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Fan Z, Pan H, Qu N, Wang X, Cao L, Chen L, Liu M. LncRNA taurine upregulated gene 1 in liver disease. Clin Chim Acta 2024; 560:119752. [PMID: 38821337 DOI: 10.1016/j.cca.2024.119752] [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: 04/10/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
Long non-coding RNAs (lncRNAs) are RNA sequences exceeding 200 nucleotides in length that lack protein-coding capacity and participate in diverse biological processes in the human body, particularly exerting a pivotal role in disease surveillance, diagnosis, and progression. Taurine upregulated gene 1 (TUG1) is a versatile lncRNA, and recent studies have revealed that the aberrant expression or function of TUG1 is intricately linked to the pathogenesis of liver diseases. Consequently, we have summarized the current understanding of the mechanism of TUG1 in liver diseases such as liver fibrosis, fatty liver, cirrhosis, liver injury, hepatitis, and liver cancer. Moreover, mounting evidence suggests that interventions targeting TUG1 or its downstream pathways may hold therapeutic promise for liver diseases. This review elucidates the characteristics, mechanisms, and targets of TUG1 in liver diseases, offering a theoretical basis for the prevention, diagnosis, treatment, and prognostic biomarkers of liver diseases.
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Affiliation(s)
- Zihao Fan
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Hao Pan
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Na Qu
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Xin Wang
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Lianrui Cao
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China
| | - Lijiang Chen
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China.
| | - Mingxia Liu
- School of Pharmaceutical Sciences, Liaoning University, No. 66, Chongshan Mid Road, Shenyang 110036, China.
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Chiang YP, Li Z, He M, Jones Q, Pan M, Han X, Jiang XC. Sphingomyelin synthase-related protein SMSr is a phosphatidylethanolamine phospholipase C that promotes nonalcoholic fatty liver disease. J Biol Chem 2023; 299:105162. [PMID: 37586586 PMCID: PMC10494463 DOI: 10.1016/j.jbc.2023.105162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/28/2023] [Accepted: 08/04/2023] [Indexed: 08/18/2023] Open
Abstract
Sphingomyelin synthase (SMS)-related protein (SMSr) is a phosphatidylethanolamine phospholipase C (PE-PLC) that is conserved and ubiquitous in mammals. However, its biological function is still not clear. We previously observed that SMS1 deficiency-mediated glucosylceramide accumulation caused nonalcoholic fatty liver diseases (NAFLD), including nonalcoholic steatohepatitis (NASH) and liver fibrosis. Here, first, we evaluated high-fat diet/fructose-induced NAFLD in Smsr KO and WT mice. Second, we evaluated whether SMSr deficiency can reverse SMS1 deficiency-mediated NAFLD, using Sms1/Sms2 double and Sms1/Sms2/Smsr triple KO mice. We found that SMSr/PE-PLC deficiency attenuated high-fat diet/fructose-induced fatty liver and NASH, and attenuated glucosylceramide accumulation-induced NASH, fibrosis, and tumor formation. Further, we found that SMSr/PE-PLC deficiency reduced the expression of many inflammatory cytokines and fibrosis-related factors, and PE supplementation in vitro or in vivo mimicked the condition of SMSr/PE-PLC deficiency. Furthermore, we demonstrated that SMSr/PE-PLC deficiency or PE supplementation effectively prevented membrane-bound β-catenin transfer to the nucleus, thereby preventing tumor-related gene expression. Finally, we observed that patients with NASH had higher SMSr protein levels in the liver, lower plasma PE levels, and lower plasma PE/phosphatidylcholine ratios, and that human plasma PE levels are negatively associated with tumor necrosis factor-α and transforming growth factor β1 levels. In conclusion, SMSr/PE-PLC deficiency causes PE accumulation, which can attenuate fatty liver, NASH, and fibrosis. These results suggest that SMSr/PE-PLC inhibition therapy may mitigate NAFLD.
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Affiliation(s)
- Yeun-Po Chiang
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Zhiqiang Li
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Mulin He
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Quiana Jones
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Meixia Pan
- Lipidomics Core, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Xianlin Han
- Lipidomics Core, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Xian-Cheng Jiang
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System, Brooklyn, New York, USA.
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Abdel-Rahman RF, Fayed HM, Asaad GF, Ogaly HA, Hessin AF, Salama AAA, Abd El-Rahman SS, Arbid MS, Mohamed MAE. The involvement of TGF-β1 /FAK/α-SMA pathway in the antifibrotic impact of rice bran oil on thioacetamide-induced liver fibrosis in rats. PLoS One 2021; 16:e0260130. [PMID: 34965258 PMCID: PMC8716044 DOI: 10.1371/journal.pone.0260130] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/03/2021] [Indexed: 12/29/2022] Open
Abstract
The objective of the current study is to investigate the effect of rice bran oil (RBO) on hepatic fibrosis as a characteristic response to persistent liver injuries. Rats were randomly allocated into five groups: the negative control group, thioacetamide (TAA) group (thioacetamide 100 mg/kg thrice weekly for two successive weeks, ip), RBO 0.2 and 0.4 groups (RBO 0.2mL and 0.4 mL/rat/day, po) and standard group (silymarin 100 mg/kg/day, po) for two weeks after TAA injection. Blood and liver tissue samples were collected for biochemical, molecular, and histological analyses. Liver functions, oxidative stress, inflammation, liver fibrosis markers were assessed. The obtained results showed that RBO reduced TAA-induced liver fibrosis and suppressed the extracellular matrix formation. Compared to the positive control group, RBO dramatically reduced total bilirubin, AST, and ALT blood levels. Furthermore, RBO reduced MDA and increased GSH contents in the liver. Simultaneously RBO downregulated the NF-κβ signaling pathway, which in turn inhibited the expression of some inflammatory mediators, including Cox-2, IL-1β, and TNF-α. RBO attenuated liver fibrosis by suppressing the biological effects of TGF-β1, α-SMA, collagen I, hydroxyproline, CTGF, and focal adhesion kinase (FAK). RBO reduced liver fibrosis by inhibiting hepatic stellate cell activation and modulating the interplay among the TGF-β1 and FAK signal transduction. The greater dosage of 0.4 mL/kg has a more substantial impact. Hence, this investigation presents RBO as a promising antifibrotic agent in the TAA model through inhibition of TGF-β1 /FAK/α-SMA.
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Affiliation(s)
- Rehab F. Abdel-Rahman
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Hany M. Fayed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Gihan F. Asaad
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Hanan A. Ogaly
- Department of Chemistry, College of Science, King Khalid University, Abha, Kingdom of Saudi Arabia
- Department of Biochemistry, College of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Alyaa F. Hessin
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Abeer A. A. Salama
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | | | - Mahmoud S. Arbid
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Marawan Abd Elbaset Mohamed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
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Li Z, Chiang YP, He M, Worgall TS, Zhou H, Jiang XC. Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation. iScience 2021; 24:103449. [PMID: 34927020 PMCID: PMC8649732 DOI: 10.1016/j.isci.2021.103449] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/21/2021] [Accepted: 11/11/2021] [Indexed: 11/30/2022] Open
Abstract
Glucosylceramide (GluCer) was accumulated in sphingomyelin synthase 1 (SMS1) but not SMS2 deficient mouse tissues. In current study, we studied GluCer accumulation-mediated metabolic consequences. Livers from liver-specific Sms1/global Sms2 double-knockout (dKO) exhibited severe steatosis under a high-fat diet. Moreover, chow diet-fed ≥6-month-old dKO mice had liver impairment, inflammation, and fibrosis, compared with wild type and Sms2 KO mice. RNA sequencing showed 3- to 12-fold increases in various genes which are involved in lipogenesis, inflammation, and fibrosis. Further, we found that direct GluCer treatment (in vitro and in vivo) promoted hepatocyte to secrete more activated TGFβ1, which stimulated more collagen 1α1 production in hepatic stellate cells. Additionally, GluCer promoted more β-catenin translocation into the nucleus, thus promoting tumorigenesis. Importantly, human NASH patients had higher liver GluCer synthase and higher plasma GluCer. These findings implicated that GluCer accumulation is one of triggers promoting the development of NAFLD into NASH, then, fibrosis, and tumorigenesis.
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Affiliation(s)
- Zhiqiang Li
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | - Yeun-po Chiang
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | - Mulin He
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
| | | | | | - Xian-Cheng Jiang
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
- Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System, New York, USA
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MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness. Cell Death Dis 2021; 12:1076. [PMID: 34772924 PMCID: PMC8589861 DOI: 10.1038/s41419-021-04370-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/18/2021] [Accepted: 10/29/2021] [Indexed: 12/14/2022]
Abstract
Deregulated mitochondrial energetics is a metabolic hallmark of cancer cells. However, the causative mechanism of the bioenergetic deregulation is not clear. In this study, we show that somatic copy number alteration (SCNA) of mitoribosomal protein (MRP) genes is a key mechanism of bioenergetic deregulation in hepatocellular carcinoma (HCC). Association analysis between the genomic and transcriptomic profiles of 82 MRPs using The Cancer Genome Atlas-Liver HCC database identified eight key SCNA-dependent MRPs: MRPS31, MRPL10, MRPL21, MRPL15, MRPL13, MRPL55, and DAP3. MRPS31 was the only downregulated MRP harboring a DNA copy number (DCN) loss. MRPS31 loss was associated specifically with the DCN losses of many genes on chromosome 13q. Survival analysis revealed a unique dependency of HCC on the MRPS31 deficiency, showing poor clinical outcome. Subclass prediction analysis using several public classifiers indicated that MRPS31 loss is linked to aggressive HCC phenotypes. By employing hepatoma cell lines with SCNA-dependent MRPS31 expression (JHH5, HepG2, Hep3B, and SNU449), we demonstrated that MRPS31 deficiency is the key mechanism, disturbing the whole mitoribosome assembly. MRPS31 suppression enhanced hepatoma cell invasiveness by augmenting MMP7 and COL1A1 expression. Unlike the action of MMP7 on extracellular matrix destruction, COL1A1 modulated invasiveness via the ZEB1-mediated epithelial-to-mesenchymal transition. Finally, MRPS31 expression further stratified the high COL1A1/DDR1-expressing HCC groups into high and low overall survival, indicating that MRPS31 loss is a promising prognostic marker. SIGNIFICANCE: Our results provide new mechanistic insight for mitochondrial deregulation in HCC and present MRPS31 as a novel biomarker of HCC malignancy.
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Al-Qarni R, Iqbal M, Al-Otaibi M, Al-Saif F, Alfadda AA, Alkhalidi H, Bamehriz F, Hassanain M. Validating candidate biomarkers for different stages of non-alcoholic fatty liver disease. Medicine (Baltimore) 2020; 99:e21463. [PMID: 32898995 PMCID: PMC7478685 DOI: 10.1097/md.0000000000021463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common chronic condition caused by the accumulation of fat in the liver. NAFLD may range from simple steatosis to advanced cirrhosis, and affects more than 1 billion people around the world. To date, there has been no effective treatment for NAFLD. In this study, we evaluated the expression of 4 candidate NAFLD biomarkers to assess their possible applicability in the classification and treatment of the disease.Twenty-six obese subjects, who underwent bariatric surgery, were recruited and their liver biopsies obtained. Expression of 4 candidate biomarker genes, PNPLA3, COL1A1, PPP1R3B, and KLF6 were evaluated at gene and protein levels by RT-qPCR and enzyme-linked immunosorbent assay (ELISA), respectively.A significant increase in the levels of COL1A1 protein (P = .03) and PNPLA3 protein (P = .03) were observed in patients with fibrosis-stage NAFLD compared to that in patients with steatosis-stage NAFLD. However, no significant differences were found in abundance of PPP1R3B and KLF6 proteins or at the gene level for any of the candidate.This is the first study, to our knowledge, to report on the expression levels of candidate biomarker genes for NAFLD in the Saudi population. Although PNPLA3 and PPP1R3B had been previously suggested as biomarkers for steatosis and KLF6 as a possible marker for the fibrosis stage of NAFLD, our results did not support these findings. However, other studies that had linked PNPLA3 to fibrosis in advanced NAFLD supported our current finding of high PNPLA3 protein in patients with fibrosis. Additionally, our results support COL1A1 protein as a potential biomarker for the fibrosis stage of NAFLD, and indicate its use in the screening of patients with NAFLD. Further studies are required to validate the use of COL1A1 as a biomarker for advanced NAFLD in a larger cohort.
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Affiliation(s)
| | | | | | - Faisal Al-Saif
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | | | - Fahad Bamehriz
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mazen Hassanain
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Oncology, McGill University, Montreal, Quebec, Canada
- Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
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Zhao W, Jiang X, Yang S. lncRNA TUG1 Promotes Cell Proliferation, Migration, and Invasion in Hepatocellular Carcinoma via Regulating miR-29c-3p/ COL1A1 Axis. Cancer Manag Res 2020; 12:6837-6847. [PMID: 32821161 PMCID: PMC7425090 DOI: 10.2147/cmar.s256624] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 07/14/2020] [Indexed: 12/18/2022] Open
Abstract
Background Taurine upregulated gene 1 (TUG1) has been recognized as a novel oncogenic gene. The current study was established to explore the function and regulatory mechanism of TUG1 in hepatocellular carcinoma (HCC). Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of TUG1, miR-29c-3p, and COL1A1 in tissues and cell lines. MTT assay, wound-healing and transwell assay were utilized for the detection of cell viability, migration and invasion, respectively. The interactions between miR-29c-3p and TUG1/COL1A1 were predicted by starBase v2.0 (http://starbase.sysu.edu.cn/) and verified by the dual-luciferase reporter or RNA immunoprecipitation assay. Western blot assay was performed to determine the protein levels of COL1A1, cyclin D1, E-cadherin, N-cadherin, Bcl-2, and Bax. Results Dramatically increased expression of TUG1 was noticed in HCC tissues and cell lines. TUG1 knockdown restrained the proliferation, migration, and invasion, and promoted the apoptosis of HCC cells. TUG1 targeted miR-29c-3p and inhibited miR-29c-3p expression. Overexpression of miR-29c-3p inhibited the proliferation, migration and invasion of HCC cells. MiR-29c-3p directly targeted COL1A1 and down-regulated COL1A1 expression. In addition, downregulation of miR-29c-3p and upregulation of COL1A1 both reversed the effects of TUG1 knockdown on the proliferation, apoptosis, migration, and invasion of HCC cells. Conclusion TUG1 could promote the proliferation, migration and invasion of HCC cells through regulating miR-29c-3p/COL1A1 axis. This novel finding might provide a latent target for the treatment of HCC.
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Affiliation(s)
- Wei Zhao
- Department of Functional Examination, The Sixth People's Hospital of Qingdao, Qingdao City, Shandong Province 266033, People's Republic of China
| | - Xue Jiang
- Health Examination Center, The Sixth People's Hospital of Qingdao, Qingdao City, Shandong Province 266033, People's Republic of China
| | - Shuxia Yang
- Health Examination Center, The Sixth People's Hospital of Qingdao, Qingdao City, Shandong Province 266033, People's Republic of China
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Wu SY, Yang WY, Cheng CC, Hsiao MC, Tsai SL, Lin HK, Lin KH, Yuh CH. Low Molecular Weight Fucoidan Prevents Radiation-Induced Fibrosis and Secondary Tumors in a Zebrafish Model. Cancers (Basel) 2020; 12:cancers12061608. [PMID: 32570707 PMCID: PMC7353073 DOI: 10.3390/cancers12061608] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 12/15/2022] Open
Abstract
Radiotherapy often causes unwanted side effects such as radiation-induced fibrosis and second malignancies. Fucoidan, a sulfated polysaccharide extracted from brown seaweed, has many biological effects including anti-inflammation and anti-tumor. In the present study, we investigated the radioprotective effect of Oligo-Fucoidan (OF) using a zebrafish animal model. Adult zebrafish of wild-type and transgenic fish with hepatocellular carcinoma were orally fed with Oligo-Fucoidan before irradiation. Quantitative PCR, Sirius red stain, hematoxylin, and eosin stain were used for molecular and pathological analysis. Whole genomic microarrays were used to discover the global program of gene expression after Oligo-Fucoidan treatment and identified distinct classes of up- and downregulated genes/pathways during this process. Using Oligo-Fucoidan oral gavage in adult wild-type zebrafish, we found Oligo-Fucoidan pretreatment decreased irradiation-induced fibrosis in hepatocyte. Using hepatitis B virus X antigen (HBx), Src and HBx, Src, p53−/+ transgenic zebrafish liver cancer model, we found that Oligo-Fucoidan pretreatment before irradiation could lower the expression of lipogenic factors and enzymes, fibrosis, and cell cycle/proliferation markers, which eventually reduced formation of liver cancer compared to irradiation alone. Gene ontology analysis revealed that Oligo-Fucoidan pretreatment increased the expression of genes involved in oxidoreductase activity in zebrafish irradiation. Oligo-Fucoidan also decreased the expression of genes involved in transferase activity in wild-type fish without irradiation (WT), nuclear outer membrane-endoplasmic reticulum membrane network, and non-homologous end-joining (NHEJ) in hepatocellular carcinoma (HCC) transgenic fish. Rescue of those genes can prevent liver cancer formation. Conclusions: Our results provide evidence for the ability of Oligo-Fucoidan to prevent radiation-induced fibrosis and second malignancies in zebrafish.
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Affiliation(s)
- Szu-Yuan Wu
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung 42354, Taiwan;
- Division of Radiation Oncology, Department of Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265, Taiwan
- Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Wan-Yu Yang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan; (W.-Y.Y.); (C.-C.C.); (S.-L.T.); (H.-K.L.); (K.-H.L.)
| | - Chun-Chia Cheng
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan; (W.-Y.Y.); (C.-C.C.); (S.-L.T.); (H.-K.L.); (K.-H.L.)
- Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital at Linkou, Taoyuan 33302, Taiwan
| | - Ming-Chen Hsiao
- Research and Development Center, Hi-Q Marine Biotech International Ltd., Songshan District, Taipei 10561, Taiwan;
| | - Shin-Lin Tsai
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan; (W.-Y.Y.); (C.-C.C.); (S.-L.T.); (H.-K.L.); (K.-H.L.)
| | - Hua-Kuo Lin
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan; (W.-Y.Y.); (C.-C.C.); (S.-L.T.); (H.-K.L.); (K.-H.L.)
| | - Kuan-Hao Lin
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan; (W.-Y.Y.); (C.-C.C.); (S.-L.T.); (H.-K.L.); (K.-H.L.)
| | - Chiou-Hwa Yuh
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan; (W.-Y.Y.); (C.-C.C.); (S.-L.T.); (H.-K.L.); (K.-H.L.)
- Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu 30013, Taiwan
- Department of Biological Science & Technology, National Chiao Tung University, Hsinchu 30010, Taiwan
- Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +886-37-246-166 (ext. 3538); Fax: +886-37-586-459
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Stratton M, Ramachandran A, Camacho EJM, Patil S, Waris G, Grice KA. Anti-fibrotic activity of gold and platinum complexes - Au(I) compounds as a new class of anti-fibrotic agents. J Inorg Biochem 2020; 206:111023. [PMID: 32163811 DOI: 10.1016/j.jinorgbio.2020.111023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 02/06/2020] [Accepted: 02/09/2020] [Indexed: 12/11/2022]
Abstract
Molecular gold(I) and platinum(II) species were examined for the inhibition of liver fibrosis and the hepatitis C virus (HCV). Determination of inhibition efficiency was conducted via morphological analysis, cell viability, western blot analysis, and quantitative reverse transcription polymerase chain reaction (RT-PCR). Auranofin and Ph3PAuCl demonstrated the greatest inhibition of liver fibrosis amongst the tested gold species in human hepatic stellate LX-2 cells. Western blot analysis indicated that auranofin and Ph3PAuCl prevent signal transducer and activator of transcription 3 (STAT3) phosphorylation, which may be a key connection to fibrosis and inflammation. Auranofin and Ph3PAuCl also reduced expression of HCV-nonstructural protein 3 (NS3) and HCV-NS5a proteins in a HCV subgenomic replicon system. These results demonstrate significant promise for the use of gold compounds in treating liver diseases such as HCV.
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Affiliation(s)
- Matthew Stratton
- Department of Microbiology and Immunology, Center for Cancer Cell Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
| | - Akshaya Ramachandran
- Department of Microbiology and Immunology, Center for Cancer Cell Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
| | | | - Shivaputra Patil
- Pharmaceutical Sciences Department, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
| | - Gulam Waris
- Department of Microbiology and Immunology, Center for Cancer Cell Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
| | - Kyle A Grice
- Department of Chemistry and Biochemistry, College of Science and Health, DePaul University, Chicago, IL 60614, USA.
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Jia Z, Zhao C, Wang M, Zhao X, Zhang W, Han T, Xia Q, Han Z, Lin R, Li X. Hepatotoxicity assessment of Rhizoma Paridis in adult zebrafish through proteomes and metabolome. Biomed Pharmacother 2020; 121:109558. [DOI: 10.1016/j.biopha.2019.109558] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/08/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022] Open
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Collagen 1A1 (COL1A1) Is a Reliable Biomarker and Putative Therapeutic Target for Hepatocellular Carcinogenesis and Metastasis. Cancers (Basel) 2019; 11:cancers11060786. [PMID: 31181620 PMCID: PMC6627889 DOI: 10.3390/cancers11060786] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 05/27/2019] [Accepted: 06/01/2019] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence shows that hepatocellular carcinoma (HCC) is a principal cause of cancer-related mortality globally, especially among Asian and African populations. Collagen type I α1 (COL1A1) is the major component of type I collagen. While aberrant expression of COL1A1 and COL1A2 is implicated in numerous cancers, the differential role of COL1A1 in malignant, premalignant and normal tissues remains unclear, and its clinical significance in HCC has not been elucidated. In this study, using bioinformatics analysis of publicly-available HCC microarray data from Gene Expression Omnibus (GEO) and RNAseq data from The Cancer Genome Atlas (TCGA) database, we determined that COL1A1 is significantly upregulated in HCC tumor tissues in comparison to normal tissues. Our analysis also revealed that COL1A1 confers survival advantage and enhanced oncogenicity on HCC cells. Interestingly, the siRNA-mediated silencing of COL1A1 expression (siCOLIA1) suppressed HCC cells clonogenicity, motility, invasiveness and tumorsphere formation. Concomitantly, siCOL1A1 abrogated Slug-dependent epithelial-to-mesenchymal transition (EMT) and HCC stemness gene-signature, by attenuating expression of stemness markers SOX2, OCT4 and CD133. The present study provides some mechanistic insight into COL1A1 activity in HCC and highlights its putative role as an important diagnostic biomarker and potential therapeutic target in early development and metastasis of HCC.
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Nahar S, Nakashima Y, Miyagi-Shiohira C, Kinjo T, Toyoda Z, Kobayashi N, Saitoh I, Watanabe M, Noguchi H, Fujita J. Cytokines in adipose-derived mesenchymal stem cells promote the healing of liver disease. World J Stem Cells 2018; 10:146-159. [PMID: 30631390 PMCID: PMC6325075 DOI: 10.4252/wjsc.v10.i11.146] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/07/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023] Open
Abstract
Adipose-derived mesenchymal stem cells (ADSCs) are a treatment cell source for patients with chronic liver injury. ADSCs are characterized by being harvested from the patient's own subcutaneous adipose tissue, a high cell yield (i.e., reduced immune rejection response), accumulation at a disease nidus, suppression of excessive immune response, production of various growth factors and cytokines, angiogenic effects, anti-apoptotic effects, and control of immune cells via cell-cell interaction. We previously showed that conditioned medium of ADSCs promoted hepatocyte proliferation and improved the liver function in a mouse model of acute liver failure. Furthermore, as found by many other groups, the administration of ADSCs improved liver tissue fibrosis in a mouse model of liver cirrhosis. A comprehensive protein expression analysis by liquid chromatography with tandem mass spectrometry showed that the various cytokines and chemokines produced by ADSCs promote the healing of liver disease. In this review, we examine the ability of expressed protein components of ADSCs to promote healing in cell therapy for liver disease. Previous studies demonstrated that ADSCs are a treatment cell source for patients with chronic liver injury. This review describes the various cytokines and chemokines produced by ADSCs that promote the healing of liver disease.
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Affiliation(s)
- Saifun Nahar
- Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Yoshiki Nakashima
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Chika Miyagi-Shiohira
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Takao Kinjo
- Department of Basic Laboratory Sciences, School of Health Sciences in the Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Zensei Toyoda
- Department of Basic Laboratory Sciences, School of Health Sciences in the Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | | | - Issei Saitoh
- Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata 951-8514, Japan
| | - Masami Watanabe
- Department of Urology, Okayama Univer sity Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hirofumi Noguchi
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
| | - Jiro Fujita
- Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
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Kim MK, Kim MA, Yim JH, Lee DH, Cho SK, Yang SG. Ramalin, an antioxidant compound derived from Antarctic lichen, prevents progression of liver fibrosis induced by dimethylnitrosamine (DNM) in rats. Biochem Biophys Res Commun 2018; 504:25-33. [PMID: 30172374 DOI: 10.1016/j.bbrc.2018.08.103] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 08/15/2018] [Indexed: 12/24/2022]
Abstract
Hepatic fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM), primarily collagen, within the liver. Because reactive oxygen species (ROS) has been implicated in its pathogenesis, the use of antioxidants as a potential treatment has been broadly explored. Here, we investigated the hepatoprotective properties of ramalin (RM), a compound extracted from the Antarctic lichen Ramalina terebrata, against hepatic fibrosis in vitro and in vivo. RM suppressed hepatic stellate cell (HSC) activation in vitro without any significant signs of adverse effects on the cells tested, and the accumulation of ECM was dramatically reduced in the liver tissue. Oral administration of RM in rats noticeably improved the gross appearance of the liver with increased body and liver weight relative to the DMN injected rats, and all of the serum biochemical markers returned to the normal range. RM treatment have ameliorated hepatic fibrosis in rats induced by DMN by repressing α-smooth muscle actin (α-SMA) and upregulating heme oxygenase-1 (HO-1). In addition, RM significantly reduced collagen accumulation, and levels of malondialdehyde (MDA) and hydroxyproline (HP) in the liver tissue of DMN injected rats. The efficacy exerted by RM was through erythroid 2-related factor 2 (Nrf2) mediated antioxidant response proteins such as HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO-1). Our results show the beneficial effect of RM against the progression of hepatic fibrosis.
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Affiliation(s)
- Min-Kyoung Kim
- World Class Smart Lab, Department of New Drug Development, College of Medicine, Inha University, Incheon, 22332, Republic of Korea
| | - Min A Kim
- World Class Smart Lab, Department of New Drug Development, College of Medicine, Inha University, Incheon, 22332, Republic of Korea
| | - Joung Han Yim
- Division of Life Sciences, Korea Polar Research Institute, KOPRI, Incheon, 406-840, Republic of Korea
| | - Don-Haeng Lee
- Division of Gastroenterology & Hepatology, Inha University Hospital, Incheon, 400-711, Republic of Korea
| | - Steve K Cho
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea; School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea.
| | - Su-Geun Yang
- World Class Smart Lab, Department of New Drug Development, College of Medicine, Inha University, Incheon, 22332, Republic of Korea.
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Qi Y, Xu F, Chen L, Li Y, Xu Z, Zhang Y, Wei W, Su N, Zhang T, Fan F, Wang X, Qin X, Zhang L, Liu Y, Xu P. Quantitative proteomics reveals FLNC as a potential progression marker for the development of hepatocellular carcinoma. Oncotarget 2018; 7:68242-68252. [PMID: 27626164 PMCID: PMC5354476 DOI: 10.18632/oncotarget.11921] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 09/02/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) infection is one of the most life-threatening human cancers in China. However, the pathogenesis of HCC development is still unclear. Here, we systemically analyzed liver tissues from different stages of HCC patients through 8-plex Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) approach. A total of 4,620 proteins were identified and 3,781 proteins were quantified. When T1, T2 and T3 tumor tissues were compared with T1 non-tumor cells, 330, 365 and 387 differentially expressed proteins were identified respectively. IPA (Ingenuity Pathway Analysis) analysis revealed that these differentially expressed proteins were involved in endothelial cancer, cell spreading, cell adhesion and cell movement of tumor cell lines pathway and so on. Further study showed that the filamin C (FLNC) protein was significantly overexpressed with the development of HCC, which might play an important role in HCC invasion and metastasis. These results were also confirmed with western blot (WB). The mRNA levels were significantly increased in 50 pairs of tumor and adjacent non-tumor tissues from TCGA database. The higher expression of FLNC in HCC might be a common phenomenon, thereby shedding new light on molecular mechanism and biomarker for the diagnosis purpose of HCC development.
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Affiliation(s)
- Yingzi Qi
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Feng Xu
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Lingsheng Chen
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530005, China
| | - Yanchang Li
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Zhongwei Xu
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Yao Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China.,Institute of Microbiology, Chinese Academy of Science, Beijing 100101, China
| | - Wei Wei
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Na Su
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Tao Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Fengxu Fan
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China.,Anhui Medical University, Hefei 230032, China
| | - Xing Wang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Xue Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Lingqiang Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China
| | - Yinkun Liu
- Cancer Research Center, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Ping Xu
- State Key Laboratory of Proteomics, National Center for Protein Sciences Beijing, Beijing Proteome Research Center, Institute of Radiation Medicine, Beijing 102206, China.,Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education and Wuhan University School of Pharmaceutical Sciences, Wuhan 430072, China.,Anhui Medical University, Hefei 230032, China
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15
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Zhang R, Zhang LJ, Yang ML, Huang LS, Chen G, Feng ZB. Potential role of microRNA‑223‑3p in the tumorigenesis of hepatocellular carcinoma: A comprehensive study based on data mining and bioinformatics. Mol Med Rep 2017; 17:2211-2228. [PMID: 29207133 PMCID: PMC5783470 DOI: 10.3892/mmr.2017.8167] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 10/02/2017] [Indexed: 02/07/2023] Open
Abstract
The aims of the present study were to examine the potential role of microRNA‑233‑3p (miR)‑223‑3p in the tumorigenesis of hepatocellular carcinoma (HCC), and to investigate its diagnostic accuracy and potential molecular mechanisms. The expression data of miR‑223‑3p in HCC were obtained from the Gene Expression Omnibus (GEO). Data for the precursor miR‑223 were obtained from The Cancer Genome Atlas (TCGA). The diagnostic role of miR‑223‑3p was identified by the receiver operating curve (ROC), and the diagnostic value of miR‑223‑3p in HCC was calculated from qualified reports in the literature. In addition, associated data from the GEO, TCGA and qualified experiments were pooled for comprehensive meta‑analysis. Genes, which intersected between online prediction databases, natural language processing and differentially expressed genes from TCGA were regarded as potential targets of miR‑223‑3p in HCC. The Gene Ontology enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes pathways of potential targets were performed using the Database for Annotation, Visualization and Integrated Discovery. The protein‑protein interactions were mapped using the Search Tool for the Retrieval of Interacting Genes. Among 15 qualified microarray data sets from GEO, seven showed that a significantly lower level of miR‑223‑3p was present in the HCC tissues, compared with that in non‑cancerous tissues (P<0.05). In addition, five GEO data sets revealed diagnostic values of miR‑223‑3p, with an area under the curve (AUC) of >0.80 (P<0.05). The diagnostic accuracy of the precursor miR‑223 in TCGA was also calculated (AUC=0.78, P<0.05). Similarly, the precursor miR‑223 showed a higher level of downregulation in HCC tissues, compared with that in healthy controls in TCGA (P<0.001). A summary ROC was also calculated as 0.89 (95% CI, 0.85‑0.91) in the meta‑analysis. A total of 72 potential targets were extracted, mainly involved in the terms 'microRNAs in cancer', 'ATP binding' and 'prostate cancer'. Five potential target genes were considered the hub genes of miR‑223‑3p in HCC, including checkpoint kinase 1, DNA methyltransferase 1, baculoviral IAP repeat containing 5, kinesin family member 23, and collagen, type I, α1. Based on TCGA, the hub genes were significantly upregulated in HCC (P<0.05). Collectively, these results showed that miR‑223‑3p may be crucial in HCC carcinogenesis showing high diagnostic accuracy, and may be mediated by several hub genes.
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Affiliation(s)
- Rui Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Li-Jie Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Mei-Ling Yang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Lan-Shan Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhen-Bo Feng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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16
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Bomb R, Heckle MR, Sun Y, Mancarella S, Guntaka RV, Gerling IC, Weber KT. Myofibroblast secretome and its auto-/paracrine signaling. Expert Rev Cardiovasc Ther 2016; 14:591-8. [PMID: 26818589 DOI: 10.1586/14779072.2016.1147348] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Myofibroblasts (myoFb) are phenotypically transformed, contractile fibroblast-like cells expressing α-smooth muscle actin microfilaments. They are integral to collagen fibrillogenesis with scar tissue formation at sites of repair irrespective of the etiologic origins of injury or tissue involved. MyoFb can persist long after healing is complete, where their ongoing turnover of collagen accounts for a progressive structural remodeling of an organ (a.k.a. fibrosis, sclerosis or cirrhosis). Such persistent metabolic activity is derived from a secretome consisting of requisite components in the de novo generation of angiotensin (Ang) II. Autocrine and paracrine signaling induced by tissue AngII is expressed via AT1 receptor ligand binding to respectively promote: i) regulation of myoFb collagen synthesis via the fibrogenic cytokine TGF-β1-Smad pathway; and ii) dedifferentiation and protein degradation of atrophic myocytes immobilized and ensnared by fibrillar collagen at sites of scarring. Several cardioprotective strategies in the prevention of fibrosis and involving myofibroblasts are considered. They include: inducing myoFb apoptosis through inactivation of antiapoptotic proteins; AT1 receptor antagonist to interfere with auto-/paracrine myoFb signaling or to induce counterregulatory expression of ACE2; and attacking the AngII-AT1R-TGF-β1-Smad pathway by antibody or the use of triplex-forming oligonucleotides.
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Affiliation(s)
- Ritin Bomb
- a Division of Cardiovascular Diseases , University of Tennessee Health Science Center , Memphis , TN , USA
| | - Mark R Heckle
- b Department of Medicine , University of Tennessee Health Science Center , Memphis , TN , USA
| | - Yao Sun
- a Division of Cardiovascular Diseases , University of Tennessee Health Science Center , Memphis , TN , USA
| | - Salvatore Mancarella
- c Department of Physiology , University of Tennessee Health Science Center , Memphis , TN , USA
| | - Ramareddy V Guntaka
- d Department of Microbiology, Immunology and Biochemistry , University of Tennessee Health Science Center , Memphis , TN , USA
| | - Ivan C Gerling
- e Division of Endocrinology , University of Tennessee Health Science Center , Memphis , TN , USA
| | - Karl T Weber
- a Division of Cardiovascular Diseases , University of Tennessee Health Science Center , Memphis , TN , USA
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Abstract
Over the recent decade oligonucleotides have become an important new class of molecules, allowing therapeutic intervention through targets previously thought 'undruggable'. One of the new avenues opened up by oligonucleotide-based drugs was specific gene upregulation, which, historically, has been difficult to achieve using small-molecule drugs. This article will focus on patents covering this important development in the oligonucleotide field and highlight the different mechanisms through which the oligonucleotide-mediated gene upregulation can work, including inhibition of activity of natural antisense transcripts, interaction with promoter binding sites of noncoding regulatory RNAs, blocking of regulatory and/or miRNA binding sites in 3' UTRs, blocking splice inhibitor/enhancer sites or blocking interactions with polycomb repressive complex 2. Understanding the particular mechanism through which an oligonucleotide drug exerts its effects is highly important in drug development, as it determines the design of the drug molecule.
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18
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Hayashi M, Nomoto S, Hishida M, Inokawa Y, Kanda M, Okamura Y, Nishikawa Y, Tanaka C, Kobayashi D, Yamada S, Nakayama G, Fujii T, Sugimoto H, Koike M, Fujiwara M, Takeda S, Kodera Y. Identification of the collagen type 1 α 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma. BMC Cancer 2014; 14:108. [PMID: 24552139 PMCID: PMC4015503 DOI: 10.1186/1471-2407-14-108] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 02/13/2014] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death especially among Asian and African populations. It is urgent that we identify carcinogenesis-related genes to establish an innovative treatment strategy for this disease. Methods Triple-combination array analysis was performed using one pair each of HCC and noncancerous liver samples from a 68-year-old woman. This analysis consists of expression array, single nucleotide polymorphism array and methylation array. The gene encoding collagen type 1 alpha 1 (COL1A1) was identified and verified using HCC cell lines and 48 tissues from patients with primary HCC. Results Expression array revealed that COL1A1 gene expression was markedly decreased in tumor tissues (log2 ratio –1.1). The single nucleotide polymorphism array showed no chromosomal deletion in the locus of COL1A1. Importantly, the methylation value in the tumor tissue was higher (0.557) than that of the adjacent liver tissue (0.008). We verified that expression of this gene was suppressed by promoter methylation. Reactivation of COL1A1 expression by 5-aza-2′-deoxycytidine treatment was seen in HCC cell lines, and sequence analysis identified methylated CpG sites in the COL1A1 promoter region. Among 48 pairs of surgical specimens, 13 (27.1%) showed decreased COL1A1 mRNA expression in tumor sites. Among these 13 cases, 10 had promoter methylation at the tumor site. The log-rank test indicated that mRNA down-regulated tumors were significantly correlated with a poor overall survival rate (P = 0.013). Conclusions Triple-combination array analysis successfully identified COL1A1 as a candidate survival-related gene in HCCs. Epigenetic down-regulation of COL1A1 mRNA expression might have a role as a prognostic biomarker of HCC.
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Affiliation(s)
| | - Shuji Nomoto
- Gastroenterological Surgery (Department of Surgery II), Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
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Abstract
The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection.
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Papadakis G, Gizeli E. In silico search of DNA drugs targeting oncogenes. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2012; 9:1826-1830. [PMID: 23221090 DOI: 10.1109/tcbb.2012.127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Triplex forming oligonucleotides (TFOs) represent a class of drug candidates for antigene therapy. Based on strict criteria, we investigated the potential of 25 known oncogenes to be regulated by TFOs in the mRNA synthesis level and we report specific target sequences found in seven of these genes.
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Affiliation(s)
- George Papadakis
- Department of Biology, University of Crete and Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology Hellas (FORTH), 100 Nikolaou Plastira str, Heraklion 70013, Greece.
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Yang N, Singh S, Mahato RI. Targeted TFO delivery to hepatic stellate cells. J Control Release 2011; 155:326-30. [PMID: 21763370 PMCID: PMC3347642 DOI: 10.1016/j.jconrel.2011.06.037] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 06/04/2011] [Accepted: 06/26/2011] [Indexed: 12/27/2022]
Abstract
Triplex-forming oligonucleotides (TFOs) represent an antigene approach for gene regulation through direct interaction with genomic DNA. While this strategy holds great promise owing to the fact that only two alleles need silencing to impact gene regulation, delivering TFOs to target cells in vivo is still a challenge. Our recent efforts have focused on conjugating TFOs to carrier molecules like cholesterol to enhance their cellular uptake and mannose-6-phosphate-bovine serum albumin (M6P-BSA) to target TFO delivery to hepatic stellate cells (HSCs) for treating liver fibrosis. These approaches however are rendered less effective owing to a lack of targeted delivery, as seen with lipid-conjugates, and the potential immune reactions due to repeated dosing with high molecular weight BSA conjugated TFO. In this review, we discuss our latest efforts to enhance the effectiveness of TFO for treating liver fibrosis. We have shown that conjugation of TFOs to M6P-HPMA can enhance TFO delivery to HSCs and has the potential to treat liver fibrosis by inhibiting collagen synthesis. This TFO conjugate shows negligible immunogenicity owing to the use of HPMA, one of the least immunogenic copolymers, thereby making it a suitable and more effective candidate for antifibrotic therapy.
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Affiliation(s)
- Ningning Yang
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38103
| | - Saurabh Singh
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38103
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38103
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