulus-dependent rhythmic transient depolarizations generated by ICC of the deep muscular plexus (ICC-DMP), was recently hypothesized to underlie the orchestration of the segmentation motor pattern. The aim of the present study was to increase our understanding of phase-amplitude coupling through modeling. In particular the importance of propagation velocity of the ICC-DMP component was investigated. The outcome of the modeling was compared with motor patterns recorded from the rat or mouse intestine from which propagation velocities within the different patterns were measured. The results show that the classical segmentation motor pattern occurs when the ICC-DMP component has a low propagation velocity (<0.05 cm/s). When the ICC-DMP component has a propagation velocity in the same order of magnitude as that of the slow wave activity (∼1 cm/s), cluster type propulsive activity occurs which is in fact the dominant propulsive activity of the intestine. Hence, the only difference between the generation of propagating cluster contractions and the Cannon-type segmentation motor pattern is the propagation velocity of the low-frequency component, the rhythmic transient depolarizations originating from the ICC-DMP. Importantly, the proposed mechanism explains why both motor patterns have distinct rhythmic waxing and waning of the amplitude of contractions. The hypothesis is brought forward that the velocity is modulated by neural regulation of gap junction conductance within the ICC-DMP network.
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http://dx.doi.org/10.1152/ajpcell.00414.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572367PMC
September 2015

Genome-wide distribution comparative and composition analysis of the SSRs in Poaceae.

BMC Genet 2015 Feb 15;16:18. Epub 2015 Feb 15.

Key Laboratory of Crop Biology of China, Shandong Agricultural University, Taian, 271018, China.

Background: The Poaceae family is of great importance to human beings since it comprises the cereal grasses which are the main sources for human food and animal feed. With the rapid growth of genomic data from Poaceae members, comparative genomics becomes a convinent method to study genetics of diffierent species. The SSRs (Simple Sequence Repeats) are widely used markers in the studies of Poaceae for their high abundance and stability.

Results: In this study, using the genomic sequences of 9 Poaceae species, we detected 11,993,943 SSR loci and developed 6,799,910 SSR primer pairs. The results show that SSRs are distributed on all the genomic elements in grass. Hexamer is the most frequent motif and AT/TA is the most frequent motif in dimer. The abundance of the SSRs has a positive linear relationship with the recombination rate. SSR sequences in the coding regions involve a higher GC content in the Poaceae than that in the other species. SSRs of 70-80 bp in length showed the highest AT/GC base ratio among all of these loci. The result shows the highest polymorphism rate belongs to the SSRs ranged from 30 bp to 40 bp. Using all the SSR primers of Japonica, nineteen universal primers were selected and located on the genome of the grass family. The information of SSR loci, the SSR primers and the tools of mining and analyzing SSR are provided in the PSSRD (Poaceae SSR Database, http://biodb.sdau.edu.cn/pssrd/).

Conclusions: Our study and the PSSRD database provide a foundation for the comparative study in the Poaceae and it will accelerate the study on markers application, gene mapping and molecular breeding.
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http://dx.doi.org/10.1186/s12863-015-0178-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333251PMC
February 2015

The origin of segmentation motor activity in the intestine.

Nat Commun 2014 ;5:3326

Department of Medicine, Faculty of Health Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N3Z5.

The segmentation motor activity of the gut that facilitates absorption of nutrients was first described in the late 19th century, but the fundamental mechanisms underlying it remain poorly understood. The dominant theory suggests alternate excitation and inhibition from the enteric nervous system. Here we demonstrate that typical segmentation can occur after total nerve blockade. The segmentation motor pattern emerges when the amplitude of the dominant pacemaker, the slow wave generated by interstitial cells of Cajal associated with the myenteric plexus (ICC-MP), is modulated by the phase of induced lower frequency rhythmic transient depolarizations, generated by ICC associated with the deep muscular plexus (ICC-DMP), resulting in a waxing and waning of the amplitude of the slow wave and a rhythmic checkered pattern of segmentation motor activity. Phase-amplitude modulation of the slow waves points to an underlying system of coupled nonlinear oscillators originating in the networks of ICC.
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http://dx.doi.org/10.1038/ncomms4326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885742PMC
November 2015

On the origin of rhythmic contractile activity of the esophagus in early achalasia, a clinical case study.

Front Neurosci 2013 21;7:77. Epub 2013 May 21.

Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University and Wuhan University Institute of Digestive and Liver diseases Wuhan, China.

A patient with early achalasia presented spontaneous strong rhythmic non-propulsive contractions at ~7/min, independent of swallows. Our aim was to evaluate characteristics of the rhythmic contractions, provide data on the structure of pacemaker cells in the esophagus and discuss a potential role for interstitial cells of Cajal (ICC) in the origin of rhythmicity. We hypothesize that intramuscular ICC (ICC-IM) are the primary pacemaker cells. The frequency but not the amplitude of the rhythmic contractions was inhibited by the phosphodiesterase inhibitor drotaverine consistent with cAMP inhibiting pacemaker currents in ICC-IM. The frequency increased by wet swallows but not dry swallows, consistent with stretch causing increase in slow wave frequency in ICC-IM. New studies on archival material showed that ICC-IM were present throughout the human esophageal musculature and were not diminished in early achalasia. Although ICC-IM exhibited a low density, they were connected to PDGFRα-positive fibroblast-like cells with whom they formed a dense gap junction coupled network. Nitrergic innervation of ICC was strongly diminished in early achalasia because of the loss of nitrergic nerves. It therefore appears possibly that ICC-IM function as pacemaker cells in the esophagus and that the network of ICC and PDGFRα-positive cells allows for coupling and propagation of the pacemaker activity. Loss of nitrergic innervation to ICC in achalasia may render them more excitable such that its pacemaker activity is more easily expressed. Loss of propagation in achalasia may be due to loss of contraction-induced aboral nitrergic inhibition.
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http://dx.doi.org/10.3389/fnins.2013.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659367PMC
June 2013

Neurogenic and myogenic properties of pan-colonic motor patterns and their spatiotemporal organization in rats.

PLoS One 2013 5;8(4):e60474. Epub 2013 Apr 5.

Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University and Wuhan University Institute of Digestive and Liver Diseases, Wuhan, Hubei, China.

Background And Aims: Better understanding of intrinsic control mechanisms of colonic motility will lead to better treatment options for colonic dysmotility. The aim was to investigate neurogenic and myogenic control mechanisms underlying pan-colonic motor patterns.

Methods: Analysis of in vitro video recordings of whole rat colon motility was used to explore motor patterns and their spatiotemporal organizations and to identify mechanisms of neurogenic and myogenic control using pharmacological tools.

Results: Study of the pan-colonic spatiotemporal organization of motor patterns revealed: fluid-induced or spontaneous rhythmic propulsive long distance contractions (LDCs, 0.4-1.5/min, involving the whole colon), rhythmic propulsive motor complexes (RPMCs) (0.8-2.5/min, dominant in distal colon), ripples (10-14/min, dominant in proximal colon), segmentation and retrograde contractions (0.1-0.8/min, prominent in distal and mid colon). Spontaneous rhythmic LDCs were the dominant pattern, blocked by tetrodotoxin, lidocaine or blockers of cholinergic, nitrergic or serotonergic pathways. Change from propulsion to segmentation and distal retrograde contractions was most prominent after blocking 5-HT3 receptors. In the presence of all neural blockers, bethanechol consistently evoked rhythmic LDC-like propulsive contractions in the same frequency range as the LDCs, indicating the existence of myogenic mechanisms of initiation and propulsion.

Conclusions: Neurogenic and myogenic control systems orchestrate distinct and variable motor patterns at different regions of the pan-colon. Cholinergic, nitrergic and serotonergic pathways are essential for rhythmic LDCs to develop. Rhythmic motor patterns in presence of neural blockade indicate the involvement of myogenic control systems and suggest a role for the networks of interstitial cells of Cajal as pacemakers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060474PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618275PMC
October 2013

Arabidopsis thaliana plants differentially modulate auxin biosynthesis and transport during defense responses to the necrotrophic pathogen Alternaria brassicicola.

New Phytol 2012 Sep 25;195(4):872-882. Epub 2012 Jun 25.

State Key Laboratory of Plant Genomics, National Centre for Plant Gene Research (Beijing), Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Datun Road, Beijing 100101, China.

Although the role of auxin in biotrophic pathogenesis has been extensively studied, relatively little is known about its role in plant resistance to necrotrophs. Arabidopsis thaliana mutants defective in different aspects of the auxin pathway are generally more susceptible than wild-type plants to the necrotrophic pathogen Alternaria brassicicola. We show that A. brassicicola infection up-regulates auxin biosynthesis and down-regulates the auxin transport capacities of infected plants, these effects being partially dependent on JA signaling. We also show that these effects of A. brassicicola infection together lead to an enhanced auxin response in host plants. Application of IAA and MeJA together synergistically induces the expression of defense marker genes PDF1.2 (PLANT DEFENSIN 1.2) and HEL (HEVEIN-LIKE), suggesting that enhancement of JA-dependent defense signaling may be part of the auxin-mediated defense mechanism involved in resistance to necrotrophic pathogens. Our results provide molecular evidence supporting the hypothesis that JA and auxin interact positively in regulating plant resistance to necrotrophic pathogens and that activation of auxin signaling by JA may contribute to plant resistance to necrotrophic pathogens.
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http://dx.doi.org/10.1111/j.1469-8137.2012.04208.xDOI Listing
September 2012
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