Publications by authors named "Ye Yao"

143 Publications

YY1-mediated reticulocalbin-2 upregulation promotes the hepatocellular carcinoma progression via activating MYC signaling.

Am J Cancer Res 2021 15;11(5):2238-2251. Epub 2021 May 15.

Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University Wuhan 430071, Hubei, People's Republic of China.

Hepatocellular carcinoma (HCC) is a common digestive tumor with high fatality worldwide. Previous studies have shown that Reticulocalbin-2 (RCN2) was a crucial factor for HCC proliferation, but invasion and migration mechanism of RCN2 contributing to HCC is poorly investigated. In this study, we estimated the RCN2 expression in both patient tissues and cell lines by polymerase chain reaction (PCR) and western blotting (WB), as well as the clinical information of HCC patients from public databases. Biological function induced by RCN2 in and was also researched through multiple functional experiments. Upstream and downstream signal of RCN2 was identified by bioinformatics. We found that up-regulated RCN2 was related to poorer prognosis in HCC patients and attached significance to HCC proliferation, invasion and migration. Luciferase reporter assay and chromatin immunoprecipitation validated that YY1 as the upstream transcription factor of RCN2, facilitating the expression of RCN2. Gene set enrichment analysis indicated that HCC progression induced by RCN2 might be related to MYC signaling. Furthermore, we demonstrated RCN2 reduced proteasomal degradation of MYC and lead to HCC progression. The effects of overexpressed RCN2 in HCC were attenuated by MYC silencing. In conclusion, our study highlighted the vital role of RCN2 in tumor progression and the potential benefit for the treatment of HCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167676PMC
May 2021

Ge-Gen-Jiao-Tai-Wan Affects Type 2 Diabetic Rats by Regulating Gut Microbiota and Primary Bile Acids.

Evid Based Complement Alternat Med 2021 16;2021:5585952. Epub 2021 Apr 16.

Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.

The Ge-Gen-Jiao-Tai-Wan (GGJTW) formula has been used to treat type 2 diabetes mellitus (T2DM) in China for a long time. Our previous study has proved that GGJTW could alleviate the type 2 diabetic symptoms, but the underlying mechanisms are still unclear. This study aimed to investigate the changes in gut microbiota and primary bile acids (PBAs) to determine the potential mechanisms of GGJTW in treating T2DM.The fecal transplant method and pseudogerm-free rats were used in our study.The16S rRNA gene sequencing method was used to analyze the changes in the intestinal flora, and PBAs in the colon contents were detected. Finally, the expression of farnesoid receptor (FXR), protein-coupled membrane receptor 5 (TGR5), and glucagon-like peptide-1 (GLP-1) was assessed. Following GGJTW treatment, we observed a decrease in blood glucose levels and improvements in glucose tolerance and serum lipid levels. Furthermore, we found that GGJTW could regulate the composition of the gut microbiota and upregulate the diabetic beneficial phylum and bile-acid-related genus . PBAs in the colon contents were increased in the GGJTW-treated group, accompanied by upregulated expression of the bile acid receptors FXR and TGR5 and increased concentrations of GLP-1. These results indicated that GGJTW could alleviate symptoms of type 2 diabetic rats by regulating the gut microbiota, promoting the production of PBAs, and upregulating the PBA-FXR/TGR5-GLP-1 pathway.
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http://dx.doi.org/10.1155/2021/5585952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064793PMC
April 2021

Serum deprivation-response protein induces apoptosis in hepatocellular carcinoma through ASK1-JNK/p38 MAPK pathways.

Cell Death Dis 2021 Apr 30;12(5):425. Epub 2021 Apr 30.

Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.

Serum deprivation-response protein (SDPR), a phosphatidylserine-binding protein, which is known to have a promising role in caveolar biogenesis and morphology. However, its function in hepatocellular carcinoma (HCC) was still largely unknown. In this study, we discussed the characterization and identification of SDPR, and to present it as a novel apoptosis candidate in the incidence of HCC. We identified 81 HCC cases with lower SDPR expression in the tumor tissues with the help of qRT-PCR assay, and lower SDPR expression was potentially associated with poor prognostication. The phenotypic assays revealed that cell proliferation, invasion, and migration were profoundly connected with SDPR, both in vivo and in vitro. The data obtained from the gene set enrichment analysis (GSEA) carried out on the liver hepatocellular carcinoma (LIHC), and also The Cancer Genome Atlas (TCGA) findings indicated that SDPR was involved in apoptosis and flow cytometry experiments further confirmed this. Furthermore, we identified the interaction between SDPR and apoptosis signal-regulating kinase 1 (ASK1), which facilitated the ASK1 N-terminus-mediated dimerization and increased ASK1-mediated signaling, thereby activating the JNK/p38 mitogen-activated protein kinases (MAPKs) and finally enhanced cell apoptosis. Overall, this work identified SDPR as a tumor suppressor, because it promoted apoptosis by activating ASK1-JNK/p38 MAPK pathways in HCC.
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http://dx.doi.org/10.1038/s41419-021-03711-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087765PMC
April 2021

Preliminary Study on the Clinical and Genetic Characteristics of Hereditary Spherocytosis in 15 Chinese Children.

Front Genet 2021 18;12:652376. Epub 2021 Mar 18.

The Affiliated Children's Hospital of Nanchang University, Nanchang, China.

Objective: To investigate the clinical and genetic characteristics of hereditary spherocythemia (HS) in Chinese children, and to analyze the potential genotypic/phenotypic associations.

Methods: The clinical data and gene test results of children with HS were collected. All patients were diagnosed by gene test results, and the laboratory results were obtained before splenectomy. The data of red blood cell (RBC), hemoglobin (HB), mean red blood cell volume (MCV), mean red blood cell hemoglobin (MCH), mean red blood cell hemoglobin concentration (MCHC), and hematocrit (HCT) were statistically analyzed according to different mutation genes. Statistical methods for comparison between groups Mann-Whitney test analysis, two-terminal < 0.05 was considered significant difference.

Results: A total of 15 children were enrolled in our hospital, and 14 variants were found (nine variants have not been reported before), including 10 ANK1 mutations (seven ANK1 truncated mutations) and five SPTB mutations. Patients with ANK1 mutations had more severe anemia than those with SPTB mutations (significantly lower RBC, HB, MCHC, and HCT).

Conclusion: This is one of the few studies on the genetic and clinical characteristics of children with HS in China. This study identified the unique genetic and clinical characteristics of Chinese children with HS and analyzed the pathogenic genotype-phenotypic association. The results confirmed that the anemia degree of HS patients caused by ANK1 was more serious than that of patients with SPTB deficiency. However, further study of the correlation between genotype and phenotype requires a larger sample size.
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http://dx.doi.org/10.3389/fgene.2021.652376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044778PMC
March 2021

Anaerobic biodegradation of levofloxacin by enriched microbial consortia: Effect of electron acceptors and carbon source.

J Hazard Mater 2021 07 24;414:125520. Epub 2021 Feb 24.

Jiangsu Key Laboratory of Anaerobic Biotechnology, School of Environment and Civil Engineering, Jiangnan University, Wuxi 214122, China.

For improving the understanding of anaerobic degradation mechanism of fluoroquinolone antibiotics (FQs), the degradation of a representative FQs, levofloxacin (LEV), by six enriched anaerobic consortia were explored in this study. The effect of sulfate and nitrate as the electron acceptor and glucose as the carbon source on LEV anaerobic degradation were investigated. Addition of glucose and nitrate alone deteriorated LEV removal from 36.5% to 32.7% and 29.1%, respectively. Addition of sulfate slightly improved LEV removal to 39.6%, while simultaneous addition of glucose and sulfate significantly enhanced LEV removal to 53.1%. Twelve biodegradation intermediates were identified, which indicated that cleavage of piperazine ring is prior to that of quinolone ring, and hydroxylation, defluorination, demethylation, and decarboxylation were the primary steps of LEV anaerobic degradation. Lactobacillus, unclassified _f_Enterobacteriaceae, and Bacillus were enriched by simultaneous addition of glucose and sulfate, with relative abundance of 63.5%, 32.7%, and 3.3%, respectively. The predicted high gene abundance of xenobiotics biodegradation & metabolism, carbohydrate metabolism, and assimilatory sulfate reduction in the consortium, indicated a co-metabolism between carbohydrate metabolism, sulfate metabolism, and LEV degradation under glucose and sulfate added condition. The study revealed that simultaneous addition of glucose and sulfate is the favorable condition for LEV anaerobic degradation.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125520DOI Listing
July 2021

Lead in Synergism With IFNγ Acts on Bone Marrow-Resident Macrophages to Increase the Quiescence of Hematopoietic Stem Cells.

Toxicol Sci 2021 04;180(2):369-382

School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China.

Lead (Pb) is a highly toxic heavy metal that broadly exists in our living environment. Although Pb has been shown to influence the development of immune cells, to date, the impact of Pb on hematopoietic stem cells (HSCs) in the bone marrow (BM) remains unknown. As people are ubiquitously exposed to Pb and HSC are essential for human health, understanding the impact of Pb on HSC is significant for public health. In this study, we found that wild-type B6 mice treated with 1250 ppm Pb, but not 125 ppm Pb via drinking water for 8 weeks had increased quiescence of HSC in the BM. Functional analyses demonstrated that wild-type mice treated with 1250 ppm Pb had increased potential for HSC to repopulate the immune system and engraft to the niche in the BM under a competitive chimeric microenvironment of lethally irradiated recipients. Moreover, we found that Pb-increased quiescence of HSC critically relied on a synergetic action of Pb and interferon γ (IFNγ) on BM-resident macrophages (BM-MΦ), but not a direct action of Pb on HSC. Specifically, in steady state, BM-MΦ promoted HSC proliferation; and upon Pb treatment, IFNγ was induced in the BM, and thereafter Pb in synergism with IFNγ acted on BM-MΦ to cause BM-MΦ to become suppressive for HSC proliferation, thus leading to increased quiescence of HSC. Our study suggests that Pb increased the quiescence of HSC via a synergetic action of Pb and IFNγ on BM-MΦ, which was previously unrecognized toxicity of Pb.
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http://dx.doi.org/10.1093/toxsci/kfab001DOI Listing
April 2021

Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Trophoblast Functions.

Int J Mol Sci 2021 Jan 4;22(1). Epub 2021 Jan 4.

Center of Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, Ludwig-Maximilians University of Munich, Marchioninistr. 15, 81377 Munich, Germany.

Peroxisome proliferator-activated receptors (PPARα, PPAR, and PPAR) belong to the transcription factor family, and they are highly expressed in all types of trophoblast during pregnancy. The present review discusses currently published papers that are related to the regulation of PPARs via lipid metabolism, glucose metabolism, and amino acid metabolism to affect trophoblast physiological conditions, including differentiation, maturation, secretion, fusion, proliferation, migration, and invasion. Recent pieces of evidence have proven that the dysfunctions of PPARs in trophoblast lead to several related pregnancy diseases such as recurrent miscarriage, preeclampsia, intrauterine growth restriction, and gestational diabetes mellitus. Moreover, the underlying mechanisms of PPARs in the control of these processes have been discussed as well. Finally, this review's purposes are to provide more knowledge about the role of PPARs in normal and disturbed pregnancy with trophoblast, so as to find PPAR ligands as a potential therapeutic target in the treatment and prevention of adverse pregnancy outcomes.
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http://dx.doi.org/10.3390/ijms22010433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795665PMC
January 2021

Bach2 Deficiency Promotes Intestinal Epithelial Regeneration by Accelerating DNA Repair in Intestinal Stem Cells.

Stem Cell Reports 2021 01 30;16(1):120-133. Epub 2020 Dec 30.

Institute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai 200032, China; Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China. Electronic address:

Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury, although the repair mechanisms are unclear. Here, we found that Bach2 deficiency promotes intestinal epithelial cell proliferation during homeostasis. Moreover, genetic inactivation of Bach2 in mouse intestinal epithelium facilitated crypt regeneration after irradiation, resulting in a reduction in mortality. RNA-sequencing analysis of isolated crypts revealed that Bach2 deficiency altered the expression of numerous genes, including those regulating double-strand break repair. Mechanistic characterizations indicated that Bach2 deletion facilitated DNA repair in intestinal crypt cells, as evidenced by faster resolution of γ-H2AX and 53BP1 foci in Bach2 crypt cells, compared with Bach2 control. Together, our studies highlight that Bach2 deficiency promotes intestinal regeneration by accelerating DNA repair in intestinal stem cells after radiation damage.
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http://dx.doi.org/10.1016/j.stemcr.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897581PMC
January 2021

Intranasal delivery of MSC-derived exosomes attenuates allergic asthma via expanding IL-10 producing lung interstitial macrophages in mice.

Int Immunopharmacol 2021 Feb 24;91:107288. Epub 2020 Dec 24.

School of Medicine, Nankai University, Tianjin, China. Electronic address:

Mesenchymal stem cells (MSCs) have been investigated in preventing and treating allergic asthma in many reports. Recently, MSC-derived exosomes (MSC-Exo) were showed a promising alternative to stem cell-based therapy in many kinds of diseases. However, the effect of MSC-Exo on allergic asthma has not been investigated thoroughly thus far. Here, we aimed to investigate the immunomodulation effect of MSC-Exo in a murine model of asthma and explore the underlying mechanisms. BALB/c mice were sensitized and challenged by OVA to establish asthma model. MSC-Exo were intranasally delivered before or during challenge and the protective effect were assessed after the last OVA challenge. Allergic airway inflammation elicited by OVA were significantly attenuated by intranasal delivery of MSC-Exo. To explore the protective mechanism of MSC-Exo, lung interstitial macrophages (IMs) and alveolar macrophages (AMs) were analyzed by flow cytometry and the origin of IMs were traced. Lung IMs ratios were significantly enhanced and high level of IL-10 was produced after MSC-Exo intranasal delivery. IMs ratios were not obviously affected by CCR2 inhibitor or Clodronate liposome administration, whereas significantly decreased in splenectomized mice. Cx3cr1 cell specific IL-10 conditionally deficient mice were used to further examine the role of IL-10 producing IMs in allergic asthma. IMs-mediated protection was dependent on IL-10, given that the protection disappeared in Cx3cr1-IL-10mice. In conclusion, intranasal delivery of MSC-Exo could substantially expand lung IL-10-producing IMs, which may originate from spleen, thus contribute to protection against allergic asthma in mice.
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http://dx.doi.org/10.1016/j.intimp.2020.107288DOI Listing
February 2021

SIRT1 inhibitors mitigate radiation-induced GI syndrome by enhancing intestinal-stem-cell survival.

Cancer Lett 2021 Mar 24;501:20-30. Epub 2020 Dec 24.

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. Electronic address:

High-dose radiation exposure induces gastrointestinal (GI) stem cell death, resulting in denudation of the intestinal mucosa and lethality from GI syndrome, for which there is currently no effective therapy. Studying an intestinal organoid-based functional model, we found that Sirtuin1(SIRT1) inhibition through genetic knockout or pharmacologic inhibition significantly improved mouse and human intestinal organoid survival after irradiation. Remarkably, mice administered with two doseages of SIRT1 inhibitors at 24 and 96 h after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, with improved mouse survival (88.89% of mice in the treated group vs. 0% of mice in the control group). Moreover, our data revealed that SIRT1 inhibition increased p53 acetylation, resulting in the stabilization of p53 and likely contributing to the survival of intestinal epithelial cells post-radiation. These results demonstrate that SIRT1 inhibitors are effective clinical countermeasures to mitigate GI toxicity from potentially lethal radiation exposure.
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http://dx.doi.org/10.1016/j.canlet.2020.12.034DOI Listing
March 2021

Identification of an Immune-Related Gene Signature to Improve Prognosis Prediction in Colorectal Cancer Patients.

Front Genet 2020 4;11:607009. Epub 2020 Dec 4.

Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: Despite recent advance in immune therapy, great heterogeneity exists in the outcomes of colorectal cancer (CRC) patients. In this study, we aimed to analyze the immune-related gene (IRG) expression profiles from three independent public databases and develop an effective signature to forecast patient's prognosis.

Methods: IRGs were collected from the ImmPort database. The CRC dataset from The Cancer Genome Atlas (TCGA) database was used to identify a prognostic gene signature, which was verified in another two CRC datasets from the Gene Expression Omnibus (GEO). Gene function enrichment analysis was conducted. A prognostic nomogram was built incorporating the IRG signature with clinical risk factors.

Results: The three datasets had 487, 579, and 224 patients, respectively. A prognostic six-gene-signature (CCL22, LIMK1, MAPKAPK3, FLOT1, GPRC5B, and IL20RB) was developed through feature selection that showed good differentiation between the low- and high-risk groups in the training set ( < 0.001), which was later confirmed in the two validation groups (log-rank < 0.05). The signature outperformed tumor TNM staging for survival prediction. GO and KEGG functional annotation analysis suggested that the signature was significantly enriched in metabolic processes and regulation of immunity ( < 0.05). When combined with clinical risk factors, the model showed robust prediction capability.

Conclusion: The immune-related six-gene signature is a reliable prognostic indicator for CRC patients and could provide insight for personalized cancer management.
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http://dx.doi.org/10.3389/fgene.2020.607009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746810PMC
December 2020

Risk assessment and evaluation of China's policy to prevent COVID-19 cases imported by plane.

PLoS Negl Trop Dis 2020 12 7;14(12):e0008908. Epub 2020 Dec 7.

Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China.

As of October 5, 2020, China has reported 2,921 cases imported from overseas. Assessing the effectiveness of China's current policies on imported cases abroad is very important for China and other countries that are facing or will face overseas imported cases. In April, we used a susceptible-exposed-infectious-recovered metapopulation model to simulate the epidemic in seven foreign countries, China and the three Chinese key cities. Based on the model outside China, we estimated the proportion of people in incubation period and calculated the risk indexes for Chinese cities through analyzing aviation traffic data from these countries. Based on the model in China and the three key cities, we collected information on control measures and quantified the effectiveness of implementing the current policies at different times and intensities. Our model results showed that Shanghai, Beijing, Qingdao, Guangzhou, and Tianjin have the top five risk indexes. As of April 20, 2020, under current measures, the number of confirmed cases could be reduced by 99% compared with no air traffic restrictions and isolation measures; the reduction could be 93% with isolation of passengers only from key countries. If the current policy were postponed for 7, 10, or 20 days, the increase in the number of confirmed cases would be 1,329, 5,524, and 779,245 respectively, which is 2.1, 5.7, and 662.9 times the number of confirmed cases under current measures. Our research indicates that the importation control measures currently taken by China were implemented at an appropriate time to prevent the epidemic spreading and have achieved relatively good control results. However, it is necessary to remain vigilant; otherwise, another outbreak peak could occur.
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http://dx.doi.org/10.1371/journal.pntd.0008908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746261PMC
December 2020

Procalcitonin Levels in Post TACE Infection.

Cancer Manag Res 2020 26;12:12197-12203. Epub 2020 Nov 26.

Department of Surgical Oncology, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, People's Republic of China.

Purpose: This study aimed to evaluate the value of serum procalcitonin (PCT) levels in the diagnosis of abscess and sepsis following transarterial chemoembolization (TACE) therapy among patients with hepatocellular carcinoma (HCC).

Patients And Methods: In this study, a retrospective review of patient charts was performed in 2221 patients who suffered from hepatocellular carcinoma and had undergone 8656 TACE procedures from January 2012 to January 2018. According to the diagnosis of infection and abscess after TACE, these participants were divided into infection group (group A, n=48) and abscess group (group B, n=35). Group B included subgroup B1 (suffered from liver abscess but no sepsis, n=16) and subgroup B2 (suffered from liver abscess and sepsis, n=19). The main observational indexes included sociodemographic characteristics and laboratory and clinical parameters.

Results: The results showed that the mean PCT and C-reactive protein (CRP) levels were higher in group B, but receiver-operating characteristic (ROC) analysis showed low sensitivity and specificity. Only the mean PCT level was higher in subgroup B2 than in subgroup B1 (P<0.001); the ROC analysis had high sensitivity and specificity. However, all other data such as NEUT (neutrophil count) and NEUTP (neutrophil percentage) showed no significant differences.

Conclusion: Serum PCT level was a promising inexpensive marker for the diagnosis of liver abscess and sepsis following TACE therapy among patients with primary liver cancer. A cutoff level of 5.1 ng/mL for PCT had high sensitivity and specificity in predicting liver abscess with sepsis.
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http://dx.doi.org/10.2147/CMAR.S281667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705265PMC
November 2020

A novel long non-coding RNA RP11-286H15.1 represses hepatocellular carcinoma progression by promoting ubiquitination of PABPC4.

Cancer Lett 2021 02 28;499:109-121. Epub 2020 Nov 28.

Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, PR China. Electronic address:

Hepatocellular carcinoma (HCC) is a malignancy found at high frequency around the world. Unfortunately, the scarcity of effective early diagnostic methods invariably results in poor outcomes. Long noncoding RNAs (lncRNAs) are known to regulate the progression of hepatocellular carcinoma (HCC). A novel lncRNA RP11-286H15.1(OTTHUMG00000186042) has been identified and associated with HCC; however, the potential role of RP11-286H15.1 in HCC remains undefined. The transcript abundance of RP11-286H15.1 in 80 pairs of HCC samples and cell lines was evaluated by qRT-PCR analysis. The functional role of RP11-286H15.1 in HCC was tested in vivo and in vitro. The mechanisms underlying the role of RP11-286H15.1 in HCC were explored by RNA pulldown, transcriptome sequencing, and RNA immunoprecipitation (RIP), ubiquitination and fluorescence in situ hybridization (FISH) assays as well as Western blot analysis. The qRT-PCR and FISH assays revealed that RP11-286H15.1 was significantly decreased in HCC, and implied a shorter survival time. RP11-286H15.1 overexpression inhibited HCC cell proliferation and metastasis in vitro and in vivo, whereas RP11-286H15.1 knockdown produced the opposite results. Furthermore, we confirmed that RP11-286H15.1 (620-750 nucleotides) binds to poly(A) binding protein 4 (PABPC4) and promotes its ubiquitination, thus, reducing the stability of TRIM37 and CDC27 mRNAs. Our study demonstrates that a novel lncRNA, RP11-286H15.1, represses HCC progression by promoting PABPC4 ubiquitination. These findings highlight potential therapeutic targets for HCC.
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http://dx.doi.org/10.1016/j.canlet.2020.11.038DOI Listing
February 2021

Warmer weather unlikely to reduce the COVID-19 transmission: An ecological study in 202 locations in 8 countries.

Sci Total Environ 2021 Jan 9;753:142272. Epub 2020 Sep 9.

School of Public Health, Key Lab of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. Electronic address:

Purpose: To examine the association between meteorological factors (temperature, relative humidity, wind speed, and UV radiation) and transmission capacity of COVID-19.

Methods: We collected daily numbers of COVID-19 cases in 202 locations in 8 countries. We matched meteorological data from the NOAA National Centers for Environmental Information. We used a time-frequency approach to examine the possible association between meteorological conditions and basic reproductive number (R) of COVID-19. We determined the correlations between meteorological factors and R of COVID-19 using multiple linear regression models and meta-analysis. We further validated our results using a susceptible-exposed-infectious-recovered (SEIR) metapopulation model to simulate the changes of daily cases of COVID-19 in China under different temperatures and relative humidity conditions.

Principal Results: Temperature did not exhibit significant association with R of COVID-19 (meta p = 0.446). Also, relative humidity (meta p = 0.215), wind speed (meta p = 0.986), and ultraviolet (UV) radiation (meta p = 0.491) were not significantly associated with R either. The SEIR model in China showed that with a wide range of meteorological conditions, the number of COVID-19 confirmed cases would not change substantially.

Conclusions: Meteorological conditions did not have statistically significant associations with the R of COVID-19. Warmer weather alone seems unlikely to reduce the COVID-19 transmission.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480263PMC
January 2021

Do the existing staging systems for primary liver cancer apply to combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma?

Hepatobiliary Pancreat Dis Int 2021 Feb 27;20(1):13-20. Epub 2020 Oct 27.

Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China. Electronic address:

Background: The incidence of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma (cHCC-ICC) is relatively low, and the knowledge about the prognosis of cHCC-ICC remains obscure. In the study, we aimed to screen existing primary liver cancer staging systems and shed light on the prognosis and risk factors for cHCC-ICC.

Methods: We retrospectively reviewed 206 cHCC-ICC patients who received curative surgical resection from April 1999 to March 2017. The correlation of survival measures with the histological types or with tumor staging systems was determined and predictive values of tumor staging systems with cHCC-ICC prognosis were compared.

Results: The histological type was not associated with overall survival (OS) (P = 0.338) or disease-free survival (DFS) (P = 0.843) of patients after curative surgical resection. BCLC, TNM for HCC, and TNM for ICC stages correlated with both OS and DFS in cHCC-ICC (all P < 0.05). The predictive values of TNM for HCC and TNM for ICC stages were similar in terms of predicting postoperative OS (P = 0.798) and DFS (P = 0.191) in cHCC-ICC. TNM for HCC was superior to BCLC for predicting postoperative OS (P = 0.022) in cHCC-ICC.

Conclusion: The TNM for HCC staging system should be prioritized for clinical applications in predicting cHCC-ICC prognosis.
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http://dx.doi.org/10.1016/j.hbpd.2020.10.002DOI Listing
February 2021

Regulation of the regeneration of intestinal stem cells after irradiation.

Ann Transl Med 2020 Sep;8(17):1063

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.

Background: Radiation enteritis is common in cancer patients with abdominal and pelvic malignant tumors that have received radiotherapy. Regeneration of intestinal stem cells is a critical process for intestine self-repairing post-irradiation. In this study, we attempted to find out the molecules that promote the regeneration of intestinal stem cells to repair the irradiation damage.

Methods: Male C57BL/6 mice were given a single dose of 12 Gy irradiation, and cultured organoids were given 6 Gy X-rays to construct the regeneration of intestinal stem cells. Hematoxylin and eosin (H&E) staining was performed for morphological observation. In situ hybridization was used to detect the expression of Lgr5, and immunofluorescence staining was adopted to detect the expression of CD44. FACS was used to sort CD44 positive cells of crypts. RNA was then extracted, and RNA-Seq was performed. The Wnt11 over-expression cell line was constructed to collect the Wnt11 conditioned medium (CM).

Results: The results showed both Lgr5 and CD44 located at the bottom of normal crypts. The expression of Lgr5 was lower at day 3.5, 5, but recovered at day 10 post-irradiation compared with the control. However, the expression of CD44 was higher at day 3.5, 5, but recovered at day 10 post-irradiation compared with the control group. The quantitative real-time polymerase chain reaction (qRT-PCR) assay showed consistent results. RNA-Seq results showed that Wnt11 was over-expressed in the irradiation group. After irradiation adding Wnt11 condition medium to culture, the intestinal organoids resulted in a bigger size and more buddings of the newborn organoids compared with the control group.

Conclusions: The expression of CD44 increases during the radiation-induced regeneration of intestinal stem cells while Lgr5 decreases, adding Wnt11 CM can facilitate the proliferation of the newborn organoids after irradiation. Wnt11 is a potential target to promote the regeneration of intestinal stem cells to repair the radiation injury.
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http://dx.doi.org/10.21037/atm-20-4542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575967PMC
September 2020

How Does Chronic Intermittent Hypoxia Influence Upper Airway Stability in Rats?

Nat Sci Sleep 2020 15;12:749-758. Epub 2020 Oct 15.

Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang, People's Republic of China.

Background: Obstructive sleep apnea (OSA) is characterized by repetitive episodes of upper airway collapse during sleep. The contraction of upper airway dilator muscles plays a crucial role in maintaining UA patency. Chronic intermittent hypoxia (CIH) is the most important pathophysiological process of OSA. Exposure to CIH induced not only the damage of dilator muscles but also the plasticity of the muscles. This study aimed to dynamically assess the influence of CIH on the upper airway.

Methods: The experiments were performed on 44 rats. They were randomly divided into a normoxia (NO) group (n=22) and CIH group (n=22). In each group (n=6, respectively), EMG, transcranial magnetic stimulation (TMS) response, and critical pressure (Pcrit) value were recorded on day 0 (the day before exposure), and the 7th, 14th, 21st, and 28th day of air/CIH exposure. For each group, 16 rats were used for transmission electron microscopy observations on day 0, and the 7th, 14th and 28th day of air/CIH exposure (n=4 for every time point).

Results: Compared to the NO group at the same point, the CIH group showed a damaged ultrastructure of genioglossus, increased activity of genioglossus corticomotor area, and increased Pcrit of the upper airway from the 7th to the 28th day of CIH. Increased EMG activity occurred at the 14th day of CIH and lasted for 2 weeks.

Conclusion: The elevated genioglossus corticomotor excitability in response to the CIH could not counterbalance the damage effect of CIH on upper airway dilator muscles, which ultimately increased the collapsibility of the upper airway.
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http://dx.doi.org/10.2147/NSS.S249948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573330PMC
October 2020

Association between childhood trauma and risk for obesity: a putative neurocognitive developmental pathway.

BMC Med 2020 10 15;18(1):278. Epub 2020 Oct 15.

Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Shanghai, 200433, People's Republic of China.

Background: Childhood trauma increases the risk for adult obesity through multiple complex pathways, and the neural substrates are yet to be determined.

Methods: Participants from three population-based neuroimaging cohorts, including the IMAGEN cohort, the UK Biobank (UKB), and the Human Connectome Project (HCP), were recruited. Voxel-based morphometry analysis of both childhood trauma and body mass index (BMI) was performed in the longitudinal IMAGEN cohort; validation of the findings was performed in the UKB. White-matter connectivity analysis was conducted to study the structural connectivity between the identified brain region and subdivisions of the hypothalamus in the HCP.

Results: In IMAGEN, a smaller frontopolar cortex (FPC) was associated with both childhood abuse (CA) (β = - .568, 95%CI - .942 to - .194; p = .003) and higher BMI (β = - .086, 95%CI - .128 to - .043; p < .001) in male participants, and these findings were validated in UKB. Across seven data collection sites, a stronger negative CA-FPC association was correlated with a higher positive CA-BMI association (β = - 1.033, 95%CI - 1.762 to - .305; p = .015). Using 7-T diffusion tensor imaging data (n = 156), we found that FPC was the third most connected cortical area with the hypothalamus, especially the lateral hypothalamus. A smaller FPC at age 14 contributed to higher BMI at age 19 in those male participants with a history of CA, and the CA-FPC interaction enabled a model at age 14 to account for some future weight gain during a 5-year follow-up (variance explained 5.8%).

Conclusions: The findings highlight that a malfunctioning, top-down cognitive or behavioral control system, independent of genetic predisposition, putatively contributes to excessive weight gain in a particularly vulnerable population, and may inform treatment approaches.
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http://dx.doi.org/10.1186/s12916-020-01743-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559717PMC
October 2020

Ambient nitrogen dioxide pollution and spreadability of COVID-19 in Chinese cities.

Ecotoxicol Environ Saf 2021 Jan 30;208:111421. Epub 2020 Sep 30.

Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032, China; Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China; Shanghai Key Laboratory of Meteorology and Health, Shanghai 200032, China. Electronic address:

This study aims to explore the relationship between ambient NO levels and the transmission ability (basic reproductive number, R) of COVID-19 in 63 Chinese cities. After adjustment for temperature and relative humidity, R was positively associated with NO concentration at city level. The temporal analysis within Hubei province indicated that all the 11 Hubei cities (except Xianning City) had significant positive correlations between NO concentration (with 12-day time lag) and R (r > 0.51, p < 0.005). Since the association between ambient NO and R indicated NO may increase underlying risk of infection in the transmission process of COVID-19. In addition, NO is also an indicator of traffic-related air pollution, the association between NO and COVID-19's spreadability suggest that reduced population movement may have reduced the spread of the SARS-CoV-2.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524685PMC
January 2021

Expression of trophoblast derived prostaglandin E2 receptor 2 (EP2) is reduced in patients with recurrent miscarriage and EP2 regulates cell proliferation and expression of inflammatory cytokines.

J Reprod Immunol 2020 11 1;142:103210. Epub 2020 Oct 1.

LMU Munich, University Hospital, Department of Obstetrics and Gynaecology, Marchioninistr. 15, 81377 Munich, Germany.

Backgroud: Prostaglandin E2 (PGE2), an inflammatory mediator, modulates cytokines, regulates immune responses in reproductive processes and stimulates inflammatory reactions via the prostaglandin E2 receptor 2 (EP2). However, the regulatory effects of EP2 signaling on trophoblasts and its role in unexplained recurrent miscarriage (uRM) remains unclear.

Patients And Methods: A total of 19 placentas from patients with a history of more than two consecutive pregnancy losses of unknown cause (uRM group) and placentas of 19 healthy patients following a legal termination of their pregnancy were used for PGE2 receptor (EP1, EP2 and EP4) expression analyses via immunohistochemistry. Double immunofluorescence was also used to identify EP2 expressing cells in the decidua. Finally, HTR-8/SVneo cells were used to clarify the role of EP2 in in vitro experiments.

Results: The expression of EP2 and EP4 was found to be reduced in the syncytiotrophoblast and decidua of uRM patients. A selective EP2 receptor antagonist (PF-04,418,948) reduced the proliferation and secretion of ß-hCG, inhibited interleukin -6 (IL-6) and interleukin-8 (IL-8) and up-regulated the production of the tumor necrosis factor-α (TNF-α) and plasminogen activator inhibitor type 1 (PAI-1) in HTR-8/SVneo cells in vitro.

Conclusion: PGE2-EP2 signaling pathway may represent a novel therapy option for uRM. The involvement of EP2 in uRM acts perhaps via inflammatory cytokines and indicates that the PGE2-EP2 signaling pathway might represent an unexplored etiology for uRM.
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http://dx.doi.org/10.1016/j.jri.2020.103210DOI Listing
November 2020

Formate-Dependent Acetogenic Utilization of Glucose by the Fecal Acetogen .

Appl Environ Microbiol 2020 11 10;86(23). Epub 2020 Nov 10.

School of Environmental and Civil Engineering, Jiangsu Key Laboratory of Anaerobic Biotechnology, Jiangsu Engineering Laboratory for Biomass Energy and Carbon Reduction Technology, Jiangnan University, Wuxi, China

Acetogenic bacteria are a diverse group of anaerobes that use the reductive acetyl coenzyme A (acetyl-CoA) (Wood-Ljungdahl) pathway for CO fixation and energy conservation. The conversion of 2 mol CO into acetyl-CoA by using the Wood-Ljungdahl pathway as the terminal electron accepting process is the most prominent metabolic feature for these microorganisms. However, here, we describe that the fecal acetogen strain BXX displayed poor metabolic capabilities of autotrophic acetogenesis, and acetogenic utilization of glucose occurred only with the supplementation of formate. Genome analysis of revealed that it contains almost the complete genes of the Wood-Ljungdahl pathway but lacks the gene encoding formate dehydrogenase, which catalyzes the reduction of CO to formate as the first step of the methyl branch of the Wood-Ljungdahl pathway. The lack of a gene encoding formate dehydrogenase was verified by PCR, reverse transcription-PCR analysis, enzyme activity assay, and its formate-dependent acetogenic utilization of glucose on DNA, RNA, protein, and phenotype level, respectively. The lack of a formate dehydrogenase gene may be associated with the adaption to a formate-rich intestinal environment, considering the isolating source of strain BXX. The formate-dependent acetogenic growth of provides insight into a unique metabolic feature of fecal acetogens. The acetyl-CoA pathway is an ancient pathway of CO fixation, which converts 2 mol of CO into acetyl-CoA. Autotrophic growth with H and CO via the acetyl-CoA pathway as the terminal electron accepting process is the most unique feature of acetogenic bacteria. However, the fecal acetogen strain BXX displayed poor metabolic capabilities of autotrophic acetogenesis, and acetogenic utilization of glucose occurred only with the supplementation of formate. The formate-dependent acetogenic growth of was associated with its lack of a gene encoding formate dehydrogenase, which may result from adaption to a formate-rich intestinal environment. This study gave insight into a unique metabolic feature of fecal acetogens. Because of the requirement of formate for the acetogenic growth of certain acetogens, the ecological impact of acetogens could be more complex and important in the formate-rich environment due to their trophic interactions with other microbes.
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http://dx.doi.org/10.1128/AEM.01870-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657615PMC
November 2020

Berberine alleviates type 2 diabetic symptoms by altering gut microbiota and reducing aromatic amino acids.

Biomed Pharmacother 2020 Nov 13;131:110669. Epub 2020 Sep 13.

Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China; Hunan Key Laboratory of Traditional Chinese Medicine for Gan of State Administration, Central South University, Changsha, 410008, China. Electronic address:

Objective: Berberine (BBR), which is extracted from traditional Chinese herb, is abundant in Coptis chinensis and Berberis vulgaris, with a treatment on type 2 diabetes mellitus (T2DM). However, its oral bioavailability is poor. Therefore, the ability of BBR to regulate gut microbiota and intestinal metabolites might exist. This study aimed to investigate changes in gut microbiota and intestinal metabolites, and to reveal the potential mechanism of BBR.

Methods: To observe the role of gut microbiota in the treatment of T2DM by BBR, antibiotics intervened gut microbiota was used in this study, and the therapeutic effects of BBR were evaluated. A 16S rRNA gene sequencing approach was utilized to analyze gut microbiota alterations, and UHPLC-QTOF/MS-based untargeted metabolomics analysis of colon contents was used to identity differential intestinal metabolites. Finally, serum aromatic amino acids (AAAs) were absolutely quantified using LC/MS.

Results: Inhibition of the blood glucose levels, and improvements in glucose tolerance and serum lipid parameters were observed in the BBR treated group. Type 2 diabetic symptoms in rats in the BA group (treated with antibotics and BBR) were alleviated. However, the therapeutical effects are weaker in the BA group compared with the BBR group, indicating that BBR can be used to treat type 2 diabetic rats immediately, and modulation of gut microbiota is related to the mechanism of BBR in the treatment of T2DM. The community richness and diversity of the gut microbiota were significantly increased by BBR, and the relative abundance of Bacteroidetes was increased in the BBR group, which was accompanied by a decreased relative abundance of Proteobacteria and Verrucomicrobia at the phylum level. At the family level, a probiotic Lactobacillaceae was significantly upregulated not only in the BBR group but also in the BA group and was negatively associated with the risk of T2DM. Metabolomic analysis of colon contents identified 55 differential intestinal metabolites between the BBR group and the model group. AAAs, including tyrosine, tryptophan and phenylalanine, were obviously decreased in the BBR group not only in the colon contents but also in the serum.

Conclusions: These results demonstrated that BBR could alleviate symptoms in type 2 diabetic rats by affecting gut microbiota composition and reducing the concentration of AAAs.
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http://dx.doi.org/10.1016/j.biopha.2020.110669DOI Listing
November 2020

Up-regulation of CLIC1 activates MYC signaling and forms a positive feedback regulatory loop with MYC in Hepatocellular carcinoma.

Am J Cancer Res 2020 1;10(8):2355-2370. Epub 2020 Aug 1.

Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University Wuhan 430071, Hubei, PR China.

Hepatocellular carcinoma (HCC) is leading cause of tumor-related deaths worldwide. The intracellular chloride channel protein (CLIC1) plays a role in the occurrence and progression of HCC, although the underlying mechanisms are still unclear. We evaluated the CLIC1 mRNA and protein levels in both patient tissues and HCC cell lines, and analyzed the correlation between CLIC1 expression and clinical features. The biological function of CLIC1 in HCC was examined in vivo and in vitro. The upstream regulatory factors were identified by bioinformatics programs, and downstream mechanisms affecting HCC behavior have also been explored and validated. CLIC1 was up-regulated in HCC tissues and cell lines, and promoted the proliferation, invasion and migration of HCC cells in vivo and in vitro. TP53 was identified as the upstream transcription factor of CLIC1. MiR-122-5p also regulated CLIC1 levels by degrading the transcripts. More importantly, we found that the increased CLIC1 was significantly related to the activation of MYC signaling. By binding with MYC, CLIC1 enhanced the transcription activity of MYC to downstream genes, rather than by altering its expression. Finally, a positive feedback regulatory loop between CLIC1 and MYC was established. CLIC1 is closely related to the occurrence, progression and prognosis of HCC, and a promising novel therapeutic target.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471371PMC
August 2020

Important roles of estrogen receptor alpha in tumor progression and anti-estrogen therapy of pancreatic ductal adenocarcinoma.

Life Sci 2020 Nov 19;260:118302. Epub 2020 Aug 19.

Department of Pharmaceutics, School of Pharmaceutical Science, Peking University Health Science Center, Beijing 100191, China. Electronic address:

Aims: The roles of estrogen receptors (ERs) and the efficacy of anti-estrogen (E2) therapies in pancreatic cancer stay controversial. The main objectives of this study were to investigate the potential roles of ERs in tumor progression and endocrine therapies.

Main Methods: The ER expression status in PANC-1 and SW1990 pancreatic cancer cell lines was determined. SRB assay, colony formation assay and proliferation assay were used to investigate the responses of these cells to E2. ERα-selective agonist propylpyrazoletriol (PPT), ERβ-selective agonist diarylpropionitrile (DPN), ERα over-expressed SW1990 cells, ERα knock-out PANC-1 cells and patient-derived xenografts (PDX) were applied to investigate the potential roles of ERα in pancreatic cancer. The phosphorylation of ERα-related signaling molecules extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) were investigated. The in vivo anti-tumor efficacy and safety of letrozole (LTZ) combined with leuprorelin acetate (LA) and gemcitabine (GEM) were also preliminarily studied.

Key Findings: PANC-1 cells expressed much more ERα than SW1990 cells, and ERβ level was with less diversity. Accordingly, the proliferation of PANC-1 rather than SW1990 cells could be stimulated by E2, and only PANC-1 could respond to LTZ endocrine therapy in female but not male mice. The phosphorylation of ERK1/2 but not AKT was altered by over-expressed or knocking out of ERα with or without the addition of E2 and LTZ. The combination therapy of LTZ and GEM showed acceptable efficacy and safety.

Significance: This study showed the important roles of ERα in tumor progression and endocrine therapies of pancreatic cancer in women.
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http://dx.doi.org/10.1016/j.lfs.2020.118302DOI Listing
November 2020

Autophagy and Tumor Database: ATdb, a novel database connecting autophagy and tumor.

Database (Oxford) 2020 01;2020

Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.

Autophagy is an essential cellular process that is closely implicated in diverse pathophysiological processes and a variety of human diseases, especially tumors. Autophagy is regarded as not only an anti-cancer process in tumorigenesis but also a pro-tumor process in progression and metastasis according to current research. It means the role of autophagy in tumor is considered to be complex, controversial and context dependent. Hence, a comprehensive database is of great significance to obtain an in-depth understanding of such complex correlations between autophagy and tumor. To achieve this objective, here we developed the Autophagy and Tumor Database (named as ATdb, http://www.bigzju.com/ATdb/#/) to compile the published information concerning autophagy and tumor research. ATdb connected 25 types of tumors with 137 genes required for autophagy-related pathways, containing 219 population filters, 2650 hazard ratio trend plots, 658 interacting microRNAs, 266 interacting long non-coding RNAs, 155 post-translational modifications, 298 DNA methylation records, 331 animal models and 70 clinical trials. ATdb could enable users to search, browse, download and carry out efficient online analysis. For instance, users can make prediction of autophagy gene regulators in a context-dependent manner and in a precise subpopulation and tumor subtypes. Also, it is feasible in ATdb to cluster tumors into distinguished groups based on the gene-related long non-coding RNAs to gain novel insights into their potential functional implications. Thus, ATdb offers a powerful online database for the autophagy community to explore the complex world of autophagy and tumor. Database URL: http://www.bigzju.com/ATdb/#/.
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http://dx.doi.org/10.1093/database/baaa052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340339PMC
January 2020

Temporal association between particulate matter pollution and case fatality rate of COVID-19 in Wuhan.

Environ Res 2020 10 15;189:109941. Epub 2020 Jul 15.

Fudan University, Shanghai, China. Electronic address:

The coronavirus (COVID-19) epidemic reported for the first time in Wuhan, China at the end of 2019, which has caused 4648 deaths in China as of July 10, 2020. This study explored the temporal correlation between the case fatality rate (CFR) of COVID-19 and particulate matter (PM) in Wuhan. We conducted a time series analysis to examine the temporal day-by-day associations. We observed a higher CFR of COVID-19 with increasing concentrations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 μm or less (PM) and fine PM with an aerodynamic diameter of 2.5 μm or less (PM) in the temporal scale. This association may affect patients with mild to severe disease progression and affect their prognosis.
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http://dx.doi.org/10.1016/j.envres.2020.109941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361083PMC
October 2020

Hyperglycemia suppresses the regulatory effect of hypoxia-inducible factor-1α in pulmonary Aspergillus fumigatus infection.

Pathog Dis 2020 07;78(5)

Department of Respiratory and Critical Care Medicine, The First Hospital of China Medical University, Shenyang, 110000, China.

Aspergillus fumigatus is one of the most common fungal infections involved in the pulmonary diseases. Hypoxia-inducible factor-1α (HIF-1α) is important for antifungal immunity. Diabetes is a risk factor of pulmonary A. fumigatus infection and could affect the expression of HIF-1α. The aim of this investigation was to evaluate the role of HIF-1α in pulmonary A. fumigatus infection in diabetes. In murine model, we found diabetic mice had aggravated pulmonary A. fumigatus infection and declined expression of HIF-1α following pulmonary A. fumigatus infection. And these changes could be corrected by dimethyloxalylglycine (DMOG), the agonist of HIF-1α. In cell experiment, after A. fumigatus stimulation, hyperglycemic state was with a decreased HIF-1α expression and increased NLRP3/IL-1β signal pathway. The percentages of Th1 and Treg cells decreased, while percentages of Th2 and Th17 increased in hyperglycemic group. DMOG suppressed A. fumigatus-stimulated NLRP3 and IL-1β expressions in hyperglycemic group and corrected Th and Treg cells differentiation. These regulatory effects of DMOG could be dampened by activating of NLRP3. These data indicated that hyperglycemia suppressed the regulatory effect of HIF-1α in pulmonary A. fumigatus infection, which can affect Th and Treg cells differentiation by regulating the NLRP3/IL-1β signal pathway.
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http://dx.doi.org/10.1093/femspd/ftaa038DOI Listing
July 2020

Cyclocarya paliurus polysaccharides alleviate type 2 diabetic symptoms by modulating gut microbiota and short-chain fatty acids.

Phytomedicine 2020 Oct 30;77:153268. Epub 2020 Jun 30.

Institute of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha,410008, China; Hunan Key Laboratory of Traditional Chinese Medicine for Gan of State Administration, Central South University, Changsha, 410008, China. Electronic address:

Background: Cyclocarya paliurus polysaccharide (CCPP), a primary active component in the leaves of Cyclocarya paliurus (Batal.) Iljinsk (C. paliurus), has the ability to treat type 2 diabetes mellitus (T2DM), but cannot be digested by our digestive system. Therefore, mechanisms of regulating the gut microbiota and intestinal metabolites might exist.

Purpose: To reveal the potential mechanism of CCPP treatment, this study aimed to investigate the alterations of the gut microbiota and intestinal metabolites especially short chain fatty acids (SCFAs) in type 2 diabetic rats.

Study Design And Methods: Type 2 diabetic rat models were developed, and the therapeutic effects of CCPP were evaluated. Metagenomics analysis was utilized to analyze the alterations to the gut microbiota, and UHPLC-QTOF/MS-based untargeted metabolomics analysis of colon contents was used to identify the differential intestinal metabolites. GC/MS was used to measure the SCFAs in rat's colon contents and human fecal inoculums. Furthermore, the expression of SCFA receptors including GPR41, GPR43 and GPR109a was verified by qRT-PCR and the concentration of glucagon-like peptide-1(GLP-1) and peptide tyrosinetyrosine (PYY) was measured by Elisa.

Results: Inhibition of the blood glucose levels and improvements in glucose tolerance and serum lipid parameters were observed after CCPP treatment. Eleven SCFA-producing species including Ruminococcus_bromii, Anaerotruncus_colihominis, Clostridium_methylpentosum, Roseburia_intestinalis, Roseburia_hominis, Clostridium_asparagiforme, Pseudoflavonifractor_capillosus, Intestinimonas_butyriciproducens, Intestinimonas_sp._GD2, Oscillibacter_valericigenes and Oscillibacter_ruminantium were clearly increased in the CCPP group. Furthermore, our study indicated that CCPP increases the production of SCFAs both in vivo and in vitro, and the gut microbiota are the key factor of this process. The SCFA receptors including GPR41, GPR43 and GPR109a, were significantly stimulated in the CCPP treated rats, which was accompanied by the upregulated expression of GLP-1 and PYY.

Conclusion: These results demonstrated that CCPP could alleviate type 2 diabetic symptoms by increasing the SCFA-producing bacteria, promoting the production of SCFAs and upregulating SCFA-GLP1/PYY associated sensory mediators.
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http://dx.doi.org/10.1016/j.phymed.2020.153268DOI Listing
October 2020