Publications by authors named "Shu-kun Yao"

39 Publications

Submucosal hematoma with a wide range of lesions, severe condition and atypical clinical symptoms: A case report.

World J Clin Cases 2021 Jul;9(20):5683-5688

Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250011, Shandong Province, China.

Background: Submucosal hematoma (SH) is one of the rare causes of upper gastrointestinal bleeding. As a rare and critical disease in clinical practice, it should be paid more attention to by clinicians to avoid missed diagnosis and misdiagnosis. Most of the esophageal submucosal hematomas have clear causes, including retrosternal pain, dysphagia, Here, we report a rare case of SH extending from the hypopharynx to the lower esophagus caused by oral administration of hirudin and panax notoginseng powder, with atypical clinical manifestation. Such a long submucosal hematoma has rarely been reported.

Case Summary: The patient was a 60-year-old male with a history of gastritis, hypertension, coronary heart disease, and coronary stent implantation. The patient developed chest tiredness and heartburn after taking 10 capsules of a homemade mixture of hirudin and notoginseng powder in the previous 2 d. He did not have hematemesis or black stool. Gastroscopy and chest computed tomography confirmed the diagnosis of SH, which ranged from the pharynx to the lower esophagus and was 35-40 cm in length. After the diagnosis was confirmed, we performed active conservative treatment on the patient, and the patient recovered well and remained asymptomatic during the 26-mo follow-up.

Conclusion: SH is rare, and cases with atypical clinical symptoms may lead to misdiagnosis and missed diagnosis. Ignorance of this disease can lead to serious clinical consequences. Conservative therapy is effective and the prognosis is good.
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http://dx.doi.org/10.12998/wjcc.v9.i20.5683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281432PMC
July 2021

Altered profiles of fecal bile acids correlate with gut microbiota and inflammatory responses in patients with ulcerative colitis.

World J Gastroenterol 2021 Jun;27(24):3609-3629

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease. Several clinical studies have recently shown that patients with ulcerative colitis (UC) have altered profiles of fecal bile acids (BAs). It was observed that BA receptors Takeda G-protein-coupled receptor 5 (TGR5) and vitamin D receptor (VDR) participate in intestinal inflammatory responses by regulating NF-ĸB signaling. We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.

Aim: To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.

Methods: The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls (HCs). Fecal BAs were measured by targeted metabolomics approaches. Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry, and serum inflammatory cytokine levels were detected by ELISA.

Results: Thirty-two UC patients and twenty-three HCs were enrolled in this study. It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs. , , , , , and were significantly decreased in patients with UC ( = 3.75E-05, = 8.28E-07, = 0.0002, = 0.003, = 0.0003, and = 0.0004, respectively). , , , , and were significantly enriched in the UC group ( = 2.99E-09, = 3.63E-05, = 8.59E-05, 0.003, and = 0.016, respectively). The concentrations of fecal secondary BAs, such as lithocholic acid, deoxycholic acid, glycodeoxycholic acid, glycolithocholic acid, and taurolithocholate, in UC patients were significantly lower than those in HCs ( = 8.1E-08, = 1.2E-07, = 3.5E-04, = 1.9E-03, and = 1.8E-02, respectively) and were positively correlated with , , , , and ( < 0.01). The concentrations of primary BAs, such as taurocholic acid, cholic acid, taurochenodeoxycholate, and glycochenodeoxycholate, in UC patients were significantly higher than those in HCs ( = 5.3E-03, = 4E-02, = 0.042, and = 0.045, respectively) and were positively related to , , , and pro-inflammatory cytokines ( < 0.01). The expression of TGR5 was significantly elevated in UC patients (0.019 ± 0.013 0.006 ± 0.003, 0.0003). VDR expression in colonic mucosal specimens was significantly decreased in UC patients (0.011 ± 0.007 0.016 ± 0.004, = 0.033).

Conclusion: Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines. Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses the BA receptors TGR5 and VDR.
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http://dx.doi.org/10.3748/wjg.v27.i24.3609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240054PMC
June 2021

Identification of the circRNA-miRNA-mRNA regulatory network and its prognostic effect in colorectal cancer.

World J Clin Cases 2021 Jun;9(18):4520-4541

Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China.

Background: The high morbidity and mortality of colorectal cancer (CRC) have posed great threats to human health. Circular RNA (CircRNA) and microRNA (miRNA), acting as competing endogenous RNAs (ceRNAs), have been found to play vital roles in carcinogenesis. However, the biological function of ceRNAs in CRC pathogenesis and prognosis remains largely unexplored.

Aim: To identify the CRC-specific circRNA-miRNA-mRNA regulatory network and uncover the subnetwork associated with its prognosis.

Methods: CircRNAs, miRNAs and mRNAs differentially expressed (DE) in CRC tissues were selected by expression file analysis in the Gene Expression Omnibus (GEO) database, and the downstream target molecules of circRNAs and miRNAs were predicted. Then, the intersection of differentially expressed RNA molecules with the predicted targets was determined to obtain a ceRNA network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the possible mechanism of pathogenesis. A survival analysis using the gene profiles and clinical information in The Cancer Genome Atlas (TCGA) database was performed to identify the mRNAs associated with the clinical outcome of CRC patients and construct a prognostic subnetwork.

Results: We downloaded three datasets (GSE126095, GSE41655 and GSE41657) of large-scale CRC samples from the GEO database. There were 55 DEcircRNAs, 114 DEmiRNAs and 267 DEmRNAs in CRC tissues compared with normal tissues. After intersecting these molecules with predicted targets, 19 circRNAs, 13 miRNAs and 28 mRNAs were chosen to develop a circRNA-miRNA-mRNA network. GO and KEGG functional enrichment analyses indicated that the retinol metabolic process, leukocyte chemotaxis, extracellular matrix remodeling, endoplasmic reticulum stress, alcohol dehydrogenase activity, gastric acid secretion, nitrogen metabolism and NOD-like receptor signaling pathway might participate in the tumorigenesis of CRC. After verifying the identified mRNA effect in the TCGA database, we finally recognized 3 mRNAs ( and ) that were significantly associated with the overall survival of CRC patients and constructed a ceRNA subnetwork including 5 circRNAs (hsa_circ_0080210, hsa_circ_0007158, hsa_circ_0000375, hsa_circ_0018909 and hsa_circ_0011536) and 3 miRNAs (hsa-miR-601, hsa-miR-671-5p and hsa-miR-765), which could contain innovative and noninvasive indicators for the early screening and prognostic prediction of CRC.

Conclusion: We proposed a circRNA-miRNA-mRNA regulatory network closely associated with the progression and clinical outcome of CRC that might include promising biomarkers for carcinogenesis and therapeutic targets.
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http://dx.doi.org/10.12998/wjcc.v9.i18.4520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223824PMC
June 2021

Differences in dietary habits of people with without irritable bowel syndrome and their association with symptom and psychological status: A pilot study.

World J Clin Cases 2021 Apr;9(11):2487-2502

Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China.

Background: Previous studies have demonstrated that dietary factors are involved in irritable bowel syndrome (IBS), but the role of diet was evaluated mostly based on food frequency questionnaire. Whether food categories, quantity per time, and intake frequency are different between IBS patients and non-IBS individuals has not been clearly clarified.

Aim: To explore differences in dietary habits of people with without IBS and their correlation with symptom and psychological status.

Methods: A total of 220 questionnaires were administered in a community population and the Rome IV criteria was applied to diagnose IBS. The dietary questionnaire used in this study was multidimensional from food categories, quantity per time, and intake frequency, in contrast to "yes or no" classification used in previous studies. Questionnaires including IBS symptom severity scale (IBS-SSS), IBS quality of life, visceral sensitivity index, hospital anxiety and depression score (HADS), and gastrointestinal symptom rating scale were used to assess the participants. Rank sum test was used to compare the quantity per time and intake frequency between IBS patients and non-IBS participants. The correlation between psychological factors and diet was evaluated by Spearman correlation analysis. Logistic regression analysis was used to assess the possible dietary risk factors for IBS.

Results: In total, 203 valid questionnaires were collected (response rate 92.3%). Twenty-five participants met the Rome IV criteria for IBS, including 15 (60.0%) women and 10 (40.0%) men. Compared with the non-IBS group, the quantity per time and intake frequency of soybean and its products, spicy food, and dry-fried nuts were statistically significant in IBS participants ( < 0.05). They were positively associated with IBS-SSS and HADS anxiety and depression scores ( < 0.05). Besides, seafood, soft drinks, vegetables, and fruits differed only in quantity per time. The intake frequencies of egg, barbecue, and coarse grain were statistically significant in IBS patients ( < 0.05). We also found that the frequency of soybean and its products (≥ 7 times/week, odds ratio = 11.613, 95% confidence interval: 2.145-62.855, = 0.004) was an independent risk factor for IBS.

Conclusion: Both quantity per time and intake frequency, especially soybean, differ between IBS patients and non-IBS participants. Dietary habits might play potential roles in the pathophysiology of IBS.
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http://dx.doi.org/10.12998/wjcc.v9.i11.2487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040167PMC
April 2021

Mining The Cancer Genome Atlas database for tumor mutation burden and its clinical implications in gastric cancer.

World J Gastrointest Oncol 2021 Jan;13(1):37-57

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Tumor mutational burden (TMB) is an important independent biomarker for the response to immunotherapy in multiple cancers. However, the clinical implications of TMB in gastric cancer (GC) have not been fully elucidated.

Aim: To explore the landscape of mutation profiles and determine the correlation between TMB and microRNA (miRNA) expression in GC.

Methods: Genomic, transcriptomic, and clinical data from The Cancer Genome Atlas were used to obtain mutational profiles and investigate the statistical correlation between mutational burden and the overall survival of GC patients. The difference in immune infiltration between high- and low-TMB subgroups was evaluated by Wilcoxon rank-sum test. Furthermore, miRNAs differentially expressed between the high- and low-TMB subgroups were identified and the least absolute shrinkage and selection operator method was employed to construct a miRNA-based signature for TMB prediction. The biological functions of the predictive miRNAs were identified with DIANA-miRPath v3.0.

Results: C>T single nucleotide mutations exhibited the highest mutation incidence, and the top three mutated genes were , , and in GC. High TMB values (top 20%) were markedly correlated with better survival outcome, and multivariable regression analysis indicated that TMB remained prognostic independent of TNM stage, histological grade, age, and gender. Different TMB levels exhibited different immune infiltration patterns. Significant differences between the high- and low-TMB subgroups were observed in the infiltration of CD8+ T cells, M1 macrophages, regulatory T cells, and CD4+ T cells. In addition, we developed a miRNA-based signature using 23 differentially expressed miRNAs to predict TMB values of GC patients. The predictive performance of the signature was confirmed in the testing and the whole set. Receiver operating characteristic curve analysis demonstrated the optimal performance of the signature. Finally, enrichment analysis demonstrated that the set of miRNAs was significantly enriched in many key cancer and immune-related pathways.

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http://dx.doi.org/10.4251/wjgo.v13.i1.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805270PMC
January 2021

Untargeted metabolomics characteristics of nonobese nonalcoholic fatty liver disease induced by high-temperature-processed feed in Sprague-Dawley rats.

World J Gastroenterol 2020 Dec;26(46):7299-7311

School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.

Background: Nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases in the world. In our early clinical data and questionnaire analysis of NAFLD, it was found that the body mass index of some patients did not meet the diagnostic criteria for overweight or obesity. The consumption of high-temperature-processed foods such as fried food, hot pot and barbecue is closely related to the occurrence of nonobese NAFLD. Reducing the intake of this kind of food can reduce disease severity and improve prognosis.

Aim: To explore the untargeted metabolomics characteristics of nonobese nonalcoholic fatty liver disease in Sprague-Dawley rats induced by high-temperature-processed feed.

Methods: Fifty-four male Sprague-Dawley rats were divided into three groups: The control group received a standard diet; the nonfried soybeans (NDFS) group received 60% NDFS and 40% basic feed and the dry-fried soybeans (DFS) group received 60% DFS and 40% basic feed. Six rats were sacrificed at week 4, 8, and 12 in each group. The food intake, body weight, Lee's index, liver index, serological index and hepatic histopathology were assessed. Untargeted metabolomics characteristics were used to analyze the changes in liver metabolites of rats at week 12. Correlations between metabolites and pathology scores between the DFS and control groups and between the DFS and NDFS groups were analyzed. We selected some of the metabolites, both within the pathway and outside of the pathway, to explain preliminarily the difference in liver pathology in the three groups of rats.

Results: There were no statistically significant differences in the food intake, body weight, Lee's index or serological index between the DFS group and the control group ( > 0.05). At week 8 and week 12, the steatosis scores in the DFS group were significantly higher than those in the other two groups ( < 0.05). At week 12, the liver index of the DFS group was the lowest (NDFS group DFS group, < 0.05). The fibrosis score in the DFS group was significantly higher than those in the other two groups ( < 0.05). The correlation analysis of the liver pathology score and differential metabolites in the DFS and NDFS groups showed that there were 10 strongly correlated substances: Five positively correlated substances and five negatively correlated substances. The positively correlated substances included taurochenodeoxycholate-3-sulfate, acetylcarnitine, 20a,22b-dihydroxycholesterol, 13E-tetranor-16-carboxy-LTE4 and taurocholic acid. The negatively correlated substances included choline, cholesterane-3,7,12,25-tetrol-3-glucuronide, nicotinamide adenine dinucleotide phosphate, lysoPC [16:1 (9Z)] and glycerol 3-phosphate. The correlation analysis of the liver pathology score and differential metabolites in the DFS and control groups showed that there were 13 strongly correlated substances: Four positively correlated substances and 9 negatively correlated substances. The positively correlated substances included 4-hydroxy-6-eicosanone, 3-phosphoglyceric acid, 13-hydroxy-9-methoxy-10-oxo-11-octadecenoic acid and taurochenodeoxycholate-3-sulfate. The negatively correlated substances included lysoPC [16:1(9Z)], S-(9-hydroxy-PGA1)-glutathione, lysoPC [20:5 (5Z, 8Z, 11Z, 14Z, 17Z)], SM (d18:1/14:0), nicotinamide adenine dinucleotide phosphate, 5,10-methylene-THF, folinic acid, N-lactoyl-glycine and 6-hydroxy-5-methoxyindole glucuronide.

Conclusion: We successfully induced liver damage in rats by using a specially prepared high-temperature-processed feed and explored the untargeted metabolomics characteristics.
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http://dx.doi.org/10.3748/wjg.v26.i46.7299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739162PMC
December 2020

Alteration of fecal tryptophan metabolism correlates with shifted microbiota and may be involved in pathogenesis of colorectal cancer.

World J Gastroenterol 2020 Dec;26(45):7173-7190

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Gut tryptophan (Trp) metabolites are produced by microbiota and/or host metabolism. Some of them have been proven to promote or inhibit colorectal cancer (CRC) and animal models. We hypothesized that there is an alteration of gut Trp metabolism mediated by microbiota and that it might be involved in the pathogenesis of cancer in patients with CRC.

Aim: To investigate the features of Trp metabolism in CRC and the correlation between fecal Trp metabolites and gut microbiota.

Methods: Seventy-nine patients with colorectal neoplastic lesions (33 with colon adenoma and 46 with sporadic CRC) and 38 healthy controls (HCs) meeting the inclusion and exclusion criteria were included in the study. Their demographic and clinical features were collected. Fecal Trp, kynurenine (KYN), and indoles (metabolites of Trp metabolized by gut microbiota) were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. Gut barrier marker and indoleamine 2,3-dioxygenase 1 () mRNA were analyzed by quantitative real-time polymerase chain reaction. Zonula occludens-1 (ZO-1) protein expression was analyzed by immunohistochemistry. The gut microbiota was detected by 16S ribosomal RNA gene sequencing. Correlations between fecal metabolites and other parameters were examined in all patients.

Results: The absolute concentration of KYN [1.51 (0.70, 3.46) nmol/g 0.81 (0.64, 1.57) nmol/g, = 0.036] and the ratio of KYN to Trp [7.39 (4.12, 11.72) × 10 5.23 (1.86, 7.99) × 10, = 0.032] were increased in the feces of patients with CRC compared to HCs, while the indoles to Trp ratio was decreased [1.34 (0.70, 2.63) 2.46 (1.25, 4.10), = 0.029]. The relative mRNA levels in patients with CRC (0.27 ± 0.24) were significantly lower than those in HCs (1.00 ± 0.31) ( < 0.001), and the relative mRNA levels in patients with CRC [1.65 (0.47-2.46)] were increased ( = 0.035). mRNA levels were positively associated with the KYN/Trp ratio ( = 0.327, = 0.003). ZO-1 mRNA and protein levels were positively correlated with the indoles/Trp ratio ( = 0.035 and = 0.009, respectively). In addition, the genera (Actinobacteria) and (Bacteroidetes) and members of the phylum Firmicutes ( and ) decreased in CRC and exhibited a positive correlation with indoles in all subjects.

Conclusion: Alteration of fecal Trp metabolism mediated by microbiota is associated with intestinal barrier function and tissue Trp metabolism, and may be involved in the pathogenesis of CRC.
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http://dx.doi.org/10.3748/wjg.v26.i45.7173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723673PMC
December 2020

Altered metabolism of bile acids correlates with clinical parameters and the gut microbiota in patients with diarrhea-predominant irritable bowel syndrome.

World J Gastroenterol 2020 Dec;26(45):7153-7172

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Bile acids (BAs) have attracted attention in the research of irritable bowel syndrome with predominant diarrhea (IBS-D) due to their ability to modulate bowel function and their tight connection with the gut microbiota. The composition of the fecal BA pool in IBS-D patients is reportedly different from that in healthy populations. We hypothesized that BAs may participate in the pathogenesis of IBS-D and the altered BA profile may be correlated with the gut microbiome.

Aim: To investigate the role of BAs in the pathogenesis of IBS-D and the correlation between fecal BAs and gut microbiota.

Methods: Fifty-five IBS-D patients diagnosed according to the Rome IV criteria and twenty-eight age-, sex-, and body mass index-matched healthy controls (HCs) were enrolled in this study at the gastroenterology department of China-Japan Friendship Hospital. First, clinical manifestations were assessed with standardized questionnaires, and visceral sensitivity was evaluated the rectal distension test using a high-resolution manometry system. Fecal primary BAs including cholic acid (CA) and chenodeoxycholic acid (CDCA), secondary BAs including deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) as well as the corresponding tauro- and glyco-BAs were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. The gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between fecal BAs with clinical features and gut microbiota were explored.

Results: Fecal CA (IBS-D: 3037.66 [282.82, 6917.47] nmol/g, HC: 20.19 [5.03, 1304.28] nmol/g; < 0.001) and CDCA (IBS-D: 1721.86 [352.80, 2613.83] nmol/g, HC: 57.16 [13.76, 1639.92] nmol/g; < 0.001) were significantly increased, while LCA (IBS-D: 1621.65 [58.99, 2396.49] nmol/g, HC: 2339.24 [1737.09, 2782.40]; = 0.002] and UDCA (IBS-D: 8.92 [2.33, 23.93] nmol/g, HC: 17.21 [8.76, 33.48] nmol/g; = 0.025) were significantly decreased in IBS-D patients compared to HCs. Defecation frequency was positively associated with CA ( = 0.294, = 0.030) and CDCA ( = 0.290, = 0.032) and negatively associated with DCA ( = -0.332, = 0.013) and LCA ( = -0.326, = 0.015) in IBS-D patients. In total, 23 of 55 IBS-D patients and 15 of 28 HCs participated in the visceral sensitivity test. The first sensation threshold was negatively correlated with CDCA ( = -0.459, = 0.028) in IBS-D patients. Furthermore, the relative abundance of the family was significantly decreased in IBS-D patients ( < 0.001), and 12 genera were significantly lower in IBS-D patients than in HCs ( < 0.05), with 6 belonging to . Eleven of these genera were negatively correlated with primary BAs and positively correlated with secondary BAs in all subjects.

Conclusion: The altered metabolism of BAs in the gut of IBS-D patients was associated with diarrhea and visceral hypersensitivity and might be ascribed to dysbiosis, especially the reduction of genera in .
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http://dx.doi.org/10.3748/wjg.v26.i45.7153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723672PMC
December 2020

Serotonin transporter and cholecystokinin in diarrhea-predominant irritable bowel syndrome: Associations with abdominal pain, visceral hypersensitivity and psychological performance.

World J Clin Cases 2020 May;8(9):1632-1641

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome (IBS). Previous studies have found that cholecystokinin (CCK) can enhance colon movement and that serotonin transporter (SERT) is a transmembrane transport protein with high affinity for 5-hydroxytryptamine, which can rapidly reuptake 5-hydroxytryptamine and then regulate its action time and intensity. We speculate that SERT and CCK might play a role in the pathogenesis of diarrhea-predominant IBS (IBS-D) by affecting visceral sensitivity and the brain-gut axis.

Aim: To determine SERT and CCK levels in IBS-D patients diagnosed using Rome IV criteria and to analyze their associations with abdominal pain, visceral hypersensitivity and psychological performance.

Methods: This study collected data from 40 patients with IBS-D at the China-Japan Friendship Hospital from September 2017 to April 2018 and 18 healthy controls. The severity of abdominal pain, visceral sensitivity and psychological performance were evaluated in IBS-D patients and healthy controls, the levels of SERT and CCK in plasma and colonic mucosa were evaluated, and the correlations between them were analyzed.

Results: There were significant differences in the initial sensation threshold (31.00 ± 8.41 mL 52.22 ± 8.09 mL, < 0.001), defecating sensation threshold (51.75 ± 13.57 mL 89.44 ± 8.73 mL, < 0.001) and maximum tolerable threshold (97.25 ± 23.64 mL 171.11 ± 20.83 mL, < 0.001) between the two groups. IBS-D patients had more severe anxiety (7.78 ± 2.62 2.89 ± 1.02, < 0.001) and depressive (6.38 ± 2.43 2.06 ± 0.73, < 0.001) symptoms than healthy controls. Significant differences were also found in mucosal CCK (2.29 ± 0.30 1.66 ± 0.17, < 0.001) and SERT (1.90 ± 0.51 3.03 ± 0.23, < 0.001) between the two groups. There was a significant positive correlation between pain scores and mucosal CCK ( = 0.96, 0.93, 0.94, < 0.001). Significant negative correlations between anxiety (r = -0.98; < 0.001), depression ( = -0.99; < 0.001), pain evaluation (r = -0.96, -0.93, -0.95, < 0.001) and mucosal SERT were observed.

Conclusion: IBS-D patients had psychosomatic disorders and visceral hypersensitivity. SERT and CCK might be involved in the pathogenesis of IBS-D by regulating the brain-gut axis and affecting visceral sensitivity. This provides a new potential method for identifying a more specific and effective therapeutic target.
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http://dx.doi.org/10.12998/wjcc.v8.i9.1632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211531PMC
May 2020

Altered profiles of fecal metabolites correlate with visceral hypersensitivity and may contribute to symptom severity of diarrhea-predominant irritable bowel syndrome.

World J Gastroenterol 2019 Nov;25(43):6416-6429

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Fecal metabolites are associated with gut visceral sensitivity, mucosal immune function and intestinal barrier function, all of which have critical roles in the pathogenesis of irritable bowel syndrome (IBS). However, the metabolic profile and pathophysiology of IBS are still unclear. We hypothesized that altered profiles of fecal metabolites might be involved in the pathogenesis of IBS with predominant diarrhea (IBS-D).

Aim: To investigate the fecal metabolite composition and the role of metabolites in IBS-D pathophysiology.

Methods: Thirty IBS-D patients and 15 age- and sex-matched healthy controls (HCs) underwent clinical and psychological assessments, including the IBS Symptom Severity System (IBS-SSS), an Italian modified version of the Bowel Disease Questionnaire, the Bristol Stool Form Scale (BSFS), the Hospital Anxiety and Depression Scale, and the Visceral Sensitivity Index. Visceral sensitivity to rectal distension was tested using high-resolution manometry system by the same investigator. Fecal metabolites, including amino acids and organic acids, were measured by targeted metabolomics approaches. Correlation analyses between these parameters were performed.

Results: The patients presented with increased stool water content, more psychological symptoms and increased visceral hypersensitivity compared with the controls. In fecal metabolites, His [IBS-D: 0.0642 (0.0388, 0.1484), HC: 0.2636 (0.0780, 0.3966), = 0.012], Ala [IBS-D: 0.5095 (0.2826, 0.9183), HC: 1.0118 (0.6135, 1.4335), = 0.041], Tyr [IBS-D: 0.1024 (0.0173, 0.4527), HC: 0.5665 (0.2436, 1.3447), = 0.018], Phe [IBS-D: 0.1511 (0.0775, 0.3248), HC: 0.3967 (0.1388, 0.7550), = 0.028], and Trp [IBS-D: 0.0323 (0.0001, 0.0826), HC: 0.0834 (0.0170, 0.1759), = 0.046] were decreased in IBS-D patients, but isohexanoate [IBS-D: 0.0127 (0.0060, 0.0246), HC: 0.0070 (0.0023, 0.0106), = 0.028] was significantly increased. Only Tyr was mildly correlated with BSFS scores in all subjects ( = -0.347, = 0.019). A possible potential biomarker panel was identified to correlate with IBS-SSS score ( = 0.693, < 0.001). In this regression model, the levels of Tyr, Val, hexanoate, fumarate, and pyruvate were significantly associated with the symptom severity of IBS-D. Furthermore, visceral sensation, including abdominal pain and visceral hypersensitivity, was correlated with isovalerate, valerate and isohexanoate.

Conclusion: Altered profiles of fecal metabolites may be one of the origins or exacerbating factors of symptoms in IBS-D increasing visceral sensitivity.
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http://dx.doi.org/10.3748/wjg.v25.i43.6416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881512PMC
November 2019

Increased expression of brain-derived neurotrophic factor is correlated with visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome.

World J Gastroenterol 2019 Jan;25(2):269-281

Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.

Background: Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome (IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor (BDNF) was found to mediate visceral hypersensitivity facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS (IBS-D).

Aim: To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.

Methods: Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 age- and sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.

Results: The patients had a higher anxiety score [median (interquartile range), 6.0 (2.0-10.0) 3.0 (1.0-4.0), = 0.003] and visceral sensitivity index score [54.0 (44.0-61.0) 21.0 (17.3-30.0), < 0.001] than controls. The defecating sensation threshold [60.0 (44.0-80.0) 80.0 (61.0-100.0), = 0.009], maximum tolerable threshold [103.0 (90.0-128.0) 182.0 (142.5-209.3), < 0.001] and rectoanal inhibitory reflex threshold [30.0 (20.0-30.0) 30.0 (30.0-47.5), = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46E-2 (3.06E-2-4.44E-2) 3.07E-2 (2.91E-2-3.48E-2), = 0.031] and mRNA [1.57 (1.31-2.61) 1.09 (0.74-1.42), = 0.001] expression and nerve fiber density [4.12E-2 (3.07E-2-7.46E-2) 1.98E-2 (1.21E-2-4.25E-2), = 0.002] were significantly elevated in the patients. Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.

Conclusion: Elevated mucosal BDNF may participate in the pathogenesis of IBS-D facilitating mucosal nerve growth and increasing visceral sensitivity.
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http://dx.doi.org/10.3748/wjg.v25.i2.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337018PMC
January 2019

Erratum to: A cross-sectional study of irritable bowel syndrome in nurses in China: prevalence and associated psychological and lifestyle factors.

J Zhejiang Univ Sci B 2018 Aug.;19(8):662

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.

The original version of this article unfortunately contained a mistake. In p.590, the address of Yan-li ZHANG, one of the corresponding authors, is incorrect. The correct address should be: 1Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.
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http://dx.doi.org/10.1631/jzus.B13e0159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102186PMC
December 2018

Increased intestinal mucosal leptin levels in patients with diarrhea-predominant irritable bowel syndrome.

World J Gastroenterol 2018 Jan;24(1):46-57

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.

Aim: To measure the leptin levels in patients with diarrhea-predominant irritable bowel syndrome (IBS-D) and analyze the relationship of leptin with clinical features, visceral sensitivity, mast cells, and nerve fibers.

Methods: Forty-two patients with IBS-D fulfilling the Rome III criteria and 20 age- and sex-matched healthy controls underwent clinical and psychological evaluations using validated questionnaires (including IBS Symptom Severity Scale, IBS-specific Quality of Life, Hamilton Anxiety Scale, and Hamilton Depression Scale), along with colonoscopy, colonic mucosal biopsy, and visceral sensitivity testing. Serum leptin levels were assayed using enzyme-linked immunosorbent assay. Mucosal leptin expression and localization were evaluated using immunohistochemistry and immunofluorescence. Mucosal leptin mRNA levels were quantified using quantitative real-time reverse transcription polymerase chain reaction. Mast cell counts and activation rates were investigated by toluidine blue staining. Correlation analyses between these parameters were performed.

Results: There were no statistically significant differences in age, gender, or body mass index between the IBS-D group and the control group. The median IBS Symptom Severity Scale score in the IBS-D group was 225.0 (range, 100-475). IBS-D patients had significantly increased anxiety [IBS-D: median, 6.5; interquartile range (IQR), 3.3; control: median, 2.0; IQR, 2.0; < 0.001] and depression (IBS-D: median, 7.0; IQR, 3.0; control: median, 3.0; IQR, 2.0; < 0.001) scores. IBS-D patients had significantly lower first sensation threshold (IBS-D: median, 50.6; IQR, 25.9; control: median, 80.5; IQR, 18.6; < 0.001), defecation sensation threshold (IBS-D: median, 91.5; IQR, 29.3; control: median, 155.0; IQR, 21.1; < 0.001) and maximum tolerable threshold (IBS-D: median, 163.2; IQR, 71.2; control: median, 226.2; IQR, 39.3; < 0.001). Mucosal leptin expression, as reflected by integrated optical density (IBS-D: median, 4424.71; IQR, 4533.63; control: median, 933.65; IQR, 888.10; < 0.001), leptin mRNA expression (IBS-D: median, 1.1226; IQR, 1.6351; control: median, 0.8947; IQR, 0.4595; = 0.009), and mast cell activation rate (IBS-D: median, 71.2%; IQR, 12.9%; control group: median, 59.4%; IQR, 18.88%; < 0.001) were significantly increased in IBS-D patients. The colocalization of leptin and leptin receptors was observed on mast cells and PGP9.5-positive nerve fibers in the intestinal mucosa. Also, leptin expression was positively correlated with anxiety, depression, and the mast cell activation rate, but negatively correlated with the defecation sensation threshold and the maximum tolerance threshold during visceral sensitivity testing (adjusted < 0.0038).

Conclusion: Increased levels of mucosal leptin may interact with mast cells and the nervous system to contribute to the pathogenesis of IBS-D.
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http://dx.doi.org/10.3748/wjg.v24.i1.46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757124PMC
January 2018

Importance of SALL4 in the development and prognosis of hepatocellular carcinoma.

World J Gastroenterol 2016 Mar;22(9):2837-43

Fei Yin, Xin Han, Department of Gastroenterology, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China.

Aim: To detect the expression of sal-like protein 4 (SALL4) and to explore its relationship with clinicopathological characteristics and prognosis of hepatocellular carcinoma (HCC).

Methods: One hundred and twenty-six samples of HCC tissue, 44 of adjacent noncancerous cirrhotic tissue and 10 of liver hemangioma tissue, were obtained from patients who underwent hepatectomy for HCC at the Fourth Hospital of Hebei Medical University. None of the patients had received any form of treatment before the operation. After resection, all the tissues were fixed in 10% neutral formaldehyde and embedded in paraffin. Expression of SALL4 was detected by immunohistochemistry. Patients were followed up for postoperative survival until February 2014. The relationships between SALL4 expression level and clinicopathological data and prognosis of HCC were analyzed.

Results: SALL4 expression was negative in the 10 samples of tissue from liver hemangioma, was weakly positive in the two samples from adjacent noncancerous cirrhotic tissue, and positive in 58 samples of HCC tissues. The differences were statistically significant (P < 0.05). Expression of SALL4 was higher in patients with higher α-fetoprotein (AFP) levels, portal vein tumor thrombus, and later clinical stage based on the Barcelona Clinic Liver Cancer classification (P < 0.05). Among patients with negative expression, weakly positive expression, positive expression, and strongly positive expression of SALL4, the median survival time was 39, 25, 23, and 9 mo, respectively (P < 0.001). When both AFP and SALL4 were detected, patients who were negative for both AFP and SALL4, SALL4-positive only, AFP-positive only, and positive for both AFP and SALL4, had a median survival time of 41, 38, 31, and 12 mo, respectively (P < 0.001).

Conclusion: Expression of SALL4 is relevant to the prognosis of HCC patients. Patients with higher expression levels of SALL4 and AFP have worse prognosis.
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http://dx.doi.org/10.3748/wjg.v22.i9.2837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778006PMC
March 2016

Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?

J Zhejiang Univ Sci B 2016 Jan;17(1):1-9

Gastroenterology Department, China-Japan Friendship Hospital, Beijing 100029, China.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS (IBS-D) is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnormality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hypersensitivity (VH), altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS-D, especially the role of various neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor (NGF) has diverse biological effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D.
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http://dx.doi.org/10.1631/jzus.B1500181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710835PMC
January 2016

Matrine-induced autophagy regulated by p53 through AMP-activated protein kinase in human hepatoma cells.

Int J Oncol 2015 Aug 28;47(2):517-26. Epub 2015 May 28.

The Department of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, P.R. China.

Matrine, one of the main extract components of Sophora flavescens, has been shown to exhibit inhibitory effects on some tumors through autophagy. However, the mechanism underlying the effect of matrine remains unclear. The cultured human hepatocellular carcinoma cell line HepG2 and SMMC‑7721 were treated with matrine. Signal transduction and gene expression profile were determined. Matrine stimulated autophagy in SMMC‑7721 cells in a mammalian target of rapamycin (mTOR)-dependent manner, but in an mTOR-independent manner in HepG2 cells. Next, in HepG2 cells, autophagy induced by matrine was regulated by p53 inactivation through AMP-activated protein kinase (AMPK) signaling transduction, then AMPK suppression switched autophagy to apoptosis. Furthermore, the interferon (IFN)-inducible genes, including interferon α-inducible protein 27 (IFI27) and interferon induced transmembrane protein 1 (IFITM1), which are downstream effector of p53, might be modulated by matrine-induced autophagy. In addition, we found that the p53 protein isoforms, p53β, p53γ, ∆133p53, and ∆133p53γ, due to alternative splicing of intron 9, might be regulated by the p53-mediated autophagy. These results show that matrine induces autophagy in human hepatoma cells through a novel mechanism, which is p53/AMPK signaling pathway involvement in matrine-promoted autophagy.
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http://dx.doi.org/10.3892/ijo.2015.3023DOI Listing
August 2015

Oral oxymatrine preparation for chronic hepatitis B: A systematic review of randomized controlled trials.

Chin J Integr Med 2016 Feb 26;22(2):141-9. Epub 2015 May 26.

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, 100029, China.

Objective: To evaluate the efficacy and safety of oral oxymatrine preparation for the treatment of chronic hepatitis B (CHB).

Methods: Randomized controlled trials (RCTs) on oral oxymatrine preparation in treating patients with CHB were retrieved until October 2013 by searching PubMed, the Cochrane Library, Embase and four Chinese databases, irrespective of language and publication status. Data extraction and data analyses were conducted according to the Cochrane standards. The risk of bias for each included trials and the quality of evidence on pre-specified outcomes were assessed. The RevMan software was used for statistical analyses.

Results: Totally 52 RCTs enrolling 5,227 participants were included, of which 51 RCTs were included in meta-analyses. Oral oxymatrine preparation including oxymatrine capsule and oxymatrine tablet were associated with statistically significant effect on the clearance of hepatitis B virus (HBV) DNA, HBV surface antigen and HBV e antigen, and were beneficial to the normalization of serum alanine aminotransferase and aspartate aminotransferase. Nevertheless, the overall methodological quality and the quality of evidence in the included trials were poor. In addition, safety of oral oxymatrine preparation was not confirmed.

Conclusions: Oral oxymatrine preparation showed some potential benefits for patients with CHB. However, the overall quality of evidence was limited and the safety of oral oxymatrine preparation for CHB patients was still unproven. More high quality evidence from rigorously designed RCTs is warranted to support the clinical use of oral oxymatrine preparation for patients with CHB.
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http://dx.doi.org/10.1007/s11655-015-2143-0DOI Listing
February 2016

Visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction and low-grade inflammation in a subset of irritable bowel syndrome patients.

J Zhejiang Univ Sci B 2014 Oct;15(10):907-14

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China; Graduate School, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China; Beijing University of Chinese Medicine, Beijing 100029, China.

The pathophysiology of irritable bowel syndrome (IBS) is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhea-predominant IBS (D-IBS). Sixty-two patients with D-IBS and 20 control subjects participated in the study. Using the ascending method of limits (AML) protocol, we demonstrated that D-IBS patients had significantly lower sensory thresholds compared with healthy controls (P<0.001). Using diverse methods, especially the ischemic sensitivity test, for the first time in China, we confirmed that D-IBS patients have somatic hypersensitivity. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. Compared with the control group, D-IBS patients had a significantly higher level of calprotectin (P<0.001). We also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. Our findings may provide valuable suggestions for the treatment of D-IBS.
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http://dx.doi.org/10.1631/jzus.B1400143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201319PMC
October 2014

A cross-sectional study of irritable bowel syndrome in nurses in China: prevalence and associated psychological and lifestyle factors.

J Zhejiang Univ Sci B 2014 Jun;15(6):590-7

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China; Graduate School, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China; Peking University Health Science Center, Beijing 100151, China.

The prevalence of irritable bowel syndrome (IBS) and associated factors, especially psychological and lifestyle factors, in nurses in China have not been investigated previously. The aims of this study were to assess the prevalence of IBS in nurses, to evaluate whether factors, such as psychological disorders, are associated with IBS, and to determine whether psychological disorders can influence the severity of symptoms of IBS and quality of life (QOL). A cross-sectional study was conducted for Chinese nurses from November 2012 to February 2013. Participants were asked to complete questionnaires. The prevalence of IBS was 17.4%. The revised symptom checklist 90 (SCL-90-R) scores were significantly higher for nurses with IBS than for those without IBS (P<0.001), and no difference in scores between IBS subtypes was found (F=1.893, P=0.142). The scores of QOL for nurses with and without IBS were 77.18±21.93 and 88.44±11.89 (P<0.001), respectively. Psychological disorders did not show statistically significant correlations with severity of symptoms of IBS or QOL. Alcohol consumption, low level of exercise, and psychological disorders were risk factors for IBS. In summary, nurses in China show a high prevalence of IBS. Psychological disorders and some related lifestyle factors are probably responsible for the development of IBS in nurses.
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http://dx.doi.org/10.1631/jzus.B1300159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116852PMC
June 2014

Involvement of β-catenin in matrine-induced autophagy and apoptosis in WB-F344 cells.

Mol Med Rep 2014 Jun 2;9(6):2547-53. Epub 2014 Apr 2.

Department of Gastroenterology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China.

Matrine, one of the main components extracted from Sophora flavescens, has exhibited pharmacological effects on the differentiation in rat liver oval cells. However, its function and mechanism have not yet been fully elucidated. To further investigate them, an in vitro model was established using a rat liver oval cell line called WB-F344 and treated with matrine. Initially, a significant increase in the number of monodansylcadaverine-positive cells and in the levels of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, which is a specific marker for detecting autophagy, was observed in matrine-treated cells. This indicated that autophagy was stimulated by matrine, which was further confirmed by transmission electron microscopy. Additionally, the apoptotic oval cells were easily detected under matrine treatment using an Annexin-V-fluorescein isothiocyanate/propidium iodide assay, indicating that autophagy and apoptosis were synchronously induced by matrine. A decrease in B-cell lymphoma (Bcl-2) mRNA expression, but an increase in Bcl2-associated X protein (Bax) mRNA expression were observed in matrine-treated cells, which led to an upregulation of the Bax/Bcl-2 ratio, a molecular marker for determining the extent of apoptosis. Next, the molecular mechanism of matrine-induced autophagy and apoptosis was analyzed in WB-F344 cells. β-catenin degradation was downregulated by matrine and rapamycin, a foregone chemical agonist of autophagy, whereas it was upregulated by 3-methyladenine, a specific inhibitor of autophagy. Additionally, β-catenin activation induced an increase in LC3-II levels and reversed the Bax/Bcl-2 mRNA ratio under matrine treatment, whereas inhibition of β-catenin by RNA interference induced a decrease of the LC3-II amount and of the Bax/Bcl-2 mRNA ratio. Finally, matrine treatment attenuated p53; however, with little or no change in LC3-II levels, but a decrease in β-catenin levels occurred in WB-F344 cells upon treatment with pifithrin-α, a chemical inhibitor of p53, revealing that p53, interfering with β-catenin, may not be involved in matrine-induced autophagy in WB-F344 cells. These results demonstrate that β-catenin is involved in matrine-induced autophagy and apoptosis in WB-F344 cells, while β-catenin is negatively regulated by autophagy and positively by p53, indicating that β-catenin may be involved in the crosstalk between autophagy and apoptosis in WB-F344 cells.
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http://dx.doi.org/10.3892/mmr.2014.2107DOI Listing
June 2014

Potential role of diabetes mellitus in the progression of cirrhosis to hepatocellular carcinoma: a cross-sectional case-control study from Chinese patients with HBV infection.

Hepatobiliary Pancreat Dis Int 2013 Aug;12(4):385-93

Department of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, China.

Background: Diabetes mellitus (DM) is regarded as a new risk factor for hepatocellular carcinoma (HCC), but few studies have focused on the potential role of DM in the progression of cirrhosis to HCC as well as in patients with simple HBV infection.

Methods: A cohort of 1028 patients, treated at our hospital and with a hospital discharge diagnosis of HCC and/or cirrhosis, was screened. Among them, 558 were diagnosed with chronic HBV infection and 370 were analyzed statistically according to the diagnostic, inclusion and exclusion criteria. The demographic, clinical, metabolic, virological, biochemical, radiological and pathological features were analyzed and the multivariate logistic regression model was used to determine the potential role of DM.

Results: In 248 cirrhotic patients, 76 were diabetic and their mean duration of DM was 4.6 years. In 122 HCC patients with cirrhosis, 25 were diabetic and their mean duration of DM was 4.4 years. Univariate analysis showed that compared with cirrhotic patients, the HCC patients had a higher percentage in males (P=0.001), a lower percentage in DM patients (P=0.039), a higher percentage in cigarette smokers (P=0.005), a higher percentage in patients with AFP>400 ng/mL (P<0.001), higher values of white blood cells (P<0.001), hemoglobin (P<0.001) and platelet (P<0.001), increased levels of ALT (P<0.001) and GGT (P<0.001), higher total bilirubin (P=0.018) and albumin levels (P<0.001), and a lower international normalized ratio (P<0.001). Multivariate logistic regression analysis showed that DM was an independent associated factor for HCC [odds ratio (OR)=0.376; 95% CI, 0.175-0.807; P=0.012]. Even after the HCC patients were restricted to those with decompensated cirrhosis and compared with decompensated cirrhotic patients, the similar result was observed (OR=0.192; 95% CI, 0.054-0.679; P=0.010).

Conclusions: DM is an independent factor in the progression of cirrhosis to HCC, but the role may be contrary to our current viewpoint. To clarify the causal relationship of DM and HCC, prospective and experimental studies are required.
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http://dx.doi.org/10.1016/s1499-3872(13)60060-0DOI Listing
August 2013

Increased international normalized ratio level in hepatocellular carcinoma patients with diabetes mellitus.

World J Gastroenterol 2013 Apr;19(15):2395-403

Department of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, China.

Aim: To determine the association of diabetes mellitus (DM) and international normalized ratio (INR) level in hepatocellular carcinoma (HCC) patients.

Methods: Our present study included 375 HCC patients who were treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period from January 2003 to April 2012, and with a hospital discharge diagnosis of HCC. The demographic, clinical, laboratory, metabolic and instrumental features were analyzed. χ² test, Student's t test and Mann-Whitney U test were used to compare the differences between HCC patients with and without DM. Unconditional multivariable logistic regression analysis was used to determine the association of DM and INR level in HCC patients. A sub-group analysis was performed to assess the effect of liver cirrhosis or hepatitis B virus (HBV) infection on the results. The Pearson correlation test was used to determine the relationship between INR level and fasting glucose. In addition, association between diabetes duration, and diabetes treatment and INR level was determined considering the potentially different effects.

Results: Of the total, 63 (16.8%) patients were diabetic (diabetic group) and 312 (83.2%) patients were diagnosed without diabetes (non-diabetic group). Their mean age was 56.4 ± 11.0 years and 312 (83.2%) patients were male. Compared with patients without DM, the HCC patients with diabetes were older (59.5 ± 10.3 vs 55.8 ± 11.1, P = 0.015), had a lower incidence of HBV infection (79.4% vs 89.1%, P = 0.033), had increased levels of systolic blood pressure (SBP) (133 ± 17 vs 129 ± 16 mmHg, P = 0.048) and INR (1.31 ± 0.44 vs 1.18 ± 0.21, P = 0.001), had lower values of hemoglobin (124.4 ± 23.9 vs 134.2 ± 23.4, P = 0.003) and had a platelet count (median/interquartile-range: 113/64-157 vs 139/89-192, P = 0.020). There was no statistically significant difference in the percentages of males, overweight or obesity, drinking, smoking, cirrhosis and Child classification. After controlling for the confounding effects of age, systolic blood pressure, hemoglobin, platelet count and HBV infection by logistic analyses, INR was shown as an independent variable [odds ratio (OR) = 3.650; 95%CI: 1.372-9.714, P = 0.010]. Considering the effect of liver cirrhosis on results, a sub-group analysis was performed and the study population was restricted to those patients with cirrhosis. Univariate analysis showed that diabetic patients had a higher INR than non-diabetic patients (1.43 ± 0.51 vs 1.25 ± 0.23, P = 0.041). After controlling for confounding effect of age, SBP, hemoglobin, platelet count and HBV infection by logistic analyses, INR level remained as the sole independent variable (OR = 5.161; 95%CI: 1.618-16.455, P = 0.006). No significant difference in the relationship between INR level and fasting glucose was shown by Pearson test (r = 0.070, P = 0.184). Among the 63 diabetic patients, 35 (55.6%) patients had been diagnosed with DM for more than 5 years, 23 (36.5%) received oral anti-diabetic regimens, 11 (17.5%) received insulin, and 30 (47.6%) reported relying on diet alone to control serum glucose levels. No significant differences were found for the association between DM duration/treatment and INR level, except for the age at diabetes diagnosis.

Conclusion: The INR level was increased in HCC patients with DM and these patients should be monitored for the coagulation function in clinical practice.
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http://dx.doi.org/10.3748/wjg.v19.i15.2395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631993PMC
April 2013

[Expression and clinical significance of Notch1 in human hepatocellular carcinoma].

Zhonghua Gan Zang Bing Za Zhi 2012 Aug;20(8):628-9

Department of Gastroenterology, the Fourth Hopsital of Hebei Medical University, Shijiazhuang, China.

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August 2012

Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis.

Scand J Gastroenterol 2013 Jan 9;48(1):78-87. Epub 2012 Nov 9.

Department of Gastroenterology, China-Japan Friendship Hospital, Peking University Health Science Center, Beijing, PR China.

Objectives: Recent epidemiological studies suggest that metformin treatment may reduce the risks of cancer and overall cancer mortality among patients with diabetes mellitus (DM). However, data on hepatocellular carcinoma (HCC) are very limited and inconsistent. This meta-analysis was designed to pool data currently available to determine the association between metformin use and HCC among diabetic patients.

Methods: The Medline and Embase databases were searched to identify the relevant studies between January 1966 and December 2011. The overall analysis was derived using a random-effects meta-analysis model (DerSimonian and Laird method). Subgroup analysis was performed to explore the source of heterogeneity and validate the results from overall analysis. The Newcastle-Ottawa Quality assessment scales were adopted for quality assessment; Begg's funnel plot and Egger's regression asymmetry test were used to detect the publication bias.

Results: A total of seven studies were identified, including three cohort studies and four case-control studies. Based on the available data, the overall prevalence of HCC was 3.40% (562/16,549) in DM patients. The overall analysis showed a significantly reduced risk of HCC in metformin users versus nonusers in diabetic patients (relative risk (RR) 0.24, 95% confidence interval (CI) 0.13-0.46, p < 0.001). Fifteen subgroup analyses were performed, and most of them (12/15 = 80%) provided supporting evidence for the results of overall analysis. Begg's (Z = -0.15, p = 0.8819) and Egger's test (t = -0.79, p = 0.468) showed no significant risk of having a publication bias.

Conclusion: Metformin treatment was associated with reduced risk of HCC in diabetic patients. To clarify this relationship, more high-quality studies are required.
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http://dx.doi.org/10.3109/00365521.2012.719926DOI Listing
January 2013

[Effect of baicalin on liver fatty acid binding protein in oxidative stress model in vitro].

Zhonghua Gan Zang Bing Za Zhi 2011 Dec;19(12):927-31

Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.

Objective: To investigate the effect of baicalin on liver fatty acid binding protein in oxidative stress model in vitro.

Methods: (1) Cellular oxidative stress in vitro was induced by incubating cells with 400μmol/L hydrogen peroxide (H₂O₂) for 20 minutes at 37 degrees C in the dark. After Chang liver cell line was treated with different dose of baicalin for 24, 48 and 72 hours. MTT assay was employed to detect cell viability, and then the hydrogen peroxide (TC50) of the different dose of baicalin was calculated. (2) Based on MTT assay, cells were treated with three different doses of baicalin (25, 50, 100 μmol/L) for 24 and 48 hours before being exposed to 400 μmol/L H₂O₂ for 20 minutes at 37 degrees C. Then, reactive oxygen species (ROS) assay and activity assays of superoxide dismutase (SOD) and reduced glutathione hormone (GSH) were evaluated. (3) Realtime PCR and Western blotting were applied to explore the influence of baicalin on the expression level of L-FABP. (4) One-way ANOVA was used for results statistical analysis.

Result: (1) MTT assay showed baicalin treatment at 25, 50, 100 μmol/L for 24 and 48 hours was feasible (83.60% ± 3.47%, 72.36% ± 2.18%, 70.16% ± 2.04% for 24 hours; 84.93% ± 3.11%, 76.16% ± 2.45%, 72.72% ± 2.31% for 48 hours, P > 0.05, F = 386.24, 475.92 respectively). Meanwhile, we found by the linear regression model that the median toxic concentration of baicalin for 48 hours was 170.6 μmol/L, and the median toxic concentration of baicalin for 24 hours was 153.2 μmol/L. (2) ROS assay showed dichlorofluorescin in all baicalin-treated cells after stress was significantly reduced (37.0 ± 3.30, 22.90 ± 3.84, 29.60 ± 2.52 for 24 hours respectively, P < 0.05, F = 70.06; 35.77 ± 2.35, 21.80 ± 3.10, 23.87 ± 1.98 for 48 hours respectively, P < 0.05, F = 110.92) as compared with the H₂O₂-treated cells. Moreover, 50 μmol/L baicalin treatment for 48 hours was the optimal condition against ROS generation (21.80 ± 3.10, P < 0.01, F = 110.92). Furthermore, the activities of intracellular SOD and GSH was increased significantly (51.53 ± 1.91 μg/mg for SOD, P < 0.05, F = 93.81; 49.85 ± 1.45 U/mg for GSH, P < 0.05, F = 92.51). (3) Although realtime PCR analysis indicated 50 μmol/L baicalin treatment for 48 hours could have no changes of the level of L-FABP expression under the oxidative stress condition, western blotting analysis indicated 50 μmol/L baicalin treatment for 48 hours could increase up to about 80% for the level of L-FABP expression.

Conclusion: Baicalin was suggested to be able to enhance both L-FABP expression and activity of intracellular SOD and GSH, and therefore protected hepatocytes from oxidative stress.
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http://dx.doi.org/10.3760/cma.j.issn.1007-3418.2011.12.011DOI Listing
December 2011

Autophagy inhibition enhances etoposide-induced cell death in human hepatoma G2 cells.

Int J Mol Med 2011 Apr 27;27(4):599-606. Epub 2011 Jan 27.

Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, P.R. China.

Induction of autophagy usually acts as a survival mechanism of cancer cells in response to chemotherapy. However, the function and molecular mechanism of autophagy in human hepatoma cells under drug treatment is still not clear. To address this issue, we established an experimental model in which HepG2 cells were treated with etoposide, a widely used anticancer agent. We demonstrate the etoposide-induced accumulation of GFP-LC3 dots by fluorescent microscopy, the up-regulation of LC3-II protein expression by Western blotting and the increased number of autophagic vacuoles by electron microscopy, confirming the activation of autophagy by etoposide in HepG2 cells. Inhibition of autophagy by either 3-methyladenine (3MA) or beclin-1 small interfering RNA enhanced etoposide-induced cell death. Furthermore, activation of p53 and AMPK was detected in etoposide-treated cells and inhibition of AMPK triggered apoptosis through suppression of autophagy. On the other hand, inactivation of p53 promoted cell survival through augmentation of autophagy. Collectively, these findings indicate that etoposide-induced autophagy promotes hepatoma cell adaptation and survival, and that autophagy inhibition improves the chemotherapeutic effect of etoposide. Moreover, AMPK activation is clearly associated with etoposide-induced autophagy. We conclude that manipulation of AMPK may be a promising approach of adjuvant chemotherapy for hepatocellular carcinoma.
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http://dx.doi.org/10.3892/ijmm.2011.607DOI Listing
April 2011

Diabetes mellitus and hepatocellular carcinoma: comparison of Chinese patients with and without HBV-related cirrhosis.

World J Gastroenterol 2010 Sep;16(35):4467-75

Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.

Aim: To determine the role of diabetes mellitus (DM) and other associated factors in Chinese hepatocellular carcinoma (HCC) patients with cirrhosis, compared with those HCC patients without cirrhosis, in the single setting of hepatitis B virus (HBV) infection, after other known concomitant diseases were excluded.

Methods: A total of 482 patients, treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period January 2003 to June 2009, and with a hospital discharge diagnosis of HCC, were included. Demographic, clinical, laboratory, metabolic and instrumental features were analyzed.

Results: Of the total, 310 patients were diagnosed with HBV infection and, following the inclusion and exclusion criteria, 224 were analyzed, including 122 patients (54.5%) with cirrhosis (the case group) and 102 patients without cirrhosis (the control group). Twenty-seven patients (12.1%) were diabetic, including 19 in the case group and 8 in the control group (19/122 = 15.6% vs 8/102 = 7.8%, P = 0.077). Thirty-one possible relevant parameters were compared by univariate analysis, and 9 variables were selected for multivariable analysis, including DM (P = 0.077), past history of HBV infection (P = 0.005), total bilirubin (P < 0.001), albumin level (P < 0.001), international normalized ratio (INR) (P < 0.001), alanine aminotransferase (P = 0.050), platelet (P < 0.001), total cholesterol (P = 0.047), and LDL cholesterol (P = 0.002) levels. Diabetes showed a statistical difference by multivariable analysis [odds ratio (OR) 4.88, 95% confidence interval (CI): 1.08-21.99, P = 0.039], although no significant difference was found in univariate analysis. In addition, three cirrhosis-related parameters remained statistically different, including INR (OR 117.14, 95% CI: 4.19-3272.28, P = 0.005), albumin (OR 0.89, 95% CI: 0.80-0.99, P = 0.027), and platelet count (OR 0.992, 95% CI: 0.987-0.999, P = 0.002).

Conclusion: Besides the three cirrhosis-related parameters, DM was found to be the sole independent factor associated with HCC in patients with HBV-related cirrhosis, compared with those without cirrhosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941072PMC
http://dx.doi.org/10.3748/wjg.v16.i35.4467DOI Listing
September 2010

Diabetes mellitus: a "true" independent risk factor for hepatocellular carcinoma?

Hepatobiliary Pancreat Dis Int 2009 Oct;8(5):465-73

Department of Gastroenterology, China-Japan Friendship Hospital, Ministry of Health, Beijing 100029, China.

Background: Diabetes mellitus (DM) is thought to be associated with an increased risk of hepatocellular carcinoma (HCC) in some published studies. However, can we draw the conclusion that DM is a "true" independent risk factor for HCC based on these references?

Data Sources: MEDLINE and PubMed searches were conducted for published studies (between January 1966 and June 2009) to identify relevant articles using the keywords "diabetes", "insulin resistance" and "hepatocellular carcinoma", including "primary liver cancer". Because of the very limited number of relevant articles most were reviewed.

Results: This systematic review was conducted from 4 aspects: (1) the significant synergy between DM, hepatitis virus infection, and heavy alcohol consumption in HCC; (2) the role of DM independently in HCC cases while other identified risk factors were controlled or excluded; (3) obesity, DM, and nonalcoholic fatty liver disease in HCC patients; and (4) the impact of DM for the prognosis or surgical treatment in HCC patients with DM. No consensus has been reached among these studies and it is too early to draw the conclusion that DM is a "true" independent risk factor for HCC.

Conclusions: DM can be regarded as a risk factor for HCC. However, whether DM itself directly predisposes to HCC or whether it is a "true" independent risk factor remains unclear. Related issues should be clarified by more research.
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October 2009

[Expression and significance of minichromosome maintenance protein7 in hepatocellular carcinoma].

Zhonghua Gan Zang Bing Za Zhi 2008 Jan;16(1):55-6

Department of Gastroenterology, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.

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January 2008

[Effect of Qingre Liqi Granule on clinical therapeutic efficacy, electrogastrogram and gastric emptying in patients with functional dyspepsia].

Zhongguo Zhong Xi Yi Jie He Za Zhi 2007 Jun;27(6):505-8

The 4th Hospital of Hebei Medical University, Shijiazhuang.

Objective: To evaluate the effects of Qingre Liqi Granule (QLG) on clinical therapeutic efficacy, electrogastrogram (EGG) and gastric emptying in patients with functional dyspepsia (FD).

Methods: Thirty-two FD patients of dyskinesis type enrolled were treated with QLG by oral taking for 6 days. Scoring on 8 kinds of symptoms, including abdominal distension, abdominal pain, morning gastric fullness, belching, regurgitation, nausea, vomiting, and anorexia, fasting EGG and the gastric emptying determination were performed using single photon emission computed tomography (SPECT) before and after treatment.

Results: The total and individual scores of clinical symptoms, expect that of vomiting, significantly decreased after treatment (P < 0.05), and the percentage of patients with tachygastria and bradygastria significantly decreased (P<0.01) at the same time. EGG after treatment showed significantly elevated rates of normal slow wave dominant power, and nearly normalized dominant frequency. An increased gastric emptying rate at different phases after 75 min (P < 0.05), and significantly shortened gastric emptying half-time (P < 0.01) were shown meanwhile in gastric emptying detection. The improvement of symptom score and gastric emptying half-time showed significant positive linear correlation (r =0.8929, P < 0.01).

Conclusion: QLG can improve symptoms of FD patients by regulating the rhythm and power of gastric electro-wave, increasing gastric motility and enhancing gastric emptying function.
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June 2007
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