Publications by authors named "Lin Gao"

448 Publications

CBP-JMF: An Improved Joint Matrix Tri-Factorization Method for Characterizing Complex Biological Processes of Diseases.

Front Genet 2021 23;12:665416. Epub 2021 Apr 23.

School of Computer Science and Technology, Xidian University, Xi'an, China.

Multi-omics molecules regulate complex biological processes (CBPs), which reflect the activities of various molecules in living organisms. Meanwhile, the applications to represent disease subtypes and cell types have created an urgent need for sample grouping and associated CBP-inferring tools. In this paper, we present CBP-JMF, a practical tool primarily for discovering CBPs, which underlie sample groups as disease subtypes in applications. Differently from existing methods, CBP-JMF is based on a joint non-negative matrix tri-factorization framework and is implemented in Python. As a pragmatic application, we apply CBP-JMF to identify CBPs for four subtypes of breast cancer. The result shows significant overlapping between genes extracted from CBPs and known subtype pathways. We verify the effectiveness of our tool in detecting CBPs that interpret subtypes of disease.
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http://dx.doi.org/10.3389/fgene.2021.665416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103031PMC
April 2021

The peripheral and core regions of virus-host network of COVID-19.

Brief Bioinform 2021 May 6. Epub 2021 May 6.

School of Computer Science and Technology, Xidian University, Xi'an 710071, China.

Two thousand nineteen novel coronavirus SARS-CoV-2, the pathogen of COVID-19, has caused a catastrophic pandemic, which has a profound and widespread impact on human lives and social economy globally. However, the molecular perturbations induced by the SARS-CoV-2 infection remain unknown. In this paper, from the perspective of omnigenic, we analyze the properties of the neighborhood perturbed by SARS-CoV-2 in the human interactome and disclose the peripheral and core regions of virus-host network (VHN). We find that the virus-host proteins (VHPs) form a significantly connected VHN, among which highly perturbed proteins aggregate into an observable core region. The non-core region of VHN forms a large scale but relatively low perturbed periphery. We further validate that the periphery is non-negligible and conducive to identifying comorbidities and detecting drug repurposing candidates for COVID-19. We particularly put forward a flower model for COVID-19, SARS and H1N1 based on their peripheral regions, and the flower model shows more correlations between COVID-19 and other two similar diseases in common functional pathways and candidate drugs. Overall, our periphery-core pattern can not only offer insights into interconnectivity of SARS-CoV-2 VHPs but also facilitate the research on therapeutic drugs.
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http://dx.doi.org/10.1093/bib/bbab169DOI Listing
May 2021

Improving Single-Cell RNA-seq Clustering by Integrating Pathways.

Brief Bioinform 2021 May 3. Epub 2021 May 3.

Computer Science at the University of British Columbia Okanagan (UBC Okanagan), Canada.

Single-cell clustering is an important part of analyzing single-cell RNA-sequencing data. However, the accuracy and robustness of existing methods are disturbed by noise. One promising approach for addressing this challenge is integrating pathway information, which can alleviate noise and improve performance. In this work, we studied the impact on accuracy and robustness of existing single-cell clustering methods by integrating pathways. We collected 10 state-of-the-art single-cell clustering methods, 26 scRNA-seq datasets and four pathway databases, combined the AUCell method and the similarity network fusion to integrate pathway data and scRNA-seq data, and introduced three accuracy indicators, three noise generation strategies and robustness indicators. Experiments on this framework showed that integrating pathways can significantly improve the accuracy and robustness of most single-cell clustering methods.
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http://dx.doi.org/10.1093/bib/bbab147DOI Listing
May 2021

NAT1 is a critical prognostic biomarker and inhibits proliferation of colorectal cancer through modulation of PI3K/Akt/mTOR.

Future Oncol 2021 Apr 28. Epub 2021 Apr 28.

Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, 350001, PR China.

The aim of this study was to analyze the correlations between NAT1 and clinicopathological features of and prognosis in colorectal cancer (CRC). RNA sequencing data and clinical information were retrieved from The Cancer Genome Atlas database. Wilcoxon test, logistic regression and Kaplan-Meier method were used to estimate the association between NAT1 and prognosis in CRC. experiments were conducted to confirm the role of NAT1. is significantly less expressed in CRC and independently associated with poor prognosis in CRC patients. The authors further confirmed that expression of was significantly lower in SW116 colon cancer cells than in NCM460 cells. Overexpressed obviously inhibited the growth of CRC cells by downregulating phosphorylation of the PI3K/Akt/mTOR signaling pathway. NAT1 may be a potential therapeutic target for CRC.
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http://dx.doi.org/10.2217/fon-2020-0992DOI Listing
April 2021

Acinar cell NLRP3 inflammasome and GSDMD activation mediates pyroptosis and systemic inflammation in acute pancreatitis.

Br J Pharmacol 2021 Apr 19. Epub 2021 Apr 19.

Center of Severe Acute Pancreatitis (CASP), Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.

Background And Purpose: Pyroptosis is a lytic form of proinflammatory cell death characterised as caspase-1-dependent with canonical NLRP3 inflammasome-induced gasdermin D (GSDMD) activation. We aimed to investigate the role of acinar pyroptotic cell death in pancreatic injury and systemic inflammation in acute pancreatitis (AP).

Experimental Approach: Pancreatic acinar pyroptotic cell death pathway activation upon pancreatic toxin stimulation in vitro and in vivo were investigated. Effects of pharmacological (NLRP3 and caspase-1 inhibitors), constitutive (Nlrp3 , Caspase-1 and Gsdmd ) and acinar cell conditional (Pdx1 Nlrp3 and Pdx1 Gsdmd ) genetic inhibition on pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation were assessed using mouse AP models (caerulein, sodium taurocholate, L-arginine). Effects of Pdx1 Gsdmd vs myeloid conditional knockout (Lyz2 Gsdmd ) and Gsdmd vs receptor interacting protein 3 (RIP3) inhibitor were compared in caerulein-induced AP (CER-AP).

Key Results: There was consistent pyroptotic acinar cell death upon pancreatic toxin stimulation both in vitro and in vivo which was significantly reduced by pharmacological or genetic pyroptosis inhibition. Pdx1 Gsdmd but not Lyz2 Gsdmd mice significantly reduced pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation in CER-AP. Co-application of RIP3 inhibitor on Gsdmd mice further increased protection on CER-AP.

Conclusion And Implications: This work demonstrates a critical role for NLRP3 inflammasome and GSDMD activation-mediated pyroptosis in acinar cells, linking pancreatic necrosis and systemic inflammation in AP. Targeting pyroptosis signalling pathways holds promise for specific AP therapy.
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http://dx.doi.org/10.1111/bph.15499DOI Listing
April 2021

CytoTalk: De novo construction of signal transduction networks using single-cell transcriptomic data.

Sci Adv 2021 Apr 14;7(16). Epub 2021 Apr 14.

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Single-cell technology enables study of signal transduction in a complex tissue at unprecedented resolution. We describe CytoTalk for de novo construction of cell type-specific signaling networks using single-cell transcriptomic data. Using an integrated intracellular and intercellular gene network as the input, CytoTalk identifies candidate pathways using the prize-collecting Steiner forest algorithm. Using high-throughput spatial transcriptomic data and single-cell RNA sequencing data with receptor gene perturbation, we demonstrate that CytoTalk has substantial improvement over existing algorithms. To better understand plasticity of signaling networks across tissues and developmental stages, we perform a comparative analysis of signaling networks between macrophages and endothelial cells across human adult and fetal tissues. Our analysis reveals an overall increased plasticity of signaling networks across adult tissues and specific network nodes that contribute to increased plasticity. CytoTalk enables de novo construction of signal transduction pathways and facilitates comparative analysis of these pathways across tissues and conditions.
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http://dx.doi.org/10.1126/sciadv.abf1356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046375PMC
April 2021

Role of Medium-Chain Fatty Acids in Healthy Metabolism: A Clinical Perspective.

Trends Endocrinol Metab 2021 Jun 5;32(6):351-366. Epub 2021 Apr 5.

School of Biomedical Science and Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Australia. Electronic address:

Medium-chain fatty acids (MCFAs) serve not only as an energy source but also regulate glucose and lipid metabolism. The unique transport and rapid metabolism of MCFAs provide additional clinical benefits over other substrates such as long-chain fatty acids (LCFAs) and have prompted interest in the use of MCFAs for treating metabolic and neurological disorders. This review focuses on the metabolic role of MCFAs in modulating cellular signaling and regulating key circulating metabolites and hormones. The potential of MCFAs in treating various metabolic diseases in a clinical setting has also been analyzed.
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http://dx.doi.org/10.1016/j.tem.2021.03.002DOI Listing
June 2021

The Proresolving Lipid Mediator Maresin1 Alleviates Experimental Pancreatitis via Switching Macrophage Polarization.

Mediators Inflamm 2021 9;2021:6680456. Epub 2021 Mar 9.

Department of Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Southeast University, No. 305 Zhongshan East Road, Nanjing, 210002 Jiangsu, China.

Method: Repeated caerulein injection was used to induce AP and chronic pancreatitis (CP) models in mice. The histopathological and serological changes were examined for evaluating the severity of the AP model, and flow cytometry was used for detecting macrophage phagocytosis and phenotype. Meanwhile, clodronate liposomes were used for macrophage depletion in mice. Finally, the CP model was adopted to further observe the protective effect of MaR1.

Result: MaR1 administration manifested the improved histopathological changes and the lower serum levels of amylase and lipase. However, MaR1 played no protective role in the pancreatic acinar cell line . It obviously reduced the macrophage infiltration in the injured pancreas, especially M1-type macrophages. After macrophage clearance, MaR1 showed no further protection . This study also demonstrated that MaR1 could alleviate fibrosis to limit AP progression in the CP model.

Conclusion: Our data suggests that MaR1 was a therapeutic and preventive target for AP in mice, likely operating through its effects on decreased macrophage infiltration and phenotype switch.
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http://dx.doi.org/10.1155/2021/6680456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969117PMC
March 2021

The efficacy and efficiency of stent-assisted percutaneous endoscopic necrosectomy for infected pancreatic necrosis: a pilot clinical study using historical controls.

Eur J Gastroenterol Hepatol 2021 Mar 12. Epub 2021 Mar 12.

Center of Severe Acute Pancreatitis, Department of General Surgery, Jinling Hospital, Medical school of Nanjing University, Nanjing National Institute of Healthcare Data Science at Nanjing University Center of Severe Acute Pancreatitis, Department of General Surgery, Jinling Hospital, the first school of Clinical Medicine, Southern Medical University Center of Severe Acute Pancreatitis, Department of General Surgery, Jinling Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu Province, China GI Unit, Department of General Surgery, Auckland City Hospital Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Objectives: Minimally invasive interventions have become standard treatment for infected pancreatic necrosis (IPN). Despite the marginal clinical advantage of endoscopic approaches over the surgical approach shown in recent studies, percutaneous techniques still have a role when endoscopic treatment is not indicated. Stent-assisted percutaneous endoscopic necrosectomy (SAPEN) is an alternative option for surgical necrosectomy, but the theoretical advantages to this procedure remain unproven. This study aimed to report the efficacy and efficiency of SAPEN in patients with IPN.

Methods: This is a retrospective, historically-controlled, cohort study. All IPN patients admitted to our center from January 2015 to December 2018 were screened for eligibility. Patients admitted between January 2015 and October 2017 were historical controls, and patients admitted thereafter were treated with additional self-expandable metal stent (SEMS). The primary endpoint was a composite of major complications and/or death. Other outcomes, including individual components of the primary endpoint, new-onset sepsis, length of ICU and hospital stay, and pancreatic fistula, were also compared.

Results: There were 73 historical-control patients and 37 patients who had SAPEN included for analysis. The introduction of the SAPEN procedure failed to reduce the incidence of the primary endpoint (35 versus 52%, P = 0.095). However, significantly shorter hospital stay (38 versus 48 days, P = 0.035) and lower incidence of new-onset sepsis were observed in the SAPEN group (35 versus 56%, P = 0.037).

Conclusion: The application of SEMS in percutaneous endoscopic necrosectomy procedures shortened hospital stay, decreased new-onset sepsis, and allowed earlier necrosectomy.
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http://dx.doi.org/10.1097/MEG.0000000000002127DOI Listing
March 2021

Identification and Analysis of An Epigenetically Regulated Five-lncRNA Signature Associated With Outcome and Chemotherapy Response in Ovarian Cancer.

Front Cell Dev Biol 2021 23;9:644940. Epub 2021 Feb 23.

Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China.

The deregulation of long non-coding RNAs (lncRNAs) by epigenetic alterations has been implicated in cancer initiation and progression. However, the epigenetically regulated lncRNAs and their association with clinical outcome and therapeutic response in ovarian cancer (OV) remain poorly investigated. This study performed an integrative analysis of DNA methylation data and transcriptome data and identified 419 lncRNAs as potential epigenetically regulated lncRNAs. Using machine-learning and multivariate Cox regression analysis methods, we identified and developed an epigenetically regulated lncRNA expression signature (EpiLncRNASig) consisting of five lncRNAs from the list of 17 epigenetically regulated lncRNAs significantly associated with outcome. The EpiLncRNASig could stratify patients into high-risk groups and low-risk groups with significantly different survival and chemotherapy response in different patient cohorts. Multivariate Cox regression analyses, after adjusted by other clinical features and treatment response, demonstrated the independence of the DEpiLncSig in predicting survival. Functional analysis for relevant protein-coding genes of the DEpiLncSig indicated enrichment of known immune-related or cancer-related biological pathways. Taken together, our study not only provides a promising prognostic biomarker for predicting outcome and chemotherapy response but also will improve our understanding of lncRNA epigenetic regulation mechanisms in OV.
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http://dx.doi.org/10.3389/fcell.2021.644940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940383PMC
February 2021

The Change Mechanism of Structural Characterization and Thermodynamic Properties of Tannase from Aspergillus niger NL112 Under High Temperature.

Appl Biochem Biotechnol 2021 Mar 9. Epub 2021 Mar 9.

State Key Laboratory of Food Science and Technology & College of Food Science and Technology, Nanchang University, Nanchang, 330047, Jiangxi, China.

Tannase from Aspergillus niger NL112 was purified 5.1-fold with a yield of 50.44% via ultrafiltration, DEAE-Sepharose Fast Flow column chromatography, and Sephadex G-100 column chromatography. The molecular weight of the purified tannase was estimated as 45 kDa. The optimum temperature and pH for its activity were 45 °C and 5.0, respectively. The results of circular dichroism, FT-IR (Fourier transform infrared) spectroscopy, and fluorescence spectra indicated that high temperature could lead to the change of tannase secondary and tertiary structures. Tannase had a greater affinity for tannic acid at 40 °C with a K value of 2.12 mM and the greatest efficiency hydrolysis (K/K) at 45 °C. The rate of inactivation (k) increased with the increase of temperature and the half-life (t) gradually decreased. It was found to be 1.0 of the temperature quotient (Q) value for tannic acid hydrolysis by tannase. The thermodynamic parameters of the interaction system were calculated at various temperatures. The positive enthalpy (ΔH) values and decreasing ΔH values with the increase of temperature indicated that the hydrolysis of tannase was an endothermic process. Our results indicated that elevated temperature could change the tertiary structure of tannase and reduce its thermostability, which caused a gradual decrease of tannase activity with an increase in temperature.
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http://dx.doi.org/10.1007/s12010-021-03488-xDOI Listing
March 2021

Differential proteomic analysis of children infected with respiratory syncytial virus.

Braz J Med Biol Res 2021 26;54(4):e9850. Epub 2021 Feb 26.

Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Respiratory syncytial virus (RSV) infection is the main cause of lower respiratory tract infection in children. However, there is no effective treatment for RSV infection. Here, we aimed to identify potential biomarkers to aid in the treatment of RSV infection. Children in the acute and convalescence phases of RSV infection were recruited and proteomic analysis was performed to identify differentially expressed proteins (DEPs). Subsequently, promising candidate proteins were determined by functional enrichment and protein-protein interaction network analysis, and underwent further validation by western blot both in clinical and mouse model samples. Among the 79 DEPs identified in RSV patient samples, 4 proteins (BPGM, TPI1, PRDX2, and CFL1) were confirmed to be significantly upregulated during RSV infection. Functional analysis showed that BPGM and TPI1 were mainly involved in glycolysis, indicating an association between RSV infection and the glycolysis metabolic pathway. Our findings provide insights into the proteomic profile during RSV infection and indicated that BPGM, TPI1, PRDX2, and CFL1 may be potential therapeutic biomarkers or targets for the treatment of RSV infection.
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http://dx.doi.org/10.1590/1414-431X20209850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917709PMC
March 2021

[Qualitative analysis of Gynostemma longipes for medicinal usage].

Zhongguo Zhong Yao Za Zhi 2021 Feb;46(4):951-965

Tianjin University of Traditional Chinese Medicine Tianjin 301617,China Institute of Radiation Medicine,Academy of Military Medical Sciences,Academy of Military Sciences Beijing 100850,China.

The Qinling-Daba Mountains area is the main producing areas of Gynostemma longipes for medicinal usage, and samples of wild whole plants in Pingli, Shaanxi Province and Qingchuan, Sichuan Province were collected. The ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS~E) was used to profile the chemical compositions and analyze the similarities and differences of G. longipes samples in these areas. Based on the accurate molecular weight and fragment information obtained from Q-TOF-MS~E, the structures of the main components were identified by combining with the mass spectra, chromatographic behaviors of reference standards and related literatures. The results showed that the components of wild G. longipes from different places among Qinling-Daba Mountains area were similar. Forty-five chemical components were identified in the whole plant of G. longipes from Pingli, Shaanxi Province, including 43 triterpenoid saponins and 2 flavonoids which contain all main peaks in its fingerprint. The main components are dammarane-type triterpenoid saponins, such asgypenoside ⅩLⅨ, gypenoside A and its malonylated product of glycosyl.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200623.204DOI Listing
February 2021

CeNet Omnibus: an R/Shiny application to the construction and analysis of competing endogenous RNA network.

BMC Bioinformatics 2021 Feb 18;22(1):75. Epub 2021 Feb 18.

School of Computer Science and Technology, Xidian University, Xi'an, Shaanxi, China.

Background: The competing endogenous RNA (ceRNA) regulation is a newly discovered post-transcriptional regulation mechanism and plays significant roles in physiological and pathological progress. CeRNA networks provide global views to help understand the regulation of ceRNAs. CeRNA networks have been widely used to detect survival biomarkers, select candidate regulators of disease genes, and predict long noncoding RNA functions. However, there is no software platform to provide overall functions from the construction to analysis of ceRNA networks.

Results: To fill this gap, we introduce CeNet Omnibus, an R/Shiny application, which provides a unified framework for the construction and analysis of ceRNA network. CeNet Omnibus enables users to select multiple measurements, such as Pearson correlation coefficient (PCC), mutual information (MI), and liquid association (LA), to identify ceRNA pairs and construct ceRNA networks. Furthermore, CeNet Omnibus provides a one-stop solution to analyze the topological properties of ceRNA networks, detect modules, and perform gene enrichment analysis and survival analysis. CeNet Omnibus intends to cover comprehensiveness, high efficiency, high expandability, and user customizability, and it also offers a web-based user-friendly interface to users to obtain the output intuitionally.

Conclusion: CeNet Omnibus is a comprehensive platform for the construction and analysis of ceRNA networks. It is highly customizable and outputs the results in intuitive and interactive. We expect that CeNet Omnibus will assist researchers to understand the property of ceRNA networks and associated biological phenomena. CeNet Omnibus is an R/Shiny application based on the Shiny framework developed by RStudio. The R package and detailed tutorial are available on our GitHub page with the URL https://github.com/GaoLabXDU/CeNetOmnibus .
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http://dx.doi.org/10.1186/s12859-021-04012-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890952PMC
February 2021

Extracellular vesicles from anoxia preconditioned mesenchymal stem cells alleviate myocardial ischemia/reperfusion injury.

Aging (Albany NY) 2021 02 12;13(4):6156-6170. Epub 2021 Feb 12.

Shanghai Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Extracellular vesicles (EVs) produced by anoxia-preconditioned mesenchymal stem cells (MSCs) may afford greater cardioprotection against myocardial ischemia-reperfusion injury (MIRI) than EVs derived from normoxic MSCs. Here, we isolated EVs from mouse adipose-derived MSCs (ADSCs) subjected to anoxia preconditioning or normoxia and evaluated their ability to promote survival of mouse cardiomyocytes following MIRI and anoxia/reoxygenation (AR) . Injection of anoxia-preconditioned ADSC EVs (Int-EVs) reduced both infarct size and cardiomyocyte apoptosis to a greater extent than normoxic ADSC EVs (NC-EVs) in mice subjected to MIRI. Sequencing EV-associated miRNAs revealed differential upregulation of ten miRNAs predicted to bind thioredoxin-interacting protein (TXNIP), an inflammasome- and pyroptosis-related protein. We confirmed direct binding of miRNA224-5p, the most upregulated miRNA in Int-EVs, to TXNIP and asserted through western blotting and apoptosis assays a critical protective role for this miRNA against AR-induced cardiomyocyte death. Our results suggest that ischemia-reperfusion triggers TXNIP-induced inflammasome activation in cardiomyocytes, which leads to apoptosis rather than pyroptosis due to low basal levels of the pyroptosis executioner protein gasdermin D in these cells. The antiapoptotic effect of EV-associated miRNA224-5p would in turn result from TXNIP downregulation, which prevents caspase-1-mediated degradation of GATA4 and sustains the expression of Bcl-2.
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http://dx.doi.org/10.18632/aging.202611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950238PMC
February 2021

Predicting therapeutic drugs for hepatocellular carcinoma based on tissue-specific pathways.

PLoS Comput Biol 2021 Feb 9;17(2):e1008696. Epub 2021 Feb 9.

Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, 72, Jimo District, Qingdao, Shandong, China.

Hepatocellular carcinoma (HCC) is a significant health problem worldwide with poor prognosis. Drug repositioning represents a profitable strategy to accelerate drug discovery in the treatment of HCC. In this study, we developed a new approach for predicting therapeutic drugs for HCC based on tissue-specific pathways and identified three newly predicted drugs that are likely to be therapeutic drugs for the treatment of HCC. We validated these predicted drugs by analyzing their overlapping drug indications reported in PubMed literature. By using the cancer cell line data in the database, we constructed a Connectivity Map (CMap) profile similarity analysis and KEGG enrichment analysis on their related genes. By experimental validation, we found securinine and ajmaline significantly inhibited cell viability of HCC cells and induced apoptosis. Among them, securinine has lower toxicity to normal liver cell line, which is worthy of further research. Our results suggested that the proposed approach was effective and accurate for discovering novel therapeutic options for HCC. This method also could be used to indicate unmarked drug-disease associations in the Comparative Toxicogenomics Database. Meanwhile, our method could also be applied to predict the potential drugs for other types of tumors by changing the database.
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http://dx.doi.org/10.1371/journal.pcbi.1008696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920387PMC
February 2021

Early versus delayed intervention in necrotizing acute pancreatitis complicated by persistent organ failure.

Hepatobiliary Pancreat Dis Int 2021 Jan 14. Epub 2021 Jan 14.

Medical School of Southeast University, 87 Dingjiaqiao, Nanjing 210009, China; Center of Severe Acute Pancreatitis (CSAP), Department of General Surgery, Jinling Hospital, Medical School of Southeast University, No. 305 Zhongshan East Road, Nanjing 210002, China.

Background: Current guidelines for the treatment of patients with necrotizing acute pancreatitis (NAP) recommend that invasive intervention for pancreatic necrosis should be deferred to 4 or more weeks from disease onset to allow necrotic collections becoming "walled-off". However, for patients showing signs of clinical deterioration, especially those with persistent organ failure (POF), it is controversial whether this delayed approach should always be adopted. In this study, we aimed to assess the impact of differently timed intervention on clinical outcomes in a group of NAP patients complicated by POF.

Methods: All NAP patients admitted to our hospital from January 2013 to December 2017 were screened for potential inclusion. They were divided into two groups based on the timing of initial intervention (within 4 weeks and beyond 4 weeks). All the data were extracted from a prospectively collected database.

Results: Overall, 131 patients were included for analysis. Among them, 100 (76.3%) patients were intervened within 4 weeks and 31 (23.7%) underwent delayed interventions. As for organ failure prior to intervention, the incidences of respiratory failure, renal failure and cardiovascular failure were not significantly different between the two groups (P > 0.05). The mortality was not significantly different between the two groups (35.0% vs. 32.3%, P = 0.83). The incidences of new-onset multiple organ failure (8.0% vs. 6.5%, P = 1.00), gastrointestinal fistula (29.0% vs. 12.9%, P = 0.10) and bleeding (35.0% vs. 35.5%, P = 1.00), length of ICU (30.0 vs. 22.0 days, P = 0.61) and hospital stay (42.5 vs. 40.0 days, P = 0.96) were comparable between the two groups.

Conclusion: Intervention within 4 weeks did not worsen the clinical outcomes in NAP patients complicated by POF.
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http://dx.doi.org/10.1016/j.hbpd.2020.12.019DOI Listing
January 2021

The risk factors for acute respiratory distress syndrome in patients with severe acute pancreatitis: A retrospective analysis.

Medicine (Baltimore) 2021 Jan;100(2):e23982

ICU, Ganzhou People's Hospital, GanZhou, JiangXi Province, China.

Abstract: Acute respiratory distress syndrome (ARDS) is very common in patients with severe acute pancreatitis (SAP), the early interventions are essential to the prognosis of SAP patients. We aimed to evaluate the risk factors for ARDS in SAP patients, to provide insights into the management of SAP.SAP patients treated in our hospital from June 1, 2018 to May 31, 2020 were included. The characteristics and lab test results were collected and compared, and we conducted the logistic regression analyses were conducted to identify the potential risk factors for ARDS in patients with SAP.A total of 281 SAP patients were included finally, the incidence of ARDS in patients with SAP was 30.60%. There were significant differences on the respiratory rate, heart rate, APACHE II and Ranson score between 2 groups (all P < .05). And there were significant differences on the polymorphonuclear, procalcitonin, C-reactive protein, serum creatinine, albumin and PO2/FiO2 between 2 groups (all P < .05), and no significant differences on the K+, Na+, Ca+, white blood cell, neutrophils, urine and blood amylase, trypsin, lipase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, triglyceride, total cholesterol, total bilirubin, fasting blood glucose, and pH were found (all P > .05). Respiratory rate >30/min (odds ratio [OR]: 2.405, 95% confidence interval[CI]: 1.163-4.642), APACHE II score >11 (OR: 1.639, 95% CI: 1.078-2.454), Ranson score >5 (OR: 1.473, 95% CI: 1.145-2.359), polymorphonuclear >14 × 109/L (OR: 1.316, 95% CI: 1.073-2.328), C-reactive protein >150 mg/L (OR: 1.127, 95% CI: 1.002-1.534), albumin ≤30 g/L (OR: 1.113, 95% CI: 1.005-1.489) were the independent risk factors for ARDS in patients with SAP (all P < .05).The incidence of ARDS in SAP patients is relatively high, and it is necessary to carry out targeted early prevention and treatment for the above risk factors.
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http://dx.doi.org/10.1097/MD.0000000000023982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808542PMC
January 2021

New steroidal glycosides from the roots of .

J Asian Nat Prod Res 2021 Mar 18;23(3):205-216. Epub 2021 Jan 18.

Beijing Institute of Radiation Medicine, Beijing 100850, China.

Steroidal saponins were the main active constituents of the traditional medicinal herb . A phytochemical investigation of roots led to the isolation of nine new steroidal glycosides () and seven known analogues (-). Their structures were established by spectroscopic analyses as well as necessary chemical evidence.
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http://dx.doi.org/10.1080/10286020.2021.1873956DOI Listing
March 2021

Highly Flowable Nano TiO/Porous Organic Polymer (POP) Supports for Efficient Metallocene Catalysts.

Nanomaterials (Basel) 2020 Dec 29;11(1). Epub 2020 Dec 29.

Lanzhou Petrochemical Research Center, Petrochemical Research Institute, PetroChina, Lanzhou 730060, China.

Porous organic polymers (POPs) have proven to be an efficient support in the olefin polymerization catalyst field. In this paper, nano TiO beads were used to modulate the pore structure, bulk density, and surface morphology and flowability of the prepared POPs. With the incorporation of the hydrophilic nano TiO beads, the prepared TiO/POP supports obtained reasonable specific surface area (100-300 m/g) and higher bulk density (0.26-0.35 g/mL) and flowability than the pure POP supports. The results show that bulk density of the prepared TiO/POP particles increased when adding an increased amount of TiO, and when 37.5% TiO (weight percent to the total comonomers divinylbenzene (DVB) and 2-hydroxyethyl methacrylate (HEMA)) and 3:1 DVB/HEMA (molar ratio) were added, highly flowable TiO/POP composites (POP-6 and POP-7) were obtained. With the modulation of the nano TiO template during the support synthesis, the prepared POP-7 particles successfully achieved a normal distribution with a narrow particle size distribution (PSD) of 0.717 and average particle size of 24.1 m, a specific surface area (SSA) of 279 m/g, and relatively high bulk density of 0.30 g/mL. Furthermore, all the prepared TiO/POP supports obtained higher ethylene polymerization activity than silica gel-supported commercial metallocene catalyst. The immobilized (n-BuCp)ZrCl/MAO@POP-7 catalyst exhibited the highest ethylene polymerization activity of 4794 kg PE/mol Zr.bar.h and productivity of 389 g PE/g cat, more than twice that of the commercial counterpart. Even higher catalyst productivity (3197 g PE/g cat) and bulk density of the produced PE (0.36 g/mL) could be obtained in higher ethylene partial pressure at 80 ∘C for 2 h, and the prepared TiO/POP catalyst shows no obvious Zr active sites decay during the ethylene polymerization.
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http://dx.doi.org/10.3390/nano11010060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823374PMC
December 2020

BTF3 promotes stemness and inhibits TypeⅠInterferon signaling pathway in triple-negative breast cancer.

Biochem Biophys Res Commun 2021 01 28;537:22-28. Epub 2020 Dec 28.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, Shandong University, School of Basic Medical Sciences, 250012, Jinan, China; Department of Pathology, Shandong University Qilu Hospital, 250012, Jinan, China. Electronic address:

Triple-negative breast cancer (TNBC) is a major challenge in clinical practice due to its aggressiveness and lack of targeted treatment. Cancer stem-like traits contribute to tumorigenesis and immune privilege of TNBC. However, the relationship of stemness and immunosurveillance remains unclear. Here, we demonstrate that BTF3 expression is related with stem-like properties in TNBC cells. BTF3 modulates stemness, migration and proliferation of TNBC in vitro. Bioinformatics analysis revealed that interferon signaling pathways and IRF7, both of which participate in the immune escape of TNBC, are closely related to BTF3 in TNBC cells. Knockdown of BTF3 activates IRF7 expression through increased degradation of BMI1, a protein that can represses IRF7 transcription by directly binding to its promotor region. BTF3 links stem-like traits and the interferon signaling pathway, revealing the potential connection of stemness and immunomodulation in TNBC. Clinically, we suggest that BTF3 is predictive of poor prognosis in patients with TNBC. Together, our findings highlight an important role of BTF3 in regulating the progression of TNBC cells.
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http://dx.doi.org/10.1016/j.bbrc.2020.12.060DOI Listing
January 2021

An Ultrahigh Sensitive Paper-Based Pressure Sensor with Intelligent Thermotherapy for Skin-Integrated Electronics.

Nanomaterials (Basel) 2020 Dec 17;10(12). Epub 2020 Dec 17.

State Key Laboratory of Electronic Thin Films and Integrated Devices, School of Optoelectronic Science and Engineering, University of Electronic Science and Technology of China (UESTC), Jianshe North Road, Chengdu 610054, China.

Porous microstructure pressure sensors that are highly sensitive, reliable, low-cost, and environment-friendly have aroused wide attention in intelligent biomedical diagnostics, human-machine interactions, and soft robots. Here, an all-tissue-based piezoresistive pressure sensor with ultrahigh sensitivity and reliability based on the bottom interdigitated tissue electrode and the top bridge of a microporous tissue/carbon nanotube composite was proposed. Such pressure sensors exhibited ultrahigh sensitivity (≈1911.4 kPa), fast response time (<5 ms), low fatigue of over 2000 loading/unloading cycles, and robust environmental degradability. These enabled sensors can not only monitor the critical physiological signals of the human body but also realize electrothermal conversion at a specific voltage, which enhances the possibility of creating wearable thermotherapy electronics for protecting against rheumatoid arthritis and cervical spondylosis. Furthermore, the sensor successfully transmitted wireless signals to smartphones via Bluetooth, indicating its potential as reliable skin-integrated electronics. This work provides a highly feasible strategy for promoting high-performance wearable thermotherapy electronics for the next-generation artificial skin.
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http://dx.doi.org/10.3390/nano10122536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765889PMC
December 2020

Molecular Mechanisms of Acute Oxygen Sensing by Arterial Chemoreceptor Cells. Role of Hif2α.

Front Physiol 2020 23;11:614893. Epub 2020 Nov 23.

Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.

Carotid body glomus cells are multimodal arterial chemoreceptors able to sense and integrate changes in several physical and chemical parameters in the blood. These cells are also essential for O homeostasis. Glomus cells are prototypical peripheral O sensors necessary to detect hypoxemia and to elicit rapid compensatory responses (hyperventilation and sympathetic activation). The mechanisms underlying acute O sensing by glomus cells have been elusive. Using a combination of mouse genetics and single-cell optical and electrophysiological techniques, it has recently been shown that activation of glomus cells by hypoxia relies on the generation of mitochondrial signals (NADH and reactive oxygen species), which modulate membrane ion channels to induce depolarization, Ca influx, and transmitter release. The special sensitivity of glomus cell mitochondria to changes in O tension is due to Hif2α-dependent expression of several atypical mitochondrial subunits, which are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O availability. A mitochondrial-to-membrane signaling model of acute O sensing has been proposed, which explains existing data and provides a solid foundation for future experimental tests. This model has also unraveled new molecular targets for pharmacological modulation of carotid body activity potentially relevant in the treatment of highly prevalent medical conditions.
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http://dx.doi.org/10.3389/fphys.2020.614893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719705PMC
November 2020

Effect of astragaloside on diaphragm cell apoptosis in chronic obstructive pulmonary disease.

Food Sci Nutr 2020 Dec 18;8(12):6357-6366. Epub 2020 Nov 18.

Department of Respiratory and Critical Medicine Jinling Hospital Nanjing Medical University Nanjing China.

Purpose: This study aimed to discuss the effects and relative mechanisms of astragaloside (AST) on diaphragm cell apoptosis in mice with chronic obstructive pulmonary disease (COPD).

Materials And Methods: The mouse models of COPD were established by passive smoking. The pathological changes in lung and diaphragm tissues were observed by hematoxylin and eosin staining and evaluating the number of apoptotic cells of the diaphragm via a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The relative protein expression levels of AKT, p-AKT, caspase-3, and caspase-9 were measured through immunohistochemistry and Western blot assay.

Results: In comparison with the normal control mice, the pathological change and number of apoptotic cells deteriorated in the lung and diaphragm tissues of COPD model mice. With AST supplement, the pathological change and the number of apoptotic cells significantly improved ( < .05). With AKT inhibitor intervention, the effects of AST treatment disappeared. p-AKT, caspase-3, and caspase-9 protein expression was stimulated in the model group but was depressed in the AST-treated groups.

Conclusion: Our in vivo study revealed that AST improved COPD-induced diaphragm apoptosis by regulating and depressing AKT activities.
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http://dx.doi.org/10.1002/fsn3.1751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723181PMC
December 2020

Two in One: Echocardiographic Features of Right-Ventricular Diverticulum and Left-Ventricular Aneurysm in the Same Patient.

CJC Open 2020 Nov 29;2(6):719-721. Epub 2020 Jul 29.

Department of Internal Medicine, Division of Cardiology, University of Texas Medical Branch, Galveston, Texas, USA.

Ventricular diverticulum is a rare congenital heart defect that is usually found incidentally upon imaging, such as 2-dimensional transthoracic echocardiogram. We report a case in which an isolated right-ventricular diverticulum and a left-ventricular aneurysm were both found on transthoracic echocardiogram in the setting of a pulmonary embolism. This case highlights how to distinguish between an aneurysm and a diverticulum based on wall motion on echocardiogram, as well as potential complications that may arise from either anomaly.
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http://dx.doi.org/10.1016/j.cjco.2020.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711003PMC
November 2020

Recent progress in engineering functional biohybrid robots actuated by living cells.

Acta Biomater 2021 02 5;121:29-40. Epub 2020 Dec 5.

Department of Mechanical Engineering, Xian Jiaotong University, 28 Xianning West Road, Xian Shaanxi 710049, China; State Key Lab for Manufacturing Systems Engineering, Xian Jiaotong University, Xian Shaanxi 710049, China.

Living cells are highly scalable biological actuators found in nature, and they are efficient technological solutions to actuate robotic systems. Recent advancements in biofabrication and tissue engineering have bridged the gap to interface muscle cells with artificial technology. In this review, we summarize the recent progress in engineering the attributes of individual components for the development of fully functional biohybrid robots. First, we address the fabrication of biological actuators for biohybrid robots with muscle cells and tissues, including cardiomyocytes, skeletal muscles, insect tissues, and neuromuscular tissues, in well-organized pattern of 2D sheets and 3D constructs. Next, we discuss the performance of biohybrid robots for various biomimetic tasks such as swimming, walking, gripping, and pumping. Finally, the challenges and future directions in the development of biohybrid robots are described from different viewpoints of living material engineering, multiscale modeling, 3D printing for manufacturing, and multifunctional robotic system development.
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http://dx.doi.org/10.1016/j.actbio.2020.12.002DOI Listing
February 2021

KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer.

Cancer Res 2021 02 4;81(4):1026-1039. Epub 2020 Dec 4.

The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target. SIGNIFICANCE: These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1965DOI Listing
February 2021

Small molecules combined with collagen hydrogel direct neurogenesis and migration of neural stem cells after spinal cord injury.

Biomaterials 2021 Feb 15;269:120479. Epub 2020 Nov 15.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Complete spinal cord injury (SCI) leads to cell death, interruption of axonal connections and permanent functional impairments. In the development of SCI treatments, cell transplantation combined with biomaterial-growth factor-based therapies have been widely studied. Another avenue worth exploring is the generation of neurons from endogenous neural stem cells (NSCs) or reactive astrocytes activated by SCI. Here, we screened a combination of four small molecules, LDN193189, SB431542, CHIR99021 and P7C3-A20, that can increase neuronal differentiation of mouse and rat spinal cord NSCs. Moreover, the small molecules loaded in an injectable collagen hydrogel induced neurogenesis and inhibited astrogliogenesis of endogenous NSCs in the injury site, which usually differentiate into astrocytes under pathological conditions. Meanwhile, induced neurons migrated into the non-neural lesion core, and genetic fate mapping showed that neurons mainly originated from NSCs in the parenchyma, but not from the central canal of the spinal cord. The neuronal regeneration in the lesion sites resulted in some recovery of locomotion. Our findings indicate that the combined treatment of small molecules and collagen hydrogel is a potential therapeutic strategy for SCI by inducing in situ endogenous NSCs to form neurons and restore damaged functions.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120479DOI Listing
February 2021

Effects of the protein GCP4 on gametophyte development in Arabidopsis thaliana.

Protoplasma 2021 May 6;258(3):483-493. Epub 2020 Nov 6.

Higher Education Key Laboratory of Plant Molecular and Environmental Stress Response, Shanxi Normal University, Linfen, 041000, Shanxi, People's Republic of China.

γ-Tubulin complex protein 4 (GCP4, encoded by AT3G53760) participates in microtubule (MT) nucleation in Arabidopsis thaliana, affecting the MT nucleation angles in cortical MTs, and the formation of the spindle and phragmoplasts during mitosis. Here, we report that GCP4 plays a critical role in gametophyte development. The results indicate that the gcp4 mutant caused by T-DNA insertion may express an aberrant gene product interfering with normal GCP4 expression, ultimately leading to the formation of desiccated ovules and aborted seeds. An analysis of transmission efficiency (TE) indicated that female gametophytes were more impaired in development than male gametophytes, and so observation and analysis of gametophyte defects were conducted. Complementation lines obtained by the native promoter and GCP4-coded CDS gene sequence fused with GFP reduced the numbers of lethal phenotypes of the gcp4 mutant. The localization of GCP4 in the gametophyte was detected in cytoplasm around nuclei and in vicinity of plasma membrane of pollen grains, and also detected in full cytoplasm and around the nuclei of ovules in complementation line. Thus, it was established that GCP4 influences the functionality of gametophytes during gametophyte development.
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http://dx.doi.org/10.1007/s00709-020-01520-1DOI Listing
May 2021

Hic-5 is required for activation of pancreatic stellate cells and development of pancreatic fibrosis in chronic pancreatitis.

Sci Rep 2020 11 5;10(1):19105. Epub 2020 Nov 5.

Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.

Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.
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http://dx.doi.org/10.1038/s41598-020-76095-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645689PMC
November 2020