|
1
|
Nikapitiya C, Jayathilaka EHTT, Edirisinghe SL, Oh C, De Zoysa M. Characterization, microRNA profiling, and immunomodulatory role of plasma-derived exosomes from olive flounder (Paralichthys olivaceus) in response to viral hemorrhagic septicemia virus. FISH & SHELLFISH IMMUNOLOGY 2025; 162:110316. [PMID: 40239934 DOI: 10.1016/j.fsi.2025.110316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 04/02/2025] [Accepted: 04/07/2025] [Indexed: 04/18/2025]
Abstract
Viral hemorrhagic septicemia virus (VHSV) is a highly pathogenic virus that frequently infects olive flounder (Paralichthys olivaceus), causing viral hemorrhagic septicemia (VHS), and posing a significant threat to global aquaculture. This study characterizes plasma-derived exosomes from olive flounder following VHSV challenge (VHSV-Exo) or phosphate buffered saline (PBS) injection (PBS-Exo), comparing their morphology, physicochemical properties, molecular profiles, and immunomodulatory functions. Both PBS-Exo (118.3 ± 8.6 nm) and VHSV-Exo (82.6 ± 5.9 nm) exhibited the typical cup-shaped morphology of exosomes. The successful isolation and purity of exosomes were confirmed by the presence of exosome markers (CD81, CD9, and CD63) and the absence of albumin. High-throughput sequencing identified 13 differentially expressed (DE) microRNAs (miRNAs) between PBS-Exo and VHSV-Exo, including six upregulated and seven downregulated miRNAs (log2 fold change ≥1 or ≤ -1). Toxicity assessments revealed that neither PBS-Exo nor VHSV-Exo were toxic to murine macrophage Raw 264.7 cells or zebrafish larvae at tested doses (up to 100 and 400 μg/mL, respectively). The absence of green fluorescence at 96 h post-treatment of VHSV-Exo indicated minimal reactive oxygen species generation, further supporting exosome safety. Functional studies demonstrated that both in vitro (Raw 264.7 cells) and in vivo (adult zebrafish) treatments with exosomes regulated immune-related genes and proteins expression. Notabaly, VHSV-Exo exhibited superior immunomodulatory effects, as evidenced by enhanced immune gene and protein expression. To our knowledge, this is the first study demonstrating the immunomodulatory potential of VHSV-Exo. These findings highlight VHSV-Exo as a promising immunomodulatory agent, with potential applications as a prophylactic vaccine candidate against VHSV infection in aquaculture.
Collapse
Affiliation(s)
- Chamilani Nikapitiya
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - E H T Thulshan Jayathilaka
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - Shan Lakmal Edirisinghe
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea
| | - Chulhong Oh
- Jeju Bio Research Center, Korea Institute of Ocean Science and Technology, Gujwa-eup, Jeju, 2670, Republic of Korea
| | - Mahanama De Zoysa
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Yuseong-gu, Daejeon, 34134, Republic of Korea.
| |
Collapse
|
|
2
|
Tian M, Zhou Y, Guo Y, Xia Q, Wang Z, Zheng X, Shen J, Guo J, Duan S, Wang L. MicroRNAs in adipose tissue fibrosis: Mechanisms and therapeutic potential. Genes Dis 2025; 12:101287. [PMID: 40242037 PMCID: PMC12002615 DOI: 10.1016/j.gendis.2024.101287] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 03/07/2024] [Indexed: 04/18/2025] Open
Abstract
Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.
Collapse
Affiliation(s)
- Mei Tian
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
- Geriatric Medicine Center, Department of Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Yang Zhou
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Yitong Guo
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Qing Xia
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Zehua Wang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Xinying Zheng
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Jinze Shen
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Junping Guo
- Rainbowfish Rehabilitation and Nursing School, Hangzhou Vocational & Technical College, Hangzhou, Zhejiang 310018, China
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Shiwei Duan
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang 310015, China
| | - Lijun Wang
- Geriatric Medicine Center, Department of Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| |
Collapse
|
|
3
|
Zhang J, Qiu X, Lei Y, Chen H, Wu D, Wang T, Sui X, Xiao J, Jiang C, Zhang H, Liu Y, Liu X, Zhang Y, Che X, Lin Y, Yao J, Pan Z, Li R, Zheng J. Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells. Exp Mol Med 2025; 57:584-600. [PMID: 40025174 PMCID: PMC11958733 DOI: 10.1038/s12276-025-01413-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 11/30/2024] [Accepted: 12/12/2024] [Indexed: 03/04/2025] Open
Abstract
Fibrosis is a disease that negatively affects liver regeneration, resulting in severe complications after liver surgery. However, there is still no clinically effective treatment for promoting fibrotic liver regeneration because the underlying hepatocellular mechanism remains poorly understood. Through microRNA microarrays combined with the application of AAV6, we found that high expression of miR-181a-5p in activated hepatic stellate cells (HSCs) suppressed the expression of hepatic growth factor (HGF) and partially contributed to impaired regeneration potential in mice with hepatic fibrosis that had undergone two-thirds partial hepatectomy. As nanotherapeutics, mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) have been verified as effective treatments for liver regeneration. Here we observe that MSC-EVs can also promote fibrotic liver regeneration via enriched lncEEF1G, which acts as a competing endogenous RNA to directly sponge miR-181a-5p, leading to the upregulated expression of HGF in HSCs. Finally, engineered MSC-EVs with high expression of lncEEF1G (lncEEF1GOE-EVs) were constructed, suggesting greater potential for this model. In summary, our findings indicate that lncEEF1GOE-EVs have a nanotherapeutic effect on promoting regeneration of fibrotic livers by modulating the miR-181a-5p/HGF pathway in HSCs, which highlights the potential of extracellular vesicle engineering technology for patients with hepatic fibrosis who have undergone hepatic surgery. Engineered mesenchymal stem cells that overexpress lncEEF1G can secrete extracellular vesicles that are rich in lncEEF1G (lncEEF1GOE-EVs). Upon injection of lncEEF1GOE-EVs into a fibrotic 70% partial hepatectomy mouse model, lncEEF1G competitively binds to miR-181a-5p in hepatic stellate cells, preventing the interaction between miR-181a-5p and the messenger RNA of hepatocyte growth factor. This consequently leads to an increase in the secretion of hepatocyte growth factor and the promotion of hepatocyte proliferation.
Collapse
Affiliation(s)
- Jiebin Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaotong Qiu
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yunguo Lei
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haitian Chen
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Dongwei Wu
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tingting Wang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xin Sui
- Surgical ICU, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiaqi Xiao
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chenhao Jiang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huayao Zhang
- Shaoguan Maternal and Child Health Hospital, Shaoguan, Guangdong, China
| | - Yasong Liu
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoquan Liu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yingcai Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xu Che
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Ye Lin
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jia Yao
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Zihao Pan
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Rong Li
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Jun Zheng
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| |
Collapse
|
|
4
|
Sartorius K, Wang Y, Sartorius B, Antwi SO, Li X, Chuturgoon A, Yu C, Lu Y, Wang Y. The interactive role of microRNA and other non-coding RNA in hepatitis B (HBV) associated fibrogenesis. Funct Integr Genomics 2025; 25:24. [PMID: 39847120 DOI: 10.1007/s10142-024-01519-4] [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: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
One of the outstanding features of chronic hepatitis B infection (CHB) is its strong association with liver fibrosis. CHB induced inflammation and injury trigger multiple biochemical and physical changes that include the promotion of a wide range of cytokines, chemokines and growth factors that activate hepatic stellate cells (HSCs) CHB induced activation of hepatic stellate cells (HSCs) is regarded as a central event in fibrogenesis to directly promote the synthesis of myofibroblasts and the expression of a range of materials to repair injured liver tissue. Fibrogenesis is modulated by the mainstream epigenetic machinery, as well as by non-coding RNA (ncRNA) that are often referred to as an ancillary epigenetic response to fine tune gene expression. Although extensive research has explained the regulatory role of ncRNA in liver fibrogenesis, most of this research relates to non-CHB etiologies. This review paper outlines the complex interactive regulatory role of microRNA (miRNA) and their interaction with long non-coding RNA (lncRNA), circular RNA (circRNA) and the mainstream epigenetic machinery in CHB induced liver fibrosis. The paper also illustrates some of the difficulties involved in translating candidate ncRNA into approved drugs or diagnostic tools. In conclusion, the important regulatory role of ncRNA in CHB induced liver fibrosis warrants further investigation to exploit their undoubted potential as diagnostic and therapeutic agents.
Collapse
Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa.
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
| | - Yanglong Wang
- Department of General Surgery, Xinyi People's Hospital, Xinyi, Jiangsu, China
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, Australia
| | - Samuel O Antwi
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
- Division of Epidemiology Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, AL, USA
| | - Xiaodong Li
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, UKZN, Durban, South Africa
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunjie Lu
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Yu Wang
- Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University, 213200, Changzhou, Jiangsu, China.
| |
Collapse
|
|
5
|
Hu C, Wang L. Advances in the treatment of liver injury based on mesenchymal stem cell-derived exosomes. Stem Cell Res Ther 2024; 15:474. [PMID: 39696473 DOI: 10.1186/s13287-024-04087-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have shown a great potential role in treating liver injury. MSCs can promote liver regeneration by differentiating into hepatocytes, and can also secrete exosomes to participate in the repair of liver injury. Increasing evidence has shown that mesenchymal stem cell-derived exosomes (MSC-EXOs) play an important role in treating liver injury. In this review, the biogenesis and function of exosomes and the characteristics of MSC-EXOs were analyzed based on recent research results. MSC-EXOs are significant in liver injuries such as liver fibrosis, liver failure, hepatocellular carcinoma, oxidative stress, and lipid steatosis, and participate in the process of liver regeneration.
Collapse
Affiliation(s)
- Changlong Hu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China.
| |
Collapse
|
|
6
|
Yang X, Zhang D, Li M, Shao Y, Zhang X, Xue Y. P4HA1: an important target for treating fibrosis related diseases and cancer. Front Pharmacol 2024; 15:1493420. [PMID: 39568592 PMCID: PMC11576223 DOI: 10.3389/fphar.2024.1493420] [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: 09/09/2024] [Accepted: 10/28/2024] [Indexed: 11/22/2024] Open
Abstract
Fibrosis is significantly associated with a wide variety of diseases and is involved in their progression. Fibrosis activated under the influence of different combinations of factors is considered a double-edged sword. Although there has been much research on organ fibrosis in recent years, a variety of organ fibrosis diseases and cancers are not well controlled in terms of prevention, treatment, and prognosis. Clinical studies still lack exploration and discovery of effective targets for the pathogenesis of organ fibrosis. Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) is a protein kinase and the synthesis and secretion of collagen are related to the sustained activation of P4HA1. As further studies are being conducted, the potential role of P4HA1 in the development of fibrosis-associated diseases and cancer is becoming clear. Consequently, we conducted a systematic review and discussion on the role of P4HA1 in the pathogenesis of various fibrosis-related diseases and cancers. We reviewed the possible strategies of P4HA1 in the diagnosis and treatment of fibrosis-related diseases and cancers, and analyzed its potential relevance as a biomarker in the diagnosis and treatment of fibrosis-related diseases and cancer.
Collapse
Affiliation(s)
- Xuewen Yang
- Department of Pharmacology, Institute of Pharmacokinetics and Liver Molecular Pharmacology, Baotou Medical College, Baotou, China
| | - Dong Zhang
- Department of Pharmacology, Institute of Pharmacokinetics and Liver Molecular Pharmacology, Baotou Medical College, Baotou, China
| | - Mengmeng Li
- Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin, China
| | - Yingchun Shao
- The Affiliated Hospital of Qingdao University, Qingdao Cancer Institute, Qingdao University, Qingdao, China
| | - Xiyang Zhang
- Faculty of Basic Medicine, Chongqing Three Gorges Medical College, Chongqing, China
| | - Yongzhi Xue
- Department of Pharmacology, Institute of Pharmacokinetics and Liver Molecular Pharmacology, Baotou Medical College, Baotou, China
| |
Collapse
|
|
7
|
Jin Y, Kozan D, Young ED, Hensley MR, Shen MC, Wen J, Moll T, Anderson JL, Kozan H, Rawls JF, Farber SA. A high-cholesterol zebrafish diet promotes hypercholesterolemia and fasting-associated liver steatosis. J Lipid Res 2024; 65:100637. [PMID: 39218217 PMCID: PMC11913794 DOI: 10.1016/j.jlr.2024.100637] [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: 10/19/2023] [Revised: 07/22/2024] [Accepted: 08/07/2024] [Indexed: 09/04/2024] Open
Abstract
Zebrafish are an ideal model organism to study lipid metabolism and to elucidate the molecular underpinnings of human lipid-associated disorders. Unlike murine models, to which various standardized high lipid diets such as a high-cholesterol diet (HCD) are available, there has yet to be a uniformly adopted zebrafish HCD protocol. In this study, we have developed an improved HCD protocol and thoroughly tested its impact on zebrafish lipid deposition and lipoprotein regulation in a dose- and time-dependent manner. The diet stability, reproducibility, and fish palatability were also validated. Fish fed HCD developed hypercholesterolemia as indicated by significantly elevated ApoB-containing lipoproteins (ApoB-LPs) and increased plasma levels of cholesterol and cholesterol esters. Feeding of the HCD to larvae for 8 days produced hepatic steatosis that became more stable and sever after 1 day of fasting and was associated with an opaque liver phenotype (dark under transmitted light). Unlike larvae, adult fish fed HCD for 14 days followed by a 3-day fast did not develop a stable fatty liver phenotype, though the fish had higher ApoB-LP levels in plasma and an upregulated lipogenesis gene fasn in adipose tissue. In conclusion, our HCD zebrafish protocol represents an effective and reliable approach for studying the temporal characteristics of the physiological and biochemical responses to high levels of dietary cholesterol and provides insights into the mechanisms that may underlie fatty liver disease.
Collapse
Affiliation(s)
- Yang Jin
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA; Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Aas, Norway
| | - Darby Kozan
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA; Department of Biology, Johns Hopkins University, Baltimore, MD, USA
| | - Eric D Young
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA; Division of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Monica R Hensley
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA
| | - Meng-Chieh Shen
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA
| | - Jia Wen
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Tabea Moll
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA; Department of Biology, Johns Hopkins University, Baltimore, MD, USA
| | - Jennifer L Anderson
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA
| | - Hannah Kozan
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA
| | - John F Rawls
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Steven A Farber
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, USA; Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
| |
Collapse
|
|
8
|
Mezentsev A, Durymanov M, Makarov VA. A Comprehensive Review of Protein Biomarkers for Invasive Lung Cancer. Curr Oncol 2024; 31:4818-4854. [PMID: 39329988 PMCID: PMC11431409 DOI: 10.3390/curroncol31090360] [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: 07/25/2024] [Revised: 08/16/2024] [Accepted: 08/22/2024] [Indexed: 09/28/2024] Open
Abstract
Invasion and metastasis are important hallmarks of lung cancer, and affect patients' survival. Early diagnostics of metastatic potential are important for treatment management. Recent findings suggest that the transition to an invasive phenotype causes changes in the expression of 700-800 genes. In this context, the biomarkers restricted to the specific type of cancer, like lung cancer, are often overlooked. Some well-known protein biomarkers correlate with the progression of the disease and the immunogenicity of the tumor. Most of these biomarkers are not exclusive to lung cancer because of their significant role in tumorigenesis. The dysregulation of others does not necessarily indicate cell invasiveness, as they play an active role in cell division. Clinical studies of lung cancer use protein biomarkers to assess the invasiveness of cancer cells for therapeutic purposes. However, there is still a need to discover new biomarkers for lung cancer. In the future, minimally invasive techniques, such as blood or saliva analyses, may be sufficient for this purpose. Many researchers suggest unconventional biomarkers, like circulating nucleic acids, exosomal proteins, and autoantibodies. This review paper aims to discuss the advantages and limitations of protein biomarkers of invasiveness in lung cancer, to assess their prognostic value, and propose novel biomarker candidates.
Collapse
Affiliation(s)
- Alexandre Mezentsev
- Medical Informatics Laboratory, Yaroslav-the-Wise Novgorod State University, 173003 Veliky Novgorod, Russia; (M.D.); (V.A.M.)
- Center for Theoretical Problems of Physicochemical Pharmacology, 109029 Moscow, Russia
| | - Mikhail Durymanov
- Medical Informatics Laboratory, Yaroslav-the-Wise Novgorod State University, 173003 Veliky Novgorod, Russia; (M.D.); (V.A.M.)
| | - Vladimir A. Makarov
- Medical Informatics Laboratory, Yaroslav-the-Wise Novgorod State University, 173003 Veliky Novgorod, Russia; (M.D.); (V.A.M.)
| |
Collapse
|
|
9
|
Gao R, Mao J. Noncoding RNA-Mediated Epigenetic Regulation in Hepatic Stellate Cells of Liver Fibrosis. Noncoding RNA 2024; 10:44. [PMID: 39195573 DOI: 10.3390/ncrna10040044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/09/2024] [Accepted: 08/01/2024] [Indexed: 08/29/2024] Open
Abstract
Liver fibrosis is a significant contributor to liver-related disease mortality on a global scale. Despite this, there remains a dearth of effective therapeutic interventions capable of reversing this condition. Consequently, it is imperative that we gain a comprehensive understanding of the underlying mechanisms driving liver fibrosis. In this regard, the activation of hepatic stellate cells (HSCs) is recognized as a pivotal factor in the development and progression of liver fibrosis. The role of noncoding RNAs (ncRNAs) in epigenetic regulation of HSCs transdifferentiation into myofibroblasts has been established, providing new insights into gene expression changes during HSCs activation. NcRNAs play a crucial role in mediating the epigenetics of HSCs, serving as novel regulators in the pathogenesis of liver fibrosis. As research on epigenetics expands, the connection between ncRNAs involved in HSCs activation and epigenetic mechanisms becomes more evident. These changes in gene regulation have attracted considerable attention from researchers in the field. Furthermore, epigenetics has contributed valuable insights to drug discovery and the identification of therapeutic targets for individuals suffering from liver fibrosis and cirrhosis. As such, this review offers a thorough discussion on the role of ncRNAs in the HSCs activation of liver fibrosis.
Collapse
Affiliation(s)
- Ruoyu Gao
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Jingwei Mao
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| |
Collapse
|
|
10
|
Chen W, Lin F, Feng X, Yao Q, Yu Y, Gao F, Zhou J, Pan Q, Wu J, Yang J, Yu J, Cao H, Li L. MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation. Asian J Pharm Sci 2024; 19:100889. [PMID: 38419761 PMCID: PMC10900800 DOI: 10.1016/j.ajps.2024.100889] [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: 07/13/2023] [Revised: 12/13/2023] [Accepted: 01/14/2024] [Indexed: 03/02/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis, with no curative treatment available, and liver transplantation is inevitable for end-stage patients. Human placental mesenchymal stem cell (hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis, inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease. Here, we prepared hpMSC-derived exosomes (ExoMSC) and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2-/- mice and multicellular organoids established from PSC patients. The results showed that ExoMSC ameliorated liver fibrosis in Mdr2-/- mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis, and the percentage of CD4+IL-17A+T cells was reduced both in ExoMSC-treated Mdr2-/- mice (Mdr2-/--Exo) in vivo and ExoMSC-treated Th17 differentiation progressed in vitro. Furthermore, ExoMSC improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids. Thus, our data demonstrate the anti-fibrosis effect of ExoMSC in PSC disease by inhibiting Th17 differentiation, and ameliorating the Th17-induced microenvironment, indicating the promising potential therapeutic role of ExoMSC in liver fibrosis of PSC or Th17-related diseases.
Collapse
Affiliation(s)
- Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Feiyan Lin
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xudong Feng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yingduo Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiahang Zhou
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qiaoling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jinfeng Yang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
| |
Collapse
|
|
11
|
Cao J, Zhong Q, Huang Y, Zhu M, Wang Z, Xiong Z. Identification and validation of INHBE and P4HA1 as hub genes in non-alcoholic fatty liver disease. Biochem Biophys Res Commun 2023; 686:149180. [PMID: 37922570 DOI: 10.1016/j.bbrc.2023.149180] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 11/07/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent type of liver disease and a worldwide disease threatening human health. This study aims to identify the novel diagnostic biomarkers of NAFLD by comprehensive bioinformatics and machine learning, and to validate our results in hepatocyte and animal models. METHODS We used Gene Expression Omnibus (GEO) databases on NAFLD patients for differential gene expression analyses. Intersections were taken with genes from the key modules of WGCNA and differentially expressed genes (DEGs). Machine learning algorithms like LASSO regression analysis, SVM-RFE, and RandomForest were used to screen hub genes. In addition, a nomogram model and calibration curves were built in order to forecast the probability of NAFLD occurrence. Then, the relationship between hub genes and immune cells was verified using Spearman analysis. Finally, we further verified the expression of key genes by constructing a steatosis hepatocyte model and animal model. RESULTS Key genes (INHBE and P4HA1) were identified by comprehensive bioinformatics analysis and machine learning. INHBE and P4HA1 were up-regulated and down-regulated in the steatosis hepatocyte model, respectively. Animal experiments also showed that INHBE was up-regulated in the liver of mice fed with high fat diet (HFD). CONCLUSION INHBE and P4HA1 are the hub genes of NAFLD. Our findings may contribute to a greater understanding of the occurrence and development of NAFLD and provide potential biomarkers and possible therapeutic targets for future clinical diagnosis and treatment.
Collapse
Affiliation(s)
- Jiali Cao
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Qiangqiang Zhong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Yumei Huang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Mengpei Zhu
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Ziwen Wang
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430077, China
| | - Zhifan Xiong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430077, China.
| |
Collapse
|
|
12
|
Jin Y, Kozan D, Anderson JL, Hensley M, Shen MC, Wen J, Moll T, Kozan H, Rawls JF, Farber SA. A high-cholesterol zebrafish diet promotes hypercholesterolemia and fasting-associated liver triglycerides accumulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.01.565134. [PMID: 37961364 PMCID: PMC10635069 DOI: 10.1101/2023.11.01.565134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Zebrafish are an ideal model organism to study lipid metabolism and to elucidate the molecular underpinnings of human lipid-associated disorders. In this study, we provide an improved protocol to assay the impact of a high-cholesterol diet (HCD) on zebrafish lipid deposition and lipoprotein regulation. Fish fed HCD developed hypercholesterolemia as indicated by significantly elevated ApoB-containing lipoproteins (ApoB-LP) and increased plasma levels of cholesterol and cholesterol esters. Feeding of the HCD to larvae (8 days followed by a 1 day fast) and adult female fish (2 weeks, followed by 3 days of fasting) was also associated with a fatty liver phenotype that presented as severe hepatic steatosis. The HCD feeding paradigm doubled the levels of liver triacylglycerol (TG), which was striking because our HCD was only supplemented with cholesterol. The accumulated liver TG was unlikely due to increased de novo lipogenesis or inhibited β-oxidation since no differentially expressed genes in these pathways were found between the livers of fish fed the HCD versus control diets. However, fasted HCD fish had significantly increased lipogenesis gene fasn in adipose tissue and higher free fatty acids (FFA) in plasma. This suggested that elevated dietary cholesterol resulted in lipid accumulation in adipocytes, which supplied more FFA during fasting, promoting hepatic steatosis. In conclusion, our HCD zebrafish protocol represents an effective and reliable approach for studying the temporal characteristics of the physiological and biochemical responses to high levels of dietary cholesterol and provides insights into the mechanisms that may underlie fatty liver disease.
Collapse
Affiliation(s)
- Yang Jin
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, United States
- Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, Aas, Norway
| | - Darby Kozan
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, United States
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States
| | - Jennifer L Anderson
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, United States
| | - Monica Hensley
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, United States
| | - Meng-Chieh Shen
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, United States
| | - Jia Wen
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, United States
| | - Tabea Moll
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, United States
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States
| | - Hannah Kozan
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, United States
| | - John F. Rawls
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, United States
| | - Steven A. Farber
- Department of Embryology, Carnegie Institution for Science, Baltimore, MD, United States
- Department of Biology, Johns Hopkins University, Baltimore, MD, United States
| |
Collapse
|
|
13
|
Chen S, Ma Y, Qiu X, Liu M, Zhang P, Wei C, Dai Y, Ge L, Zhu H, Zhang Y, Zhang J, Lin X. MicroRNA-122-5p alleviates endometrial fibrosis via inhibiting the TGF-β/SMAD pathway in Asherman's syndrome. Reprod Biomed Online 2023; 47:103253. [PMID: 37677924 DOI: 10.1016/j.rbmo.2023.06.008] [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: 12/15/2022] [Revised: 05/17/2023] [Accepted: 06/14/2023] [Indexed: 09/09/2023]
Abstract
RESEARCH QUESTION What is the effect of miR-122 on the progression and recovery of fibrosis in Asherman's syndrome? DESIGN Endometrial tissue was collected from 21 patients, 11 with intrauterine adhesion (IUA) and 10 without IUA. Quantitative real-time polymerase chain reaction, immunofluorescence and Western blot were applied to observe the expression of mRNAs/miRNAs and protein, respectively. The endometrial physical injury was carried out in C57BL/6 mice to create an endometrial fibrosis model, with intrauterine injection of adenovirus to compare the antifibrosis and repair function of miR-122 on endometrium. The morphology of the uterus was observed using haematoxylin and eosin staining, and fibrosis markers were detected by immunohistochemistry. RESULTS miR-122 expression was reduced in patients with IUAs, accompanied by fibrosis. MiR-122 overexpression reduced the degree of fibrosis in endometrial stromal cells. Further molecular analyses demonstrated that miR-122 inhibited fibrosis through the TGF-β/SMAD pathway by directly targeting the 3' untranslated region of SMAD family member 3, suppressing its expression. Notably, miR-122 promoted endometrial regeneration and recovery of pregnancy capacity in a mouse endometrial injury model. CONCLUSIONS miR-122 is a critical regulator for repair of endometrial fibrosis and provided new insight for the clinical treatment of intrauterine adhesions.
Collapse
Affiliation(s)
- Sijia Chen
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Yana Ma
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Xiaoxiao Qiu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Department of Obstetrics and Gynecology, Taizhou Municipal Hospital, Taizhou, 318000, China
| | - Mengying Liu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Peipei Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Department of Obstetrics and Gynecology, Tiantai People's Hospital of Zhejiang Province, Taizhou, 317200, China
| | - Cheng Wei
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Yongdong Dai
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Linyan Ge
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Haiyan Zhu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Yanling Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Jiaren Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Xiaona Lin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.; Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. Qingchun East Road, Jianggan District, Hangzhou, 310016, China..
| |
Collapse
|
|
14
|
Yao M, Lian D, Wu M, Zhou Y, Fang Y, Zhang S, Zhang W, Yang Y, Li R, Chen H, Chen Y, Shen A, Peng J. Isoliensinine Attenuates Renal Fibrosis and Inhibits TGF-β1/Smad2/3 Signaling Pathway in Spontaneously Hypertensive Rats. Drug Des Devel Ther 2023; 17:2749-2762. [PMID: 37701045 PMCID: PMC10494865 DOI: 10.2147/dddt.s414179] [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: 04/12/2023] [Accepted: 07/18/2023] [Indexed: 09/14/2023] Open
Abstract
Purpose This study aimed to investigate the molecular mechanisms of isoliensinine, a kind of bibenzyl isoquinoline alkaloid which isolated from a TCM named Lotus Plumule (Nelumbo nucifera Gaertn), in treating renal interstitial fibrosis (RIF) by using RNA sequencing, KEGG analysis and in vivo experimental approaches. Methods Spontaneous hypertension rats (SHRs) were randomly assigned into five groups, consisting of SHR, SHR+Isoliensinine-L (2.5 mg/kg/day), SHR+Isoliensinine-M (5 mg/kg/day), SHR+Isoliensinine-H (10 mg/kg/day), and SHR+Valsartan (10 mg/kg/day) groups (n = 6 for each group). A control group of Wistar Kyoto rats (n = 6) was also included. Rats were treated intragastrically with isoliensinine, valsartan, or double-distilled water of equal volume for 10 weeks. To examine the therapeutic impact on hypertensive renal injury, fibrosis, and its underlying mechanisms, multiple techniques were employed, including hematoxylin and eosin staining, Masson trichrome staining, RNA sequencing, gene ontology (GO) function and pathway enrichment analysis and immunohistochemistry. Results Resultantly, the use of isoliensinine at different concentrations or valsartan showed significant improvement in renal pathological injury in SHRs. RNA sequencing and KEGG analysis uncovered 583 differentially expressed transcripts and pathways enriched in collagen formation and ECM-receptor interaction after treatment with isoliensinine. There was also a reduction in the increase of collagen and upregulation of collagen I & III, TGF-β1, p-Smad2, and p-Smad3 in the renal tissue of SHRs. Thus, isoliensinine ameliorated renal injury and collagen deposition in hypertensive rats, and inhibiting the activation of the TGF-β1/Smad2/3 pathway might be one of the underlying mechanisms. Conclusion This study showed that treatment with isoliensinine effectively reduced the renal injury and fibrosis in SHRs. In addition, isoliensinine inhibited the TGF-β1/Smad2/3 signaling in-vivo. These findings provided strong evidence for the therapeutic benefits of isoliensinine in combating renal injury and fibrosis.
Collapse
Affiliation(s)
- Mengying Yao
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| | - Dawei Lian
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| | - Meizhu Wu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| | - Yuting Zhou
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| | - Yi Fang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
- Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Siyu Zhang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| | - Wenqiang Zhang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| | - Yanyan Yang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
- Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Renfeng Li
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| | - Hong Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| | - Youqin Chen
- Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA
| | - Aling Shen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
- Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China
| |
Collapse
|
|
15
|
Jiang T, Leng W, Zhong S. Diagnostic Role of Circulating miRNAs in the Grading of Chronic Hepatitis B-Related Liver Fibrosis: A Systematic Review and Meta-Analysis. Lab Med 2023; 54:479-488. [PMID: 36637253 DOI: 10.1093/labmed/lmac151] [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] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE miRNAs are considered potential biomarkers that can be used for the grading of chronic hepatitis B (CHB)-related liver fibrosis. This meta-analysis aims to elucidate the diagnostic performance of miRNAs. METHODS Databases were used to search for meta-analyses. A bivariate model was used to calculate pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). In addition, the area under the summary receiver operating characteristic curve (AUC) and 95% confidence intervals (CIs) were calculated. RESULTS A total of 9 studies with 1159 patients with CHB-related liver fibrosis were assessed. For diagnosis of significant liver fibrosis, the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.73 (95% CI, 0.68-0.78), 0.78 (95% CI, 0.70-0.84), 3.32 (95% CI, 2.52-4.37), 0.34 (95% CI, 0.30-0.39), 9.70 (95% CI, 7.10-13.24), and 0.81 (95% CI, 0.77-0.84), respectively. CONCLUSION miRNAs are potential biomarkers of CHB-related liver fibrosis.
Collapse
Affiliation(s)
- Ting Jiang
- Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Infectious Disease, Chengdu First People's Hospital, Chengdu, China
| | - Wenying Leng
- Emergency Department, Chengdu First People's Hospital, Chengdu, China
| | - Sen Zhong
- Department of Infectious Disease, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
16
|
Waldrep KM, Rodgers JI, Garrett SM, Wolf BJ, Feghali-Bostwick CA. The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis. Int J Mol Sci 2023; 24:11234. [PMID: 37510994 PMCID: PMC10378869 DOI: 10.3390/ijms241411234] [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: 03/22/2023] [Revised: 06/29/2023] [Accepted: 07/02/2023] [Indexed: 07/30/2023] Open
Abstract
Pulmonary fibrosis (PF) associated with systemic sclerosis (SSc) results in significant morbidity and mortality. We previously reported that insulin-like growth factor-II (IGF-II) is overexpressed in lung tissues and fibroblasts from SSc patients, and IGF-II fosters fibrosis by upregulating collagen type I, fibronectin, and TGFβ. We now show that IGF-II augments mRNA levels of profibrotic signaling molecules TGFβ2 (p ≤ 0.01) and TGFβ3 (p ≤ 0.05), collagen type III (p ≤ 0.01), and the collagen posttranslational modification enzymes P4HA2 (p ≤ 0.05), P3H2 (p ≤ 0.05), LOX (p = 0.065), LOXL2 (p ≤ 0.05), LOXL4 (p ≤ 0.05) in primary human lung fibroblasts. IGF-II increases protein levels of TGFβ2 (p ≤ 0.01), as well as COL3A1, P4HA2, P4Hβ, and LOXL4 (p ≤ 0.05). In contrast, IGF-II decreases mRNA levels of the collagen degradation enzymes cathepsin (CTS) K, CTSB, and CTSL and protein levels of CTSK (p ≤ 0.05). The SRY-box transcription factor 9 (SOX9) is overexpressed in SSc lung tissues at the mRNA (p ≤ 0.05) and protein (p ≤ 0.01) levels compared to healthy controls. IGF-II induces SOX9 in lung fibroblasts (p ≤ 0.05) via the IGF1R/IR hybrid receptor, and SOX9 regulates TGFβ2 (p ≤ 0.05), TGFβ3 (p ≤ 0.05), COL3A1 (p ≤ 0.01), and P4HA2 (p ≤ 0.001) downstream of IGF-II. Our results identify a novel IGF-II signaling axis and downstream targets that are regulated in a SOX9-dependent and -independent manner. Our findings provide novel insights on the role of IGF-II in promoting pulmonary fibrosis.
Collapse
Affiliation(s)
- Kristy M. Waldrep
- Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA; (K.M.W.); (J.I.R.); (S.M.G.)
| | - Jessalyn I. Rodgers
- Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA; (K.M.W.); (J.I.R.); (S.M.G.)
| | - Sara M. Garrett
- Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA; (K.M.W.); (J.I.R.); (S.M.G.)
| | - Bethany J. Wolf
- Department of Public Health Sciences, Biostatistics and Bioinformatics, Medical University of South Carolina, Charleston, SC 29425, USA;
| | - Carol A. Feghali-Bostwick
- Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA; (K.M.W.); (J.I.R.); (S.M.G.)
| |
Collapse
|
|
17
|
Research progress of metformin in the treatment of liver fibrosis. Int Immunopharmacol 2023; 116:109738. [PMID: 36696857 DOI: 10.1016/j.intimp.2023.109738] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023]
Abstract
Liver fibrosis is a disease with significant morbidity and mortality. It is a chronic pathological process characterized by an imbalance of extracellular matrix production and degradation in liver tissue. Metformin is a type of hypoglycemic biguanide drug, which can be used in the treatment of liver fibrosis, but its anti-fibrotic effect and mechanism of action are unclear. The purpose of this article is to review the research progress of metformin in the treatment of liver fibrosis and to provide a theoretical basis for its application in the treatment of liver fibrosis.
Collapse
|
|
18
|
Liu Y, Zheng Y, Yang Y, Liu K, Wu J, Gao P, Zhang C. Exosomes in liver fibrosis: The role of modulating hepatic stellate cells and immune cells, and prospects for clinical applications. Front Immunol 2023; 14:1133297. [PMID: 37020547 PMCID: PMC10067730 DOI: 10.3389/fimmu.2023.1133297] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/01/2023] [Indexed: 04/07/2023] Open
Abstract
Liver fibrosis is a global health problem caused by chronic liver injury resulting from various factors. Hepatic stellate cells (HSCs) have been found to play a major role in liver fibrosis, and pathological stimuli lead to their transdifferentiation into myofibroblasts. Complex multidirectional interactions between HSCs, immune cells, and cytokines are also critical for the progression of liver fibrosis. Despite the advances in treatments for liver fibrosis, they do not meet the current medical needs. Exosomes are extracellular vesicles of 30-150 nm in diameter and are capable of intercellular transport of molecules such as lipids, proteins and nucleic acids. As an essential mediator of intercellular communication, exosomes are involved in the physiological and pathological processes of many diseases. In liver fibrosis, exosomes are involved in the pathogenesis mainly by regulating the activation of HSCs and the interaction between HSCs and immune cells. Serum-derived exosomes are promising biomarkers of liver fibrosis. Exosomes also have promising therapeutic potential in liver fibrosis. Exosomes derived from mesenchymal stem cells and other cells exhibit anti-liver fibrosis effects. Moreover, exosomes may serve as potential therapeutic targets for liver fibrosis and hold promise in becoming drug carriers for liver fibrosis treatment.
Collapse
Affiliation(s)
- Yufei Liu
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuhong Zheng
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yang Yang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ke Liu
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jianying Wu
- Department of Digestive Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Peiyang Gao
- Department of Critical Care Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Chuantao Zhang, ; Peiyang Gao,
| | - Chuantao Zhang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Chuantao Zhang, ; Peiyang Gao,
| |
Collapse
|
|
19
|
Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
Collapse
Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| |
Collapse
|
|
20
|
Mesenchymal stem cell-derived exosomes and non-coding RNAs: Regulatory and therapeutic role in liver diseases. Biomed Pharmacother 2023; 157:114040. [PMID: 36423545 DOI: 10.1016/j.biopha.2022.114040] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/22/2022] Open
Abstract
Liver disease has become a major health problem worldwide due to its high morbidity and mortality. In recent years, a large body of literature has shown that mesenchymal stem cell-derived exosomes (MSC-Exo) are able to play similar physiological roles as mesenchymal stem cells (MSCs). More importantly, there is no immune rejection caused by transplanted cells and the risk of tumor formation, which has become a new strategy for the treatment of various liver diseases. Moreover, accumulating evidence suggests that non-coding RNAs (ncRNAs) are the main effectors by which they exert hepatoprotective effects. Therefore, by searching the databases of Web of Science, PubMed, ScienceDirect, Google Scholar and CNKI, this review comprehensively reviewed the therapeutic effects of MSC-Exo and ncRNAs in liver diseases, including liver injury, liver fibrosis, and hepatocellular carcinoma. According to the data, the therapeutic effects of MSC-Exo and ncRNAs on liver diseases are closely related to a variety of molecular mechanisms, including inhibition of inflammatory response, alleviation of liver oxidative stress, inhibition of apoptosis of hepatocytes and endothelial cells, promotion of angiogenesis, blocking the cell cycle of hepatocellular carcinoma, and inhibition of activation and proliferation of hepatic stellate cells. These important findings will provide a direction and basis for us to explore the potential of MSC-Exo and ncRNAs in the clinical treatment of liver diseases in the future.
Collapse
|
|
21
|
Wang L, Feng J, Deng Y, Yang Q, Wei Q, Ye D, Rong X, Guo J. CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding. RESEARCH (WASHINGTON, D.C.) 2022; 2022:9891689. [PMID: 36299447 PMCID: PMC9575473 DOI: 10.34133/2022/9891689] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/18/2022] [Indexed: 07/29/2023]
Abstract
CCAAT/enhancer-binding proteins (C/EBPs) are a family of at least six identified transcription factors that contain a highly conserved basic leucine zipper domain and interact selectively with duplex DNA to regulate target gene expression. C/EBPs play important roles in various physiological processes, and their abnormal function can lead to various diseases. Recently, accumulating evidence has demonstrated that aberrant C/EBP expression or activity is closely associated with the onset and progression of fibrosis in several organs and tissues. During fibrosis, various C/EBPs can exert distinct functions in the same organ, while the same C/EBP can exert distinct functions in different organs. Modulating C/EBP expression or activity could regulate various molecular processes to alleviate fibrosis in multiple organs; therefore, novel C/EBPs-based therapeutic methods for treating fibrosis have attracted considerable attention. In this review, we will explore the features of C/EBPs and their critical functions in fibrosis in order to highlight new avenues for the development of novel therapies targeting C/EBPs.
Collapse
Affiliation(s)
- Lexun Wang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiaojiao Feng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanyue Deng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Qianqian Yang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Quxing Wei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Dewei Ye
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xianglu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China
- Guangdong Key Laboratory of Metabolic Disease Prevention and Treatment of Traditional Chinese Medicine, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| |
Collapse
|
|
22
|
MicroRNAs in non-alcoholic fatty liver disease: Progress and perspectives. Mol Metab 2022; 65:101581. [PMID: 36028120 PMCID: PMC9464960 DOI: 10.1016/j.molmet.2022.101581] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease ranging from simple hepatic steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) which may progress to cirrhosis and liver cancer. NAFLD is rapidly becoming a global health challenge, and there is a need for improved diagnostic- and prognostic tools and for effective pharmacotherapies to treat NASH. The molecular mechanisms of NAFLD development and progression remain incompletely understood, though ample evidence supports a role of microRNAs (miRNAs) - small non-coding RNAs regulating gene expression - in the progression of metabolic liver disease. SCOPE OF REVIEW In this review, we summarise the currently available liver miRNA profiling studies in people with various stages of NAFLD. We further describe the mechanistic role of three of the most extensively studied miRNA species, miR-34a, miR-122 and miR-21, and highlight selected findings on novel NAFLD-linked miRNAs. We also examine the literature on exosomal microRNAs (exomiRs) as inter-hepatocellular or -organ messengers in NAFLD. Furthermore, we address the status for utilizing circulating NAFLD-associated miRNAs as minimally invasive tools for disease diagnosis, staging and prognosis as well as their potential use as NASH pharmacotherapeutic targets. Finally, we reflect on future directions for research in the miRNA field. MAJOR CONCLUSIONS NAFLD is associated with changes in hepatic miRNA expression patterns at early, intermediate and late stages, and specific miRNA species appear to be involved in steatosis development and NAFL progression to NASH and cirrhosis. These miRNAs act either within or between hepatocytes and other liver cell types such as hepatic stellate cells and Kupffer cells or as circulating inter-organ messengers carrying signals between the liver and extra-hepatic metabolic tissues, including the adipose tissues and the cardiovascular system. Among circulating miRNAs linked to NAFLD, miR-34a, miR-122 and miR-192 are the best candidates as biomarkers for NAFLD diagnosis and staging. To date, no miRNA-targeting pharmacotherapy has been approved for the treatment of NASH, and no such therapy is currently under clinical development. Further research should be conducted to translate the contribution of miRNAs in NAFLD into innovative therapeutic strategies.
Collapse
|
|
23
|
Zhang Y, Jiao Z, Chen M, Shen B, Shuai Z. Roles of Non-Coding RNAs in Primary Biliary Cholangitis. Front Mol Biosci 2022; 9:915993. [PMID: 35874606 PMCID: PMC9305664 DOI: 10.3389/fmolb.2022.915993] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune-mediated chronic cholestatic liver disease, fatigue, and skin itching are the most common clinical symptoms. Its main pathological feature is the progressive damage and destruction of bile duct epithelial cells. Non-coding RNA (NcRNA, mainly including microRNA, long non-coding RNA and circular RNA) plays a role in the pathological and biological processes of various diseases, especially autoimmune diseases. Many validated ncRNAs are expected to be biomarkers for the diagnosis or treatment of PBC. This review will elucidate the pathogenesis of PBC and help to identify potential ncRNA biomarkers for PBC.
Collapse
Affiliation(s)
- Yaqin Zhang
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ziying Jiao
- Department of Physiology, School of Basic Medicine of Anhui Medical University, Hefei, China
| | - Mingwei Chen
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bing Shen
- Department of Physiology, School of Basic Medicine of Anhui Medical University, Hefei, China
| | - Zongwen Shuai
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Zongwen Shuai,
| |
Collapse
|
|
24
|
Ma J, Zhao Q, Chen M, Wang W, He B, Jiang Y, Li Y. microRNA-122 inhibits hepatic stellate cell proliferation and activation in vitro and represses carbon tetrachloride-induced liver cirrhosis in mice. Ann Hepatol 2022; 27:100700. [PMID: 35338010 DOI: 10.1016/j.aohep.2022.100700] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/24/2022] [Accepted: 02/24/2022] [Indexed: 02/04/2023]
Abstract
OBJECTIVE This study aimed to determine the roles of microRNA (miR)-122 in the activation of hepatic stellate cells (HSCs) and liver cirrhosis. METHODS Rat primary HSCs were incubated with transforming growth factor-beta (TGF-β), during which miR-122 and EphB2 expression was measured. miR-122 mimic and/or pcDNA3.1 EphB2 was transfected into TGF-β-induced HSCs. A mouse model of liver cirrhosis was established via an intraperitoneal injection of carbon tetrachloride (CCl4), followed by the injection of miR-122 agomir. Levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. Fibronectin (FN), alpha smooth muscle actin (α-SMA), Collagen I, miR-122, and EphB2 expression was evaluated in liver tissues and HSCs. Cell proliferation was measured using CCK-8 assay. Interactions between miR-122 and EphB2 were assessed using dual luciferase reporter assay. RESULTS miR-122 (0.15-fold) was downregulated and EphB2 (mRNA: 5.06-fold; protein: 2.35-fold) was upregulated after TGF-β induction of HSCs. Overexpressed miR-122 decreased proliferation and EphB2 (mRNA: 0.46-fold; protein: 0.62-fold), FN (mRNA: 0.45-fold; protein: 0.64-fold), α-SMA (mRNA: 0.48-fold; protein: 0.51-fold), and Collagen I (mRNA: 0.44-fold; protein: 0.51-fold) expression in HSCs, which was abrogated by EphB2 upregulation. miR-122 expression was reduced by 0.21-fold and serum ALT and AST levels were enhanced in mice following 8-week CCl4 induction along with increased expression of FN, α-SMA, and Collagen I in liver tissues, which was blocked by miR-122 overexpression. Moreover, EphB2 was a target gene of miR-122. CONCLUSION miR-122 curtails HSC proliferation and activation by targeting EphB2 and suppresses liver cirrhosis in mice.
Collapse
Affiliation(s)
- Jing Ma
- Department of Infectious Diseases, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Qiqian Zhao
- Department of Infectious Diseases, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Mengxuan Chen
- Department of Infectious Diseases, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Weihang Wang
- Department of Infectious Diseases, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Bo He
- Department of Infectious Diseases, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Yongfang Jiang
- Department of Infectious Diseases, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Yi Li
- Department of Infectious Diseases, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.
| |
Collapse
|
|
25
|
Czaja AJ. Epigenetic Aspects and Prospects in Autoimmune Hepatitis. Front Immunol 2022; 13:921765. [PMID: 35844554 PMCID: PMC9281562 DOI: 10.3389/fimmu.2022.921765] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.
Collapse
Affiliation(s)
- Albert J. Czaja
- *Correspondence: Albert J. Czaja, ; orcid.org/0000-0002-5024-3065
| |
Collapse
|
|
26
|
Czaja AJ. Examining micro-ribonucleic acids as diagnostic and therapeutic prospects in autoimmune hepatitis. Expert Rev Clin Immunol 2022; 18:591-607. [PMID: 35510750 DOI: 10.1080/1744666x.2022.2074839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or patterns in peripheral blood and liver tissue may have diagnostic value, reflect treatment response, or become therapeutic targets. The goals of this review are to present the properties and actions of micro-ribonucleic acids, indicate the key individual expressions in autoimmune hepatitis, and describe prospective clinical applications in diagnosis and management. AREAS COVERED Abstracts were identified in PubMed using the search words "microRNAs", "microRNAs in liver disease", and "microRNAs in autoimmune hepatitis". The number of abstracts reviewed exceeded 2000, and the number of full-length articles reviewed was 108. EXPERT OPINION Individual micro-ribonucleic acids, miR-21, miR-122, and miR-155, have been associated with biochemical severity, histological grade of inflammation, and pivotal pathogenic mechanisms in autoimmune hepatitis. Antisense oligonucleotides that down-regulate deleterious individual gene expressions, engineered molecules that impair targeting of gene products, and drugs that non-selectively up-regulate the biogenesis of potentially deficient gene regulators are feasible treatment options. Micro-ribonucleic acids constitute an under-evaluated area in autoimmune hepatitis that promises to improve diagnosis, pathogenic concepts, and therapy.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
27
|
Lehmann TP, Guderska U, Kałek K, Marzec M, Urbanek A, Czernikiewicz A, Sąsiadek M, Karpiński P, Pławski A, Głowacki M, Jagodziński PP. The Regulation of Collagen Processing by miRNAs in Disease and Possible Implications for Bone Turnover. Int J Mol Sci 2021; 23:91. [PMID: 35008515 PMCID: PMC8745169 DOI: 10.3390/ijms23010091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/15/2022] Open
Abstract
This article describes several recent examples of miRNA governing the regulation of the gene expression involved in bone matrix construction. We present the impact of miRNA on the subsequent steps in the formation of collagen type I. Collagen type I is a main factor of mechanical bone stiffness because it constitutes 90-95% of the organic components of the bone. Therefore, the precise epigenetic regulation of collagen formation may have a significant influence on bone structure. We also describe miRNA involvement in the expression of genes, the protein products of which participate in collagen maturation in various tissues and cancer cells. We show how non-collagenous proteins in the extracellular matrix are epigenetically regulated by miRNA in bone and other tissues. We also delineate collagen mineralisation in bones by factors that depend on miRNA molecules. This review reveals the tissue variability of miRNA regulation at different levels of collagen maturation and mineralisation. The functionality of collagen mRNA regulation by miRNA, as proven in other tissues, has not yet been shown in osteoblasts. Several collagen-regulating miRNAs are co-expressed with collagen in bone. We suggest that collagen mRNA regulation by miRNA could also be potentially important in bone metabolism.
Collapse
Affiliation(s)
- Tomasz P. Lehmann
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (U.G.); (K.K.); (M.M.); (A.U.); (A.C.); (P.P.J.)
| | - Urszula Guderska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (U.G.); (K.K.); (M.M.); (A.U.); (A.C.); (P.P.J.)
| | - Klaudia Kałek
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (U.G.); (K.K.); (M.M.); (A.U.); (A.C.); (P.P.J.)
| | - Maria Marzec
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (U.G.); (K.K.); (M.M.); (A.U.); (A.C.); (P.P.J.)
| | - Agnieszka Urbanek
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (U.G.); (K.K.); (M.M.); (A.U.); (A.C.); (P.P.J.)
| | - Alicja Czernikiewicz
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (U.G.); (K.K.); (M.M.); (A.U.); (A.C.); (P.P.J.)
| | - Maria Sąsiadek
- Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.S.); (P.K.)
| | - Paweł Karpiński
- Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.S.); (P.K.)
| | - Andrzej Pławski
- Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland;
| | - Maciej Głowacki
- Department of Paediatric Orthopaedics and Traumatology, Poznan University of Medical Sciences, 61-545 Poznan, Poland;
| | - Paweł P. Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (U.G.); (K.K.); (M.M.); (A.U.); (A.C.); (P.P.J.)
| |
Collapse
|
|
28
|
Staab-Weijnitz CA. Fighting the Fiber: Targeting Collagen in Lung Fibrosis. Am J Respir Cell Mol Biol 2021; 66:363-381. [PMID: 34861139 DOI: 10.1165/rcmb.2021-0342tr] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Organ fibrosis is characterized by epithelial injury and aberrant tissue repair, where activated effector cells, mostly fibroblasts and myofibroblasts, excessively deposit collagen into the extracellular matrix. Fibrosis frequently results in organ failure and has been estimated to contribute to at least one third of all global deaths. Also lung fibrosis, in particular idiopathic pulmonary fibrosis (IPF), is a fatal disease with rising incidence worldwide. As current treatment options targeting fibrogenesis are insufficient, there is an urgent need for novel therapeutic strategies. During the last decade, several studies have proposed to target intra- and extracellular components of the collagen biosynthesis, maturation, and degradation machinery. This includes intra- and extracellular targets directly acting on collagen gene products, but also such that anabolize essential building blocks of collagen, in particular glycine and proline biosynthetic enzymes. Collagen, however, is a ubiquitous molecule in the body and fulfils essential functions as a macromolecular scaffold, growth factor reservoir, and receptor binding site in virtually every tissue. This review summarizes recent advances and future directions in this field. Evidence for the proposed therapeutic targets and where they currently stand in terms of clinical drug development for treatment of fibrotic disease is provided. The drug targets are furthermore discussed in light of (1) specificity for collagen biosynthesis, maturation and degradation, and (2) specificity for disease-associated collagen. As therapeutic success and safety of these drugs may largely depend on targeted delivery, different strategies for specific delivery to the main effector cells and to the extracellular matrix are discussed.
Collapse
Affiliation(s)
- Claudia A Staab-Weijnitz
- Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Gesundheit und Umwelt, 9150, Comprehensive Pneumology Center/Institute of Lung Biology and Disease, Member of the German Center of Lung Research (DZL), München, Germany;
| |
Collapse
|
|
29
|
Abstract
Hepatic fibrosis is a reversible wound healing process following liver injury. Although this process is necessary for maintaining liver integrity, severe excessive extracellular matrix accumulation (ECM) could lead to permanent scar formation and destroy the liver structure. The activation of hepatic stellate cells (HSCs) is a key event in hepatic fibrosis. Previous studies show that most antifibrotic therapies focus on the apoptosis of HSCs and the prevention of HSC activation. Noncoding RNAs (ncRNAs) play a substantial role in HSC activation and are likely to be biomarkers or therapeutic targets for the treatment of hepatic fibrosis. This review summarizes and discusses the previously reported ncRNAs, including the microRNAs, long noncoding RNAs, and circular RNAs, highlighting their regulatory roles and interactions in the signaling pathways that regulate HSC activation in hepatic fibrosis.
Collapse
|
|
30
|
Zhang L, Gao J, Zhou D, Wang X, Li J, Wang J, Chen H, Xie X, Chen T. Profiles of messenger RNAs and MicroRNAs in hypoxia-induced hepatic stellate cells. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1451. [PMID: 34734003 PMCID: PMC8506783 DOI: 10.21037/atm-21-4215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/18/2021] [Indexed: 11/18/2022]
Abstract
Background MicroRNA (miRNA) plays an important role in hepatic stellate cell (HSCs) activation and liver fibrosis. The purpose of this study is to explore the effect of hypoxia on the differential expression of mRNAs and miRNAs in rat HSCs. Methods HSC-T6 cells were treated with cobalt chloride (CoCl2), and the activity of HSC-T6 cells was measured by the CCK-8 assay. The mRNA expression levels of hypoxia inducible factor-1α (HIF-1α), collagen type I, transforming growth factor-β1 (TGF-β1), and Smad7 were measured by RT-qPCR. The protein expression levels of HIF-1α, Bax, Bcl-2, and caspase-3 were assayed by western blot. We used basal medium and 400 µmol/L CoCl2 medium to treat HSC-T6 cells for 48 h. Cells were harvested after 48 h to extract RNA. Transcriptome sequencing was performed to investigate differentially expressed miRNAs and mRNAs (fold change >2; P<0.05). Bioinformatics analysis was performed to predict the functions of differentially expressed miRNAs and mRNAs. Further, we used RT-qPCR to detect the expression of mRNAs and miRNAs to confirm the accuracy of sequencing. Results With the increase of CoCl2 concentration, the activity of HSC-T6 cells decreased (P<0.05). The mRNA expression levels of HIF-1α, collagen I, TGF-β1, and Smad7, and the protein expressions levels of HIF-1α, Bax, caspase-3, and the Bcl-2/Bax ratio were increased compared with the control group (P<0.05), while the expression of Bcl-2 decreased. A total of 54 miRNAs (20 upregulated and 34 downregulated) and 1,423 mRNAs (685 upregulated and 738 downregulated) were differentially expressed in the 400 µmol/L CoCl2 medium group compared to the control basal medium group. Further bioinformatics analysis demonstrated that the differentially expressed mRNAs and miRNAs were mainly enriched in the synthesis of extracellular matrix. In addition, we used RT-qPCR to detect the expression of mRNAs and miRNAs to confirm the accuracy of sequencing. Conclusions Our results presented the profiles of mRNAs and miRNAs in hypoxia-induced HSC-T6 cells in rats, the signaling pathways, and co-expression networks. These findings may suggest novel insights for the early diagnosis and treatment of HSC activation and liver fibrosis.
Collapse
Affiliation(s)
- Liting Zhang
- State Key Laboratory of Cryospheric Science, Northwest Institute of Eco-Environment and Resources, Chinese Academy of Sciences, Lanzhou, China.,University of Chinese Academy of Sciences, Beijing, China.,Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Jing Gao
- Respiratory Medicine Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Dan Zhou
- Department of Liver Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaojun Wang
- Department of Respiratory Medicine, Gansu Provincial Hospital, Lanzhou, China.,The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Junfeng Li
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Juan Wang
- Department of Gastroenterology, Xi'an International Medical Center, Xi'an, China
| | - Hong Chen
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, China.,Department of Gastroenterology, Xi'an International Medical Center, Xi'an, China
| | - Xiaodong Xie
- Institute of Medical Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Tuo Chen
- State Key Laboratory of Cryospheric Science, Northwest Institute of Eco-Environment and Resources, Chinese Academy of Sciences, Lanzhou, China.,University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
31
|
Ezhilararasan D, Lakshmi T, Raut B. Novel Nano-Based Drug Delivery Systems Targeting Hepatic Stellate Cells in the Fibrotic Liver. JOURNAL OF NANOMATERIALS 2021; 2021:1-9. [DOI: 10.1155/2021/4674046] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Hepatic stellate cells (HSCs) exist in the liver’s perisinusoidal space, are phenotypically activated, and acquire myofibroblast-like phenotype. This phenotypic transformation is accountable for the accumulation and production of various extracellular matrix (ECM) proteins, involving different fibril-forming collagens in the perisinusoidal space, producing altered hepatic function and portal hypertension and increased vascular resistance, fibrosis, cirrhosis, and hepatocellular carcinoma. The activated HSCs/myofibroblasts are principal collagen-producing cells in the damaged liver. Therefore, fibrosis treatments are often targeting HSCs. HSCs store most of the total body’s retinol in their cytoplasm, and hence, antifibrotic nanomedicines are often targeted with vitamin A decoration. Vitamin A-decorated nanomedicines with siRNAs for transforming growth factor-beta, collagen, and connective tissue growth factors target to inhibit fibrogenesis and the ECM-associated gene expressions, leading to fibrosis regression. Similarly, a variety of miRNAs play pro- and antifibrotic function. In the fibrotic liver, the profibrotic miRNAs are targeted with their respective antagomir and the antifibrotic miRNAs are targeted with their respective agomirs along with HSC-specific nanodecoration. These miRNA treatments reduce fibrogenesis by downregulation of ECM-related gene expressions. However, liver fibrosis is caused by the upregulation of a different type of profibrotic signaling pathways associated with ECM accumulation in the fibrotic liver. Therefore, specific gene silencing by siRNAs or targeting particularly miRNA may also not effectively reduce fibrosis to a greater extent. However, nanodecoration of a drug is useful to deliver drugs into activated HSCs in the injured liver. Therefore, the aim of this review is to focus on targeted drug delivery towards activated HSCs in the persistently damaged liver.
Collapse
Affiliation(s)
- Devaraj Ezhilararasan
- Department of Pharmacology, The Blue Lab, Molecular Medicine and Toxicology Division, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 600077, India
| | - Thangavelu Lakshmi
- Department of Pharmacology, The Blue Lab, Molecular Medicine and Toxicology Division, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu 600077, India
| | - Biond Raut
- Department of Pharmacology, Kathmandu Medical College Bhaktapur Duwakot, Kathmandu University, Dhulikhel, Kavre, Nepal
| |
Collapse
|
|
32
|
Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells 2021; 10:cells10102759. [PMID: 34685739 PMCID: PMC8534788 DOI: 10.3390/cells10102759] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
Collapse
|
|
33
|
Chang Y, Han JA, Kang SM, Jeong SW, Ryu T, Park HS, Yoo JJ, Lee SH, Kim SG, Kim YS, Kim HS, Jin SY, Ryu S, Jang JY. Clinical impact of serum exosomal microRNA in liver fibrosis. PLoS One 2021; 16:e0255672. [PMID: 34506494 PMCID: PMC8432846 DOI: 10.1371/journal.pone.0255672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIM We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. METHODS This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. RESULTS NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. CONCLUSION Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.
Collapse
Affiliation(s)
- Young Chang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jae-A. Han
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Suk Min Kang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Tom Ryu
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Han Seul Park
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - So Young Jin
- Department of Pathology, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Seongho Ryu
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul, Korea
| |
Collapse
|
|
34
|
Zhao F, Xie X, Tan X, Yu H, Tian M, Lv H, Qin C, Qi J, Zhu Q. The Functions of Hepatitis B Virus Encoding Proteins: Viral Persistence and Liver Pathogenesis. Front Immunol 2021; 12:691766. [PMID: 34456908 PMCID: PMC8387624 DOI: 10.3389/fimmu.2021.691766] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 07/26/2021] [Indexed: 12/14/2022] Open
Abstract
About 250 million people worldwide are chronically infected with Hepatitis B virus (HBV), contributing to a large burden on public health. Despite the existence of vaccines and antiviral drugs to prevent infection and suppress viral replication respectively, chronic hepatitis B (CHB) cure remains a remote treatment goal. The viral persistence caused by HBV is account for the chronic infection which increases the risk for developing liver cirrhosis and hepatocellular carcinoma (HCC). HBV virion utilizes various strategies to escape surveillance of host immune system therefore enhancing its replication, while the precise mechanisms involved remain elusive. Accumulating evidence suggests that the proteins encoded by HBV (hepatitis B surface antigen, hepatitis B core antigen, hepatitis B envelope antigen, HBx and polymerase) play an important role in viral persistence and liver pathogenesis. This review summarizes the major findings in functions of HBV encoding proteins, illustrating how these proteins affect hepatocytes and the immune system, which may open new venues for CHB therapies.
Collapse
Affiliation(s)
- Fenglin Zhao
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Xiaoyu Xie
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xu Tan
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hongli Yu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Miaomiao Tian
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Huanran Lv
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chengyong Qin
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jianni Qi
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiang Zhu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| |
Collapse
|
|
35
|
Li M, Wang Q, Zheng Q, Wu L, Zhao B, Wu Y. Prognostic and diagnostic roles of prolyl 4-hydroxylase subunit α members in breast cancer. Biomark Med 2021; 15:1085-1095. [PMID: 34387118 DOI: 10.2217/bmm-2020-0323] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Aim: We aimed to evaluate the diagnostic and prognostic values of P4HAs in breast cancer (BC) patients. Materials & methods: Kaplan-Meier plotter was used to evaluate the prognostic values of P4HAs and correlations between their expression and clinical characteristics were assessed based on The Cancer Genome Atlas and the Human Protein Atlas. Results: The current study showed that P4HAs were highly expressed in BC patients with clinical stage I compared with nontumor control and elevated P4HAs were correlated with poor survival outcomes. Subtypes analysis revealed that P4HA1 and P4HA2 were most expressed in HER2+ subtypes patients. Univariate analysis displayed that elevated P4HA1 and P4HA3 correlated with unfavorable recurrence-free survival in mutated TP53 patients. Conclusion: This study indicated the diagnostic and prognostic roles of P4HAs members and broadened the biomarker fields of early diagnosis and prognostic monitoring of BC patients.
Collapse
Affiliation(s)
- Mingjie Li
- Department of Clinical Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Qianyun Wang
- Department of Clinical Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Qinqin Zheng
- Department of Clinical Laboratory, Fuzhou Second Hospital affiliated to Xiamen University, Fuzhou, 350007, China
| | - Lin Wu
- Department of Clinical Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Bin Zhao
- Department of Clinical Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Yan'an Wu
- Department of Clinical Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| |
Collapse
|
|
36
|
Panda B, Sharma Y, Gupta S, Mohanty S. Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine: A Comprehensive Review. Life (Basel) 2021; 11:life11080784. [PMID: 34440528 PMCID: PMC8399916 DOI: 10.3390/life11080784] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 01/08/2023] Open
Abstract
Mesenchymal Stem Cells are potent therapeutic candidates in the field of regenerative medicine, owing to their immunomodulatory and differentiation potential. However, several complications come with their translational application like viability, duration, and degree of expansion, long-term storage, and high maintenance cost. Therefore, drawbacks of cell-based therapy can be overcome by a novel therapeutic modality emerging in translational research and application, i.e., exosomes. These small vesicles derived from mesenchymal stem cells are emerging as new avenues in the field of nano-medicine. These nano-vesicles have caught the attention of researchers with their potency as regenerative medicine both in nanotherapeutics and drug delivery systems. In this review, we discuss the current knowledge in the biology and handling of exosomes, with their limitations and future applications. Additionally, we highlight current perspectives that primarily focus on their effect on various diseases and their potential as a drug delivery vehicle.
Collapse
|
|
37
|
Ghafouri-Fard S, Niazi V, Hussen BM, Omrani MD, Taheri M, Basiri A. The Emerging Role of Exosomes in the Treatment of Human Disorders With a Special Focus on Mesenchymal Stem Cells-Derived Exosomes. Front Cell Dev Biol 2021; 9:653296. [PMID: 34307345 PMCID: PMC8293617 DOI: 10.3389/fcell.2021.653296] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) are produced by diverse eukaryotic and prokaryotic cells. They have prominent roles in the modulation of cell-cell communication, inflammation versus immunomodulation, carcinogenic processes, cell proliferation and differentiation, and tissue regeneration. These acellular vesicles are more promising than cellular methods because of the lower risk of tumor formation, autoimmune responses and toxic effects compared with cell therapy. Moreover, the small size and lower complexity of these vesicles compared with cells have made their production and storage easier than cellular methods. Exosomes originated from mesenchymal stem cells has also been introduced as therapeutic option for a number of human diseases. The current review aims at summarization of the role of EVs in the regenerative medicine with a focus on their therapeutic impacts in liver fibrosis, lung disorders, osteoarthritis, colitis, myocardial injury, spinal cord injury and retinal injury.
Collapse
Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mir Davood Omrani
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Basiri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
38
|
Shi R, Gao S, Zhang J, Xu J, Graham LM, Yang X, Li C. Collagen prolyl 4-hydroxylases modify tumor progression. Acta Biochim Biophys Sin (Shanghai) 2021; 53:805-814. [PMID: 34009234 DOI: 10.1093/abbs/gmab065] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
Collagen is the main component of the extracellular matrix. Hydroxylation of proline residues on collagen, catalyzed by collagen prolyl 4-hydroxylase (C-P4H), is essential for the stability of the collagen triple helix. Vertebrate C-P4H is an α2β2 tetramer with three isoenzymes differing in the catalytic α-subunits, which are encoded by P4HA1, P4HA2, and P4HA3 genes. In contrast, β-subunit is encoded by a single gene P4HB. The expressions of P4HAs and P4HB are regulated by multiple cellular factors, including cytokines, transcription factors, and microRNAs. P4HAs and P4HB are highly expressed in many tumors and participate in cancer progression. Several inhibitors of P4HAs and P4HB have been confirmed to have anti-tumor effects, suggesting that targeting C-P4H is a feasible strategy for cancer treatment. Here, we summarize recent progresses on the function and expression of regulatory mechanisms of C-P4H in cancer progression and point out the potential development of therapeutic strategies in targeting C-P4H in the future.
Collapse
Affiliation(s)
- Run Shi
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China
| | - Shanshan Gao
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China
| | - Jie Zhang
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China
| | - Jiang Xu
- Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi 832008, China
| | - Linda M Graham
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Xiaowen Yang
- Department of the First Abdominal Surgery, The Affiliated Tumor Hospital of Nanchang University, Jiangxi Cancer Center, Nanchang 330029, China
| | - Chaoyang Li
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China
| |
Collapse
|
|
39
|
Shi CX, Wang Y, Jiao FZ, Chen Q, Cao P, Pei MH, Zhang LY, Guo J, Deng W, Wang LW, Gong ZJ. Epigenetic Regulation of Hepatic Stellate Cell Activation and Macrophage in Chronic Liver Inflammation. Front Physiol 2021; 12:683526. [PMID: 34276405 PMCID: PMC8281248 DOI: 10.3389/fphys.2021.683526] [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] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/03/2021] [Indexed: 11/13/2022] Open
Abstract
Chronic liver inflammation is a complex pathological process under different stress conditions, and the roles of stellate cells and macrophages in chronic liver inflammation have been widely reported. Moderate liver inflammation can protect the liver from damage and facilitate the recovery of liver injury. However, an inflammatory response that is too intense can result in massive death of hepatocytes, which leads to irreversible damage to the liver parenchyma. Epigenetic regulation plays a key part in liver inflammation. This study reviews the regulation of epigenetics on stellate cells and macrophages to explore the new mechanisms of epigenetics on liver inflammation and provide new ideas for the treatment of liver disease.
Collapse
Affiliation(s)
- Chun-Xia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fang-Zhou Jiao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Pan Cao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mao-Hua Pei
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lu-Yi Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jin Guo
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Deng
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lu-Wen Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuo-Jiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
|
40
|
Ye M, Wang S, Sun P, Qie J. Integrated MicroRNA Expression Profile Reveals Dysregulated miR-20a-5p and miR-200a-3p in Liver Fibrosis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9583932. [PMID: 34235224 PMCID: PMC8218919 DOI: 10.1155/2021/9583932] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 05/27/2021] [Indexed: 12/23/2022]
Abstract
MicroRNAs (miRNAs) have been demonstrated to involve in liver fibrogenesis. However, the miRNA-gene regulation in liver fibrosis is still unclear. Herein, the miRNA expression profile GSE40744 was obtained to analyze the dysregulated miRNAs between liver fibrosis and normal samples. Then, we predicted the target genes of screened miRNAs by miRTarBase, followed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, the protein-protein interaction (PPI) network was constructed to identify the functional miRNA-gene regulatory modules. Furthermore, we verified the hub gene expression using the gene expression profile GSE14323. Finally, 89 DEMs were identified in fibrotic liver samples compared to normal liver samples. The top 3 upregulated DEMs (miR-200b-3p, miR-200a-3p, and miR-182-5p) and downregulated DEMs (miR-20a-5p, miR-194-3p, and miR-148a-3p) were further studied. 516 and 1416 target genes were predicted, respectively. KEGG analysis demonstrated that the predicted genes were enriched in the p53 signaling pathway and hepatitis B, etc. Through constructing a PPI network, the genes with the highest connectivity were identified as hub genes. Of note, most of the hub genes were potentially targeted by miR-20a-5p and miR-200a-3p. Based on the data from GSE14323, the expression of EGFR, STAT3, CTNNB1, and TP53 targeted by miR-200a-3p was significantly downregulated in fibrotic liver samples. Oppositely, the expression of PTEN, MYC, MAPK1, UBC, and CCND1 potentially targeted by miR-20a-5p was significantly upregulated. In conclusion, it is demonstrated that miR-20a-5p and miR-200a-3p were identified as the novel liver fibrosis-associated miRNAs, which may play critical roles in liver fibrogenesis.
Collapse
Affiliation(s)
- Mu Ye
- Department of General Surgery, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Sheng Wang
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Peilong Sun
- Department of General Surgery, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Jingbo Qie
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| |
Collapse
|
|
41
|
Robinson AD, Chakravarthi BVSK, Agarwal S, Chandrashekar DS, Davenport ML, Chen G, Manne U, Beer DG, Edmonds MD, Varambally S. Collagen modifying enzyme P4HA1 is overexpressed and plays a role in lung adenocarcinoma. Transl Oncol 2021; 14:101128. [PMID: 34049151 PMCID: PMC8170159 DOI: 10.1016/j.tranon.2021.101128] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 04/20/2021] [Accepted: 05/18/2021] [Indexed: 12/16/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths globally and is histologically defined as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), with the latter accounting for 80% of all lung cancers. The 5-year overall survival rate for lung cancer patients is low as it is often discovered at advanced stages when potential cure by surgical resection is no longer an option. To identify a biomarker and target for lung cancer, we performed analysis of multiple datasets of lung cancer gene expression data. Our analyses indicated that the collagen-modifying enzyme Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1) is overexpressed in NSCLC. Furthermore, our investigation found that overexpression of enzymes involved in this pathway predicts poor outcome for patients with lung adenocarcinoma. Our functional studies using knockdown strategies in lung cancer cell lines in vitro indicated that P4HA1 is critical for lung cancer growth, migration, and invasion. Additionally, diethyl pythiDC (PythiDC), a small molecule inhibitor, decreased the malignant phenotypes of lung cancer cells. Moreover, we found that miR-124 regulates and targets P4HA1 in lung cancer cells. Thus, our study suggests that collagen-modifying enzymes play an important role in lung cancer aggressiveness. Furthermore, our studies showed that P4HA1 is required for lung cancer cell growth and invasion, suggesting its potential as a valid therapeutic target in lung adenocarcinoma.
Collapse
Affiliation(s)
- Alyncia D Robinson
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Sumit Agarwal
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | | | - Guoan Chen
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David G Beer
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Mick D Edmonds
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, USA
| | - Sooryanarayana Varambally
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, USA; Informatics Institute, University of Alabama at Birmingham, USA.
| |
Collapse
|
|
42
|
Riaz F, Chen Q, Lu K, Osoro EK, Wu L, Feng L, Zhao R, Yang L, Zhou Y, He Y, Zhu L, Du X, Sadiq M, Yang X, Li D. Inhibition of miR-188-5p alleviates hepatic fibrosis by significantly reducing the activation and proliferation of HSCs through PTEN/PI3K/AKT pathway. J Cell Mol Med 2021; 25:4073-4087. [PMID: 33689215 PMCID: PMC8051718 DOI: 10.1111/jcmm.16376] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR‐188‐5p is dysregulated during the process of HF. However, the role of miR‐188‐5p in HF remains unclear. This study investigated the potential role of miR‐188‐5p in HSCs and HF. Firstly, we validated the miR‐188‐5p expression in primary cells isolated from liver of carbon tetrachloride (CCl4)‐induced mice, TGF‐β1‐induced LX‐2 cells, livers from 6‐month high‐fat diet (HFD)‐induced rat and 4‐month HFD‐induced mice NASH models, and human non‐alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR‐188‐5p inhibitors to investigate the therapeutic effects of miR‐188‐5p inhibition in the HFD + CCl4 induced in vivo model and the potential role of miR‐188‐5p in the activation and proliferation of HSCs. This present study reported that miR‐188‐5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR‐188‐5p resulted in the up‐regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR‐188‐5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR‐188‐5p suppressed the HF parameters, pro‐fibrotic and pro‐inflammatory genes, and fibrosis. Collectively, our results uncover the pro‐fibrotic role of miR‐188‐5p. Furthermore, we demonstrated that miR‐188‐5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.
Collapse
Affiliation(s)
- Farooq Riaz
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Qian Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Kaikai Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Ezra Kombo Osoro
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Litao Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Lina Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Rong Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Luyun Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Yimeng Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Yingli He
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Li Zhu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaojuan Du
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Muhammad Sadiq
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Xudong Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| |
Collapse
|
|
43
|
Zhang P, Hou Q, Yue Q. MiR-204-5p/TFAP2A feedback loop positively regulates the proliferation, migration, invasion and EMT process in cervical cancer. Cancer Biomark 2021; 28:381-390. [PMID: 32474464 DOI: 10.3233/cbm-191064] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
MicroRNAs (MiRNAs) have been clarified as crucial regulators of the pathological processes in various carcinomas in the past years. Interestingly, existing evidence has manifested that microRNA-204-5p (miR-204-5p) is engaged in the initiation and progression of multiple carcinomas. However, the potential of miR-204-5p in cervical cancer remains to be disentombed. This study focused on unraveling the detailed role of miR-204-5p in cervical cancer. MiR-204-5p exhibited a low level in cervical cancer cells. The functional assays demonstrated that miR-204-5p upregulation exerted suppressive impact on the functions of cervical cancer cells, including proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) process. Moreover, transcription factor AP-2 alpha (TFAP2A) was screened to be the most affected target gene by miR-204-5p, and TFAP2A was discovered to transcriptionally repress miR-204-5p in cervical cancer. The mutual regulation between TFAP2A and miR-204-5p was testified through molecular mechanism assays. Final rescued-function assays demonstrated that overexpression of TFAP2A could recover the suppressed cellular process caused by miR-204-5p upregulation. In conclusion, miR-204-5p/TFAP2A feedback loop promoted the proliferative and motorial capacities of cervical cancer cells. This finding suggested a novel modulatory loop of miR-204-5p/TFAP2A in cervical cancer, offering promising biomarkers for cervical cancer therapy.
Collapse
|
|
44
|
Grzywa TM, Klicka K, Włodarski PK. Regulators at Every Step-How microRNAs Drive Tumor Cell Invasiveness and Metastasis. Cancers (Basel) 2020; 12:E3709. [PMID: 33321819 PMCID: PMC7763175 DOI: 10.3390/cancers12123709] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial-mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis.
Collapse
Affiliation(s)
- Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Paweł K. Włodarski
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
| |
Collapse
|
|
45
|
Sabater L, Locatelli L, Oakley F, Hardy T, French J, Robinson SM, Sen G, Mann DA, Mann J. RNA sequencing reveals changes in the microRNAome of transdifferentiating hepatic stellate cells that are conserved between human and rat. Sci Rep 2020; 10:21708. [PMID: 33303921 PMCID: PMC7728773 DOI: 10.1038/s41598-020-78776-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 11/26/2020] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs are small (~ 22nt long) noncoding RNAs (ncRNAs) that regulate gene expression at the post-transcriptional level. Over 2000 microRNAs have been described in humans and many are implicated in human pathologies including tissue fibrosis. Hepatic stellate cells (HSC) are the major cellular contributors to excess extracellular matrix deposition in the diseased liver and as such are important in the progression of liver fibrosis. We employed next generation sequencing to map alterations in the expression of microRNAs occurring across a detailed time course of culture-induced transdifferentiation of primary human HSC, this a key event in fibrogenesis. Furthermore, we compared profiling of human HSC microRNAs with that of rat HSC so as to identify those molecules that are conserved with respect to modulation of expression. Our analysis reveals that a total of 229 human microRNAs display altered expression as a consequence of HSC transdifferentiation and of these 104 were modulated early during the initiation phase. Typically modulated microRNAs were targeting kinases, transcription factors, chromatin factors, cell cycle regulators and growth factors. 162 microRNAs changed in expression during transdifferentiation of rat HSC, however only 17 underwent changes that were conserved in human HSC. Our study therefore identifies widespread changes in the expression of HSC microRNAs in fibrogenesis, but suggests a need for caution when translating data obtained from rodent HSC to events occurring in human cells.
Collapse
Affiliation(s)
- Laura Sabater
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor, William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Luigi Locatelli
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor, William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor, William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Timothy Hardy
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor, William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Jeremy French
- Department of Hepatobiliary Surgery, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Stuart M Robinson
- Department of Hepatobiliary Surgery, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Gourab Sen
- Department of Hepatobiliary Surgery, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - D A Mann
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor, William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Jelena Mann
- Newcastle Fibrosis Research Group, Bioscience Institute, Faculty of Medical Sciences, Newcastle University, 4th Floor, William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
| |
Collapse
|
|
46
|
Inhibition of miR-122 reduced atherosclerotic lesion formation by regulating NPAS3-mediated endothelial to mesenchymal transition. Life Sci 2020; 265:118816. [PMID: 33278397 DOI: 10.1016/j.lfs.2020.118816] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/14/2020] [Accepted: 11/20/2020] [Indexed: 12/30/2022]
Abstract
AIMS Endothelial to mesenchymal transition (EndMT) is closely related to atherosclerosis. Herein, we aim to determine whether miR-122 is involved in EndMT and the underlying mechanism in atherosclerosis. MAIN METHODS qRT-PCR was performed to detect miR-122 expression in ApoE-/- mice and cellular EndMT model induced by H2O2. MiR-122 expression in vivo was modulated by lenti-virus injection and by genetic manipulation. Hematoxylin and eosin (HE) and Oil-red O staining were used to observe the plaque size and lipid accumulation in the aortic roots. F4/80 staining, elastin staining, and masson staining were used to observe the components of atherosclerotic lesions. MiR-122 expression in endothelial cells was modulated by transfection of miR-122 mimic and inhibitor. Western blotting and co-localization of endothelial markers (VE-cadherin, CD31) and mesenchymal markers (Vimentin, α-SMA) were carried out to determine EndMT. KEY FINDINGS MiR-122 was upregulated in the aortic intima and serum of ApoE-/- mice induced by HFD and in cellular EndMT model. Inhibition of miR-122 repressed the atherosclerotic plaque progression and vulnerable plaque formation in ApoE-/- mice. In vitro, endothelial cells acquired a spindle-shaped morphology accompanying decrease of the endothelial markers (VE-cadherin, CD31) and increase of the mesenchymal markers (Vimentin, α-SMA) in the presence of H2O2, which was inhibited by miR-122 inhibitor. Furthermore, NPAS3 functions as a target of miR-122, and NPAS3 silencing abolished the anti-EndMT effect of miR-122 inhibitor. SIGNIFICANCE Inhibition of miR-122 prevents atherosclerosis and regulates NPAS3-mediated EndMT, suggesting that miR-122 may be a novel target in the treatment of EndMT-associated diseases including atherosclerosis.
Collapse
|
|
47
|
Wang S, Shuai C, Gao S, Jiang J, Luan J, Lv X. Chemokine CXCL14 acts as a potential genetic target for liver fibrosis. Int Immunopharmacol 2020; 89:107067. [PMID: 33039963 DOI: 10.1016/j.intimp.2020.107067] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022]
Abstract
There are multiple causes of liver fibrosis, common ones include ethanol, toxins, and cholestasis. However, whether these different etiologies lead to the same pathological outcomes contain common genetic targets or signaling pathways, the current research has not attracted widespread attention. GSE40041 and GSE55747 were downloaded from the Gene Expression Omnibus (GEO) database. GSE40041 and GSE55747 represent the differential expression profiles in the liver of mice with bile duct ligation (BDL) and carbon tetrachloride (CCl4) induced liver fibrosis models, respectively. By using GEO2R, 701 differential expression genes (DEGs) in GSE40041 and 6540 DEGs in GSE55747 were identified. 260 co-DEGs were shared and extracted for gene ontology (GO) analysis. Through GO analysis, it was found that the regulation of cell migration in biological processes (BPs) was closely related to the pathogenesis of liver fibrosis, and the genes involved in this process include a key gene, chemokine (C-X-C motif) ligand 14 (CXCL14). Subsequently, further bioinformatic analysis showed that CXCL14 may be regulated by miR-122 to participate in the progression of liver fibrosis. Then real-time PCR and western blotting were performed to validate the expression of CXCL14 in liver tissue after liver fibrosis caused by different etiologies (ethanol, CCl4). The expression of CXCL4 in liver fibrosis induced by BDL was verified in another GEO dataset. Basically consistent with our bioinformatics results, our experimental results showed that the expression of CXCL14 was most significantly increased in alcoholic liver fibrosis model, followed by CCl4-induced liver fibrosis, which was also significantly increased in the BDL-induced model. Thus, CXCL14 can act as a common potential genetic target for different liver fibrosis diseases.
Collapse
Affiliation(s)
- Sheng Wang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
| | - Chen Shuai
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China
| | - Songsen Gao
- Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Jia Jiang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China
| | - Jiajie Luan
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, China.
| | - Xiongwen Lv
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Institute for Liver Disease of Anhui Medical University, Hefei, Anhui Province, China.
| |
Collapse
|
|
48
|
Wang W, Huang X, Fan X, Yan J, Luan J. Progress in evaluating the status of hepatitis C infection based on the functional changes of hepatic stellate cells (Review). Mol Med Rep 2020; 22:4116-4124. [PMID: 33000255 DOI: 10.3892/mmr.2020.11516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/18/2020] [Indexed: 11/06/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a global public health problem. Cirrhosis and hepatocellular carcinoma are the main causes of death in patients with chronic hepatitis C (CHC) infection. Liver fibrosis is an important cause of cirrhosis and end‑stage liver disease after CHC infection. Along with the course of infection, liver fibrosis exhibits a progressive exacerbation. Hepatic stellate cells (HSCs) are involved in both physiological and pathological processes of the liver. During the chronic liver injury process, the activated HSCs transform into myofibroblasts, which are important cells in the development of liver fibrosis. At present, HCV infection still lacks specific markers for the accurate detection of the disease condition and progression. Therefore, the present review focused on HSCs, which are closely related to HCV‑infected liver fibrosis, and analyzed the changes in the HSCs, including their surface‑specific markers, cytokine production, activation, cell function and morphological structure. The present review aimed to propose novel diagnostic markers, at both the cellular and molecular level, which would be of great significance for the timely diagnosis of the disease. According to this aim, the characteristic changes of HSCs during HCV infection were reviewed in the present article.
Collapse
Affiliation(s)
- Wei Wang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuelian Huang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuzhou Fan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jingmei Yan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jianfeng Luan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| |
Collapse
|
|
49
|
Podszun MC, Alawad AS, Lingala S, Morris N, Huang WCA, Yang S, Schoenfeld M, Rolt A, Ouwerkerk R, Valdez K, Umarova R, Ma Y, Fatima SZ, Lin DD, Mahajan LS, Samala N, Violet PC, Levine M, Shamburek R, Gharib AM, Kleiner DE, Garraffo HM, Cai H, Walter PJ, Rotman Y. Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis. Redox Biol 2020; 37:101710. [PMID: 32920226 PMCID: PMC7494510 DOI: 10.1016/j.redox.2020.101710] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/23/2020] [Accepted: 08/27/2020] [Indexed: 02/08/2023] Open
Abstract
Oxidative stress (OS) in non-alcoholic fatty liver disease (NAFLD) promotes liver injury and inflammation. Treatment with vitamin E (α-tocopherol, αT), a lipid-soluble antioxidant, improves liver injury but also decreases steatosis, thought to be upstream of OS, through an unknown mechanism. To elucidate the mechanism, we combined a mechanistic human trial interrogating pathways of intrahepatic triglyceride (IHTG) accumulation and in vitro experiments. 50% of NAFLD patients (n = 20) treated with αT (200-800 IU/d) for 24 weeks had a ≥ 25% relative decrease in IHTG by magnetic resonance spectroscopy. Paired liver biopsies at baseline and week 4 of treatment revealed a decrease in markers of hepatic de novo lipogenesis (DNL) that strongly predicted week 24 response. In vitro, using HepG2 cells and primary human hepatocytes, αT inhibited glucose-induced DNL by decreasing SREBP-1 processing and lipogenic gene expression. This mechanism is dependent on the antioxidant capacity of αT, as redox-silenced methoxy-αT is unable to inhibit DNL in vitro. OS by itself was sufficient to increase S2P expression in vitro, and S2P is upregulated in NAFLD livers. In summary, we utilized αT to demonstrate a vicious cycle in which NAFLD generates OS, which feeds back to augment DNL and increases steatosis. Clinicaltrials.gov: NCT01792115.
Collapse
Affiliation(s)
- Maren C Podszun
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ahmad S Alawad
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Shilpa Lingala
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Nevitt Morris
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Wen-Chun A Huang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Shanna Yang
- Nutrition Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Megan Schoenfeld
- Nutrition Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Adam Rolt
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ronald Ouwerkerk
- Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Kristin Valdez
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Regina Umarova
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yanling Ma
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Syeda Zaheen Fatima
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dennis D Lin
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Lakshmi S Mahajan
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Niharika Samala
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pierre-Christian Violet
- Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mark Levine
- Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Robert Shamburek
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ahmed M Gharib
- Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David E Kleiner
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - H Martin Garraffo
- Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Hongyi Cai
- Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Peter J Walter
- Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yaron Rotman
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
| |
Collapse
|
|
50
|
Webb LA, Ghaffari MH, Sadri H, Schuh K, Zamarian V, Koch C, Trakooljul N, Wimmers K, Lecchi C, Ceciliani F, Sauerwein H. Profiling of circulating microRNA and pathway analysis in normal- versus over-conditioned dairy cows during the dry period and early lactation. J Dairy Sci 2020; 103:9534-9547. [PMID: 32828512 DOI: 10.3168/jds.2020-18283] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 06/07/2020] [Indexed: 12/13/2022]
Abstract
The objective of this study was to determine the circulating microRNA (miRNA) profile in over-conditioned (HBCS) versus normal-conditioned (NBCS) dairy cows in combination with pathway enrichment analyses during the transition period. Thirty-eight multiparous Holstein cows were selected 15 wk before anticipated calving date based on their current and previous body condition scores (BCS) for forming either a HBCS group (n = 19) or a NBCS group (n = 19). They were fed different diets during late lactation to reach the targeted differences in BCS and backfat thickness until dry-off. A subset of 15 animals per group was selected based on their circulating concentrations of nonesterified fatty acids (on d 14 postpartum) and β-hydroxybutyrate (on d 21 postpartum), representing the greater or the lower extreme values within their BCS group. Blood serum obtained at d -49 and 21 relative to parturition (3 pools with 5 cows per each group and time point) were used to identify miRNA that were differentially expressed (DE) between groups or time points using miRNA sequencing. No DE-miRNA were discovered between NBCS versus HBCS. Comparing pooled samples from d -49 and d 21 resulted in 7 DE-miRNA in the NBCS group, of which 5 miRNA were downregulated and 2 miRNA were overexpressed on d 21 versus -49. The abundance of 5 of these DE-miRNA was validated in all individual samples via quantitative PCR and extended to additional time points (d -7, 3, 84). Group differences were observed for miR-148a, miR-122 as well as miR-455-5p, and most DE-miRNA (miR-148a, miR-122, miR-30a, miR-450b, miR-455-5p) were downregulated directly after calving. Subsequently, the DE-miRNA was used for bioinformatics analysis to identify putative target genes and the most enriched biological pathways. The most significantly enriched pathways of DE-miRNA were associated with cell cycle and insulin signaling as well as glucose and lipid metabolism. Overall, we found little differences in circulating miRNA in HBCS versus NBCS cows around calving.
Collapse
Affiliation(s)
- Laura A Webb
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - Morteza H Ghaffari
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - Hassan Sadri
- Department of Clinical Science, Faculty of Veterinary Medicine, University of Tabriz, 5166616471 Tabriz, Iran
| | - Katharina Schuh
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany; Department of Life Sciences and Engineering, Animal Nutrition and Hygiene Unit, University of Applied Sciences Bingen, 55411 Bingen am Rhein, Germany
| | - Valentina Zamarian
- Dipartimento di Medicina Veterinaria, Università di Milano, 20133 Milano, Italy
| | - Christian Koch
- Educational and Research Center for Animal Husbandry, Hofgut Neumuehle, 67728 Muenchweiler an der Alsenz, Germany
| | - Nares Trakooljul
- Leibniz-Institute for Farm Animal Biology (FBN), Institute for Genome Biology, 18196 Dummerstorf, Germany
| | - Klaus Wimmers
- Leibniz-Institute for Farm Animal Biology (FBN), Institute for Genome Biology, 18196 Dummerstorf, Germany
| | - Cristina Lecchi
- Dipartimento di Medicina Veterinaria, Università di Milano, 20133 Milano, Italy
| | - Fabrizio Ceciliani
- Dipartimento di Medicina Veterinaria, Università di Milano, 20133 Milano, Italy
| | - Helga Sauerwein
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
| |
Collapse
|