Publications by authors named "Chunyan Peng"

56 Publications

Interaction Mechanism between OVA and Flavonoids with Different Hydroxyl Groups on B-Ring and Effect on Antioxidant Activity.

Foods 2022 Apr 29;11(9). Epub 2022 Apr 29.

National R&D Center of Freshwater Fish Processing and Engineering Research Center of Freshwater Fish High-Value Utilization of Jiangxi, College of Life Science, Jiangxi Normal University, Nanchang 330022, China.

Ovalbumin (OVA) is a common carrier with high efficiency to deliver flavonoids. The aim of this study was to investigate the interaction mechanism of OVA and four flavonoids (quercetin (Que), myricetin (Myri), isorhamnetin (Ish), and kaempferol (Kaem)) with similar structures by fluorescence spectra, SDS-PAGE, FT-IR, and molecular docking analysis, and the effect on the antioxidant abilities of flavonoids was also evaluated. Results indicated that the antioxidant activity of flavonoids was positively correlated to the number of phenolic hydroxyl groups of on the B-ring, and weakened when the C-3' position was replaced by a methoxy group. The addition of OVA enhanced the antioxidant activity of Que/Kaem, while it masked the antioxidant activity of Myri. The formation of Que/Myri/Ish/Kaem-OVA complexes was a spontaneous exothermic process driven mainly by hydrogen bond and van der Waals force, which could result in the change in OVA conformation and induce the transformation of α-helix to β-sheet. Among these, Kaem exhibited the strongest binding ability with OVA, and showed the greatest impact on the secondary and conformational structure of OVA, followed by Que. The hydroxylation of C-3' and methoxylation of C-5' weaken the interaction of Kaem with OVA. Molecular docking analysis suggested that Que, Myri, Ish, and Kaem formed six, three, five, and four hydrogen bonds with OVA, and the number of hydrogen bonds was not positively correlated with their binding constants. Our findings can provide a theoretical basis for the application of OVA on improving the antioxidant activity of flavonoids, and may help to explain the delivery efficiency of OVA on different bioactive constituents.
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http://dx.doi.org/10.3390/foods11091302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099482PMC
April 2022

A deep learning-based segmentation system for rapid onsite cytologic pathology evaluation of pancreatic masses: A retrospective, multicenter, diagnostic study.

EBioMedicine 2022 May 2;80:104022. Epub 2022 May 2.

Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210008, China; Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China. Electronic address:

Background: We aimed to develop a deep learning-based segmentation system for rapid on-site cytopathology evaluation (ROSE) to improve the diagnostic efficiency of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy.

Methods: A retrospective, multicenter, diagnostic study was conducted using 5345 cytopathological slide images from 194 patients who underwent EUS-FNA. These patients were from Nanjing Drum Tower Hospital (109 patients), Wuxi People's Hospital (30 patients), Wuxi Second People's Hospital (25 patients), and The Second Affiliated Hospital of Soochow University (30 patients). A deep convolutional neural network (DCNN) system was developed to segment cell clusters and identify cancer cell clusters with cytopathological slide images. Internal testing, external testing, subgroup analysis, and human-machine competition were used to evaluate the performance of the system.

Findings: The DCNN system segmented stained cells from the background in cytopathological slides with an F1-score of 0·929 and 0·899-0·938 in internal and external testing, respectively. For cancer identification, the DCNN system identified images containing cancer clusters with AUCs of 0·958 and 0·948-0·976 in internal and external testing, respectively. The generalizable and robust performance of the DCNN system was validated in sensitivity analysis (AUC > 0·900) and was superior to that of trained endoscopists and comparable to cytopathologists on our testing datasets.

Interpretation: The DCNN system is feasible and robust for identifying sample adequacy and pancreatic cancer cell clusters. Prospective studies are warranted to evaluate the clinical significance of the system.

Funding: Jiangsu Natural Science Foundation; Nanjing Medical Science and Technology Development Funding; National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/j.ebiom.2022.104022DOI Listing
May 2022

Non-targeted metabonomic analysis of plasma in patients with atherosclerosis by liquid chromatography-mass spectrometry.

Ann Transl Med 2022 Feb;10(3):133

Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, China.

Background: This study sought to analyze non-targeted plasma metabolites in patients with atherosclerosis (AS).

Methods: The plasma of patients with AS (the patient group) and the plasma of age-matched and gender-matched healthy individuals (the control group) at the Taihe Hospital was collected. One hundred patients were included in the study (60 in the patient group and 40 in the control group). Fasting venous plasma was collected in the morning. The metabolites in the plasma were examined by liquid chromatography-mass spectrometry (LC-MS). An unsupervised principal component analysis (PCA) was conducted to observe the overall distribution of each sample and the stability of the analysis process. Next, a supervised partial least squares-discriminant analysis (PLS-DA) and an orthogonal partial least squares-discriminant analysis (OPLS-DA) were conducted to examine the overall differences among the metabolic profiles of the groups and identify different metabolites in the groups. Pathway enrichment was analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

Results: In total, 1,126 different metabolites were detected in the patient and control groups. Compared to the control group, 411 species decreased, and 715 species increased in the patient group. There were 61 different metabolites with a variable weight in the projection (VIP) >1 and a P<0.05. There were 34 types of lipid metabolites, 10 types of carbon and oxygen compounds, 8 types of organic acids and derivatives, 4 types of organoheterocyclic compounds, 3 types of nitrogen-containing organic compounds, and 2 types of nucleotides and analogs. Compared to the control group, 47 species decreased, and 14 species increased in the patient group. The following 9 metabolites had the most significant differences (|log2fold change| >1; P<0.05): 2-tetradecanone, pantothenol, all-trans-13,14-dihydroretinol, linoleoyl ethanolamide, N-oleoylethanolamine, 4-methyl-2-pentenal, Cer (d18:1/14:0), chenodeoxycholic acid glycine conjugate, and 5-acetamidovalerate. The enrichment analysis results of the 61 different metabolite pathways identified 17 metabolic pathways with significant differences (P<0.05), including the choline metabolism, lipid metabolism, autophagy, amino acid metabolism, vitamin digestion, and absorption pathways.

Conclusions: There are significant differences in non-targeted plasma metabolites between patients with AS and healthy individuals. The above-mentioned 9 most significantly different metabolites may be potential markers of AS.
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http://dx.doi.org/10.21037/atm-22-118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905000PMC
February 2022

Development and Validation of a Nomogram to Assist Monitoring Nosocomial SARS-CoV-2 Infection of Hospitalized Patients.

J Inflamm Res 2022 28;15:1471-1481. Epub 2022 Feb 28.

Center for Gene Diagnosis, Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.

Purpose: SARS-CoV-2 is extremely infectious, and the incidence of nosocomial infection is conceivably high. We aimed to develop and validate a nomogram to assist monitoring nosocomial SARS-CoV-2 infection in hospitalized patients.

Patients And Methods: There were 437 COVID-19 hospitalized cases and 420 negative inpatients enrolled from two hospitals in Hubei province, China. We compared the demographic and clinical characteristics of participants between the two groups. Then, LASSO regression and logistic regression were applied to build a nomogram for SARS-CoV-2 infection prediction in the development cohort. Our nomogram was assessed by area under the curve (AUC), calibration curve, decision curve (DCA) and clinical impact curve analysis (CICA).

Results: After LASSO regression filtration, eleven laboratory indicators were correlated with SARS-CoV-2 infection. Then, we integrated these features and constructed a nomogram, which showed a high AUC 0.863 (95% CI: 0.834-0.892) in the development cohort with a sensitivity of 80.41% and specificity of 77.38% and 0.813 (95% CI: 0.760-0.866) in validation cohort with a sensitivity of 82.98% and specificity of 70.43%. The calibration plot displayed that the predicted outcomes were in good concordance with the actual observations. DCA and CICA further showed a larger clinical net benefit.

Conclusion: We constructed and validated a nomogram that integrated eleven laboratory indexes to assist monitoring of nosocomial SARS-CoV-2 infection in hospitalized patients. Our nomogram is remarkably informative for clinical practice, which will be helpful for preventing SARS-CoV-2 further transmission in hospital and avoiding nosocomial infection.
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http://dx.doi.org/10.2147/JIR.S351509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896769PMC
February 2022

PPARγ/SOD2 Protects Against Mitochondrial ROS-Dependent Apoptosis via Inhibiting ATG4D-Mediated Mitophagy to Promote Pancreatic Cancer Proliferation.

Front Cell Dev Biol 2021 2;9:745554. Epub 2022 Feb 2.

Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognosis. Our previous study found that peroxisome proliferator activated receptor gamma (PPARγ) was capable of enhancing glycolysis in PDAC cells. However, whether PPARγ could promote PDAC progression remains unclear. In our present study, PPARγ was positively associated with tumor size and poor prognosis in PDAC patients. Functional assays demonstrated that PPARγ could promote the proliferation of pancreatic cancer cells and . Additionally, flow cytometry results showed that PPARγ decreased mitochondrial reactive oxygen species (mitochondrial ROS) production, stabilized mitochondrial membrane potential (MMP) and inhibited cell apoptosis up-regulating superoxide dismutase 2 (SOD2), followed by the inhibition of ATG4D-mediated mitophagy. Meanwhile, the activation of PPARγ might reduce pancreatic cancer cell stemness to improve PDAC chemosensitivity down-regulating ATG4D. Thus, these results revealed that PPARγ/SOD2 might protect against mitochondrial ROS-dependent apoptosis inhibiting ATG4D-mediated mitophagy to promote pancreatic cancer proliferation, further improving PDAC chemosensitivity.
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http://dx.doi.org/10.3389/fcell.2021.745554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847684PMC
February 2022

Correction to: Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling.

Stem Cell Res Ther 2022 Feb 7;13(1):65. Epub 2022 Feb 7.

Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.

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http://dx.doi.org/10.1186/s13287-022-02728-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822683PMC
February 2022

Microbial communities in swamps of four mangrove reserves driven by interactions between physicochemical properties and microbe in the North Beibu Gulf, China.

Environ Sci Pollut Res Int 2022 May 23;29(25):37582-37597. Epub 2022 Jan 23.

The Guangxi Key Laboratory of Beibu Gulf Marine Biodiversity Conservation, College of Marine Sciences, Beibu Gulf University, Qinzhou, 535011, China.

Mangroves are distributed in coastal and estuarine regions and are characterized as a sink for terrestrial pollution. It is believed that complex interactions between environmental factors and microbial communities exist in mangrove swamps. However, little is known about environment-microbe interactions. There is a need to clarify some important environmental factors shaping microbial communities and how environmental factors interact with microbial assemblages in mangrove swamps. In the present study, physicochemical and microbial characteristics in four mangrove reserves (named ZZW, Qin, Bei, and GQ) in the North Beibu Gulf were determined. The interactions between environmental factors and microbial assemblages were analyzed with statistical methods in addition to CCA and RDA. Higher concentrations of sulfate (SO-S) and Fe but lower concentrations of total phosphorus (TP) and NO-N were detected in ZZW and Qin. Nutrient elements (NO-N, NH-N, organic matter (OM), SO-S, Fe, and TP) were more important than heavy metals for determining the microbial assemblages, and NO-N was the most important factor. NO-N, SO-S, TP, and Fe formed a significant co-occurrence network in conjunction with some bacterial taxa, most of which were Proteobacteria. Notably, comparatively elevated amounts of sulfate-reducing bacteria (Desulfatibacillum, Desulfomonile, and Desulfatiglans) and sulfur-oxidizing bacteria (Thioprofundum and Thiohalophilus) were found in ZZW and Qin. The co-occurrence network suggested that some bacteria involved in sulfate reduction and sulfur oxidation drive the transformation of P and N, resulting in the reduction of P and N in mangrove swamps. Through the additional utilization of multivariate regression tree (MRT) and co-occurrence network analysis, our research provides a new perspective for understanding the interactions between environmental factors and microbial communities in mangroves.
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http://dx.doi.org/10.1007/s11356-021-18134-6DOI Listing
May 2022

Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling.

Stem Cell Res Ther 2021 07 13;12(1):396. Epub 2021 Jul 13.

Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.

Background: Effective treatments for acute-on-chronic liver failure (ACLF) are lacking. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been applied in tissue regeneration and repair, acting through paracrine effects, cell fusion, and actual transdifferentiation. The present study was designed to investigate the therapeutic potential of hUC-MSCs in acute-on-chronic liver injury (ACLI) and ACLF rat models.

Methods: Wistar rats aged 6 weeks were intraperitoneally administered porcine serum (PS) at a dose of 0.5 mL twice per week for 11 weeks to generate an immune liver fibrosis model. After 11 weeks, rats with immune liver fibrosis were injected intravenously with lipopolysaccharide (LPS) to induce an ACLI model or combined LPS and D-galactosamine (D-GalN) to induce an ACLF model. The rats with ACLI or ACLF were injected intravenously with 2×10 hUC-MSCs, 4×10 hUC-MSCs, or 0.9% sodium chloride as a control. The rats were sacrificed at 1, 2, 4, and 6 weeks (ACLI rats) or 4, 12, and 24 h (ACLF rats). The blood and liver tissues were collected for biochemical and histological investigation.

Results: The application of hUC-MSCs in rats with ACLI and ACLF led to a significant decrease in the serum levels of ALT, AST, TBil, DBil, ALP, ammonia, and PT, with ALB gradually returned to normal levels. Inflammatory cell infiltration and collagen fiber deposition in liver tissues were significantly attenuated in ACLI rats that received hUC-MSCs. Inflammatory cell infiltration and apoptosis in liver tissues of ACLF rats that received hUC-MSCs were significantly attenuated. Compared with those in the rats that received 0.9% sodium chloride, a significant reduction in proinflammatory cytokine levels and elevated serum levels of hepatocyte growth factor (HGF) were found in ACLF rats that received hUC-MSCs. Furthermore, Notch, IFN-γ/Stat1, and IL-6/Stat3 signaling were inhibited in ACLI/ACLF rats that received hUC-MSCs.

Conclusions: hUC-MSC transplantation can improve liver function, the degree of fibrosis, and liver damage and promote liver repair in rats with ACLI or ACLF, mediated most likely by inhibiting Notch signaling and reversing the imbalance of the Stat1/Stat3 pathway.
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http://dx.doi.org/10.1186/s13287-021-02468-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278604PMC
July 2021

Validation of the Nanjing Criteria for Diagnosing Pyrrolizidine Alkaloids-induced Hepatic Sinusoidal Obstruction Syndrome.

J Clin Transl Hepatol 2021 Jun 31;9(3):345-352. Epub 2021 Mar 31.

Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.

Background And Aims: Hepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury to sinusoidal endothelial cells in the liver. The intake of pyrrolizidine alkaloids (PAs) in some Chinese herbal remedies/plants remains the major etiology for HSOS in China. Recently, new diagnostic criteria for PA-induced HSOS (i.e. PA-HSOS) have been developed; however, the efficacy has not been clinically validated. This study aimed to assess the performance of the Nanjing criteria for PA-HSOS.

Methods: Data obtained from consecutive patients in multiple hospitals, which included 86 PA-HSOS patients and 327 patients with other liver diseases, were retrospectively analyzed. Then, the diagnostic performance of the Nanjing criteria and simplified Nanjing criteria were evaluated and validated. The study is registered in www.chictr.org.cn (ID: ChiCTR1900020784).

Results: The Nanjing criteria have a sensitivity and specificity of 95.35% and 100%, respectively, while the simplified Nanjing criteria have a sensitivity and specificity of 96.51% and 96.33%, respectively, for the diagnosis of PA-HSOS. Notably, a proportion of patients with Budd-Chiari syndrome (11/49) was misdiagnosed as PA-HSOS on the basis of the simplified Nanjing criteria, and this was mainly due to the overlapping features in the enhanced computed tomography/magnetic resonance imaging examinations. Furthermore, most of these patients (10/11) had occlusion or thrombosis of the hepatic vein, and communicating vessels in the liver were found in 8/11 patients, which were absent in PA-HSOS patients.

Conclusions: The Nanjing criteria and simplified Nanjing criteria exhibit excellent performance in diagnosing PA-HSOS. Thus, both could be valuable diagnostic tools in clinical practice.
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http://dx.doi.org/10.14218/JCTH.2020.00124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237138PMC
June 2021

Glucagonoma with diffuse enlargement of pancreas mimicking autoimmune pancreatitis diagnosed by EUS-guided FNA.

Gastrointest Endosc 2021 10 28;94(4):862-863.e1. Epub 2021 May 28.

Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.

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http://dx.doi.org/10.1016/j.gie.2021.05.033DOI Listing
October 2021

Differential prognostic implications of gastric adenocarcinoma based on Lauren's classification: a Surveillance, Epidemiology, and End Results (SEER)-based cohort study.

Ann Transl Med 2021 Apr;9(8):646

Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.

Background: Our study aims to analyze the association between Lauren's classification and gastric adenocarcinoma prognosis using comprehensive statistical analyses.

Methods: According to the selection criteria, patients were included from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression, propensity score matching, and a multivariate competing risk model were used to investigate the association between Lauren's classification and prognosis. Subgroup analysis was used to investigate the role of confounding factors on the association between Lauren types and prognosis.

Results: After exclusion, a total of 20,218 patients from the SEER database were included, with 14,374 intestinal types and 5,844 diffuse types. The univariate Cox regression analysis revealed that the diffuse type had a poorer cancer-specific survival (CSS) rate [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.38-1.50]. After adjusting for confounding variables, the diffuse type also showed a higher risk of cancer-specific death (HR, 1.20; 95% CI, 1.15-1.20). Sensitivity analysis showed that after propensity score matching, the diffuse type had a poorer CSS rate (HR, 1.23; 95% CI, 1.10-1.36), and the competing risk model further validated these results [subdistribution HR (SHR), 1.32; 95% CI, 1.23-1.41]. Moreover, subgroup analysis demonstrated stable results in the subgroups, except for patients with T1 stage (HR, 1.06; 95% CI, 0.87-1.28) and a tumor size <2 cm (HR, 1.00; 95% CI, 0.83-1.21).

Conclusions: Diffuse-type gastric adenocarcinoma had an overall poorer prognosis compared to the intestinal type. However, in patients with T1 stage and tumor size <2 cm, the diffuse type had a comparable survival rate with the intestinal type.
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http://dx.doi.org/10.21037/atm-20-7953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106066PMC
April 2021

Risk factors of poor prognosis in patients with pyrrolidine alkaloid-induced hepatic sinusoidal obstruction syndrome after transjugular intrahepatic portosystemic shunt.

Hepatol Int 2021 Jun 28;15(3):720-729. Epub 2021 Jan 28.

Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321#, Zhongshan Road, Nanjing, 210008, Jiangsu, China.

Aims: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective method in treating patients with severe hepatic sinusoidal obstruction syndrome induced by pyrrolidine alkaloids (PA-HSOS). However, some patients still have poor postoperative prognosis. So, we aim to evaluate the predictors associated with poor outcomes in PA-HSOS patients receiving TIPS.

Methods: Patients who were diagnosed as PA-HSOS and received TIPS in our hospital between January 2013 and April 2019 were reviewed retrospectively. Baseline information and clinical data were collected. The hazard ratios (HRs) of factors associated with poor prognosis were analyzed by Cox proportional hazard analysis. The Kaplan-Meier method was used to analyze and compare the cumulative incidence of the poor results and survival rate of patients.

Results: During a median of 19.25-month follow-up, death occurred in 17 patients. We found that prothrombin time at baseline with an adjusted HR 1.110 (95% confidence interval 1.014-1.216, p = 0.024) and serum total bilirubin of 9 mg/dl 5 days after TIPS with an adjusted HR 1.114 (95% confidence interval 1.042-1.190, p = 0.001) were independent risk factors for death. The 1-year and 5-year survival rate were 86.2% and 82.1%, respectively. The 1-year survival rate in patients with prothrombin time > 17.85 s at baseline and serum total bilirubin > 9 mg/dl at 5 days after TIPS was significantly lower than that of patients below the corresponding threshold, respectively.

Conclusions: Prolonged prothrombin time at baseline and increased serum total bilirubin levels 5 days after TIPS are independent risk factors for predicting death after TIPS treatment in PA-HSOS patients.
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http://dx.doi.org/10.1007/s12072-020-10126-xDOI Listing
June 2021

Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner.

Clin Epigenetics 2021 01 26;13(1):18. Epub 2021 Jan 26.

Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.

Background: Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored.

Methods: A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism.

Results: We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT.

Conclusions: This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.
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http://dx.doi.org/10.1186/s13148-021-01016-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836598PMC
January 2021

Identification of two novel PRPF31 mutations in Chinese families with non-syndromic autosomal dominant retinitis pigmentosa.

Mol Genet Genomic Med 2020 12 21;8(12):e1537. Epub 2020 Oct 21.

The Key Laboratory for Human Disease Gene Study of Sichuan Province, Prenatal Diagnosis Center, Sichuan Provincial People's Hospital, the University of Electronic Science and Technology of China, Chengdu, PR China.

Background: Retinitis pigmentosa is a heterogeneous group of inherited retinal diseases leading to progressive vision loss. It has been estimated that the etiology is still unclear in 22%-40% of cases, indicating that many novel pathogenic variations related to RP remain unidentified in many patients. In this study, our aim was to investigate the disease-causing variants and function of the variants in two Chinese families with non-syndromic autosomal dominant retinitis pigmentosa (adRP).

Methods: Clinical data and peripheral blood DNA samples were collected. Whole exome sequencing (WES) was conducted to screen for variations. Then, the expression of green fluorescent protein (GFP)-fused wild-type PRPF31 protein and its variants was evaluated via western blotting and GFP fluorescence detection in vitro.

Results: Two novel heterozygous variants of PRPF31 (NM_015629.4): c.855+5G>A and c.849_855del (p.Pro284Ilefs*35) were identified respectively in two families. The variant c.855+5G>A is co-segregated with the disease in adRP-01 family. The pedigree analysis result for c.849_855del (p. Pro284Ilefs*35) shows an inheritance pattern with incomplete penetrance for adRP-02 family. The RT-PCR analysis shows the PRPF31 gene c.855+5G>A leading to the missing from the 997th to the 1405th positions of the PRPF31 gene (NM_015629.4) cDNA. The expressions of the mutant GFP-fused PRPF31 protein were not detected in HEK293 cells or Cos7 cells via western blotting and immunofluorescence.

Conclusions: Our findings identified two novel variants in PRPF31 in two Chinese families with adRP, expanding the mutational spectrum of this gene. Functional analysis reveals that these variants lead to the truncation of the PRPF31 protein.
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http://dx.doi.org/10.1002/mgg3.1537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767543PMC
December 2020

Dysregulated circulating SOCS3 and haptoglobin expression associated with stable coronary artery disease and acute coronary syndrome: An integrated study based on bioinformatics analysis and case-control validation.

Anatol J Cardiol 2020 09;24(3):160-174

Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine; Hubei-P.R. China.

Objective: To extensively use blood transcriptome analysis to identify potential diagnostic and therapeutic targets for cardiovascular diseases.

Methods: Two gene expression datasets (GSE59867 and GSE62646) were downloaded from GEO DataSets to identify altered blood transcriptomes in patients with ST-segment elevation myocardial infarction (STEMI) compared to stable coronary artery disease (CAD). Thereafter, several computational approaches were taken to determine functional roles and regulatory networks of differentially expressed genes (DEGs). Finally, the expression of dysregulated two hub genes-suppressor of cytokine signaling 3 (SOCS3) and haptoglobin (HP)-were validated in a case-control study.

Results: A total of 119 DEGs were identified in the discovery phase, consisting of 71 downregulated genes and 48 upregulated genes; two hub modules consisting of two hub genes-SOCS3 and HP-were identified. In the validation phase, both SOCS3 and HP were significantly downregulated in the stable CAD and acute coronary syndrome (ACS) patients when compared with healthy controls. Meanwhile, HP was significantly upregulated in STEMI patients when compared with stable CAD patients (p=0.041). Logistic regression analysis indicated that: downregulated expression of HP correlated with increased risk of CAD [odds ratio (OR)=0.52, 95% confidence interval (CI)=0.31~0.87, p=0.013]; and downregulated expression of SOCS3 correlated with increased risk of ACS (OR=0.66, 95% CI=0.46~0.94, p=0.023) when age, gender, history of hyperlipidemia, diabetes and hypertension were included as covariates.

Conclusion: Future clarification of how SOCS3 and HP influence the pathogenesis of disease may pave the way for the development of novel diagnostic and therapeutic methods.
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http://dx.doi.org/10.14744/AnatolJCardiol.2020.56346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585973PMC
September 2020

Development, application, and evaluation of a problem-based learning method in clinical laboratory education.

Clin Chim Acta 2020 Nov 27;510:681-684. Epub 2020 Aug 27.

Department of Laboratory Medicine, Taihe hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China; Department of Clinical laboratory Science, Hubei University of Medicine, Shiyan 442000, Hubei, China; Hubei Key Laboratory of Embryonic Stem Cell research, Hubei University of Medicine, Shiyan 442000, Hubei, China. Electronic address:

Background: There is a big gap between theory and real clinical practice with respect to the structure of clinical laboratory medicine (CLM) education in China. An integrated teaching method is urgently required, to improve student competency and prepare students to deal with complex challenges in the working environment.

Methods: A total of 122 fourth-year CLM students studying at Hubei University between 2018 and 2019 were randomly assigned to a traditional teaching methods group or a problem-based learning (PBL) group. In the PBL group students were instructed to exchange their thoughts, identify information gaps, rehearse and perform simulated clinical scenarios, and incorporate the new information into cases in small groups. Theory tests, questionnaires, and clinical performance assessments were used to evaluate the effectiveness of PBL and compare it with that of traditional teaching methods.

Results: PBL resulted in significantly better theory test scores, better student feedback scores, and clinical performance assessments, and a higher rate of satisfaction among students and teachers.

Conclusion: PBL is an effective way to help CLM students develop comprehensive abilities to deal with real clinical laboratory work. It is a promising education method and should be generalized to all subtypes of clinical laboratory curriculums in the future.
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http://dx.doi.org/10.1016/j.cca.2020.08.037DOI Listing
November 2020

Pharmacokinetic and Lipidomic Assessment of the In Vivo Effects of Parishin A-Isorhynchophylline in Rat Migraine Models.

J Anal Methods Chem 2020 6;2020:9101598. Epub 2020 Jul 6.

Jiangxi University of Traditional Chinese Medicine, Nanchang, China.

Migraine is a chronic brain disease that leads to periodic neurological attacks. Parishin A and isorhynchophylline (PI) is the active monomer component extracted from the traditional antimigraine Chinese medicinal combination of Gastrodia and Uncaria, respectively. In this study, using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) technology, we performed pharmacokinetic and lipidomic study on migraine model rats after administration of PI. For the detection of the compounds in plasma, AB Sciex Triple Quad™ 4500 was applied for quantitative analysis, and the COSMOSIL C column (2.1 × 100 mm, 2.6 m) was used for separation. Isorhynchophylline (ISO: / 384.8-241.2) and its main metabolite rhynchophylline (RHY: / 384.8-160.2) were simultaneously detected under positive ion modes. Besides, parishin A (PA: / 995.1-726.9) and its main metabolite gastrodin (GAS: / 331.1-123.0) were simultaneously detected with negative ion modes. For the analysis of endogenous lipid components, Dionex Ultimate 3000 (UHPLC) Thermo Orbitrap Elite was applied for the detection, and the Waters UPLCRBEH C column (1.7 m 100  2.1 mm) was used for separation. Chloroform/methanol (2 : 1,  : ) was used for extraction. The results demonstrated that PI exists significant difference in metabolism between single- and coadministration and can regulate lipid levels associated with migraine.
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http://dx.doi.org/10.1155/2020/9101598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362284PMC
July 2020

EUS-guided portal pressure gradient measurement in patients with acute or subacute portal hypertension.

Gastrointest Endosc 2021 03 29;93(3):565-572. Epub 2020 Jun 29.

Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Background And Aims: EUS-guided portal pressure gradient (EUS-PPG) measurement is a novel method to evaluate portal hypertension severity. In this study, we determined the consistency between EUS-PPG and hepatic venous pressure gradient (HVPG) measurements in patients with acute or subacute portal hypertension.

Methods: Twelve patients were prospectively enrolled. EUS-PPG measurements were performed using a 22-gauge FNA needle and a central venous pressure measurement monitor. The HVPG measurements were performed using the transjugular approach. If an HVPG measurement was not attainable and the patient underwent transjugular intrahepatic portosystemic shunt (TIPS) treatment, a PPG was recorded as a reference standard during the procedure. We assessed the feasibility and safety of EUS-PPG and calculated the correlation between the 2 measurements.

Results: EUS-PPG measurements were successful in 11 patients (91.7%). Subsequent HVPG measurements failed in 2 patients with Budd-Chiari syndrome (hepatic vein occlusion subtype), 1 of whom underwent TIPS treatment to obtain transjugular PPG data. A small shunt was found during 1 HVPG measurement that introduced inaccuracy. Nine patients were included in the statistical analysis. Mean EUS-PPG and HVPG/PPG (transjugular) were 18.07 ± 4.32 mm Hg and 18.82 ± 3.43 mm Hg, respectively. Pearson's correlation coefficient between the 2 methods was .923 (P < .001).

Conclusions: EUS-PPG measurement using a 22-gauge FNA needle was a safe and accurate method to evaluate portal hypertension and has the potential to supplement the measurement of HVPG in liver diseases. (Clinical trial registration number: ChiCTR1800017317.).
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http://dx.doi.org/10.1016/j.gie.2020.06.065DOI Listing
March 2021

ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism.

Front Oncol 2020 16;10:915. Epub 2020 Jun 16.

Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

The aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is a key enzyme associated with a variety of metabolic processes, including glucose metabolism. We recently uncovered that glucose metabolism played an essential role in promoting metastasis of pancreatic ductal adenocarcinoma (PDAC). As ALDH1A3 labels an aggressive subtype of PDAC, we hypothesized that ALDH1A3 functionally promoted PDAC metastasis via its metabolic effect on glucose metabolism. Expression of ALDH1A3 was detected in human PDAC tissues by immunohistochemistry. ALDH1A3 was knocked down or overexpressed in PDAC cells by either shRNA or overexpression vector. The functional roles of ALDH1A3 were characterized and . Transcriptional profiling via RNA-sequencing was used to explore the possible underlying molecular mechanisms. Glucose uptake, extracellular lactate, and ATP production were measured to access the metabolic influence of ALDH1A3 on PDAC cells. ALDH1A3 was associated with poor prognosis in PDAC patients. Functionally, ALDH1A3 promoted PDAC metastasis and . Further studies revealed that ALDH1A3 activated PI3K/AKT/mTOR signaling pathway and its downstream target-PPARγ (peroxisome proliferator-activated receptor gamma). This led to increase the expression of HK2 (hexokinase 2), which subsequently enhanced the glycolysis in PDAC cells. Additionally, the pharmacological inhibition of PPARγ activity in ALDH1A3-positive cells impaired glycolytic genes expression, PI3K/AKT/mTOR activity and cellular glycolysis. ALDH1A3 promotes PDAC metastasis via its metabolic influence on glucose metabolism. PPARγ and its downstream PI3K/AKT/mTOR signaling pathway maybe involved in this process.
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http://dx.doi.org/10.3389/fonc.2020.00915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308463PMC
June 2020

A nomogram to predict the risk of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in Cirrhotic Patients.

Sci Rep 2020 06 10;10(1):9381. Epub 2020 Jun 10.

Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China.

Background And Aim: Hepatic encephalopathy (HE) is a serious complication of decompensated liver cirrhosis, affecting the prognosis of patients underwent transjugular intrahepatic portosystemic shunts (TIPS). We aim to create a nomogram to predict hepatic encephalopathy- free survivals (HEFS) after TIPS in cirrhotic patients and select appropriate candidates for TIPS.

Methods: Cirrhotic patients underwent TIPS from 2015 to 2018 in our department were included. Multivariable Cox regression was conducted to estimate the predictors of overt HE (OHE) after TIPS within one year. A nomogram based on the Cox proportional hazard model using data from a retrospective training cohort (70% of the patients) was developed. Then the prediction model was validated in the remaining 30% patients by Harrell's C-indexes, ROC curves and calibration plots.

Results: Of 373 patients, 117 developed postoperative OHE (31.4%). The training and validation groups comprised 83 (31.4%) and 34 (31.2%) patients, respectively. The cumulative survival rates of patients with HE at 1, 2 and 3 years were 90%, 83% and 76%, respectively. The nomogram included the following variables: age, Child-Turcotte-Pugh class (CTP class), diabetes mellitus (DM), serum creatinine and serum sodium (C-index = 0.772). The C-index for HEFS prediction was 0.773 for the validation cohort. The ROC for predicting HEFS was 0.809 and 0.783, respectively.

Conclusions: We created a nomogram of predicting postoperative HEFS in cirrhotic patients received TIPS. This nomogram could be an important tool of HE risk prediction before TIPS to guide the therapeutic strategy in cirrhotic patients.
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http://dx.doi.org/10.1038/s41598-020-65227-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287049PMC
June 2020

Therapeutic Rationale to Target Highly Expressed Aurora kinase A Conferring Poor Prognosis in Cholangiocarcinoma.

J Cancer 2020 3;11(8):2241-2251. Epub 2020 Feb 3.

Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.

: Cholangiocarcinoma is a highly lethal neoplasm for which the currently available chemotherapeutic agents are suboptimal. Numerous studies show that alterations in expression of genes related to mitotic spindle and mitotic checkpoint are involved in chromosomal instability and tumor progression in various malignancies. This study aimed to evaluate these genes in cholangiocarcinoma patients. : Different public datasets were analyzed to examine the expression of 76 selected mitotic spindle checkpoint genes including Aurora Kinase A (AURKA) in cholangiocarcinoma. Afterwards, cell number counting, CCK-8 assay, and Caspase 3/7 assay were used to explore the antitumor effect of AURKA inhibitor Alisertib . In addition, xenograft model was used to evaluate the antitumor effect of Alisertib . Furthermore, siRNA mediated silencing of AURKA was used to verify the function of AURKA in cholangiocarcinoma. : Components of the mitotic spindle checkpoint, including AURKA, were broadly dysregulated in human cholangiocarcinoma. High AURKA mRNA expression was associated with poor survival in cholangiocarcinoma patients within different datasets. AURKA specific inhibitor Alisertib, inhibited cell growth, induced cell cycle arrest in G2/M phase, and promoted apoptosis in cholangiocarcinoma cell lines. Additionally, Alisertib also inhibited tumor growth in a cholangiocarcinoma xenograft mouse model. Furthermore, AURKA knockdown by siRNA recapitulated the antitumor effect of Alisertib. AURKA expression was also highly correlated with its interaction proteins Polo-like kinase 1(PLK1) and Targeting protein for xenopus kinesin-like protein2 (TPX2) in different cholangiocarcinoma datasets. : Highly expressed AURKA confers poor outcomes in cholangiocarcinoma and may represent a rational therapeutic target.
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http://dx.doi.org/10.7150/jca.31989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052919PMC
February 2020

Metabolomics and 16S rRNA Gene Sequencing Analyses of Changes in the Intestinal Flora and Biomarkers Induced by Treatment in a Rat Model of Chronic Migraine.

Front Pharmacol 2019 17;10:1425. Epub 2019 Dec 17.

State Key Laboratory of Innovative Drug and Efficient Energy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.

Accumulating evidence suggests that natural medicines have notable curative effects on neurological conditions, such as migraine, that are mediated by regulating the gut microbial flora. A natural medicine pair used in traditional Chinese medicine, Blume and (Miq.) Miq. ex Havil. (GU), have shown excellent effect in treating migraine, yet the role of gut microbes in the therapeutic effect of GU in chronic migraine (CMG) is unknown. Here, we performed a 16S rRNA gene sequencing and metabolomics study of the effects of GU in a nitroglycerin (NTG)-induced rat model of CMG. Our results showed that the gut microbial community structure changed significantly and was similar to that of control rats after GU administration in CMG rats. Specifically, GU increased the relative abundance of and and reduced the abundance of _1 and - in CMG rats. The metabolomics profiles of the plasma and ileum contents of CMG rats obtained with an ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) revealed similar biomarkers in both samples, and GU treatment reduced 3-indoxyl sulfate, glutamic acid, -tyrosine, and -arginine levels, and increased 5-HIAA, -tryptophan, and linoleic acid levels in plasma. Correlation analysis showed that the affected bacteria were closely related to amino acid metabolism. Most importantly, GU treatment hardly affected biomarkers in feces samples after inhibiting the activity of gut microbes. Collectively, these findings indicate that structural changes in gut flora are closely related to host metabolism and that regulating the gut microbial community structure and function may be one of the important mechanisms underlying the therapeutic effects of GU in migraine.
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http://dx.doi.org/10.3389/fphar.2019.01425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929670PMC
December 2019

Clinical efficacy and safety of anticoagulation therapy for Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: a retrospective multicenter cohort study.

Eur J Gastroenterol Hepatol 2020 09;32(9):1168-1178

Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing.

Aim: Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome(PA-HSOS) has been reported to have high mortality. We evaluated the efficacy and safety of anticoagulation therapy for the patients with PA-HSOS.

Methods: We collected clinical data on 249 PA-HSOS patients from January 2012 to December 2017 at four tertiary care hospitals. Among them, 151 patients received anticoagulation therapy, and 98 patients received supportive treatment. The outcomes were analyzed using the Fine and Gray competing risk analysis method and Cox regression model.

Results: The cumulative complete response rate was higher in the anticoagulation group than in the supportive group (60.9 vs 36.7%; P < 0.0001). The cumulative mortality was 12.6% in the anticoagulation group compared with 43.9% in the supportive group (P < 0.0001). In subgroup analysis, for mild, moderate, severe, and very severe groups, the adjusted hazard ratios [95% confidence interval (CI)] for complete response rates were 7.05 (3.00-16.59), 5.26 (2.31-12.42), 2.59 (0.85-7.87), and 2.05 (0.61-6.92), respectively; and the adjusted hazard ratios (95% CI) for mortalities were 0.02 (0.01-0.09), 0.04 (0.01-0.14), 0.19 (0.01-3.98), and 0.07 (0.02-1.27), respectively (P < 0.0001). There was no significant difference between both groups in the incidence of bleeding events (P = 0.674).

Conclusions: Anticoagulation therapy improves clinical remission and the survival in selected patients with mild or moderate PA-HSOS. Anticoagulation therapy has a similar safety profile to supportive therapy.
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http://dx.doi.org/10.1097/MEG.0000000000001630DOI Listing
September 2020

Down-regulated of SREBP-1 in circulating leukocyte is a risk factor for atherosclerosis: a case control study.

Lipids Health Dis 2019 Oct 14;18(1):177. Epub 2019 Oct 14.

Department of Laboratory Medicine, Taihe hospital, Hubei University of Medicine, Shiyan, China.

Background: Sterol regulatory-element binding proteins (SREBPs) and mir-33 (miR-33a, miR-33b), which are encoded by the introns of SREBPs, are key factors in the lipid metabolism pathway. SREBPs mRNA in circulating leucocyte and carotid plaques, along with various risk factors that associated with Coronary Atherosclerotic Disease (CAD) were investigated in a central Chinese cohort.

Methods: A total of 218 coronary atherosclerotic disease (CAD) patients, and 178 non-CAD controls, were recruited to collect leukocytes. Carotid plaques and peripheral blood were obtained from CAD patients undergoing carotid endarterectomy (CEA) (n = 12) while THP-1 and peripheral blood mononuclear cells (PBMCs) were stimulated with Oxidized low-density lipoprotein (ox-LDL) to establish an in vitro foam cell formation model. SREBPs and miR-33 levels were quantified by qPCR. Routine biochemical markers were measured using standard procedures.

Results: SREBP-1 mRNA level of circulating leucocytes in CAD patients were significantly lower than in non-CAD controls (p = 0.005). After stratification coronary artery atherosclerotic complexity, we detected a significant reduction of SREBP-1 in high-risk complexity CAD patients (SYNTAX score > 23) (p = 0.001). Logistic regression analysis indicated that decreased expression of SREBP-1 was a risk factor of CAD (odds ratio (OR) =0.48, 95% confidence interval (CI) = 0.30~0.76, p = 0.002) after adjusting clinical confounders; the mRNA levels of SREBPs in carotid plaques correlated with the corresponding value in circulating leukocytes (SREBP-1 r = 0.717, p = 0.010; SREBP-2 r = 0.612, p = 0.034). Finally, there was no significant difference in serum miR-33 levels between CAD patients and controls.

Conclusions: Our finding suggesting a potential role in the adjustment of established CAD risk. The future clarification of how SREBP-1 influence the pathogenesis of CAD might pave the way for the development of novel therapeutic methods.
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http://dx.doi.org/10.1186/s12944-019-1125-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792215PMC
October 2019

CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263.

Cell Death Dis 2019 08 9;10(8):602. Epub 2019 Aug 9.

Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China.

Cholangiocarcinoma (CCA) is a fatal disease without effective targeted therapy. We screened a small-molecule library of 116 inhibitors targeting different targets of the cell cycle and discovered several kinases, including Cyclin-dependent kinase 7 (CDK7) as vulnerabilities in CCA. Analysis of multiple CCA data sets demonstrated that CDK7 was overexpressed in CCA tissues. Further studies demonstrated that CDK7 inhibitor THZ1 inhibited cell viability and induced apoptosis in CCA cells. We also showed that THZ1 inhibited CCA cell growth in a xenograft model. RNA-sequencing followed by Gene ontology analysis showed a striking impact of THZ1 on DNA-templated transcriptional programs. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition. A number of oncogenic transcription factors and survival proteins, like MCL1, FOSL1, and RUNX1, were repressed by THZ1. MCL1, one of the antiapoptotic BCL2 family members, was significantly inhibited upon THZ1 treatment. Accordingly, combining THZ1 with a BCL2/BCL-XL inhibitor ABT-263 synergized in impairing cell growth and driving apoptosis. Our results demonstrate CDK7 as a potential target in treating CCA. Combinations of CDK7 inhibition and BCL2/BCL-XL inhibition may offer a novel therapeutic strategy for CCA.
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http://dx.doi.org/10.1038/s41419-019-1831-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688996PMC
August 2019

Classification of the cystic duct patterns and endoscopic transpapillary cannulation of the gallbladder to prevent post-ERCP cholecystitis.

BMC Gastroenterol 2019 Aug 5;19(1):139. Epub 2019 Aug 5.

Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, Jiang Su Province, China.

Background: Endoscopic transpapillary cannulation of the gallbladder is useful but challenging. This study aimed to investigate cystic duct anatomy patterns, which may guide cystic duct cannulation.

Methods: A total of 226 patients who underwent endoscopic transpapillary cannulation of the gallbladder were analyzed retrospectively.

Results: According to the cystic duct take-off, 226 cystic duct patterns were divided into 3 patterns: Type I (193, 85.4%), located on the right and angled up; Type II (7, 3.1%), located on the right and angled down; and Type III (26, 11.5%), located on the left and angled up. Type I was further divided into three subtypes: Line type, S type (S1, not surrounding the common bile duct; S2, surrounding the common bile duct), and α type (α1, forward α; α2, reverse α). Types I and III cystic ducts were easier to be cannulated with a higher success rate (85.1 and 86.4%, respectively) compared with Type II cystic duct (75%) despite no statistically significant difference. The reasons for the failure of gallbladder cannulation included invisible cyst duct take-off, severe cyst duct stenosis, impacted stones in cyst duct or neck of the gallbladder, sharply angled cyst duct, and markedly dilated cyst duct with the tortuous valves of Heister.

Conclusion: Classification of cystic duct patterns was helpful in guiding endoscopic transpapillary gallbladder cannulation.
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http://dx.doi.org/10.1186/s12876-019-1053-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683449PMC
August 2019

High-throughput sequencing and analysis of microbial communities in the mangrove swamps along the coast of Beibu Gulf in Guangxi, China.

Sci Rep 2019 06 28;9(1):9377. Epub 2019 Jun 28.

The Key Laboratory of Innate Immune Biology of Fujian Province, Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, 350117, China.

Mangrove swamp is one of the world's richest and most productive marine ecosystems. This ecosystem also has a great ecological importance, but is highly susceptible to anthropogenic disturbances. The balance of mangrove ecosystem depends largely on the microbial communities in mangrove sediments. Thus, understanding how the mangrove microbial communities respond to spatial differences is essential for more accurate assessment of mangrove ecosystem health. To this end, we performed the first medium-distance (150 km) research on the biogeographic distribution of mangrove microbial communities. The hypervariable regions of 16S rRNA gene was sequenced by Illumina to compare the microbial communities in mangrove sediments collected from six locations (i.e. Zhenzhu harbor, Yuzhouping, Maowei Sea, Qinzhou harbor, Beihai city and Shankou) along the coastline of Beibu Gulf in Guangxi province, China. Collectively, Proteobacteria, Bacteroidetes, Chloroflexi, Actinobacteria, Parvarchaeota, Acidobacteria and Cyanobacteria were the predominant phyla in the mangrove sediments of this area. At genus level, the heat map of microbial communities reflected similarities between study sites and was in agreement with their biogeographic characteristics. Interestingly, the genera Desulfococcus, Arcobacter, Nitrosopumilus and Sulfurimonas showed differences in abundance between study sites. Furthermore, the principal component analysis (PCA) and unweighted UniFrac cluster tree of beta diversity were used to study the biogeographic diversity of the microbial communities. Relatively broader variation of microbial communities was found in Beihai city and Qinzhou harbour, suggesting that environmental condition and historical events may play an important role in shaping the bacterial communities as well. This is the first report on medium-distance range distribution of bacteria in the mangrove swamp ecosystem. Our data is valuable for monitoring and evaluation of the impact of human activity on mangrove habitats from the perspective of microbiome.
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http://dx.doi.org/10.1038/s41598-019-45804-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599077PMC
June 2019

Targeting sphingosine kinase 2 suppresses cell growth and synergizes with BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation in cholangiocarcinoma.

Am J Cancer Res 2019 1;9(3):546-561. Epub 2019 Mar 1.

Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University Nanjing 210008, Jiangsu, China.

Sphingosine kinase 2 (SPHK2) is a key factor within sphingolipid metabolism, responsible for the conversion of pro-apoptotic sphingosine to the pro-survival sphingosine-1-phosphate. We have previously shown that ABC294640, a first-in-class SPHK2 inhibitor, inhibits growth of cholangiocarcinoma cells. In a Phase I study of ABC294640 in tumors, the best response was achieved in a cholangiocarcinoma patient. These data suggest SPHK2 as a novel therapeutic target of cholangiocarcinoma. However, the antitumor mechanism of ABC294640 in cholangiocarcinoma remains not clear. In the current study, we found that ABC294640 upregulated expression of pro-apoptotic NOXA. In cholangiocarcinoma patients, high NOXA mRNA expression was associated with better overall survival. Also, SPHK2 mRNA expression was negatively correlated with NOXA mRNA expression. NOXA is known to degrade MCL1, an anti-apoptotic BCL2 protein. We showed that ABC294640 directed MCL1 for proteasome degradation. Knockdown of NOXA prevented ABC294640-induced MCL1 degradation and apoptosis. In addition, ABC294640 had a synergistic effect with BCL2/BCL-XL inhibitors ABT-263 and Obatoclax in inhibiting cell growth. Combined treatment with ABC294640 and BCL2/BCL-XL inhibitors induced potent apoptosis. Silencing of MCL1 also potentiated ABT-263-induced cytotoxicity. Furthermore, we found that both SPHK2 and MCL1 protein expression were significantly higher in cholangiocarcinoma than that in nontumoral bile ducts. SPHK2 expression correlated significantly with MCL1 expression. Our study reveals that ABC294640 inhibits cholangiocarcinoma cell growth and sensitizes the antitumor effect of BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation. Combinations of ABC294640 with BCL2/BCL-XL inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448062PMC
March 2019

Knockdown of nucleophosmin 1 suppresses proliferation of triple-negative breast cancer cells through activating CDH1/Skp2/p27kip1 pathway.

Cancer Manag Res 2019 21;11:143-156. Epub 2018 Dec 21.

Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515000, China,

Background: NPM1 is a multifunctional phosphoprotein that commutes between the cytoplasm and nucleus in cell cycle process, which appears to be actively involved in tumorigenesis. Herein, we sought to investigate the possible role and prognostic value of NPM1 in triple-negative breast cancer (TNBC).

Methods: An array of public databases, including bc-GenExMiner v4.0, GOBO, GEPIA, UAL-CAN, ONCOMINE database and Kaplan-Meier plotter, were used to investigate the expression feature and potential function of NPM1 in TNBC. Immunohistochemistry, immunofluorescence, proliferation and colony formation, flow cytometry and western-blotting assays were used to analyze and verify the function and relevant mechanism of NPM1 in TNBC tissues and cells.

Results: According to analysis from bc-GenExMiner, the expression level of NPM1 was significantly higher in basal-like subtypes than luminal-A, HER-2 or normal-like subtypes of breast cancer (<0.0001). GOBO database analysis indicated that the expression of NPM1 in basal-A or basal-B was significantly higher than luminal-like breast cancer cells. Immunohistochemistry assay in 52 TNBC tissue samples showed that positive expression of Ki-67 was 93.5% in the high-NPM1-expression group and 66.7% in the low-NPM1-expression group, respectively (=0.032). Proliferation and colony formation assays demonstrated that inhibition of NPM1 suppressed cell growth by approximately 2-fold and reduced the number of colonies by 3-4-fold in MDA-MB-231 and BT549 cells. Moreover, inhibition of NPM1 in MDA-MB-231 and BT549 cells increased the percentage of cells at G0/G1 phase and decreased the percentage of cells at both S and G2/M phase, as compared with control counterparts. Western-blotting results showed that down-regulation of NPM1 could elevate CDH1 and p27kip1 expression, while decrease Skp2 expression both in MDA-MB-231 and BT549 cells. In addition, high mRNA expression of NPM1 correlated with shorter RFS (HR=1.64, =0.00013) and OS (HR=2.45, P=0.00034) in patients with TNBC.

Conclusions: NPM1 is significantly high expressed basal-like/triple-negative breast cancer and is correlated with shorter RFS and OS in this subset of patients. Knockdown of NPM1 impairs the proliferative capacity of TNBC cells via activation of the CDH1/Skp2/p27kip1 pathway. Targeting NPM1 is a potential therapeutic strategy against TNBC.
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http://dx.doi.org/10.2147/CMAR.S191176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306051PMC
December 2018

Modified prophylactic 5-fr pancreatic duct stent enhances the rate of spontaneous dislodgement: A multicenter randomized controlled trial.

United European Gastroenterol J 2018 Dec 5;6(10):1519-1526. Epub 2018 Oct 5.

Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou, China.

Background And Objectives: Prophylactic pancreatic duct stent placement effectively reduces post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients, but the optimal stent remains unclear. We modified a 5-Fr, 3 cm pancreatic stent by removing the flange on the pancreatic side and compared the rate of spontaneous dislodgement and complications with the ordinary stent.

Methods: This was a randomized controlled trial at six tertiary endoscopic centers. Patients deemed high risk for post-endoscopic retrograde cholangiopancreatography pancreatitis randomly received modified or ordinary pancreatic stent. The primary outcome was spontaneous stent dislodgement at five days and 14 days. Secondary outcomes were the success rate of stent placement and complications.

Results: A total of 276 patients were randomly assigned to receive modified stents (mS group) and ordinary stents (oS group). The placement of a pancreatic stent was successful in all 276 patients. There were no significant differences between groups with respect to age, sex, major diagnosis, or indications for stenting. At five days the spontaneous dislodgement rate was 47.72% for the mS group and 15.67% for the oS group (<0.001); at 14 days the rates were 84.21% and 42.65%, respectively ( < 0.001). Post-endoscopic retrograde cholangiopancreatography pancreatitis occurred in 6.52% of all patients. There were no significant differences regarding the incidences of post-endoscopic retrograde cholangiopancreatography pancreatitis, hemorrhage or fever.

Conclusions: The modified short 5-Fr stent has a higher spontaneous dislodgement rate than ordinary pancreatic stent, thus obviating the need for endoscopic removal. The modified pancreatic stent does not increase the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis or other complications. The endoscopist can consider removing the flange on the pancreatic duct side for prophylactic pancreatic duct manipulation.
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http://dx.doi.org/10.1177/2050640618804729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297921PMC
December 2018
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