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Chen J, Hong K, Ma L, Hao X. Effect of time series on the degradation of lignin by Trametes gibbosa: Products and pathways. Int J Biol Macromol 2024; 281:136236. [PMID: 39366598 DOI: 10.1016/j.ijbiomac.2024.136236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 08/27/2024] [Accepted: 09/30/2024] [Indexed: 10/06/2024]
Abstract
Lignin is the third most abundant organic resource in nature. The utilization of white-rot fungi for wood degradation effectively circumvents environmental pollution associated with chemical treatments, facilitating the benign decomposition of lignin. Trametes gibbosa is a typical white-rot fungus with rapid growth and strong wood decomposition ability. The lignin content decreased from 23.62 mg/mL to 17.05 mg/mL, which decreased by 27 % in 30 days. The activity of manganese peroxidase increased steadily by 9.44 times. The activities of laccase and lignin peroxidase had the same trend of change and reached peaks of 49.88 U/L and 10.43 U/L on the 25th day, respectively. The change in H2O2 content in vivo was opposite to its trend. For FTIR and GC-MS analysis, the fungi attacked the side chain structure of lignin phenyl propane polymer and benzene ring to crack into low molecular weight aromatic compounds. The side chains of low molecular weight aromatic compounds are oxidized, and long-chain carboxylic acids are formed. Additionally, the absorption peak in the vibration region of the benzene ring skeleton became complex, and the structure of the benzene rings changed. In the beginning, fungal growth was inhibited. Fungal autophagy was aggravated. The metal cation binding proteins of fungi were active, and the genes related to detoxification metabolism were upregulated. The newly produced compounds are related to xenobiotic metabolism. The degradation peak focused on the redox process, and the biological function was enriched in the regulation of macromolecular metabolism, lignin metabolism, and oxidoreductase activity acting on diphenols and related substances as donors. Notably, genes encoding key degradation enzymes, including lcc3, lcc4, phenol-2-monooxygenase, 3-hydroxybenzoate-6-hydroxylase, oxalate decarboxylase, and acetyl-CoA oxidase were significantly upregulated. On the 30th day, the N-glycan biosynthesis pathway was significantly enriched in glycan biosynthesis and metabolism. Weighted correlation network analysis was performed. A total of 1452 genes were clustered in the coral1 module, which were most related to lignin degradation. The genes were significantly enriched in oxidoreductase activity, peptidase activity, cell response to stimulation, signal transduction, lignin metabolism, and phenylpropane metabolism, while the rest were concentrated in glucose metabolism. In this study, the lignin degradation process and products were revealed by T. gibbosa. The molecular mechanism of lignin degradation in different stages was explored. The selection of an efficient utilization time of lignin will help to increase the degradation rate of lignin. This study provides a theoretical basis for the biofuel and biochemical production of lignin. SYNOPSIS: Trametes gibbosa degrades lignin in a pollution-free way, improving the utilization of carbon resources in an environmentally friendly spontaneous cycle. The products are the new way towards sustainable development and low-carbon technology.
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Affiliation(s)
- Jie Chen
- The Key Laboratory of Forest Disaster Warning and Control of Yunnan Province, College of Forestry, Southwest Forestry University, Kunming 650224, China
| | - Kai Hong
- College of Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University, Harbin 150040, China
| | - Ling Ma
- College of Forestry, Northeast Forestry University, Harbin 150040, China.
| | - Xin Hao
- The Key Laboratory of Forest Disaster Warning and Control of Yunnan Province, College of Forestry, Southwest Forestry University, Kunming 650224, China.
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Sakane S, Hikita H, Shirai K, Sakamoto T, Narumi R, Adachi J, Kakita N, Yamada Y, Toyoda H, Takahashi H, Suda G, Kai M, Tahata Y, Sakamori R, Kumazaki S, Fukumoto K, Myojin Y, Murai K, Kodama T, Tatsumi T, Tomonaga T, Sakamoto N, Morii E, Takehara T. Proteomic analysis of serum extracellular vesicles reveals Fibulin-3 as a new marker predicting liver-related events in MASLD. Hepatol Commun 2024; 8:e0448. [PMID: 38829196 PMCID: PMC11150025 DOI: 10.1097/hc9.0000000000000448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 03/05/2024] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events. METHODS We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy. RESULTS Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0 µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events. CONCLUSIONS Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD.
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Affiliation(s)
- Sadatsugu Sakane
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kumiko Shirai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tatsuya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Ryohei Narumi
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Jun Adachi
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Naruyasu Kakita
- Department of Gastroenterology and Hepatology, Kaizuka City Hospital, Osaka, Japan
| | - Yukinori Yamada
- Department of Gastroenterology and Hepatology, Kaizuka City Hospital, Osaka, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | | | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Machiko Kai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shusuke Kumazaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kenji Fukumoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuta Myojin
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazuhiro Murai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takeshi Tomonaga
- Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
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3
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Shen C, Jiang K, Zhang W, Su B, Wang Z, Chen X, Zheng B, He T. LASSO regression and WGCNA-based telomerase-associated lncRNA signaling predicts clear cell renal cell carcinoma prognosis and immunotherapy response. Aging (Albany NY) 2024; 16:9386-9409. [PMID: 38819232 PMCID: PMC11210217 DOI: 10.18632/aging.205871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 04/16/2024] [Indexed: 06/01/2024]
Abstract
OBJECTIVE To investigate whether telomerase-associated lncRNA expression affects the prognosis and anti-tumor immunity of patients with renal clear cell carcinoma (ccRCC). METHODS A series of analyses were performed to establish a prognostic risk model and validate its accuracy. Immune-related analyses were performed to assess further the association between immune status, tumor microenvironment, and prognostic risk models. RESULTS Eight telomerase-associated lncRNAs associated with prognosis were identified and applied to establish a prognostic risk model. Overall survival was higher in the low-risk group. CONCLUSION The established prognostic risk model has a good predictive ability for the prognosis of ccRCC patients and provides a new possible therapeutic target for ccRCC.
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MESH Headings
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/immunology
- Carcinoma, Renal Cell/mortality
- Carcinoma, Renal Cell/therapy
- Carcinoma, Renal Cell/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Humans
- Kidney Neoplasms/genetics
- Kidney Neoplasms/immunology
- Kidney Neoplasms/mortality
- Kidney Neoplasms/therapy
- Telomerase/genetics
- Telomerase/metabolism
- Prognosis
- Immunotherapy/methods
- Gene Expression Regulation, Neoplastic
- Tumor Microenvironment/immunology
- Tumor Microenvironment/genetics
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Signal Transduction/genetics
- Male
- Female
- Gene Regulatory Networks
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Affiliation(s)
- Cheng Shen
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Kaiyao Jiang
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Wei Zhang
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Baohui Su
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Zhenyu Wang
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Xinfeng Chen
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Bing Zheng
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Tao He
- Party Committe and Hospital Administration Office, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
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Chen L, Lin H, Qin L, Zhang G, Huang D, Chen P, Zhang X. Identification and validation of mutual hub genes in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated usual interstitial pneumonia. Heliyon 2024; 10:e28088. [PMID: 38571583 PMCID: PMC10987927 DOI: 10.1016/j.heliyon.2024.e28088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/08/2024] [Accepted: 03/12/2024] [Indexed: 04/05/2024] Open
Abstract
Objectives The study aims at exploring common hub genes and pathways in idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated usual interstitial pneumonia (RA-UIP) through integrated bioinformatics analyses. Methods The GSE199152 dataset containing lung tissue samples from IPF and RA-UIP patients was acquired from the Gene Expression Omnibus (GEO) database. The identification of overlapping differentially expressed genes (DEGs) in IPF and RA-UIP was carried out through R language. Protein-protein interaction (PPI) network analysis and module analysis were applied to filter mutual hub genes in the two diseases. Enrichment analyses were also conducted to analyze the possible biological functions and pathways of the overlapped DEGs and hub genes. The diagnostic value of key genes was assessed with R language, and the expressions of these genes in pulmonary cells of IPF and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients were analyzed with single cell RNA-sequencing (scRNA-seq) datasets. The expression levels of hub genes were validated in blood samples from patients, specimens of human lung fibroblasts, lung tissue samples from mice, as well as external GEO datasets. Results Four common hub genes (THBS2, TIMP1, POSTN, and CD19) were screened. Enrichment analyses showed that the abnormal expressions of DEGs and hub genes may be connected with the onset of IPF and RA-UIP by regulating the progression of fibrosis. ScRNA-seq analyses illustrated that for both IPF and RA-ILD patients, THBS2, TIMP1, and POSTN were mainly expressed in lung fibroblasts, while CD19 was uniquely high-expressed in B cells. The qRT-PCR and immunohistochemistry (IHC) results verified that the expression levels of hub genes were mostly in accordance with the findings obtained from the bioinformatics analyses. Conclusion Though IPF and RA-UIP are distinct diseases, they may to some extent have mutual pathogenesis in the development of fibrosis. THBS2, TIMP1, POSTN, and CD19 may be the potential biomarkers of IPF and RA-UIP, and intervention on related pathways of these genes could offer new strategies for the precision treatment of IPF and RA-UIP.
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Affiliation(s)
- Liangyu Chen
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
- Department of Respiratory and Critical Care Medicine, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, China
| | - Haobo Lin
- Department of Rheumatology, Guangdong Provincial People's Hospital, Guangzhou, China
- Guangdong Academy of Medical Sciences, Guangzhou, China
- Southern Medical University, Guangzhou, China
| | - Linmang Qin
- Department of Rheumatology, Guangdong Provincial People's Hospital, Guangzhou, China
- Guangdong Academy of Medical Sciences, Guangzhou, China
- Southern Medical University, Guangzhou, China
| | - Guangfeng Zhang
- Department of Rheumatology, Guangdong Provincial People's Hospital, Guangzhou, China
- Guangdong Academy of Medical Sciences, Guangzhou, China
- Southern Medical University, Guangzhou, China
| | - Donghui Huang
- Department of Respiratory and Critical Care Medicine, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, China
| | - Peisheng Chen
- Department of Respiratory and Critical Care Medicine, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, China
| | - Xiao Zhang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
- Department of Rheumatology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Sun Y, Chen X, Chen L, Bao B, Li C, Zhou Y. MFAP2 promotes HSCs activation through FBN1/TGF-β/Smad3 pathway. J Cell Mol Med 2023; 27:3235-3246. [PMID: 37635348 PMCID: PMC10623529 DOI: 10.1111/jcmm.17884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 07/12/2023] [Accepted: 07/19/2023] [Indexed: 08/29/2023] Open
Abstract
Liver fibrosis is a chronic inflammatory process characterized by the accumulation of extracellular matrix (ECM), which contributes to cirrhosis and hepatocellular carcinoma. Increasing evidence suggests that the activation of hepatic stellate cells (HSCs) under an inflammatory state leads to the secretion of collagens, which can cause cirrhosis. In this study, we analysed data from the Gene Expression Omnibus (GEO) databases to identify differentially expressed genes (DEGs) between quiescent and fibrotic HSCs. We found that Microfibril Associated Protein 2 (MFAP2) was elevated in carbon tetrachloride (CCl4)-induced liver fibrosis and Transforming Growth Factor-Beta 1 (TGF-β1)-activated HSCs. Knockdown of MFAP2 inhibited HSC proliferation and partially attenuated TGF-β-stimulated fibrogenesis markers. Bioinformatics analysis revealed that Fibrillin-1 (FBN1) was correlated with MFAP2, and the expression of FBN1 was significantly upregulated after MFAP2 overexpression. Silencing MFAP2 partially attenuated the activation of HSCs by inhibiting HSC proliferation and decreasing collagen deposits. In vitro results showed that the inhibition of MFAP2 alleviated hepatic fibrosis by inhibiting the activation and inducing the apoptosis of active HSCs in a CCl4-induced mouse model. In conclusion, our results suggest that MFAP2 is a potential target for the clinical treatment of liver fibrosis.
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Affiliation(s)
- Yonghong Sun
- Department of GastroenterologyThe First Hospital of Lanzhou UniversityLanzhouChina
- Department of PediatricsGansu Province People's HospitalLanzhouPeople's Republic of China
| | - Xingxing Chen
- Department of PediatricsGansu Province People's HospitalLanzhouPeople's Republic of China
| | - Lili Chen
- The First School of Clinical MedicineGansu University of Chinese MedicineLanzhouPeople's Republic of China
| | - Baixin Bao
- The First School of Clinical MedicineGansu University of Chinese MedicineLanzhouPeople's Republic of China
| | - Chunming Li
- Department of ObstetricsGansu Province People's HospitalLanzhouPeople's Republic of China
| | - Yongning Zhou
- Department of GastroenterologyThe First Hospital of Lanzhou UniversityLanzhouChina
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Ke X, Hu H, Peng Q, Ying H, Chu X. USP33 promotes nonalcoholic fatty acid disease-associated fibrosis in gerbils via the c-myc signaling. Biochem Biophys Res Commun 2023; 669:68-76. [PMID: 37267862 DOI: 10.1016/j.bbrc.2023.05.100] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/08/2023] [Accepted: 05/25/2023] [Indexed: 06/04/2023]
Abstract
Nonalcoholic fatty acid disease (NAFLD) is a common complication of obesity associated with liver fibrosis. The underlying molecular mechanisms involved in the progression from normal to fibrosis remain unclear. Liver tissues from the liver fibrosis model identified the USP33 gene as a key gene in NAFLD-associated fibrosis. USP33 knockdown inhibited hepatic stellate cell activation and glycolysis in gerbils with NAFLD-associated fibrosis. Conversely, overexpression of USP33 caused a contrast function on hepatic stellate cell activation and glycolysis activation, which was inhibited by c-Myc inhibitor 10058-F4. The copy number of short-chain fatty acids-producing bacterium Alistipes sp. AL-1, Mucispirillum schaedleri, Helicobacter hepaticus in the feces, and the total bile acid level in serum were higher in gerbils with NAFLD-associated fibrosis. Bile acid promoted USP33 expression and inhibiting its receptor reversed hepatic stellate cell activation in gerbils with NAFLD-associated fibrosis. These results suggest that the expression of USP33, an important deubiquitinating enzyme, is increased in NAFLD fibrosis. These data also point to hepatic stellate cells as a key cell type that may respond to liver fibrosis via USP33-induced cell activation and glycolysis.
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Affiliation(s)
- Xianfu Ke
- Hangzhou Medical College, Zhejiang, China.
| | - Huiying Hu
- Hangzhou Medical College, Zhejiang, China.
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7
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Zhang B, Lu J, Jiang Y, Feng Y. Asprosin contributes to nonalcoholic fatty liver disease through regulating lipid accumulation and inflammatory response via AMPK signaling. Immun Inflamm Dis 2023; 11:e947. [PMID: 37647445 PMCID: PMC10436697 DOI: 10.1002/iid3.947] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/27/2023] [Accepted: 07/08/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a primary contributor to liver-related morbidity and mortality. Asprosin has been reported to be implicated in NAFLD. AIMS This work is to illuminate the effects of Asprosin on NAFLD and the possible downstream mechanism. MATERIALS & METHODS The weight of NAFLD mice induced by a high-fat diet was detected. Quantitative reverse-transcription polymerase chain reaction (RT-qPCR) examined serum Asprosin expression. RT-qPCR and western blot analysis examined Asprosin expression in mice liver tissues. Intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) were implemented. Biochemical kits tested liver enzyme levels in mice serum and liver tissues. Hematoxylin and eosin staining evaluated liver histology. Liver weight was also tested and oil red O staining estimated lipid accumulation. RT-qPCR and western blot analysis analyzed the expression of gluconeogenesis-, fatty acid biosynthesis-, fatty acid oxidation-, and inflammation-associated factors. Besides, western blot analysis examined the expression of AMP-activated protein kinase (AMPK)/p38 signaling-associated factors. In palmitic acid (PA)-treated mice hepatocytes, RT-qPCR and western blot analysis examined Asprosin expression. Lipid accumulation, gluconeogenesis, fatty acid biosynthesis, fatty acid oxidation, and inflammation were appraised again. RESULTS Asprosin was overexpressed in the serum and liver tissues of NAFLD mice and PA-treated mice hepatocytes. Asprosin interference reduced mice body and liver weight, improved glucose tolerance and diminished liver injury in vivo. Asprosin knockdown alleviated lipid accumulation and inflammatory infiltration both in vitro and in vivo. Additionally, Asprosin absence activated AMPK/p38 signaling and AMPK inhibitor Compound C reversed the impacts of Asprosin on lipid accumulation and inflammatory response. CONCLUSION Collectively, Asprosin inhibition suppressed lipid accumulation and inflammation to obstruct NAFLD through AMPK/p38 signaling.
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Affiliation(s)
- Bo Zhang
- Department of Infectious DiseaseThe Affiliated People's Hospital of Ningbo UniversityNingbo CityZhejiang ProvinceChina
| | - Jinger Lu
- Department of EndocrineThe Affiliated People's Hospital of Ningbo UniversityNingbo CityZhejiang ProvinceChina
| | - Yuhua Jiang
- Department of Infectious DiseaseThe Affiliated People's Hospital of Ningbo UniversityNingbo CityZhejiang ProvinceChina
| | - Yan Feng
- Department of Digestive Blood EndocrinologyThe 75th Group Army Hospital of PLADali CityYunnan ProvinceChina
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Schuurman AR, Butler JM, Michels EH, Otto NA, Brands X, Haak BW, Uhel F, Klarenbeek AM, Faber DR, Schomakers BV, van Weeghel M, de Vos AF, Scicluna BP, Houtkooper RH, Wiersinga WJ, van der Poll T. Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia. iScience 2023; 26:107181. [PMID: 37496676 PMCID: PMC10366455 DOI: 10.1016/j.isci.2023.107181] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 04/21/2023] [Accepted: 06/15/2023] [Indexed: 07/28/2023] Open
Abstract
Neutrophils are potent immune cells with key antimicrobial functions. Previous in vitro work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection. Here, we combined flow cytometry, stimulation assays, transcriptomics, and metabolomics to investigate the link between inflammatory and metabolic pathways in blood neutrophils of patients with community-acquired pneumonia. Patients' neutrophils, relative to neutrophils from age- and sex- matched controls, showed increased degranulation upon ex vivo stimulation, and portrayed distinct upregulation of inflammatory transcriptional programs. This neutrophil phenotype was accompanied by a high-energy state with increased intracellular ATP content, and transcriptomic and metabolic upregulation of glycolysis and glycogenolysis. One month after hospital admission, these metabolic and transcriptomic changes were largely normalized. These data elucidate the molecular programs that underpin a balanced, yet primed state of blood neutrophils during pneumonia.
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Affiliation(s)
- Alex R. Schuurman
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Joe M. Butler
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Erik H.A. Michels
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Natasja A. Otto
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Xanthe Brands
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Bastiaan W. Haak
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Fabrice Uhel
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Augustijn M. Klarenbeek
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Daniël R. Faber
- BovenIJ Hospital, Statenjachtstraat 1, 1034 CS Amsterdam, the Netherlands
| | - Bauke V. Schomakers
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, the Netherlands
- Core Facility Metabolomics, Amsterdam UMC, 1105 AZ Amsterdam, the Netherlands
| | - Michel van Weeghel
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, the Netherlands
- Core Facility Metabolomics, Amsterdam UMC, 1105 AZ Amsterdam, the Netherlands
| | - Alex F. de Vos
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Brendon P. Scicluna
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
- Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei Hospital, University of Malta, Msida, Malta
| | - Riekelt H. Houtkooper
- Amsterdam Gastroenterology Endocrinology and Metabolism Institute, 1105 AZ Amsterdam, the Netherlands
- Amsterdam Cardiovascular Sciences Institute, 1105 AZ Amsterdam, the Netherlands
| | - W. Joost Wiersinga
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
- Division of Infectious Diseases, Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
| | - Tom van der Poll
- Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
- Division of Infectious Diseases, Amsterdam University Medical Centers - Location AMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
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Xu M, Xu K, Yin S, Sun W, Wang G, Zhang K, Mu J, Wu M, Xing B, Zhang X, Han J, Zhao X, Chang C, Wang Y, Xu D, Yu X. In-depth serum proteomics reveals the trajectory of hallmarks of cancer in hepatitis B virus-related liver diseases. Mol Cell Proteomics 2023:100574. [PMID: 37209815 PMCID: PMC10316086 DOI: 10.1016/j.mcpro.2023.100574] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 04/25/2023] [Accepted: 05/16/2023] [Indexed: 05/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent cancer in China, with chronic hepatitis B (CHB) and liver cirrhosis (LC) being high-risk factors for developing HCC. Here, we determined the serum proteomes (762 proteins) of 125 healthy controls and Hepatitis B virus-infected CHB, LC, and HCC patients and constructed the first cancerous trajectory of liver diseases. The results not only reveal that the majority of altered biological processes were involved in the hallmarks of cancer (inflammation, metastasis, metabolism, vasculature, coagulation), but also identify potential therapeutic targets in cancerous pathways (i.e., IL17 signaling pathway). Notably, the biomarker panels for detecting HCC in CHB and LC high-risk populations were further developed using machine learning in two cohorts comprised of 200 samples (discovery cohort=125, validation cohort=75). The protein signatures significantly improved the area under the receiver operating characteristic curve (AUC) of HCC (CHB discovery and validation cohort = 0.953 and 0.891, respectively; LC discovery and validation cohort = 0.966 and 0.818, respectively) compared to using the traditional biomarker, alpha-fetoprotein (AFP), alone. Finally, selected biomarkers were validated with parallel reaction monitoring (PRM) mass spectrometry in an additional cohort (n=120). Altogether, our results provide fundamental insights into the continuous changes of cancer biology processes in liver diseases and identify candidate protein targets for early detection and intervention.
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Affiliation(s)
- Meng Xu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Kaikun Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 102206, China; Research Unit of Proteomics Driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China
| | - Shangqi Yin
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Sun
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Guibin Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Kai Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Jinsong Mu
- Department of Critical Care Medicine, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100039, China
| | - Miantao Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Baocai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery I, Peking University Cancer Hospital and Institute, Beijing, 100036, China
| | - Xiaomei Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Jinyu Han
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Cheng Chang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 102206, China; Research Unit of Proteomics Driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing 102206, China.
| | - Yajie Wang
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
| | - Danke Xu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
| | - Xiaobo Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, 102206, China.
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Shen C, Chen Z, Jiang J, Zhang Y, Chen X, Xu W, Peng R, Zuo W, Jiang Q, Fan Y, Fang X, Zheng B. Identification and validation of fatty acid metabolism-related lncRNA signatures as a novel prognostic model for clear cell renal cell carcinoma. Sci Rep 2023; 13:7043. [PMID: 37120692 PMCID: PMC10148808 DOI: 10.1038/s41598-023-34027-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 04/22/2023] [Indexed: 05/01/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is a main subtype of renal cancer, and advanced ccRCC frequently has poor prognosis. Many studies have found that lipid metabolism influences tumor development and treatment. This study was to examine the prognostic and functional significance of genes associated with lipid metabolism in individuals with ccRCC. Using the database TCGA, differentially expressed genes (DEGs) associated with fatty acid metabolism (FAM) were identified. Prognostic risk score models for genes related to FAM were created using univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. Our findings demonstrate that the prognosis of patients with ccRCC correlate highly with the profiles of FAM-related lncRNAs (AC009166.1, LINC00605, LINC01615, HOXA-AS2, AC103706.1, AC009686.2, AL590094.1, AC093278.2). The prognostic signature can serve as an independent predictive predictor for patients with ccRCC. The predictive signature's diagnostic effectiveness was superior to individual clinicopathological factors. Between the low- and high-risk groups, immunity research revealed a startling difference in terms of cells, function, and checkpoint scores. Chemotherapeutic medications such lapatinib, AZD8055, and WIKI4 had better outcomes for patients in the high-risk group. Overall, the predictive signature can help with clinical selection of immunotherapeutic regimens and chemotherapeutic drugs, improving prognosis prediction for ccRCC patients.
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Affiliation(s)
- Cheng Shen
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Zhan Chen
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Jie Jiang
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Yong Zhang
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Xinfeng Chen
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Wei Xu
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Rui Peng
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China
- Medical Research Center, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Wenjing Zuo
- Department of Orthopedics, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Qian Jiang
- Department of Paediatric, Chinese Medicine Hospital of Rudong, Nantong, China
| | - Yihui Fan
- Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong, China
| | - Xingxing Fang
- Department of Nephrology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
| | - Bing Zheng
- Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
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11
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Chen J, Ye Y, Chi Y, Hao X, Zhao Q. Transcriptomics and co-expression network analysis revealing candidate genes for the laccase activity of Trametes gibbosa. BMC Microbiol 2023; 23:29. [PMID: 36703110 PMCID: PMC9878871 DOI: 10.1186/s12866-022-02727-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 12/08/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Trametes gibbosa, which is a white-rot fungus of the Polyporaceae family found in the cold temperate zone, causes spongy white rot on wood. Laccase can oxidize benzene homologs and is one of the important oxidases for white rot fungi to degrade wood. However, the pathway of laccase synthesis in white rot fungi is unknown. RESULTS The peak value of laccase activity reached 135.75 U/min/L on the 9th day. For laccase activity and RNA-seq data, gene expression was segmented into 24 modules. Turquoise and blue modules had greater associations with laccase activity (positively 0.94 and negatively -0.86, respectively). For biology function, these genes were concentrated on the cell cycle, citrate cycle, nicotinate, and nicotinamide metabolism, succinate dehydrogenase activity, flavin adenine dinucleotide binding, and oxidoreductase activity which are highly related to the laccase synthetic pathway. Among them, gene_8826 (MW199767), gene_7458 (MW199766), gene_61 (MW199765), gene_1741 (MH257605), and gene_11087 (MK805159) were identified as central genes. CONCLUSION Laccase activity steadily increased in wood degradation. Laccase oxidation consumes oxygen to produce hydrogen ions and water during the degradation of wood. Some of the hydrogen ions produced can be combined by Flavin adenine dinucleotide (FAD) to form reduced Flavin dinucleotide (FADH2), which can be transmitted. Also, the fungus was starved of oxygen throughout fermentation, and the NADH and FADH2 are unable to transfer hydrogen under hypoxia, resulting in the inability of NAD and FAD to regenerate and inhibit the tricarboxylic acid cycle of cells. These key hub genes related to laccase activity play important roles in the molecular mechanisms of laccase synthesis for exploring industrial excellent strains.
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Affiliation(s)
- Jie Chen
- grid.412246.70000 0004 1789 9091Northeast Forestry University, Harbin, China ,grid.4818.50000 0001 0791 5666Wageningen University & Research, Wageningen, Netherlands
| | - Yi Ye
- grid.412246.70000 0004 1789 9091Northeast Forestry University, Harbin, China
| | - Yujie Chi
- grid.412246.70000 0004 1789 9091Northeast Forestry University, Harbin, China
| | - Xin Hao
- grid.412246.70000 0004 1789 9091Northeast Forestry University, Harbin, China
| | - Qingquan Zhao
- grid.412246.70000 0004 1789 9091Northeast Forestry University, Harbin, China
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12
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Azam M, Zhang S, Huai Y, Abdelghany AM, Shaibu AS, Qi J, Feng Y, Liu Y, Li J, Qiu L, Li B, Sun J. Identification of genes for seed isoflavones based on bulk segregant analysis sequencing in soybean natural population. TAG. THEORETICAL AND APPLIED GENETICS. THEORETISCHE UND ANGEWANDTE GENETIK 2023; 136:13. [PMID: 36662254 DOI: 10.1007/s00122-023-04258-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 11/07/2022] [Indexed: 06/17/2023]
Abstract
We identified four hub genes for isoflavone biosynthesis based on BSA-seq and WGCNA methods and validated that GmIE3-1 positively contribute to isoflavone accumulation in soybean. Soybean isoflavones are secondary metabolites of great interest owing to their beneficial impact on human health. Herein, we profiled the seed isoflavone content by HPLC in 1551 soybean accessions grown in two locations for two years and constructed two extreme pools with high (4065.1 µg g-1) and low (1427.23 µg g-1) isoflavone contents to identify candidate genes involved in isoflavone biosynthesis pathways using bulk segregant analysis sequencing (BSA-seq) approach. The results showed that the average sequencing depths were 50.3× and 65.7× in high and low pools, respectively. A total of 23,626 polymorphic SNPs and 5299 InDels were detected between both pools and 1492 genes with different variations were identified. Based on differential genes in BSA-seq and weighted gene co-expression network analysis (WGCNA), four hub genes, Glyma.06G290400 (designated as GmIE3-1), Glyma.01G239200, Glyma.01G241500, Glyma.13G256100 were identified, encoding E3 ubiquitin-protein ligase, arm repeat protein interacting with ABF2, zinc metallopeptidase EGY3, and dynamin-related protein 3A, respectively. The allelic variation in GmIE3-1 showed a significant influence on isoflavone accumulation. The virus-induced gene silencing (VIGS) and RNAi hairy root transformation of GmIE3-1 revealed partial suppression of this gene could cause a significant decrease (P < 0.0001) of total isoflavone content, suggesting GmIE3-1 is a positive regulator for isoflavones. The present study demonstrated that the BSA-seq approach combined with WGCNA, VIGS and hairy root transformation can efficiently identify isoflavone candidate genes in soybean natural population.
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Affiliation(s)
- Muhammad Azam
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
| | - Shengrui Zhang
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
| | - Yuanyuan Huai
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
| | - Ahmed M Abdelghany
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
- Crop Science Department, Faculty of Agriculture, Damanhour University, Damanhour, 22516, Egypt
| | - Abdulwahab S Shaibu
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
- Department of Agronomy, Bayero University, Kano, Nigeria
| | - Jie Qi
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
| | - Yue Feng
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
| | - Yitian Liu
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
| | - Jing Li
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
| | - Lijuan Qiu
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China
| | - Bin Li
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China.
| | - Junming Sun
- The National Engineering Research Center of Crop Molecular Breeding, MARA Key Laboratory of Soybean Biology (Beijing), Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing, 100081, China.
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Michels EHA, Butler JM, Reijnders TDY, Cremer OL, Scicluna BP, Uhel F, Peters-Sengers H, Schultz MJ, Knight JC, van Vught LA, van der Poll T, Bos LDJ, Glas GJ, Hoogendijk AJ, van Hooijdonk RTM, Horn J, Huson MA, Schouten LRA, Straat M, Wieske L, Wiewel MA, Witteveen E, Bonten MJM, Cremer OM, Ong DSY, Frencken JF, Klouwenberg PMCK, Koster‐Brouwer ME, van de Groep K, Verboom DM. Association between age and the host response in critically ill patients with sepsis. Crit Care 2022; 26:385. [PMID: 36514130 PMCID: PMC9747080 DOI: 10.1186/s13054-022-04266-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The association of ageing with increased sepsis mortality is well established. Nonetheless, current investigations on the influence of age on host response aberrations are largely limited to plasma cytokine levels while neglecting other pathophysiological sepsis domains like endothelial cell activation and function, and coagulation activation. The primary objective of this study was to gain insight into the association of ageing with aberrations in key host response pathways and blood transcriptomes in sepsis. METHODS We analysed the clinical outcome (n = 1952), 16 plasma biomarkers providing insight in deregulation of specific pathophysiological domains (n = 899), and blood leukocyte transcriptomes (n = 488) of sepsis patients stratified according to age decades. Blood transcriptome results were validated in an independent sepsis cohort and compared with healthy individuals. RESULTS Older age was associated with increased mortality independent of comorbidities and disease severity. Ageing was associated with lower endothelial cell activation and dysfunction, and similar inflammation and coagulation activation, despite higher disease severity scores. Blood leukocytes of patients ≥ 70 years, compared to patients < 50 years, showed decreased expression of genes involved in cytokine signaling, and innate and adaptive immunity, and increased expression of genes involved in hemostasis and endothelial cell activation. The diminished expression of gene pathways related to innate immunity and cytokine signaling in subjects ≥ 70 years was sepsis-induced, as healthy subjects ≥ 70 years showed enhanced expression of these pathways compared to healthy individuals < 50 years. CONCLUSIONS This study provides novel evidence that older age is associated with relatively mitigated sepsis-induced endothelial cell activation and dysfunction, and a blood leukocyte transcriptome signature indicating impaired innate immune and cytokine signaling. These data suggest that age should be considered in patient selection in future sepsis trials targeting the immune system and/or the endothelial cell response.
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Affiliation(s)
- Erik H. A. Michels
- grid.7177.60000000084992262Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
| | - Joe M. Butler
- grid.7177.60000000084992262Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
| | - Tom D. Y. Reijnders
- grid.7177.60000000084992262Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
| | - Olaf L. Cremer
- grid.7692.a0000000090126352Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Brendon P. Scicluna
- grid.7177.60000000084992262Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands ,grid.4462.40000 0001 2176 9482Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei Hospital, University of Malta, Msida, Malta ,grid.4462.40000 0001 2176 9482Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Fabrice Uhel
- grid.7177.60000000084992262Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
| | - Hessel Peters-Sengers
- grid.7177.60000000084992262Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
| | - Marcus J. Schultz
- grid.7177.60000000084992262Department of Intensive Care, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands ,grid.10223.320000 0004 1937 0490Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand ,grid.4991.50000 0004 1936 8948Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Julian C. Knight
- grid.4991.50000 0004 1936 8948Nuffield Department of Medicine, University of Oxford, Oxford, UK ,grid.4991.50000 0004 1936 8948Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Lonneke A. van Vught
- grid.7177.60000000084992262Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands ,grid.7177.60000000084992262Department of Intensive Care, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Tom van der Poll
- grid.7177.60000000084992262Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands ,grid.7177.60000000084992262Division of Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands
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Qi X, Lai J. Exosomal microRNAs and Progression of Nonalcoholic Steatohepatitis (NASH). Int J Mol Sci 2022; 23:13501. [PMID: 36362287 PMCID: PMC9654542 DOI: 10.3390/ijms232113501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/22/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD)/metabolic associated fatty liver disease (MAFLD) is becoming a public health problem worldwide. Steatosis as the simple form and nonalcoholic steatohepatitis (NASH) as its progression form are commonly seen in liver biopsy specimens from patients with obesity, diabetes, hyperlipidemia, hypertension, and the use of certain drugs. Patients with NASH and advanced fibrosis were associated with increased risks of liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanisms regarding the progression from simple steatosis to NASH fibrosis remain incompletely understood. Because NASH-caused liver injury is a complex process and multiple cell types are involved, intercellular communication is likely mediated by extracellular vesicles. Exosomes are a type of small extracellular vesicles and contain various cellular molecules, including proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs). MiRNAs are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and may play an important role in the pathogenesis of NALFD/NASH. In this article, we review the articles about NASH and exosomal miRNAs published in the most recent English literature through PubMed search and discuss the most recent criteria for histological diagnosis, pathogenesis from steatosis to NASH, roles of exosomal miRNAs in NASH pathogenesis and progression, as well as their potential in future clinical diagnosis and treatment for patients with NASH.
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Affiliation(s)
- Xiaoyan Qi
- Department of Endocrinology and Metabolism, South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518116, China
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32601, USA
| | - Jinping Lai
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32601, USA
- Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, USA
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ATG101-related signature predicts prognosis and therapeutic option in hepatocellular carcinoma. Sci Rep 2022; 12:18066. [PMID: 36302799 PMCID: PMC9613769 DOI: 10.1038/s41598-022-22505-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 10/17/2022] [Indexed: 01/24/2023] Open
Abstract
Autophagy plays a critical role in tumor pathogenesis. However, autophagy-related signature in Hepatocellular carcinoma (HCC) has not been revealed yet. We quantified the levels of various cancer hallmarks and identified ATG101 as the major risk factor for overall survival in HCC. A robust ATG101-related gene signature (ATS) for prognosis was constructed using a combination of bioinformatic and statistical approaches. Additionally, genetic and immunological properties were measured between ATS-high and ATS-low groups. The ATS signature was associated with shortened overall survival in HCC patients independently of clinicopathological characteristics. ATS status defines an inflamed yet exhausted tumor microenvironment, in which the activities of the exhausted CD8+ or CD4+ T cells were strongly associated with ATS. The ATS signature predicts the drug resistance to the immunotherapy, thus a combination of targeted therapy and immunotherapy might be suitable for ATS-high patients. This work shed light on the function of ATG101-related genes in HCC and revealed that the ATS signature may be a useful prognostic biomarker for differentiating molecular and immunological features and predicting probable response to the therapy.
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Nguyen TB, Do DN, Nguyen-Thi ML, Hoang-The H, Tran TT, Nguyen-Thanh T. Identification of potential crucial genes and key pathways shared in Inflammatory Bowel Disease and cervical cancer by machine learning and integrated bioinformatics. Comput Biol Med 2022; 149:105996. [DOI: 10.1016/j.compbiomed.2022.105996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 07/10/2022] [Accepted: 08/14/2022] [Indexed: 11/15/2022]
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Li Y, Yuan SL, Yin JY, Yang K, Zhou XG, Xie W, Wang Q. Differences of core genes in liver fibrosis and hepatocellular carcinoma: Evidence from integrated bioinformatics and immunohistochemical analysis. World J Gastrointest Oncol 2022; 14:1265-1280. [PMID: 36051101 PMCID: PMC9305567 DOI: 10.4251/wjgo.v14.i7.1265] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/18/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver fibrosis and hepatocellular carcinoma (HCC) are common adverse consequences of chronic liver injury. The interaction of various risk factors may cause them to happen. Identification of specific biomarkers is of great significance for understanding the occurrence, development mechanisms, and determining the novel tools for diagnosis and treatment of both liver fibrosis and HCC.
AIM To identify liver fibrosis-related core genes, we analyzed the differential expression pattern of core genes in liver fibrosis and HCC.
METHODS Gene expression profiles of three datasets, GSE14323, GSE36411, and GSE89377, obtained from the Gene Expression Omnibus (GEO) database, were analyzed, and differentially expressed genes (DEGs) between patients with liver cirrhosis and healthy controls were identified by screening via R software packages and online tool for Venn diagrams. The WebGestalt online tool was used to identify DEGs enriched in biological processes, molecular functions, cellular components, and Kyoto Encyclopedia of Genes and Genomes pathways. The protein–protein interactions of DEGs were visualized using Cytoscape with STRING. Next, the expression pattern of core genes was analyzed using Western blot and immunohistochemistry in a carbon tetrachloride (CCl4)-induced liver cirrhosis mouse model and in patient liver samples. Finally, Kaplan-Meier curves were constructed using the Kaplan-Meier plotter online server.
RESULTS Forty-five DEGs (43 upregulated and 2 downregulated genes) associated with liver cirrhosis were identified from three GEO datasets. Ten hub genes were identified, which were upregulated in liver cirrhosis. Western blot and immunohistochemical analyses of the three core genes, decorin (DCN), dermatopontin (DPT), and SRY-box transcription factor 9 (SOX9), revealed that they were highly expressed in the CCl4-induced liver cirrhosis mouse model. The expression levels of DCN and SOX 9 were positively correlated with the degree of fibrosis, and SOX 9 level in HCC patients was significantly higher than that in fibrosis patients. However, high expression of DPT was observed only in patients with liver fibrosis, and its expression in HCC was low. The gene expression profiling interactive analysis server (GEPIA) showed that SOX9 was significantly upregulated whereas DCN and DPT were significantly downregulated in patients with HCC. In addition, the Kaplan-Meier curves showed that HCC patients with higher SOX9 expression had significantly lower 5-year survival rate, while patients with higher expression of DCN or DPT had significantly higher 5-year survival rates.
CONCLUSION The expression levels of DCN, DPT, and SOX9 were positively correlated with the degree of liver fibrosis but showed different correlations with the 5-year survival rates of HCC patients.
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Affiliation(s)
- Yue Li
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Shou-Li Yuan
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Beijing 100101, China
| | - Jing-Ya Yin
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Kun Yang
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Gang Zhou
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Qi Wang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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18
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Ding X, Xu Y, Nie P, Zhong L, Feng L, Guan Q, Song L. Changes in the serum metabolomic profiles of subjects with NAFLD in response to n-3 PUFAs and phytosterol ester: a double-blind randomized controlled trial. Food Funct 2022; 13:5189-5201. [PMID: 35438091 DOI: 10.1039/d1fo03921k] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease and threatens human health worldwide. As shown in our previous study, co-supplementation with phytosterol ester (PSE) (3.3 g day-1) and n-3 polyunsaturated fatty acids (PUFAs) (450 mg eicosapentaenoic acid (EPA) + 1500 mg docosahexaenoic acid (DHA) per day) was more effective at ameliorating hepatic steatosis than treatment with PSE or n-3 PUFAs alone. In the present study, we further investigated the changes in the serum metabolic profiles of subjects with NAFLD in response to n-3 PUFAs and PSE. Thirty-one differentially altered serum metabolites were annotated using the nontargeted ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF-MSE) analysis technique. Multivariable statistical and clustering analyses showed that co-supplementation of n-3 PUFAs and PSE was more effective at improving metabolic disorders in patients with NAFLD than treatment with n-3 PUFAs or PSE alone. The regulated metabolic pathways included metabolism of retinol, linoleic acid, arachidonic acid, glycerophospholipid, sphingolipid, and steroid hormone biosynthesis. Overall, the co-supplementation of n-3 PUFAs and PSE significantly increased the serum levels of PUFA-containing phosphatidylcholine (PC), lysophosphatidylcholine (LysoPC), perillyl alcohol and retinyl ester in patients with NAFLD after 12 weeks of intervention, and the levels of PC (14:0/20:5, 15:0/20:5), LysoPC (20:5, 22:6) and retinyl ester correlated negatively with the degree of hepatic steatosis. The regulatory effect of co-supplementation of n-3 PUFAs and PSE on metabolomic profiles may explain their potential role in alleviating hepatic steatosis in patients with NAFLD.
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Affiliation(s)
- Xinwen Ding
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Yinfei Xu
- The First People's Hospital of Ningyang County, Tai'an City 270018, Shandong Province, People's Republic of China
| | - Pan Nie
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Lingyue Zhong
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Lei Feng
- Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
| | - Qi Guan
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Lihua Song
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
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19
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Abedi Z, MotieGhader H, Hosseini SS, Sheikh Beig Goharrizi MA, Masoudi-Nejad A. mRNA-miRNA bipartite networks reconstruction in different tissues of bladder cancer based on gene co-expression network analysis. Sci Rep 2022; 12:5885. [PMID: 35393513 PMCID: PMC8991185 DOI: 10.1038/s41598-022-09920-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 03/24/2022] [Indexed: 12/14/2022] Open
Abstract
Bladder cancer (BC) is one of the most important cancers worldwide, and if it is diagnosed early, its progression in humans can be prevented and long-term survival will be achieved accordingly. This study aimed to identify novel micro-RNA (miRNA) and gene-based biomarkers for diagnosing BC. The microarray dataset of BC tissues (GSE13507) listed in the GEO database was analyzed for this purpose. The gene expression data from three BC tissues including 165 primary bladder cancer (PBC), 58 normal looking-bladder mucosae surrounding cancer (NBMSC), and 23 recurrent non-muscle invasive tumor tissues (RNIT) were used to reconstruct gene co-expression networks. After preprocessing and normalization, deferentially expressed genes (DEGs) were obtained and used to construct the weighted gene co-expression network (WGCNA). Gene co-expression modules and low-preserved modules were extracted among BC tissues using network clustering. Next, the experimentally validated mRNA-miRNA interaction information were used to reconstruct three mRNA-miRNA bipartite networks. Reactome pathway database and Gene ontology (GO) was subsequently performed for the extracted genes of three bipartite networks and miRNAs, respectively. To further analyze the data, ten hub miRNAs (miRNAs with the highest degree) were selected in each bipartite network to reconstruct three bipartite subnetworks. Finally, the obtained biomarkers were comprehensively investigated and discussed in authentic studies. The obtained results from our study indicated a group of genes including PPARD, CST4, CSNK1E, PTPN14, ETV6, and ADRM1 as well as novel miRNAs (e.g., miR-16-5p, miR-335-5p, miR-124-3p, and let-7b-5p) which might be potentially associated with BC and could be a potential biomarker. Afterward, three drug-gene interaction networks were reconstructed to explore candidate drugs for the treatment of BC. The hub miRNAs in the mRNA-miRNA bipartite network played a fundamental role in BC progression; however, these findings need further investigation.
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Affiliation(s)
- Zahra Abedi
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Habib MotieGhader
- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
| | - Sahar Sadat Hosseini
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | | | - Ali Masoudi-Nejad
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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20
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Wang S, Huang Z, Lei Y, Han X, Tian D, Gong J, Liu M. Celastrol Alleviates Autoimmune Hepatitis Through the PI3K/AKT Signaling Pathway Based on Network Pharmacology and Experiments. Front Pharmacol 2022; 13:816350. [PMID: 35359864 PMCID: PMC8960436 DOI: 10.3389/fphar.2022.816350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/24/2022] [Indexed: 12/02/2022] Open
Abstract
Objective: This work aims to explore the potential targets and underlying therapeutic mechanisms of celastrol in autoimmune hepatitis (AIH) through network pharmacology and experiments on Laboratory Animals. Methods: A drug-target interaction network was constructed to predict the possible targets of celastrol and their potential relationship with the drug; docking studies were also performed for validation. This study used both acute and chronic rodent models of autoimmune hepatitis. Gross appearance of liver and spleen were obtained from murine models, hematoxylin-eosin staining and Sirius red staining were performed to examine hepatic inflammation and fibrosis respectively. By combining molecular docking and enrichment analysis results, the most prominent signaling pathway was selected and further confirmed by Western blot in AIH models administered with celastrol. Results: In total, 82 common targets of celastrol and AIH were obtained from databases, identified by network pharmacology, and adequately enriched. Among them, PIK3R1, SRC, MAPK1, AKT1, and HRAS were selected as the top 5 closely related targets to celastrol. They all performed effectively in molecular docking, with AKT1 and PIK3R1 exhibiting more-prominent binding energy. Subsequently, celastrol administration significantly ameliorated hepatitis and liver fibrosis by reducing AKT1 and PI3K phosphorylation in both acute liver injury and chronic models of autoimmune hepatitis. Conclusion: In summary, celastrol significantly attenuates autoimmune hepatitis by suppressing the PI3K/AKT signaling pathway, confirmed by validated animal models. These findings may help identify the mechanism involved in the anti-inflammatory action of celastrol in autoimmune hepatitis and provide ideas for future comprehensive studies.
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Affiliation(s)
| | | | | | | | | | - Jin Gong
- *Correspondence: Jin Gong, ; Mei Liu,
| | - Mei Liu
- *Correspondence: Jin Gong, ; Mei Liu,
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21
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Identification of Five Hub Genes as Key Prognostic Biomarkers in Liver Cancer via Integrated Bioinformatics Analysis. BIOLOGY 2021; 10:biology10100957. [PMID: 34681056 PMCID: PMC8533228 DOI: 10.3390/biology10100957] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/07/2021] [Accepted: 09/18/2021] [Indexed: 12/24/2022]
Abstract
Liver cancer is one of the most common cancers and the top leading cause of cancer death globally. However, the molecular mechanisms of liver tumorigenesis and progression remain unclear. In the current study, we investigated the hub genes and the potential molecular pathways through which these genes contribute to liver cancer onset and development. The weighted gene co-expression network analysis (WCGNA) was performed on the main data attained from the GEO (Gene Expression Omnibus) database. The Cancer Genome Atlas (TCGA) dataset was used to evaluate the association between prognosis and these hub genes. The expression of genes from the black module was found to be significantly related to liver cancer. Based on the results of protein-protein interaction, gene co-expression network, and survival analyses, DNA topoisomerase II alpha (TOP2A), ribonucleotide reductase regulatory subunit M2 (RRM2), never in mitosis-related kinase 2 (NEK2), cyclin-dependent kinase 1 (CDK1), and cyclin B1 (CCNB1) were identified as the hub genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses showed that the differentially expressed genes (DEGs) were enriched in the immune-associated pathways. These hub genes were further screened and validated using statistical and functional analyses. Additionally, the TOP2A, RRM2, NEK2, CDK1, and CCNB1 proteins were overexpressed in tumor liver tissues as compared to normal liver tissues according to the Human Protein Atlas database and previous studies. Our results suggest the potential use of TOP2A, RRM2, NEK2, CDK1, and CCNB1 as prognostic biomarkers in liver cancer.
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22
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Li S, Han F, Qi N, Wen L, Li J, Feng C, Wang Q. Determination of a six-gene prognostic model for cervical cancer based on WGCNA combined with LASSO and Cox-PH analysis. World J Surg Oncol 2021; 19:277. [PMID: 34530829 PMCID: PMC8447612 DOI: 10.1186/s12957-021-02384-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
AIM This study aimed to establish a risk model of hub genes to evaluate the prognosis of patients with cervical cancer. METHODS Based on TCGA and GTEx databases, the differentially expressed genes (DEGs) were screened and then analyzed using GO and KEGG analyses. The weighted gene co-expression network (WGCNA) was then used to perform modular analysis of DEGs. Univariate Cox regression analysis combined with LASSO and Cox-pH was used to select the prognostic genes. Then, multivariate Cox regression analysis was used to screen the hub genes. The risk model was established based on hub genes and evaluated by risk curve, survival state, Kaplan-Meier curve, and receiver operating characteristic (ROC) curve. RESULTS We screened 1265 DEGs between cervical cancer and normal samples, of which 620 were downregulated and 645 were upregulated. GO and KEGG analyses revealed that most of the upregulated genes were related to the metastasis of cancer cells, while the downregulated genes mostly acted on the cell cycle. Then, WGCNA mined six modules (red, blue, green, brown, yellow, and gray), and the brown module with the most DEGs and related to multiple cancers was selected for the follow-up study. Eight genes were identified by univariate Cox regression analysis combined with the LASSO Cox-pH model. Then, six hub genes (SLC25A5, ENO1, ANLN, RIBC2, PTTG1, and MCM5) were screened by multivariate Cox regression analysis, and SLC25A5, ANLN, RIBC2, and PTTG1 could be used as independent prognostic factors. Finally, we determined that the risk model established by the six hub genes was effective and stable. CONCLUSIONS This study supplies the prognostic value of the risk model and the new promising targets for the cervical cancer treatment, and their biological functions need to be further explored.
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Affiliation(s)
- Shiyan Li
- Department of Gynecology, Heilongjiang University of Traditional Chinese Medicine, Harbin, PR China
| | - Fengjuan Han
- Department of Gynecology, Heilongjiang University of Traditional Chinese Medicine, Harbin, PR China.
| | - Na Qi
- Department of Gynecology, Heilongjiang University of Traditional Chinese Medicine, Harbin, PR China
| | - Liyang Wen
- Department of Acupuncture and Moxibustion, Heilongjiang University of Traditional Chinese Medicine, Harbin, P.R. China
| | - Jia Li
- Department of Gynecology, Heilongjiang University of Traditional Chinese Medicine, Harbin, PR China
| | - Cong Feng
- Department of Gynecology, Heilongjiang University of Traditional Chinese Medicine, Harbin, PR China
| | - Qingling Wang
- Department of Gynecology, Shenzhen Nanshan Maternal and Child Health Care Hospital, Shenzhen, P.R. China.
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23
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Lee CH, Seto WK, Lui DTW, Fong CHY, Wan HY, Cheung CYY, Chow WS, Woo YC, Yuen MF, Xu A, Lam KSL. Circulating Thrombospondin-2 as a Novel Fibrosis Biomarker of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes. Diabetes Care 2021; 44:2089-2097. [PMID: 34183428 DOI: 10.2337/dc21-0131] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/24/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Preclinical studies have suggested that thrombospondin-2 (TSP2) is implicated in liver fibrosis. However, the clinical relevance of TSP2 in nonalcoholic fatty liver disease (NAFLD) remains undefined. Here, we investigated the cross-sectional and longitudinal associations of circulating TSP2 levels with advanced fibrosis (F3 or greater [≥FE] fibrosis) in NAFLD. RESEARCH DESIGN AND METHODS Serum TSP2 levels were measured in 820 patients with type 2 diabetes and NAFLD. All participants received vibration-controlled transient elastography (VCTE) at baseline to evaluate their hepatic steatosis and fibrosis using controlled attenuation parameter (CAP) and liver stiffness (LS) measurements, respectively. Among those without advanced fibrosis at baseline, reassessment VCTE was performed to determine whether ≥F3 fibrosis had developed over time. Multivariable logistic regression analysis was used to evaluate the cross-sectional and longitudinal associations of serum TSP2 level with ≥F3 fibrosis. RESULTS Baseline serum TSP2 level was independently associated with the presence of ≥F3 fibrosis (odds ratio [OR] 5.13, P < 0.001). The inclusion of serum TSP2 level significantly improved the identification of ≥F3 fibrosis by clinical risk factors. Over a median follow-up of 1.5 years, 8.8% developed ≥F3 fibrosis. Baseline serum TSP2 level was significantly associated with incident ≥F3 fibrosis (OR 2.82, P = 0.005), independent of other significant clinical risk factors of fibrosis progression, including BMI, platelet count, and CAP at baseline. CONCLUSIONS Circulating TSP2 level was associated with both the presence and the development of advanced fibrosis and might be a potentially useful prognostic biomarker for the development and progression of liver fibrosis in patients with type 2 diabetes and NAFLD.
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Affiliation(s)
- Chi-Ho Lee
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong
| | - David Tak-Wai Lui
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Carol Ho-Yi Fong
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Helen Yilin Wan
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Chloe Yu-Yan Cheung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Wing-Sun Chow
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Yu-Cho Woo
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong.,State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong
| | - Aimin Xu
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong .,State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong
| | - Karen Siu-Ling Lam
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong .,State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong
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24
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Zheng J, Wu H, Zhang Z, Yao S. Dynamic co-expression modular network analysis in nonalcoholic fatty liver disease. Hereditas 2021; 158:31. [PMID: 34419146 PMCID: PMC8380347 DOI: 10.1186/s41065-021-00196-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 08/04/2021] [Indexed: 12/13/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting people’s health worldwide. Exploring the potential biomarkers and dynamic networks during NAFLD progression is urgently important. Material and methods Differentially expressed genes (DEGs) in obesity, NAFL and NASH were screened from GSE126848 and GSE130970, respectively. Gene set enrichment analysis of DEGs was conducted to reveal the Gene Ontology (GO) biological process in each period. Dynamic molecular networks were constructed by DyNet to illustrate the common and distinct progression of health- or obesity-derived NAFLD. The dynamic co-expression modular analysis was carried out by CEMiTool to elucidate the key modulators, networks, and enriched pathways during NAFLD. Results A total of 453 DEGs were filtered from obesity, NAFL and NASH periods. Function annotation showed that health-NAFLD sequence was mainly associated with dysfunction of metabolic syndrome pathways, while obesity-NAFLD sequence exhibited dysregulation of Cell cycle and Cellular senescence pathways. Nine nodes including COL3A1, CXCL9, CYCS, CXCL10, THY1, COL1A2, SAA1, CDKN1A, and JUN in the dynamic networks were commonly identified in health- and obesity-derived NAFLD. Moreover, CYCS, whose role is unknown in NAFLD, possessed the highest correlation with NAFLD activity score, lobular inflammation grade, and the cytological ballooning grade. Dynamic co-expression modular analysis showed that module 4 was activated in NAFL and NASH, while module 3 was inhibited at NAFLD stages. Module 3 was negatively correlated with CXCL10, and module 4 was positively correlated with COL1A2 and THY1. Conclusion Dynamic network analysis and dynamic gene co-expression modular analysis identified a nine-gene signature as the potential key regulator in NAFLD progression, which provided comprehensive regulatory mechanisms underlying NAFLD progression. Supplementary Information The online version contains supplementary material available at 10.1186/s41065-021-00196-8.
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Affiliation(s)
- Jing Zheng
- Department of Pharmacy, Zhejiang Medical & Health Group Hangzhou Hospital, No.1 Banshan Road, Kangjian nong, Hangzhou, 310022, China
| | - Huizhong Wu
- Department of Pharmacy, Zhejiang Quhua Hospital, Quzhou, 324002, China
| | - Zhiying Zhang
- Department of Pharmacy, Hangzhou Jianggan District People's Hospital, Hangzhou, 310016, China
| | - Songqiang Yao
- Department of Pharmacy, Zhejiang Medical & Health Group Hangzhou Hospital, No.1 Banshan Road, Kangjian nong, Hangzhou, 310022, China.
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25
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Subudhi S, Drescher HK, Dichtel LE, Bartsch LM, Chung RT, Hutter MM, Gee DW, Meireles OR, Witkowski ER, Gelrud L, Masia R, Osganian SA, Gustafson JL, Rwema S, Bredella MA, Bhatia SN, Warren A, Miller KK, Lauer GM, Corey KE. Distinct Hepatic Gene-Expression Patterns of NAFLD in Patients With Obesity. Hepatol Commun 2021; 6:77-89. [PMID: 34558849 PMCID: PMC8710788 DOI: 10.1002/hep4.1789] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 06/13/2021] [Indexed: 02/06/2023] Open
Abstract
Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene‐expression patterns associated with different patterns of liver injury in a high‐risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1‐4 (NASH F1‐F4). One hundred twenty‐five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma‐interferon‐inducible lysosomal thiol reductase (IFI30) and chemokine (C‐X‐C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1‐F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high‐risk individuals.
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Affiliation(s)
- Sonu Subudhi
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Hannah K Drescher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Laura E Dichtel
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lea M Bartsch
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Raymond T Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Matthew M Hutter
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Denise W Gee
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ozanan R Meireles
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Elan R Witkowski
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Louis Gelrud
- Department of Medicine, St. Mary's Hospital Bon Secours, Richmond, VA, USA
| | - Ricard Masia
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Stephanie A Osganian
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jenna L Gustafson
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Steve Rwema
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Miriam A Bredella
- Division of Musculoskeletal Radiology and Interventions, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Sangeeta N Bhatia
- Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Andrew Warren
- Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Karen K Miller
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Georg M Lauer
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kathleen E Corey
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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Using weighted gene co-expression network analysis (WGCNA) to identify the hub genes related to hypoxic adaptation in yak (Bos grunniens). Genes Genomics 2021; 43:1231-1246. [PMID: 34338989 DOI: 10.1007/s13258-021-01137-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/29/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND As a mammal living at the highest altitude in the world, the yak has strong adaptability to the harsh natural environment (such as low temperature, scarce food, especially low oxygen) of Qinghai-Tibet Plateau (QTP) after a long process of natural selection. OBJECTIVE Here, we used Weighted Correlation Network Analysis (WGCNA), a systematic biology method, to identify hypoxic adaptation-related modules and hub genes. The research of the adaptability of yak against hypoxia is of great significance to identify the genetic characteristics and yak breeding. METHODS Based on the transcriptome sequencing data (PRJNA362606), the R package DESeq2 and WGCNA were conducted to analyze differentially expressed genes (DEGs) and construct the gene co-expression network. The module hub genes were identified and characterized by the correlation of gene and trait, module membership (kME). In addition, GO and KEGG enrichment analyses were used to explore the functions of hub genes. RESULTS Our results revealed that 1098, 1429, and 1645 DEGs were identified in muscle, spleen, and lung, respectively. Besides, a total of 13 gene co-expression modules were detected, of which two hypoxic adaptation-related modules (saddlebrown and turquoise) were found. We identified 39 and 150 hub genes in these two modules. Functional enrichment analyses showed that 12 GO terms and 18 KEGG pathways were enriched in the saddlebrown module while 85 GO terms and 22 KEGG pathways were enriched in the turquoise module. The significant pathways related to hypoxia adaptation include FoxO signaling pathway, Thermogenesis pathway, and Retrograde endocannabinoid signaling pathway, etc. CONCLUSIONS: In this study, we obtained two hypoxia-related specific modules and identified hub genes based on the connectivity by constructing a weighted gene co-expression network. Function enrichment analysis of two modules revealed mitochondrion is the most important organelle for hypoxia adaptation. Moreover, the insulin-related pathways and thermogenic-related pathways played a major role. The results of this study provide theoretical guidance for further understanding the molecular mechanism of yak adaptation to hypoxia.
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Voutilainen SH, Kosola SK, Lohi J, Jahnukainen T, Pakarinen MP, Jalanko H. Expression of fibrosis-related genes in liver allografts: Association with histology and long-term outcome after pediatric liver transplantation. Clin Transplant 2021; 35:e14373. [PMID: 34043847 DOI: 10.1111/ctr.14373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 05/11/2021] [Accepted: 05/16/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Unexplained graft fibrosis and inflammation are common after pediatric liver transplantation (LT). OBJECTIVE We investigated the graft expression of fibrogenic genes and correlated the findings with transplant histopathology and outcome. METHODS Liver biopsies from 29 recipients were obtained at a median of 13.1 (IQR: 5.0-18.4) years after pediatric LT. Control samples were from six liver-healthy subjects. Hepatic expression of 40 fibrosis-related genes was correlated to histological findings: normal histology, fibrosis with no inflammation, and fibrosis with inflammation. Liver function was evaluated after a subsequent follow-up of 9.0 years (IQR: 8.0-9.4). RESULTS Patients with fibrosis and no inflammation had significantly increased gene expression of profibrotic TGF-β3 (1.17 vs. 1.02 p = .005), CTGF (1.64 vs. 0.66 p = .014), PDGF-α (1.79 vs. 0.98 p = .049), PDGF -β (0.99 vs. 0.76 p = .006), integrin-subunit-β1 (1.19 vs. 1.02 p = .045), α-SMA (1.12 vs. 0.58 p = .013), type I collagen (0.82 vs. 0.53 p = .005) and antifibrotic decorin (1.15 vs. 0.99 p = .045) compared to patients with normal histology. mRNA expression of VEGF A (0.84 vs. 1.06 p = .049) was lower. Only a few of the studied genes were upregulated in patients with both fibrosis and inflammation. The gene expression levels showed no association with later graft outcome. CONCLUSIONS Altered hepatic expression of fibrosis-related genes is associated with graft fibrosis without concurrent inflammation.
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Affiliation(s)
- Silja H Voutilainen
- Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University, Hospital and University of Helsinki, Helsinki, Finland
| | - Silja K Kosola
- Pediatric Research Center, New Children's Hospital, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland
| | - Jouko Lohi
- Department of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Timo Jahnukainen
- Department of Pediatric Nephrology and Transplantation, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Mikko P Pakarinen
- Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University, Hospital and University of Helsinki, Helsinki, Finland
| | - Hannu Jalanko
- Department of Pediatric Nephrology and Transplantation, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Li C, Yu H, Sun Y, Zeng X, Zhang W. Identification of the hub genes in gastric cancer through weighted gene co-expression network analysis. PeerJ 2021; 9:e10682. [PMID: 33717664 PMCID: PMC7938783 DOI: 10.7717/peerj.10682] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 12/09/2020] [Indexed: 02/05/2023] Open
Abstract
Background Gastric cancer is one of the most lethal tumors and is characterized by poor prognosis and lack of effective diagnostic or therapeutic biomarkers. The aim of this study was to find hub genes serving as biomarkers in gastric cancer diagnosis and therapy. Methods GSE66229 from Gene Expression Omnibus (GEO) was used as training set. Genes bearing the top 25% standard deviations among all the samples in training set were performed to systematic weighted gene co-expression network analysis (WGCNA) to find candidate genes. Then, hub genes were further screened by using the “least absolute shrinkage and selection operator” (LASSO) logistic regression. Finally, hub genes were validated in the GSE54129 dataset from GEO by supervised learning method artificial neural network (ANN) algorithm. Results Twelve modules with strong preservation were identified by using WGCNA methods in training set. Of which, five modules significantly related to gastric cancer were selected as clinically significant modules, and 713 candidate genes were identified from these five modules. Then, ADIPOQ, ARHGAP39, ATAD3A, C1orf95, CWH43, GRIK3, INHBA, RDH12, SCNN1G, SIGLEC11 and LYVE1 were screened as the hub genes. These hub genes successfully differentiated the tumor samples from the healthy tissues in an independent testing set through artificial neural network algorithm with the area under the receiver operating characteristic curve at 0.946. Conclusions These hub genes bearing diagnostic and therapeutic values, and our results may provide a novel prospect for the diagnosis and treatment of gastric cancer in the future.
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Affiliation(s)
- Chunyang Li
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Cheng, China.,Medical Big Data Center, Sichuan University, Chengdu, China
| | - Haopeng Yu
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Cheng, China.,Medical Big Data Center, Sichuan University, Chengdu, China
| | - Yajing Sun
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Cheng, China.,Medical Big Data Center, Sichuan University, Chengdu, China
| | - Xiaoxi Zeng
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Cheng, China.,Medical Big Data Center, Sichuan University, Chengdu, China
| | - Wei Zhang
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Cheng, China.,Medical Big Data Center, Sichuan University, Chengdu, China
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Kimura T, Tanaka N, Fujimori N, Yamazaki T, Katsuyama T, Iwashita Y, Pham J, Joshita S, Pydi SP, Umemura T. Serum thrombospondin 2 is a novel predictor for the severity in the patients with NAFLD. Liver Int 2021; 41:505-514. [PMID: 33386676 DOI: 10.1111/liv.14776] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/21/2020] [Accepted: 12/29/2020] [Indexed: 12/13/2022]
Abstract
AIM Thrombospondins are a family of multidomain and secretory glycoproteins. Among them, thrombospondin 2 (TSP2) encoded by TSP2 gene has been reported to be involved in various functions such as collagen/fibrin formation, maintenance of normal blood vessel density and cell adhesion properties. Microarray analyses ranked TSP2 as one of the most highly up-regulated genes in the fibrotic liver in patients with non-alcoholic fatty liver disease (NAFLD). Since TSP2 possesses unique properties as a secretory protein, we hypothesized that hepatic TSP2 gene expression levels would be reflected in serum TSP2 levels. In this study, we examined the relationship between serum TSP2 concentrations and clinicopathological findings in NAFLD patients. METHODS One hundred and thirty NAFLD patients who had undergone liver biopsy between 2009 and 2015 were retrospectively enrolled. Serum samples were collected at the time of biopsy, and TSP2 was measured by enzyme immunoassays. RESULTS Serum TSP2 levels moderately correlated with ballooning (r = 0.56, P < .001) and fibrosis stage (r = 0.53, P < .001). The AUC values of TSP2 for predicting mild fibrosis (≧F1), moderate fibrosis (≧F2) and severe fibrosis (≧F3) were 0.73, 0.76 and 0.82 respectively. Additionally, NAFLD activity score (NAS) correlated best with TSP2 (r = 0.52, P < .001) compared to conventional NAFLD-related biomarkers, such as cytokeratin 18 M30, hyaluronic acid, type IV collagen 7S, APRI and FIB-4 index. CONCLUSION Serum TSP2 levels reflected hepatocyte ballooning, fibrosis and NAS in NAFLD patients. For clinical application of serum TSP2 as a predictor of NAFLD histological activity, additional validation and mechanistic investigations are required.
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Affiliation(s)
- Takefumi Kimura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.,Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.,Research Center for Social Systems, Shinshu University, Matsumoto, Japan
| | - Naoyuki Fujimori
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takahito Katsuyama
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuichi Iwashita
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan
| | - Jonathan Pham
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Sai P Pydi
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.,Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
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Wang J, Lou Y, Lu J, Luo Y, Lu A, Chen A, Fu J, Liu J, Zhou X, Yang J. A Deep Look into the Program of Rapid Tumor Growth of Hepatocellular Carcinoma. J Clin Transl Hepatol 2021; 9:22-31. [PMID: 33604252 PMCID: PMC7868698 DOI: 10.14218/jcth.2020.00084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/12/2020] [Accepted: 12/01/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND AIMS Great efforts have been made towards increasing our understanding of the pathogenesis involved in hepatocellular carcinoma (HCC), but the rapid growth inherent to such tumor development remains to be explored. METHODS We identified distinct gene coexpression modes upon liver tumor growth using weighted gene coexpression network analysis. Modeling of tumor growth as signaling activity was employed to understand the main cascades responsible for the growth. Hub genes in the modules were determined, examined in vitro, and further assembled into the growth signature. RESULTS We revealed modules related to the different growth states in HCC, especially the fastest growth module, which is preserved among different HCC cohorts. Moreover, signaling flux in the cell cycle pathway was found to act as a driving force for rapid growth. Twenty hub genes in the module were identified and assembled into the growth signature, and two genes (NCAPH, and RAD54L) were tested for their growth potential in vitro. Genetic alteration of the growth signature affected the global gene expression. The activity of the signature was associated with tumor metabolism and immunity in HCC. Finally, the prognosis effect of the growth signature was reproduced in nine cancers. CONCLUSIONS These results collectively demonstrate the molecule organization of rapid tumor growth in HCC, which is a highly synergistic process, with implications for the future management of patients.
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Affiliation(s)
- Jie Wang
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yi Lou
- Department of Occupational Medicine, Hangzhou Red Cross Hospital, Zhejiang Provincial Integrated Chinese and Western Medicine Hospital, Hangzhou, Zhejiang, China
| | - Jianmin Lu
- Department of Orthopedics, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yuxiao Luo
- Department of Orthopedics, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Anqian Lu
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Anna Chen
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jiantao Fu
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jing Liu
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xiang Zhou
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Correspondence to: Jin Yang, Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 310015, China. Tel: +86-571-88358062, E-mail: ; Xiang Zhou, Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 310015, China. Tel: +86-571-88303403, E-mail:
| | - Jin Yang
- Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang, China
- Correspondence to: Jin Yang, Department of Translational Medicine, Affiliated Hospital of Hangzhou Normal University, Institute of Hepatology and Metabolic Diseases of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 310015, China. Tel: +86-571-88358062, E-mail: ; Xiang Zhou, Department of Liver Disease, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, Zhejiang 310015, China. Tel: +86-571-88303403, E-mail:
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Identification and characterization of dynamically regulated hepatitis-related genes in a concanavalin A-induced liver injury model. Aging (Albany NY) 2020; 12:23187-23199. [PMID: 33221747 PMCID: PMC7746381 DOI: 10.18632/aging.104089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/31/2020] [Indexed: 12/11/2022]
Abstract
Background: Concanavalin A (ConA)-induced liver damage of mice is a well-established murine model mimicking the human autoimmune hepatitis (AIH). However, the pathogenic genes of the liver injury remain to be revealed. Methods: Using time-series liver transcriptome, top dynamic genes were inferred from a set of segmented regression models, and cross-checked by weighted correlation network analysis (WGCNA). AIH murine models created by ConA were used to verify the in vivo effect of these genes. Results: We identified 115 top dynamic genes, of which most were overlapped with the hub genes determined by WGCNA. The expression of several top dynamic genes including Cd63, Saa3, Slc10a1, Nrxn1, Ugt2a3, were verified in vivo. Further, Cluster determinant 63 (Cd63) knockdown in mice treated with ConA showed significantly less liver pathology and inflammation as well as higher survival rates than the corresponding controls. Conclusion: We have identified the top dynamic genes related to the process of acute liver injury, and highlighted a targeted strategy for Cd63 might have utility for the protection of hepatocellular damage.
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32
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Perlo V, Botha FC, Furtado A, Hodgson‐Kratky K, Henry RJ. Metabolic changes in the developing sugarcane culm associated with high yield and early high sugar content. PLANT DIRECT 2020; 4:e00276. [PMID: 33204934 PMCID: PMC7656173 DOI: 10.1002/pld3.276] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 05/14/2023]
Abstract
Sugarcane, with its exceptional biomass and sugar yield, has a high potential for the production of bioenergy, biomaterials, and high-value products. Currently, the link between metabolic changes in the developing internodes in sugarcane and final yield and sugar characteristics is not well understood. In order to investigate these correlations, 1,440 internodes were collected and combined to generate a set of 360 samples across 24 sugarcane cultivars at five different developmental stages. A combination of metabolome profiling and trait co-expression analyses were conducted to reveal the interaction between the metabolome and essential agronomic traits, including Brix (total sugar), polarity (sucrose content), purity (sucrose purity), commercially extractable sucrose, fiber, and tons of cane per hectare (TCH). Metabolomic analysis revealed significant differences in metabolic patterns mainly correlated with developmental stage. Hierarchical clustering of genotypes and traits revealed clear partitioning of groups of early-, mid- and late-season sugar content, with secondary segregation by the yield trait, TCH, and fiber content. The study identified co-expression and specific metabolites associated with metabolic pathways correlated with Brix and fiber content. Knowledge of the correlation between co-expressed metabolites and diverse agronomic traits will allow more deliberate selection of genotypes for early or late sugar development and fiber content and biomass yield.
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Affiliation(s)
- Virginie Perlo
- Queensland Alliance for Agriculture and Food InnovationUniversity of QueenslandBrisbaneQLDAustralia
| | - Frederik C. Botha
- Queensland Alliance for Agriculture and Food InnovationUniversity of QueenslandBrisbaneQLDAustralia
| | - Agnelo Furtado
- Queensland Alliance for Agriculture and Food InnovationUniversity of QueenslandBrisbaneQLDAustralia
| | - Katrina Hodgson‐Kratky
- Queensland Alliance for Agriculture and Food InnovationUniversity of QueenslandBrisbaneQLDAustralia
| | - Robert J. Henry
- Queensland Alliance for Agriculture and Food InnovationUniversity of QueenslandBrisbaneQLDAustralia
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33
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Ai D, Wang Y, Li X, Pan H. Colorectal Cancer Prediction Based on Weighted Gene Co-Expression Network Analysis and Variational Auto-Encoder. Biomolecules 2020; 10:biom10091207. [PMID: 32825264 PMCID: PMC7563725 DOI: 10.3390/biom10091207] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 07/30/2020] [Accepted: 08/01/2020] [Indexed: 02/06/2023] Open
Abstract
An effective feature extraction method is key to improving the accuracy of a prediction model. From the Gene Expression Omnibus (GEO) database, which includes 13,487 genes, we obtained microarray gene expression data for 238 samples from colorectal cancer (CRC) samples and normal samples. Twelve gene modules were obtained by weighted gene co-expression network analysis (WGCNA) on 173 samples. By calculating the Pearson correlation coefficient (PCC) between the characteristic genes of each module and colorectal cancer, we obtained a key module that was highly correlated with CRC. We screened hub genes from the key module by considering module membership, gene significance, and intramodular connectivity. We selected 10 hub genes as a type of feature for the classifier. We used the variational autoencoder (VAE) for 1159 genes with significantly different expressions and mapped the data into a 10-dimensional representation, as another type of feature for the cancer classifier. The two types of features were applied to the support vector machines (SVM) classifier for CRC. The accuracy was 0.9692 with an AUC of 0.9981. The result shows a high accuracy of the two-step feature extraction method, which includes obtaining hub genes by WGCNA and a 10-dimensional representation by variational autoencoder (VAE).
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Affiliation(s)
- Dongmei Ai
- Basic Experimental Center of Natural Science, University of Science and Technology Beijing, Beijing 100083, China
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing 100083, China; (Y.W.); (X.L.); (H.P.)
- Correspondence: ; Tel.: +86-136-2105-2939
| | - Yuduo Wang
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing 100083, China; (Y.W.); (X.L.); (H.P.)
| | - Xiaoxin Li
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing 100083, China; (Y.W.); (X.L.); (H.P.)
| | - Hongfei Pan
- School of Mathematics and Physics, University of Science and Technology Beijing, Beijing 100083, China; (Y.W.); (X.L.); (H.P.)
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Blencowe M, Karunanayake T, Wier J, Hsu N, Yang X. Network Modeling Approaches and Applications to Unravelling Non-Alcoholic Fatty Liver Disease. Genes (Basel) 2019; 10:E966. [PMID: 31771247 PMCID: PMC6947017 DOI: 10.3390/genes10120966] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/18/2019] [Accepted: 11/22/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a progressive condition of the liver encompassing a range of pathologies including steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Research into this disease is imperative due to its rapid growth in prevalence, economic burden, and current lack of FDA approved therapies. NAFLD involves a highly complex etiology that calls for multi-tissue multi-omics network approaches to uncover the pathogenic genes and processes, diagnostic biomarkers, and potential therapeutic strategies. In this review, we first present a basic overview of disease pathogenesis, risk factors, and remaining knowledge gaps, followed by discussions of the need and concepts of multi-tissue multi-omics approaches, various network methodologies and application examples in NAFLD research. We highlight the findings that have been uncovered thus far including novel biomarkers, genes, and biological pathways involved in different stages of NAFLD, molecular connections between NAFLD and its comorbidities, mechanisms underpinning sex differences, and druggable targets. Lastly, we outline the future directions of implementing network approaches to further improve our understanding of NAFLD in order to guide diagnosis and therapeutics.
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Affiliation(s)
- Montgomery Blencowe
- Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA 90095, USA; (M.B.); (T.K.); (J.W.); (N.H.)
- Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA 90095, USA
| | - Tilan Karunanayake
- Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA 90095, USA; (M.B.); (T.K.); (J.W.); (N.H.)
| | - Julian Wier
- Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA 90095, USA; (M.B.); (T.K.); (J.W.); (N.H.)
| | - Neil Hsu
- Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA 90095, USA; (M.B.); (T.K.); (J.W.); (N.H.)
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA 90095, USA; (M.B.); (T.K.); (J.W.); (N.H.)
- Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA 90095, USA
- Interdepartmental Program of Bioinformatics, University of California, Los Angeles, 610 Charles E. Young Drive East, Los Angeles, CA 90095, USA
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35
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Liu Z, Li M, Hua Q, Li Y, Wang G. Identification of an eight-lncRNA prognostic model for breast cancer using WGCNA network analysis and a Cox‑proportional hazards model based on L1-penalized estimation. Int J Mol Med 2019; 44:1333-1343. [PMID: 31432096 PMCID: PMC6713414 DOI: 10.3892/ijmm.2019.4303] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 05/24/2019] [Indexed: 12/11/2022] Open
Abstract
An ever‑increasing number of long noncoding (lnc)RNAs has been identified in breast cancer. The present study aimed to establish an lncRNA signature for predicting survival in breast cancer. RNA expression profiling was performed using microarray gene expression data from the National Center for Biotechnology Information Gene Expression Omnibus, followed by the identification of breast cancer‑related preserved modules using weighted gene co‑expression network (WGCNA) network analysis. From the lncRNAs identified in these preserved modules, prognostic lncRNAs were selected using univariate Cox regression analysis in combination with the L1‑penalized (LASSO) Cox‑proportional Hazards (Cox‑PH) model. A risk score based on these prognostic lncRNAs was calculated and used for risk stratification. Differentially expressed RNAs (DERs) in breast cancer were identified using MetaDE. Gene Set Enrichment Analysis pathway enrichment analysis was conducted for these prognostic lncRNAs and the DERs related to the lncRNAs in the preserved modules. A total of five preserved modules comprising 73 lncRNAs were mined. An eight‑lncRNA signature (IGHA1, IGHGP, IGKV2‑28, IGLL3P, IGLV3‑10, AZGP1P1, LINC00472 and SLC16A6P1) was identified using the LASSO Cox‑PH model. Risk score based on these eight lncRNAs could classify breast cancer patients into two groups with significantly different survival times. The eight‑lncRNA signature was validated using three independent cohorts. These prognostic lncRNAs were significantly associated with the cell adhesion molecules pathway, JAK‑signal transducer and activator of transcription 5A pathway, and erbb pathway and are potentially involved in regulating angiotensin II receptor type 1, neuropeptide Y receptor Y1, KISS1 receptor, and C‑C motif chemokine ligand 5. The developed eight‑lncRNA signature may have clinical implications for predicting prognosis in breast cancer. Overall, this study provided possible molecular targets for the development of novel therapies against breast cancer.
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Affiliation(s)
- Zhenbin Liu
- Department of Ulcer and Vascular Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
| | - Menghu Li
- Department of Ulcer and Vascular Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
| | - Qi Hua
- Department of Ulcer and Vascular Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
| | - Yanfang Li
- Department of Ulcer and Vascular Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
| | - Gang Wang
- Department of Ulcer and Vascular Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China
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36
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Gu L, Jing R, Gong Y, Yu M, Elokil A, Li S. Gene co-expression network analysis reveals key potential gene modules in utero-vaginal junction associated with duration of fertility trait of breeder hens. Sci Rep 2019; 9:13860. [PMID: 31554832 PMCID: PMC6761187 DOI: 10.1038/s41598-019-50148-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 09/04/2019] [Indexed: 02/07/2023] Open
Abstract
The number of days (DN) when hens lay fertile eggs as well as the number of fertile eggs (FN) were produced after a single artificial insemination (AI), including the two duration of fertility (DF) traits. Indeed, they are the key production performance that associates with the production cost of hatching egg when its determination the interval between successive artificial inseminations. However, the relevant genes response for regulating the DF has not been uncovered yet. Therefore, we performed a weighted gene co-expression network analysis (WGCNA) to investigate the insight into co-expression gene modules on DF process in hens. The total mRNA was extracted from the utero-vaginal junction (UVJ, with the sperm storage function in hen’s oviduct which is the biological basis for DF) of 20 hens with several levels of DF traits, and performed transcriptome sequences of mRNA. As a result, three co-expression gene modules were identified to be highly correlated with DF traits. Moreover, the expression changes of top 5 hub genes in each module with DF traits were further confirmed in other 20 hens by RT-PCR. These findings highlighted the co-expression modules and their affiliated genes as playing important roles in the regulation of DF traits.
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Affiliation(s)
- Lantao Gu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China.,Guilin Medical University, Guilin, Guangxi, China
| | - Ruoxi Jing
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Yanzhang Gong
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Mei Yu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Abdelmotaleb Elokil
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China.,Department of Animal Production, Faculty of Agriculture, Benha University, Moshtohor, Egypt
| | - Shijun Li
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China.
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Identifying Interaction Clusters for MiRNA and MRNA Pairs in TCGA Network. Genes (Basel) 2019; 10:genes10090702. [PMID: 31514484 PMCID: PMC6770970 DOI: 10.3390/genes10090702] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 09/06/2019] [Indexed: 12/11/2022] Open
Abstract
Existing methods often fail to recognize the conversions for the biological roles of the pairs of genes and microRNAs (miRNAs) between the tumor and normal samples. We have developed a novel cluster scoring method to identify messenger RNA (mRNA) and miRNA interaction pairs and clusters while considering tumor and normal samples jointly. Our method has identified 54 significant clusters for 15 cancer types selected from The Cancer Genome Atlas project. We also determined the shared clusters across tumor types and/or subtypes. In addition, we compared gene and miRNA overlap between lists identified in our liver hepatocellular carcinoma (LIHC) study and regulatory relationships reported from human and rat nonalcoholic fatty liver disease studies (NAFLD). Finally, we analyzed biological functions for the single significant cluster in LIHC and uncovered a significantly enriched pathway (phospholipase D signaling pathway) with six genes represented in the cluster, symbols: DGKQ, LPAR2, PDGFRB, PIK3R3, PTGFR and RAPGEF3.
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Chen W, Wu X, Yan X, Xu A, Yang A, You H. Multitranscriptome analyses reveal prioritized genes specifically associated with liver fibrosis progression independent of etiology. Am J Physiol Gastrointest Liver Physiol 2019; 316:G744-G754. [PMID: 30920297 DOI: 10.1152/ajpgi.00339.2018] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Elimination or suppression of causative factors can raise the possibility of liver fibrosis regression. However, different injurious stimuli will give fibrosis from somewhat different etiologies, which, in turn, may hamper the discovery of liver fibrosis-specific therapeutic drugs. Therefore, the analogical cellular and molecular events shared by various etiology-evoked liver fibrosis should be clarified. Our present study systematically integrated five publicly available transcriptomic data sets regarding liver fibrosis with different etiologies from the Gene Expression Omnibus database and performed a series of bioinformatics analyses and experimental verifications. A total of 111 significantly upregulated and 16 downregulated genes were identified specific to liver fibrosis independent of any etiology. These genes were predominately enriched in some Kyoto Encyclopedia of Genes and Genomes pathways, including the "PI3K-AKT signaling pathway," "Focal adhesion," and "ECM-receptor interaction." Subsequently, five prioritized liver fibrosis-specific genes, including COL4A2, THBS2, ITGAV, LAMB1, and PDGFRA, were screened. These genes were positively associated with each other and liver fibrosis progression. In addition, they could robustly separate all stages of samples in both training and validation data sets with diverse etiologies when they were regarded as observed variables applied to principal component analysis plots. Expressions of all five genes were confirmed in activated primary mouse hepatic stellate cells (HSCs) and transforming growth factor β1-treated LX-2 cells. Moreover, THBS2 protein was enhanced in liver fibrosis rodent models, which could promote HSC activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs. Overall, our current study may provide potential targets for liver fibrosis therapy and aid to a deeper understanding of the molecular underpinnings of liver fibrosis. NEW & NOTEWORTHY Prioritized liver fibrosis-specific genes THBS2, COL4A2, ITGAV, LAMB1, and PDGFRA were identified and significantly associated with liver fibrosis progression and could be combined to discriminate liver fibrosis stages regardless of any etiology. Among the identified prioritized liver fibrosis-specific targets, THBS2 protein was confirmed to be enhanced in liver fibrosis rodent models, which could promote hepatic stellate cell (HSC) activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs.
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Affiliation(s)
- Wei Chen
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University , Beijing , China.,Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University , Beijing , China
| | - Xiaoning Wu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Xuzhen Yan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
| | - Anjian Xu
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University , Beijing , China.,Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University , Beijing , China
| | - Aiting Yang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University , Beijing , China.,Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University , Beijing , China
| | - Hong You
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University , Beijing , China.,Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University , Beijing , China.,Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, National Clinical Research Center of Digestive Diseases , Beijing , China
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Zhan Z, Chen Y, Duan Y, Li L, Mew K, Hu P, Ren H, Peng M. Identification of key genes, pathways and potential therapeutic agents for liver fibrosis using an integrated bioinformatics analysis. PeerJ 2019; 7:e6645. [PMID: 30923657 PMCID: PMC6432904 DOI: 10.7717/peerj.6645] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 02/17/2019] [Indexed: 12/12/2022] Open
Abstract
Background Liver fibrosis is often a consequence of chronic liver injury, and has the potential to progress to cirrhosis and liver cancer. Despite being an important human disease, there are currently no approved anti-fibrotic drugs. In this study, we aim to identify the key genes and pathways governing the pathophysiological processes of liver fibrosis, and to screen therapeutic anti-fibrotic agents. Methods Expression profiles were downloaded from the Gene Expression Omnibus (GEO), and differentially expressed genes (DEGs) were identified by R packages (Affy and limma). Gene functional enrichments of each dataset were performed on the DAVID database. Protein–protein interaction (PPI) network was constructed by STRING database and visualized in Cytoscape software. The hub genes were explored by the CytoHubba plugin app and validated in another GEO dataset and in a liver fibrosis cell model by quantitative real-time PCR assay. The Connectivity Map L1000 platform was used to identify potential anti-fibrotic agents. Results We integrated three fibrosis datasets of different disease etiologies, incorporating a total of 70 severe (F3–F4) and 116 mild (F0–F1) fibrotic tissue samples. Gene functional enrichment analyses revealed that cell cycle was a pathway uniquely enriched in a dataset from those patients infected by hepatitis B virus (HBV), while the immune-inflammatory response was enriched in both the HBV and hepatitis C virus (HCV) datasets, but not in the nonalcoholic fatty liver disease (NAFLD) dataset. There was overlap between these three datasets; 185 total shared DEGs that were enriched for pathways associated with extracellular matrix constitution, platelet-derived growth-factor binding, protein digestion and absorption, focal adhesion, and PI3K-Akt signaling. In the PPI network, 25 hub genes were extracted and deemed to be essential genes for fibrogenesis, and the expression trends were consistent with GSE14323 (an additional dataset) and liver fibrosis cell model, confirming the relevance of our findings. Among the 10 best matching anti-fibrotic agents, Zosuquidar and its corresponding gene target ABCB1 might be a novel anti-fibrotic agent or therapeutic target, but further work will be needed to verify its utility. Conclusions Through this bioinformatics analysis, we identified that cell cycle is a pathway uniquely enriched in HBV related dataset and immune-inflammatory response is clearly enriched in the virus-related datasets. Zosuquidar and ABCB1 might be a novel anti-fibrotic agent or target.
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Affiliation(s)
- Zhu Zhan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuhe Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanqin Duan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Li
- Department of Hepatic Disease, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| | - Kenley Mew
- Department of Foreign Language, Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingli Peng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.,Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Baranova A, Maltseva D, Tonevitsky A. Adipose may actively delay progression of NAFLD by releasing tumor-suppressing, anti-fibrotic miR-122 into circulation. Obes Rev 2019; 20:108-118. [PMID: 30248223 DOI: 10.1111/obr.12765] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/07/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue-cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR-122 falls, while the secretion of miRNA-containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver-supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease-associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR-122 and, possibly, some other miRNAs may be efficient for preventing NAFLD-associated hepatocellular carcinoma. The best candidates for exosome-wrapped miRNA producer are adipose tissue-derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC-derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co-manufactured along with their cargo. Exosome-delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.
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Affiliation(s)
- A Baranova
- School of Systems Biology, George Mason University, Fairfax, VA, USA.,Research Center for Medical Genetics, Moscow, Russia
| | - D Maltseva
- Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University (FEFU), Vladivostok, Russia.,Scientific Research Center Bioclinicum (SRC Bioclinicum), Moscow, Russia
| | - A Tonevitsky
- Scientific Research Center Bioclinicum (SRC Bioclinicum), Moscow, Russia.,Higher School of Economics, Moscow, Russia
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Hu Y, Pan J, Xin Y, Mi X, Wang J, Gao Q, Luo H. Gene Expression Analysis Reveals Novel Gene Signatures Between Young and Old Adults in Human Prefrontal Cortex. Front Aging Neurosci 2018; 10:259. [PMID: 30210331 PMCID: PMC6119720 DOI: 10.3389/fnagi.2018.00259] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 08/08/2018] [Indexed: 11/13/2022] Open
Abstract
Human neurons function over an entire lifetime, yet the molecular mechanisms which perform their functions and protecting against neurodegenerative disease during aging are still elusive. Here, we conducted a systematic study on the human brain aging by using the weighted gene correlation network analysis (WGCNA) method to identify meaningful modules or representative biomarkers for human brain aging. Significantly, 19 distinct gene modules were detected based on the dataset GSE53890; among them, six modules related to the feature of brain aging were highly preserved in diverse independent datasets. Interestingly, network feature analysis confirmed that the blue modules demonstrated a remarkably correlation with human brain aging progress. Besides, the top hub genes including PPP3CB, CAMSAP1, ACTR3B, and GNG3 were identified and characterized by high connectivity, module membership, or gene significance in the blue module. Furthermore, these genes were validated in mice of different ages. Mechanically, the potential regulators of blue module were investigated. These findings highlight an important role of the blue module and its affiliated genes in the control of normal brain aging, which may lead to potential therapeutic interventions for brain aging by targeting the hub genes.
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Affiliation(s)
- Yang Hu
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China.,Department of Pathology and Pathophysiology, School of Medicine, Jinan University, Guangzhou, China.,Institute of Brain Sciences, Jinan University, Guangzhou, China
| | - Junping Pan
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China
| | - Yirong Xin
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China
| | - Xiangnan Mi
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China
| | - Jiahui Wang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China
| | - Qin Gao
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China
| | - Huanmin Luo
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, China.,Institute of Brain Sciences, Jinan University, Guangzhou, China
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Wang GE, Li YF, Zhai YJ, Gong L, Tian JY, Hong M, Yao N, Wu YP, Kurihara H, He RR. Theacrine protects against nonalcoholic fatty liver disease by regulating acylcarnitine metabolism. Metabolism 2018; 85:227-239. [PMID: 29727630 DOI: 10.1016/j.metabol.2018.04.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 04/27/2018] [Accepted: 04/29/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Acylcarnitine metabolism disorder contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). There are, however, few ideal medications for NAFLD, which work by targeting acylcarnitine metabolism. The aim of this study was to investigate the protective effects of theacrine, a rare purine alkaloid isolated from Camellia assamica var. kucha, against acylcarnitine metabolism disorder in NAFLD. METHODS The pharmacological activities of theacrine were studied using high-fat diet (HFD)-fed ApoE-/- and C57BL/6J mice models. Oleate-treated HepG2 and L-02 cells were used to investigate the molecular mechanism of theacrine on acylcarnitine metabolism. The target of theacrine was confirmed in vitro as the blockade of sirtuin 3 (SIRT3) and protein kinase A. RESULTS Theacrine inhibits hepatic steatosis and liver inflammation and improves energy expenditure in HFD-fed mice. Theacrine ameliorates acylcarnitine metabolism disorder in HFD-fed mice and oleate-treated hepatocytes by improving fatty acid oxidation. The underlying mechanism involves theacrine's activation of the mitochondrial deacetylase SIRT3 and consequently, the increased activity of long-chain acyl coenzyme A dehydrogenase (LCAD) through deacetylation. CONCLUSION Theacrine promotes acylcarnitine metabolism in NAFLD through the SIRT3/LCAD signaling pathway. The target of theacrine's activities on NAFLD is identified as SIRT3.
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Affiliation(s)
- Guo-En Wang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yi-Fang Li
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yu-Jia Zhai
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Lian Gong
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jing-Yu Tian
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China
| | - Mo Hong
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Nan Yao
- Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou 510095, China
| | - Yan-Ping Wu
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Hiroshi Kurihara
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Rong-Rong He
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
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Ramnath D, Irvine KM, Lukowski SW, Horsfall LU, Loh Z, Clouston AD, Patel PJ, Fagan KJ, Iyer A, Lampe G, Stow JL, Schroder K, Fairlie DP, Powell JE, Powell EE, Sweet MJ. Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes. JCI Insight 2018; 3:120274. [PMID: 30046009 DOI: 10.1172/jci.insight.120274] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 06/12/2018] [Indexed: 12/23/2022] Open
Abstract
Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.
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Affiliation(s)
- Divya Ramnath
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Katharine M Irvine
- Centre for Liver Disease Research and.,Faculty of Medicine, Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Samuel W Lukowski
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Leigh U Horsfall
- Centre for Liver Disease Research and.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Zhixuan Loh
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | | | - Preya J Patel
- Centre for Liver Disease Research and.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | | | - Abishek Iyer
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Guy Lampe
- Pathology Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Jennifer L Stow
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Kate Schroder
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - David P Fairlie
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Joseph E Powell
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia.,Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Elizabeth E Powell
- Centre for Liver Disease Research and.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Matthew J Sweet
- Institute for Molecular Bioscience (IMB) and.,IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia
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Chen X, Yang C, Xie S, Cheung E. Long non-coding RNA GAS5 and ZFAS1 are prognostic markers involved in translation targeted by miR-940 in prostate cancer. Oncotarget 2018; 9:1048-1062. [PMID: 29416676 PMCID: PMC5787418 DOI: 10.18632/oncotarget.23254] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 12/03/2017] [Indexed: 12/30/2022] Open
Abstract
Identification of prognostic biomarkers helps facilitate the prediction of patient outcomes as well as guide treatments. Accumulating evidence now suggests that long non-coding RNAs (lncRNAs) play key roles in tumor progression with diagnostic and prognostic values. However, little is known about the biological functions of lncRNAs and how they contribute to the pathogenesis of cancer. Herein, we performed weighted correlation network analysis (WGCNA) on 380 RNA-seq samples from prostate cancer patients to create networks comprising of microRNAs, lncRNAs, and protein-coding genes. Our analysis revealed expression modules that associated with pathological parameters. More importantly, we identified a gene module that is involved in protein translation and is associated with patient survival. In this gene module, we explored the regulation axis involving GAS5, ZFAS1, and miR-940. We show that GAS5, ZFAS1, and miR-940 are up-regulated in tumors relative to normal prostate tissues, and high expression of either lncRNA is an indicator of poor patient outcome. Finally, we constructed a co-expression network involving GAS5, ZFAS1, and miR-940, as well as the targets of miR-940. Our results show that GAS5 and ZFAS1 are targeted by miR-940 via NAA10 and RPL28. Taken together, co-expression analysis of gene expression profiling from RNA-seq can accelerate the identification and functional characterization of novel prognostic markers in prostate cancer.
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Affiliation(s)
- Xin Chen
- Guangdong Key Laboratory of IoT Information Technology, School of Automation, Guangdong University of Technology, Guangzhou, China
- Faculty of Health Sciences, University of Macau, Macau, China
| | - Chao Yang
- Guangdong Key Laboratory of IoT Information Technology, School of Automation, Guangdong University of Technology, Guangzhou, China
| | - Shengli Xie
- Guangdong Key Laboratory of IoT Information Technology, School of Automation, Guangdong University of Technology, Guangzhou, China
| | - Edwin Cheung
- Faculty of Health Sciences, University of Macau, Macau, China
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Lakhani HV, Sharma D, Dodrill MW, Nawab A, Sharma N, Cottrill CL, Shapiro JI, Sodhi K. Phenotypic Alteration of Hepatocytes in Non-Alcoholic Fatty Liver Disease. Int J Med Sci 2018; 15:1591-1599. [PMID: 30588181 PMCID: PMC6299410 DOI: 10.7150/ijms.27953] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 08/31/2018] [Indexed: 02/06/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) has been recognized as the most common liver disorder in developed countries. NAFLD progresses from fat accumulation in hepatocytes to steatohepatitis to further stages of fibrosis and cirrhosis. Simple steatosis, i.e. fat deposition in the liver, is considered benign and gives way to non-alcoholic steatohepatitis (NASH) with a higher probability of progressing to cirrhosis, and liver-related mortality. Evidence has been found that this progression has been associated with marked alterations in hepatocyte histology and a shift in marker expression of healthy hepatocytes including increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), adipocyte protein (aP2), CD36, interleukin-6 (IL-6), interleukin-18 (IL-18) and adiponectin. This progression shares much in common with the obesity phenotype, which involves a transformation of adipocytes from small, healthy cells to large, dysfunctional ones that contribute to redox imbalance and the progression of metabolic syndrome. Further, activation of Src/ERK signaling via the sodium potassium adenosine triphosphatase (Na/K-ATPase) α-1 subunit in impaired hepatocytes may contribute to redox imbalance, exacerbating the progression of NAFLD. This review hypothesizes that an adipogenic transformation of hepatocytes propagates redox imbalance and that the processes occurring in adipogenesis become activated in fat-laden hepatocytes in liver, thereby driving progression to NAFLD. Further, this review discusses therapeutic interventions to reverse NAFLD including the thiazolidinediones (TZDs) and a variety of antioxidant species. The peptide, pNaKtide, which is an antagonist of Na/K-ATPase signaling, is also proposed as a potential pharmacologic option for reducing reactive oxygen species (ROS) and reversing NAFLD by inhibiting the Na/K-ATPase-modulated ROS amplification loop.
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Affiliation(s)
- Hari Vishal Lakhani
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Dana Sharma
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Michael W Dodrill
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Athar Nawab
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Nitin Sharma
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Cameron Lee Cottrill
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Joseph I Shapiro
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Komal Sodhi
- Department of Surgery, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
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Sharma DL, Lakhani HV, Klug RL, Snoad B, El-Hamdani R, Shapiro JI, Sodhi K. Investigating Molecular Connections of Non-alcoholic Fatty Liver Disease with Associated Pathological Conditions in West Virginia for Biomarker Analysis. ACTA ACUST UNITED AC 2017; 8. [PMID: 29177105 PMCID: PMC5701750 DOI: 10.4172/2155-9899.1000523] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease characterized by a steatosis of the liver that may progress to more serious pathological conditions including: nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. As the prevalence of NAFLD has increased worldwide in recent years, pathophysiology and risk factors associated with disease progression of NAFLD are at the focus of many studies. NAFLD is related to and shares common serum biomarkers with cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS). West Virginia (WV) is a state with some of the highest rates of CVD, obesity and diabetes mellitus. As NAFLD is closely related to these diseases, it is of particular interest in WV. Currently there is no cost-effective, standardized method used clinically to detect NAFLD prior to the onset of reversible complications. At this time, the diagnosis of NAFLD is made with costly radiologic studies and invasive biopsy. These studies are only diagnostic once changes to hepatic tissue have occurred. The diagnosis of NAFLD by traditional methods may not allow for successful intervention and may not be readily available in areas with already sparse medical resources. In this literature review, we identify a list of biomarkers common among CVD, T2DM, obesity, MetS and NAFLD. From this research we propose the following biomarkers are good candidates for inclusion in a panel of biomarkers for the early detection of NAFLD: adiponectin, AST, ALT, apo-B, CK18, CPS1, CRP, FABP-1, ferritin, GGT, GRP78, HDL-C, IGF-1, IL-1β, 6, 8, 10, IRS-2PAI-1, leptin, lumican, MDA SREBP-1c and TNF-α. Creating and implementing a biomarker panel for the early detection and attenuation of NAFLD, prior to the onset of irreversible complication would provide maximum benefit and decrease the disease burden on the patients and healthcare system of WV.
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Affiliation(s)
- Dana L Sharma
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Hari Vishal Lakhani
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Rebecca L Klug
- Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Brian Snoad
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Rawan El-Hamdani
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Joseph I Shapiro
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Komal Sodhi
- Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
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