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Chen JY, Yang YJ, Meng XY, Lin RH, Tian XY, Zhang Y, Lai WF, Yang C, Ma XQ, Huang MQ. Oxysophoridine inhibits oxidative stress and inflammation in hepatic fibrosis via regulating Nrf2 and NF-κB pathways. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155585. [PMID: 39068811 DOI: 10.1016/j.phymed.2024.155585] [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: 11/11/2023] [Revised: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Hepatic fibrosis (HF) runs through multiple stages of liver diseases and promotes these diseases progression. Oxysophoridine (OSR), derived from Sophora alopecuroides l., is a bioactive alkaloid that has been reported to antagonize alcoholic hepatic injury. However, whether OSR suppresses HF and the mechanisms involved in Nrf2 remain unknown. PURPOSE Since the dysregulation of inflammation and oxidative stress is responsible for the excessive accumulation of extracellular matrix (ECM) and fibrosis in the liver. We hypothesized that OSR may attenuate HF by inhibiting inflammation and oxidative stress through activating Nrf2 signaling. METHODS In this study, we employed LPS-stimulated HSC-T6 cells, RAW264.7 cells, and a CCl4-induced C57BL/6 mouse fibrotic model to evaluate its suppressing inflammation and oxidative stress, as well as fibrosis. RESULTS The result showed that OSR significantly reduced α-SMA and TGF-β1 at a low dose of 10 μM in vitro and at a dose of 50 mg/kg in vivo, which is comparable to Silymarin, the only Chinese herbal active ingredient that has been marketed for anti-liver fibrosis. Moreover, OSR effectively suppressed the expression of iNOS at a dose of 10 μM and COX-2 at a dose of 40 μM, respectively. Furthermore, OSR demonstrated inhibitory effects on the IL-1β, IL-6, and TNF-α in vitro and almost extinguished cytokine storm in vivo. OSR exhibited antioxidative effects by reducing MDA and increasing GSH, thereby protecting the cell membrane against oxidative damage and reducing LDH release. Moreover, OSR effectively upregulated the protein levels of Nrf2, HO-1, and p62, but decreased p-NF-κB p65, p-IκBα, and Keap1. Alternatively, mechanisms involved in Nrf2 were verified by siNrf2 interference, siNrf2 interference revealed that the anti-fibrotic effect of OSR was attributed to its activation of Nrf2. CONCLUSION The present study provided an effective candidate for HF involved in both activation of Nrf2 and blockage of NF-κB, which has not been reported in the published work. The present study provides new insights for the identification of novel drug development for HF.
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Affiliation(s)
- Jian-Yu Chen
- Fujian University of Traditional Chinese Medicine, No.1, Hua Tuo Road, Min Hou Shang Jie, Fuzhou 350122, PR China
| | - Ying-Jie Yang
- Fujian University of Traditional Chinese Medicine, No.1, Hua Tuo Road, Min Hou Shang Jie, Fuzhou 350122, PR China
| | - Xiong-Yu Meng
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou 310053 Zhejiang Province, PR China
| | - Ru-Hui Lin
- Fujian University of Traditional Chinese Medicine, No.1, Hua Tuo Road, Min Hou Shang Jie, Fuzhou 350122, PR China
| | - Xiao-Yun Tian
- Fujian University of Traditional Chinese Medicine, No.1, Hua Tuo Road, Min Hou Shang Jie, Fuzhou 350122, PR China
| | - Ying Zhang
- Fujian University of Traditional Chinese Medicine, No.1, Hua Tuo Road, Min Hou Shang Jie, Fuzhou 350122, PR China
| | - Wen-Fang Lai
- Fujian University of Traditional Chinese Medicine, No.1, Hua Tuo Road, Min Hou Shang Jie, Fuzhou 350122, PR China.
| | - Chunxue Yang
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518107, PR China.
| | - Xue-Qin Ma
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan 750004, PR China.
| | - Ming-Qing Huang
- Fujian University of Traditional Chinese Medicine, No.1, Hua Tuo Road, Min Hou Shang Jie, Fuzhou 350122, PR China.
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Wang YF, Zhang WL, Li ZX, Liu Y, Tan J, Yin HZ, Zhang ZC, Piao XJ, Ruan MH, Dai ZH, Wang SJ, Mu CY, Yuan JH, Sun SH, Liu H, Yang F. METTL14 downregulation drives S100A4 + monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression. Signal Transduct Target Ther 2024; 9:91. [PMID: 38627387 PMCID: PMC11021505 DOI: 10.1038/s41392-024-01797-1] [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: 10/07/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 04/19/2024] Open
Abstract
Without intervention, a considerable proportion of patients with metabolism-associated fatty liver disease (MAFLD) will progress from simple steatosis to metabolism-associated steatohepatitis (MASH), liver fibrosis, and even hepatocellular carcinoma. However, the molecular mechanisms that control progressive MAFLD have yet to be fully determined. Here, we unraveled that the expression of the N6-methyladenosine (m6A) methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD, whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation, liver injury, and fibrosis. Conversely, hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet (HFD). Notably, in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner, which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1+Ccr2+ monocyte-derived macrophages (Mo-macs). In detail, Cx3cr1+Ccr2+ Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells (HSCs) to promote liver fibrosis. Further experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1+Ccr2+ Mo-macs. Restoration of METTL14 or GLS2, or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and fibrosis. Taken together, these findings indicate potential therapies for the treatment of MAFLD progression.
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Affiliation(s)
- Yue-Fan Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Wen-Li Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
| | - Zhi-Xuan Li
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, 100048, Beijing, China
| | - Yue Liu
- The Department of Pharmaceutical Analysis, School of Pharmacy, Naval Medical University, 200433, Shanghai, China
| | - Jian Tan
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Hao-Zan Yin
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Zhi-Chao Zhang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
| | - Xian-Jie Piao
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
| | - Min-Hao Ruan
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China
| | - Zhi-Hui Dai
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Si-Jie Wang
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Chen-Yang Mu
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Ji-Hang Yuan
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Shu-Han Sun
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China
| | - Hui Liu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University, 200438, Shanghai, China.
| | - Fu Yang
- The Department of Medical Genetics, Naval Medical University, 200433, Shanghai, China.
- Key Laboratory of Biosafety Defense, Ministry of Education, 200433, Shanghai, China.
- Shanghai Key Laboratory of Medical Biodefense, 200433, Shanghai, China.
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Bai Q, Han Y, Khan S, Wu T, Yang Y, Wang Y, Tang H, Li Q, Jiang W. A Novel Endoplasmic Reticulum-Targeted Metal-Organic Framework-Confined Ruthenium (Ru) Nanozyme Regulation of Oxidative Stress for Central Post-Stroke Pain. Adv Healthc Mater 2024; 13:e2302526. [PMID: 37823717 DOI: 10.1002/adhm.202302526] [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: 08/03/2023] [Revised: 09/12/2023] [Indexed: 10/13/2023]
Abstract
Central post-stroke pain (CPSP) is a chronic neuropathic pain caused by cerebrovascular lesion or disfunction after stroke. Convincing evidence suggest that excessive reactive oxygen species (ROS), generated matrix metalloproteinase (MMPs) and neuroinflammation are largely involved in the development of pain. In this study, an effective strategy is reported for treating pain hypersensitivity using an endoplasmic reticulum (ER)-targeted metal-organic framework (MOF)-confined ruthenium (Ru) nanozyme. The Ru MOF is coated with a p-dodecylbenzene sulfonamide (p-DBSN) modified liposome with endoplasmic reticulum-targeted function. The experimental results reveals that ROS, Emmprin, MMP-2, and MMP-9 are upregulated in the brain of CPSP mice, along with the elevated expression of inflammation markers such as TNF-α and IL-6. Compared to vehicle, one-time intravenous administration of ER-Ru MOF significantly reduces mechanical hypersensitivity after CPSP for three days. Overall, ER-Ru MOF system can inhibit oxidative stress in the brain tissues of CPSP model, reduce MMPs expression, and suppress neuroinflammation response-induced injury, resulting in satisfactory prevention and effective treatment of CPSP during a hemorrhagic stroke. The ER-Ru MOF is expected to be useful for the treatment of neurological diseases associated with the vicious activation of ROS, based on the generality of the approach used in this study.
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Affiliation(s)
- Qian Bai
- Medical research center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yupeng Han
- Medical research center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Suliman Khan
- Medical research center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Tingting Wu
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Ying Yang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yingying Wang
- Medical research center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Hao Tang
- Henan Key Laboratory of Chronic Disease Management, Henan Provincial People's Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, 451464, China
| | - Qing Li
- Medical research center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Wei Jiang
- Medical research center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, 450052, China
- Henan Key Laboratory of Chronic Disease Management, Henan Provincial People's Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, 451464, China
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Liu X, Wang Y, Li J, Wu B, Wang S, Guo Q, Liu Y. To study the protective effect of Huangqi Baihe Granules on Radiation brain injury based on network pharmacology and experiment. JOURNAL OF ETHNOPHARMACOLOGY 2023:116610. [PMID: 37150423 DOI: 10.1016/j.jep.2023.116610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huangqi baihe Granules (HQBHG), which is a key Chinese medical prescription, has a remarkable efficacy in oxidative stress and inflammation. Nevertheless, the therapeutic effect on Radiation brain injury (RBI) has rarely been studied. AIM OF THE STUDY The study aimed to verify the effect of HQBHG against RBI and explore its potential mechanism. METHODS The potential targets and mechanisms of HQBHG against RBI were predicted by network pharmacology and verified by established rat model of RBI Firstly, the therapeutic effect of HQBHG in RBI was confirmed by water maze test, HE staining and Enzyme-linked immunosorbent assay (ELISA). Secondly, the potential critical anti-RBI pathway of HQBHG was further explored by water maze, HE staining, immunofluorescence assays, ELISA and western blot. RESULTS A total of 43 HQBHG anti-RBI targets were obtained. Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations showed that the treatment of HQBHG in RBI might be mainly related to oxidative stress, inflammation and PI3K/AKT pathway. Experimental studies have indicated that HQBHG can improve spatial learning and memory ability, alleviate pathological damage of brain tissue in RBI of rats. HQBHG also can down-regulate the levels of IL-1β, TNF-α, ROS and MDA, meanwhile, GSH was significantly up-regulated. In addition, the HQBHG can increase the protein expression phosphorylations PI3K (p-PI3K), phosphorylations AKT(p-AKT) and Nrf2 in the brain tissue of RBI. CONCLUSION HQBHG may alleviated RBI by regulated oxidative stress and inflammatory response through PI3K/AKT/Nrf2 pathway.
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Affiliation(s)
- Xiuzhu Liu
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
| | - Yanru Wang
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
| | - Jiawei Li
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
| | - Bingbing Wu
- 940th Hospital of Chinese People 's Liberation Army Joint Support Force, Lanzhou, 730050, Gansu Province, China.
| | - Siyu Wang
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
| | - Qingyang Guo
- 940th Hospital of Chinese People 's Liberation Army Joint Support Force, Lanzhou, 730050, Gansu Province, China.
| | - Yongqi Liu
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
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Mastronikolis S, Pagkalou M, Plotas P, Kagkelaris K, Georgakopoulos C. Emerging roles of oxidative stress in the pathogenesis of pseudoexfoliation syndrome (Review). Exp Ther Med 2022; 24:602. [PMID: 35949329 PMCID: PMC9353531 DOI: 10.3892/etm.2022.11539] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 07/06/2022] [Indexed: 11/25/2022] Open
Abstract
Pseudoexfoliation syndrome (PEXS) is a systemic disease caused by defects in the extracellular matrix (ECM) remodelling process leading to the chronic deposition of extracellular, fibrillary, white flaky pseudoexfoliation material (PEXM) throughout the body. Specifically, PEXM deposits on the lens capsule cause open-angle glaucoma, cataracts and blindness in patients with PEXS. Several gene single nucleotide polymorphisms are linked to the development of PEXS in humans, including lysyl oxidase-like 1 gene, clusterin and fibulin-5. The exact reason for the PEXM generation and its resulting pathogenesis is not well understood. However, defective ECM remodelling and oxidative stress (OS) have been hypothesized as significant events leading to the PEXM. Specifically, the link between OS and PEXS has been well studied, although the investigation is still ongoing. The present review explored recent advances in various aspects of PEXS and the involvement of OS in the eye for PEXS development.
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Affiliation(s)
| | - Marina Pagkalou
- Department of Chemistry, University of Crete, 70013 Heraklion, Greece
| | - Panagiotis Plotas
- Laboratory of Primary Health Care, School of Health Rehabilitation Sciences, University of Patras, 26334 Patras, Greece
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Hepatic Myofibroblasts: A Heterogeneous and Redox-Modulated Cell Population in Liver Fibrogenesis. Antioxidants (Basel) 2022; 11:antiox11071278. [PMID: 35883770 PMCID: PMC9311931 DOI: 10.3390/antiox11071278] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 12/19/2022] Open
Abstract
During chronic liver disease (CLD) progression, hepatic myofibroblasts (MFs) represent a unique cellular phenotype that plays a critical role in driving liver fibrogenesis and then fibrosis. Although they could originate from different cell types, MFs exhibit a rather common pattern of pro-fibrogenic phenotypic responses, which are mostly elicited or sustained both by oxidative stress and reactive oxygen species (ROS) and several mediators (including growth factors, cytokines, chemokines, and others) that often operate through the up-regulation of the intracellular generation of ROS. In the present review, we will offer an overview of the role of MFs in the fibrogenic progression of CLD from different etiologies by focusing our attention on the direct or indirect role of ROS and, more generally, oxidative stress in regulating MF-related phenotypic responses. Moreover, this review has the purpose of illustrating the real complexity of the ROS modulation during CLD progression. The reader will have to keep in mind that a number of issues are able to affect the behavior of the cells involved: a) the different concentrations of reactive species, b) the intrinsic state of the target cells, as well as c) the presence of different growth factors, cytokines, and other mediators in the extracellular microenvironment or of other cellular sources of ROS.
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Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
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Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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Fung A, Shanbhogue KP, Taffel MT, Brinkerhoff BT, Theise ND. Hepatocarcinogenesis: Radiology-Pathology Correlation. Magn Reson Imaging Clin N Am 2021; 29:359-374. [PMID: 34243923 DOI: 10.1016/j.mric.2021.05.007] [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: 02/01/2023]
Abstract
In the background of chronic liver disease, hepatocellular carcinoma develops via a complex, multistep process called hepatocarcinogenesis. This article reviews the causes contributing to the process. Emphasis is made on the imaging manifestations of the pathologic changes seen at many stages of hepatocarcinogenesis, from regenerative nodules to dysplastic nodules and then to hepatocellular carcinoma.
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Affiliation(s)
- Alice Fung
- Department of Diagnostic Radiology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L-340, Portland, OR 97239, USA.
| | - Krishna P Shanbhogue
- Department of Radiology, New York University Grossman School of Medicine, 660 First Avenue, 3rd Floor, New York, NY 10016, USA
| | - Myles T Taffel
- Department of Radiology, New York University Grossman School of Medicine, 660 First Avenue, 3rd Floor, New York, NY 10016, USA
| | - Brian T Brinkerhoff
- Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L-113, Portland, OR 97239, USA
| | - Neil D Theise
- Department of Pathology, MSB 504A, New York University Grossman School of Medicine, 560 First Avenue, New York, NY 10016, USA
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Wang B, Wu Z, Li W, Liu G, Tang Y. Insights into the molecular mechanisms of Huangqi decoction on liver fibrosis via computational systems pharmacology approaches. Chin Med 2021; 16:59. [PMID: 34301291 PMCID: PMC8306236 DOI: 10.1186/s13020-021-00473-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/17/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND The traditional Chinese medicine Huangqi decoction (HQD) consists of Radix Astragali and Radix Glycyrrhizae in a ratio of 6: 1, which has been used for the treatment of liver fibrosis. In this study, we tried to elucidate its action of mechanism (MoA) via a combination of metabolomics data, network pharmacology and molecular docking methods. METHODS Firstly, we collected prototype components and metabolic products after administration of HQD from a publication. With known and predicted targets, compound-target interactions were obtained. Then, the global compound-liver fibrosis target bipartite network and the HQD-liver fibrosis protein-protein interaction network were constructed, separately. KEGG pathway analysis was applied to further understand the mechanisms related to the target proteins of HQD. Additionally, molecular docking simulation was performed to determine the binding efficiency of compounds with targets. Finally, considering the concentrations of prototype compounds and metabolites of HQD, the critical compound-liver fibrosis target bipartite network was constructed. RESULTS 68 compounds including 17 prototype components and 51 metabolic products were collected. 540 compound-target interactions were obtained between the 68 compounds and 95 targets. Combining network analysis, molecular docking and concentration of compounds, our final results demonstrated that eight compounds (three prototype compounds and five metabolites) and eight targets (CDK1, MMP9, PPARD, PPARG, PTGS2, SERPINE1, TP53, and HIF1A) might contribute to the effects of HQD on liver fibrosis. These interactions would maintain the balance of ECM, reduce liver damage, inhibit hepatocyte apoptosis, and alleviate liver inflammation through five signaling pathways including p53, PPAR, HIF-1, IL-17, and TNF signaling pathway. CONCLUSIONS This study provides a new way to understand the MoA of HQD on liver fibrosis by considering the concentrations of components and metabolites, which might be a model for investigation of MoA of other Chinese herbs.
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Affiliation(s)
- Biting Wang
- Laboratory of Molecular Modeling and Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Zengrui Wu
- Laboratory of Molecular Modeling and Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Weihua Li
- Laboratory of Molecular Modeling and Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Guixia Liu
- Laboratory of Molecular Modeling and Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Yun Tang
- Laboratory of Molecular Modeling and Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
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Eswaran S, Babbar A, Drescher HK, Hitch TCA, Clavel T, Muschaweck M, Ritz T, Kroy DC, Trautwein C, Wagner N, Schippers A. Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts. Int J Mol Sci 2021; 22:ijms22147314. [PMID: 34298930 PMCID: PMC8306675 DOI: 10.3390/ijms22147314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/29/2021] [Accepted: 07/04/2021] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel−/−Keap1flx/flx) and littermates with selective hepatic Keap1 deletion (Lsel−/−Keap1Δhepa) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel−/−Keap1Δhepa mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel−/−Keap1flx/flx littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota.
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Affiliation(s)
- Sreepradha Eswaran
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
| | - Anshu Babbar
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
- Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Hannah K. Drescher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;
| | - Thomas C. A. Hitch
- Functional Microbiome Research Group, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (T.C.A.H.); (T.C.)
| | - Thomas Clavel
- Functional Microbiome Research Group, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (T.C.A.H.); (T.C.)
| | - Moritz Muschaweck
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
| | - Thomas Ritz
- Institute of Pathology, Ruprecht-Karls-University Heidelberg, D-69117 Heidelberg, Germany;
| | - Daniela C. Kroy
- Department of Internal Medicine III, University Hospital, RWTH Aachen, D-52074 Aachen, Germany; (D.C.K.); (C.T.)
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, D-52074 Aachen, Germany; (D.C.K.); (C.T.)
| | - Norbert Wagner
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
- Correspondence: (N.W.); (A.S.)
| | - Angela Schippers
- Department of Pediatrics, Faculty of Medicine, RWTH Aachen University, D-52074 Aachen, Germany; (S.E.); (A.B.); (M.M.)
- Correspondence: (N.W.); (A.S.)
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11
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Jahandideh A, Amini M, Porbagher H, Amini M. Evaluating the effect of cold plasma on the healing of gingival wound. J Diabetes Metab Disord 2021; 20:741-745. [PMID: 34222088 PMCID: PMC8212223 DOI: 10.1007/s40200-021-00810-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/26/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND This is the first study that conducted to the effect of cold plasma on the healing of gingival wound in diabetic rabbits. MATERIAL AND METHOD Eighteen healthy rabbits is purched from pastor institute. The aloxan was injected to the rabbits. After induction of anesthesia the gum tissue is removed. The rabbits were treated by the plasma jet for 3, 5 and 10 days each day 30 s and they were considered histological. RESULTS AND DISCUSSION After 3 days the plasma jet treatment, the production of collagen and fibroblast and migration of epithelial cells is observed. As can be seen from the results after 5 days the cold plasma treatment the increase of neovascularation, collagen and inflammatory infiltration is seen in gum tissue. Formation of granulation tissue is seen after 10 days the plasma jet treatment. CONCLUSION The cold plasma treatment is an effective way for gingival wound treatment. Cold plasma treatment resulted in reduction of inflammatory phase and accelerates the recovery phase by increase neovascularation and collagen production.
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Affiliation(s)
- Alireza Jahandideh
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Maryam Amini
- Plasma Physics Research Center, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Hoda Porbagher
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Mohammdreza Amini
- Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran
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12
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Laura D, Anna P, Nicola F, Loriano B, Rigers B, Gianfranco S. Stress granules in Ciona robusta: First evidences of TIA-1-related nucleolysin and tristetraprolin gene expression under metal exposure. Comp Biochem Physiol C Toxicol Pharmacol 2021; 243:108977. [PMID: 33465518 DOI: 10.1016/j.cbpc.2021.108977] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/04/2021] [Accepted: 01/09/2021] [Indexed: 12/17/2022]
Abstract
Stress granules are non-membranous cytoplasmic foci, composed of non-translating messenger ribonucleoproteins, translational initiation factors and other additional proteins. They represent a primary mechanism to rapidly modulate gene expression when cells are subjected to adverse environmental conditions. Very few works have been devoted to study the presence of the molecular components of stress granules in invertebrates. In this work, we characterized the transcript sequences for two important protein components of stress granules, TIA-1-related nucleolysin (TIAR) and tristetraprolin (TTP), in the solitary ascidian Ciona robusta, an invertebrate chordate, and carried out the first studies on their gene expression under stress conditions induced by metals (Cu, Zn and Cd). Data on mRNA expression levels, provided by qRT-PCR analyses, show a generalized decrease at the second day of metal-exposure for both tiar and ttp, suggesting that metal accumulation induces acute stress and the inhibition of the transcription for the two studied proteins. In-situ hybridization analyses demonstrate that TIAR and TTP antisense riboprobes recognize circulating granular amoebocytes in the hemolymph, in both blood lacunae and tunic. The results obtained in this work increase our knowledge on the evolution of anti-stress proteins in metazoans and emphasize the importance of the transcription of tiar and ttp, which represents an efficient physiological response allowing organisms to survive in the environment under stress conditions.
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Affiliation(s)
- Drago Laura
- Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
| | - Peronato Anna
- Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
| | - Franchi Nicola
- Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
| | - Ballarin Loriano
- Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy.
| | - Bakiu Rigers
- Department of Aquaculture and Fisheries, Agricultural University of Tirana, Tirana, Albania
| | - Santovito Gianfranco
- Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
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13
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Amini M, Momeni M, Jahandideh A, Ghoranneviss M, Soudmand S, Yousefi P, Khandan S, Amini M. Tendon repair by plasma jet treatment. J Diabetes Metab Disord 2021; 20:621-626. [PMID: 34178855 DOI: 10.1007/s40200-021-00789-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 03/22/2021] [Indexed: 02/01/2023]
Abstract
Objective In recent years many researchers applied cold plasma for wound healing. The cold plasma is irradiated on the surface of wound. In this paper the effect of irradiation of cold plasma on the skin for healing of injured tissue which is located inside body, such as tendon, is evaluated. Methods The male, white New Zealand, (20-week-old) were selected. Aloxan injection induced for diabetes induction and a week later the blood glucose level was measured. The standard tendon injury was created. The rabbits was divided in 3 groups. Control group, Plasma treated group at 5 kv, plasma treated group at 10 kv. Cold plasma was applied to the rabbits for 21 days. Results After 21 days the tendon tissue were considered histologically. The results show that inflammatory cells were significantly lower in the tendon treated with cold plasma at 10 kv than the others, which confirms that cold plasma treatment reduce the inflammation phase. Cold plasma treatment led to increase neovascularation and collagen production. Conclusion The results of this study confirm that the cold plasma treatment of skin has positive effect on healing of tissue inside body.
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Affiliation(s)
- Maryam Amini
- Faculty of Physics, Shahrood University of Technology, Shahrood, Iran
| | - Mahdi Momeni
- Faculty of Physics, Shahrood University of Technology, Shahrood, Iran
| | - Alireza Jahandideh
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Mahmood Ghoranneviss
- Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran
| | - Sahar Soudmand
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Paniz Yousefi
- Department of Veterinary Medicine, Tehran Azad University Science and Research Branch, Tehran, Iran
| | - Saeed Khandan
- Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran
| | - Mohammadreza Amini
- Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran
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14
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Nikolova E, Tonev D, Zhelev N, Neychev V. Prospects for Radiopharmaceuticals as Effective and Safe Therapeutics in Oncology and Challenges of Tumor Resistance to Radiotherapy. Dose Response 2021; 19:1559325821993665. [PMID: 33716590 PMCID: PMC7923993 DOI: 10.1177/1559325821993665] [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: 09/17/2020] [Revised: 01/15/2021] [Accepted: 01/17/2021] [Indexed: 12/26/2022] Open
Abstract
The rapid advances in nuclear medicine have resulted in significant advantages for the field of oncology. The focus is on the application of radiopharmaceuticals as therapeuticals. In addition, the latest developments in cell biology (the understanding of the cell structure, function, metabolism, genetics, signaling, transformation) have given a strong scientific boost to radiation oncology. In this regard, the article discusses what is soon going to be a new jump in radiation oncology based on the already accumulated considerable knowledge at the cellular level about the mechanisms of cell transformation and tumor progression, cell response to radiation, cell resistance to apoptosis and radiation and cell radio-sensitivity. The mechanisms of resistance of tumor cells to radiation and the genetically determined individual sensitivity to radiation in patients (which creates the risk of radiation-induced acute and late side effects) are the 2 major challenges to overcome in modern nuclear medicine. The paper focuses on these problems and makes a detailed summary of the significance of the differences in the ionizing properties of radiopharmaceuticals and the principle of their application in radiation oncology that will shed additional light on how to make the anti-cancer radiotherapies more efficient and safe, giving some ideas for optimizations.
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Affiliation(s)
- Ekaterina Nikolova
- Institute for Nuclear Research and Nuclear Energy, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Dimitar Tonev
- Institute for Nuclear Research and Nuclear Energy, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Nikolai Zhelev
- School of Medicine, University of Dundee, Ninewells Hospital, Dundee, Scotland, United Kingdom.,Medical University of Plovdiv, Plovdiv, Bulgaria
| | - Vladimir Neychev
- University of Central Florida, College of Medicine, Orlando, FL, USA
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15
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Abstract
Chronic infection of the liver by the hepatitis B virus (HBV) is associated with increased risk for developing hepatocellular carcinoma (HCC). A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection. Chronic inflammation, expression of specific viral proteins such as HBx, the integration site of the viral genome into the host genome, and the viral genotype, are key players contributing to HCC pathogenesis. In addition, the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis. Despite the plethora of studies, the molecular mechanism of HCC pathogenesis remains incompletely understood. In this review, the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC. Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA, acting by modifying the host chromatin structure via covalent post-translational histone modifications, changing the DNA methylation status, expression of non-coding RNAs such as microRNAs and long noncoding RNAs, and altering the spatial, 3-D organization of the chromatin of the virus-infected cell. Herein, studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation. In contrast to genetic mutations which are permanent, epigenetic alterations are dynamic and reversible. Accordingly, the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.
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Affiliation(s)
- Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
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16
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Hepatoprotective Potency of Chrysophanol 8- O-Glucoside from Rheum palmatum L. against Hepatic Fibrosis via Regulation of the STAT3 Signaling Pathway. Int J Mol Sci 2020; 21:ijms21239044. [PMID: 33261209 PMCID: PMC7730872 DOI: 10.3390/ijms21239044] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/25/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023] Open
Abstract
Rhubarb is a well-known herb worldwide and includes approximately 60 species of the Rheum genus. One of the representative plants is Rheum palmatum, which is prescribed as official rhubarb due to its pharmacological potential in the Korean and Chinese pharmacopoeia. In our bioactive screening, we found out that the EtOH extract of R. palmatum inhibited hepatic stellate cell (HSC) activation by transforming growth factor β1 (TGF-β1). Chemical investigation of the EtOH extract led to the isolation of chrysophanol 8-O-glucoside, which was determined by structural analysis using NMR spectroscopic techniques and electrospray ionization mass spectrometry (ESIMS). To elucidate the effects of chrysophanol 8-O-glucoside on HSC activation, activated LX-2 cells were treated for 48 h with chrysophanol 8-O-glucoside, and α-SMA and collagen, HSC activation markers, were measured by comparative quantitative real-time PCR (qPCR) and western blotting analysis. Chrysophanol 8-O-glucoside significantly inhibited the protein and mRNA expression of α-SMA and collagen compared with that in TGF-β1-treated LX-2 cells. Next, the expression of phosphorylated SMAD2 (p-SMAD2) and p-STAT3 was measured and the translocation of p-STAT3 to the nucleus was analyzed by western blotting analysis. The expression of p-SMAD2 and p-STAT3 showed that chrysophanol 8-O-glucoside strongly downregulated STAT3 phosphorylation by inhibiting the nuclear translocation of p-STAT3, which is an important mechanism in HSC activation. Moreover, chrysophanol 8-O-glucoside suppressed the expression of p-p38, not that of p-JNK or p-Erk, which can activate STAT3 phosphorylation and inhibit MMP2 expression, the downstream target of STAT3 signaling. These findings provided experimental evidence concerning the hepatoprotective effects of chrysophanol 8-O-glucoside against liver damage and revealed the molecular basis underlying its anti-fibrotic effects through the blocking of HSC activation.
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17
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Prolonged Lipid Accumulation in Cultured Primary Human Hepatocytes Rather Leads to ER Stress than Oxidative Stress. Int J Mol Sci 2020; 21:ijms21197097. [PMID: 32993055 PMCID: PMC7582586 DOI: 10.3390/ijms21197097] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 09/18/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022] Open
Abstract
Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of severe and irreversible liver diseases. This study aims to gain further insight into the molecular processes leading to the evolution from steatosis to steatohepatitis. Steatosis was induced in cultures of primary human hepatocytes by continuous five-day exposure to free fatty acids (FFAs). The kinetics of lipid accumulation, lipotoxicity, and oxidative stress were measured. Additionally, ER stress was evaluated by analyzing the protein expression profiles of its key players: PERK, IRE1a, and ATF6a. Our data revealed that hepatocytes are capable of storing enormous amounts of lipids without showing signs of lipotoxicity. Prolonged lipid accumulation did not create an imbalance in hepatocyte redox homeostasis or a reduction in antioxidative capacity. However, we observed an FFA-dependent increase in ER stress, revealing thresholds for triggering the activation of pathways associated with lipid stress, inhibition of protein translation, and apoptosis. Our study clearly showed that even severe lipid accumulation can be attenuated by cellular defenses, but regenerative capacities may be reduced.
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18
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Perricone C, Bartoloni E, Bursi R, Cafaro G, Guidelli GM, Shoenfeld Y, Gerli R. COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy. Immunol Res 2020. [PMID: 32681497 DOI: 10.22541/au.158880283.34604328] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Abstract
SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.
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Affiliation(s)
- Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Elena Bartoloni
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Roberto Bursi
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Giacomo Cafaro
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | | | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Aviv University, 5265601, Tel-Hashomer, Israel
- The Mosaic of Autoimmunity Project, Saint Petersburg University, Saint Petersburg, Russia
- Ministry of Health of the Russian Federation, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Roberto Gerli
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy.
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19
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Perricone C, Bartoloni E, Bursi R, Cafaro G, Guidelli GM, Shoenfeld Y, Gerli R. COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy. Immunol Res 2020; 68:213-224. [PMID: 32681497 PMCID: PMC7366458 DOI: 10.1007/s12026-020-09145-5] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.
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Affiliation(s)
- Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Elena Bartoloni
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Roberto Bursi
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Giacomo Cafaro
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | | | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Aviv University, 5265601, Tel-Hashomer, Israel
- The Mosaic of Autoimmunity Project, Saint Petersburg University, Saint Petersburg, Russia
- Ministry of Health of the Russian Federation, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Roberto Gerli
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy.
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20
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Ibrahim SA, Mohamed MZ, El-Tahawy NF, Abdelrahman AM. Antifibrotic effects of bezafibrate and pioglitazone against thioacetamide-induced liver fibrosis in albino rats. Can J Physiol Pharmacol 2020; 99:313-320. [PMID: 32721217 DOI: 10.1139/cjpp-2020-0159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Activation of hepatic stellate cells is a central event in hepatic fibrogenesis that offers multiple potential sites for therapeutic interventions. Peroxisome proliferator-activated receptors are implicated in liver fibrosis. We aimed to evaluate the effect of bezafibrate and pioglitazone on a thioacetamide (TAA) rat model of liver fibrosis and to clarify the possible underlying mechanisms. Rats received intraperitoneal injections of TAA for 6 weeks. Daily oral treatments with bezafibrate or pioglitazone were started with the first day of TAA intoxication. Serum liver function tests, hepatic malondialdehyde (MDA), total nitrite and nitrate (NOx), superoxide dismutase, and hepatic histopathology were assessed to evaluate hepatic damage. Alpha smooth muscle actin (α-SMA) and tissue inhibitor metalloproteinase-1 (TIMP-1) and caspase-3 were also assessed. The TAA group experienced significant deterioration of liver functions, increased oxidative stress, and increased liver tissue NOx. Administration of bezafibrate or pioglitazone resulted in significant improvement of all liver functions and reduced oxidative stress in hepatic tissues. Only administration of bezafibrate significantly reduced NOx levels. Liver tissues from the TAA-treated group showed disrupted normal architecture. Administration of bezafibrate or pioglitazone attenuated this picture. Stronger α-SMA expression was detected in the TAA group. Treatment with bezafibrate or pioglitazone decreased the α-SMA expression.
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Affiliation(s)
- Salwa A Ibrahim
- Department of Pharmacology, Minia University Faculty of Medicine, Minia, Egypt
| | - Mervat Z Mohamed
- Department of Pharmacology, Minia University Faculty of Medicine, Minia, Egypt
| | - Nashwa F El-Tahawy
- Department of Histology & Cell Biology, Minia University Faculty of Medicine, Minia, Egypt
| | - Aly M Abdelrahman
- Department of Pharmacology, Minia University Faculty of Medicine, Minia, Egypt
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21
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Liu X, Shen S, Zhu L, Su R, Zheng J, Ruan X, Shao L, Wang D, Yang C, Liu Y. SRSF10 inhibits biogenesis of circ-ATXN1 to regulate glioma angiogenesis via miR-526b-3p/MMP2 pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:121. [PMID: 32600379 PMCID: PMC7325155 DOI: 10.1186/s13046-020-01625-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/18/2020] [Indexed: 12/13/2022]
Abstract
Background Angiogenesis plays an important role in the progress of glioma. RNA-binding proteins (RBPs) and circular RNAs (circRNAs), dysregulated in various tumors, have been verified to mediate diverse biological behaviors including angiogenesis. Methods Quantitative real-time PCR (qRT-PCR) and western blot were performed to detect the expression of SRSF10, circ-ATXN1, miR-526b-3p, and MMP2/VEGFA. The potential function of SRSF10/circ-ATXN1/miR-526b-3p axis in glioma-associated endothelial cells (GECs) angiogenesis was further studied. Results SRSF10 and circ-ATXN1 were significantly upregulated in GECs compared with astrocyte-associated endothelial cells (AECs). Knockdown of SRSF10 or circ-ATXN1 significantly inhibited cell viability, migration and tube formation of GECs where knockdown of SRSF10 exerted its function by inhibiting the formation of circ-ATXN1. Moreover, the combined knockdown of SRSF10 and circ-ATXN1 significantly enhanced the inhibitory effects on cell viability, migration and tube formation of GECs, compared with knockdown of SRSF10 and circ-ATXN1, respectively. MiR-526b-3p was downregulated in GECs. Circ-ATXN1 functionally targeted miR-526b-3p in an RNA-induced silencing complex. Up-regulation of miR-526b-3p inhibited cell viability, migration and tube formation of GECs. Furthermore, miR-526b-3p affected the angiogenesis of GECs via negatively regulating the expression of MMP2/VEGFA. Conclusion SRSF10/circ-ATXN1/miR-526b-3p axis played a crucial role in regulating the angiogenesis of GECs. The above findings provided new targets for anti-angiogenic therapy in glioma.
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Affiliation(s)
- Xiaobai Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004, China.,Key Laboratory of Neuro-Oncology in Liaoning Province, Shenyang, 110004, China
| | - Shuyuan Shen
- Department of Neurobiology, School of life Sciences, China Medical University, Shenyang, 110122, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, 110122, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, 110122, China
| | - Lu Zhu
- Department of Neurobiology, School of life Sciences, China Medical University, Shenyang, 110122, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, 110122, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, 110122, China
| | - Rui Su
- Department of Neurobiology, School of life Sciences, China Medical University, Shenyang, 110122, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, 110122, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, 110122, China
| | - Jian Zheng
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004, China.,Key Laboratory of Neuro-Oncology in Liaoning Province, Shenyang, 110004, China
| | - Xuelei Ruan
- Department of Neurobiology, School of life Sciences, China Medical University, Shenyang, 110122, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, 110122, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, 110122, China
| | - Lianqi Shao
- Department of Neurobiology, School of life Sciences, China Medical University, Shenyang, 110122, China.,Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, 110122, China.,Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, 110122, China
| | - Di Wang
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004, China.,Key Laboratory of Neuro-Oncology in Liaoning Province, Shenyang, 110004, China
| | - Chunqing Yang
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004, China.,Key Laboratory of Neuro-Oncology in Liaoning Province, Shenyang, 110004, China
| | - Yunhui Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China. .,Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, 110004, China. .,Key Laboratory of Neuro-Oncology in Liaoning Province, Shenyang, 110004, China.
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Liu W, Zhang S, Nekhai S, Liu S. Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival. CURRENT CLINICAL MICROBIOLOGY REPORTS 2020; 7:13-19. [PMID: 32318324 PMCID: PMC7169647 DOI: 10.1007/s40588-020-00140-w] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF THE REVIEW The ongoing outbreak of novel coronavirus pneumonia (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) in China is lifting widespread concerns. Thus, therapeutic options are urgently needed, and will be discussed in this review. RECENT FINDINGS Iron-containing enzymes are required for viruses most likely including coronaviruses (CoVs) to complete their replication process. Moreover, poor prognosis occurred in the conditions of iron overload for patients upon infections of viruses. Thus, limiting iron represents a promising adjuvant strategy in treating viral infection through oral uptake or venous injection of iron chelators, or through the manipulation of the key iron regulators. For example, treatment with iron chelator deferiprone has been shown to prolong the survival of acquired immunodeficiency syndrome (AIDS) patients. Increasing intracellular iron efflux via increasing iron exporter ferroportin expression also exhibits antiviral effect on human immunodeficiency virus (HIV). The implications of other metals besides iron are also briefly discussed. SUMMARY For even though we know little about iron regulation in COVID-19 patients thus far, it could be deduced from other viral infections that iron chelation might be an alternative beneficial adjuvant in treating COVID-19.
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Affiliation(s)
- Wei Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Shuping Zhang
- Department of Hematology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062 China
- Shandong Medicinal Biotechnology Center, Jinan, 250062 China
- University Creative Research Initiatives Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250062 China
| | - Sergei Nekhai
- Center for Sickle Cell Disease and Department of Medicine, College of Medicine, Howard University, Washington, DC 20059 USA
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085 China
- University of Chinese Academy of Sciences, Beijing, 100049 China
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Khomich O, Ivanov AV, Bartosch B. Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells 2019; 9:E24. [PMID: 31861818 PMCID: PMC7016711 DOI: 10.3390/cells9010024] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/09/2019] [Accepted: 12/18/2019] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.
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Affiliation(s)
- Olga Khomich
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alexander V. Ivanov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Birke Bartosch
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
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Oncostatin M, A Profibrogenic Mediator Overexpressed in Non-Alcoholic Fatty Liver Disease, Stimulates Migration of Hepatic Myofibroblasts. Cells 2019; 9:cells9010028. [PMID: 31861937 PMCID: PMC7017087 DOI: 10.3390/cells9010028] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/17/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatic myofibroblasts (MFs) can originate from hepatic stellate cells, portal fibroblasts, or bone marrow-derived mesenchymal stem cells and can migrate towards the site of injury by aligning with nascent and established fibrotic septa in response to several mediators. Oncostatin M (OSM) is known to orchestrate hypoxia-modulated hepatic processes involving the hypoxia-inducible factor 1 (HIF-1). METHODS In vivo and in vitro experiments were performed to analyze the expression of OSM and OSM-receptor (OSMR) in three murine models of non-alcoholic-fatty liver disease (NAFLD) and -steatohepatitis (NASH) and in human NASH patients as well as the action of OSM on phenotypic responses of human MFs. RESULTS Hepatic OSM and OSMR levels were overexpressed in three murine NASH models and in NASH patients. OSM stimulates migration in human MFs by involving early intracellular ROS generation and activation of Ras/Erk, JNK1/2, PI3K/Akt as well as STAT1/STAT3 pathways and HIF-1α. OSM-dependent migration relies on a biphasic mechanism requiring early intracellular generation of reactive oxygen species (ROS) and late HIF1-dependent expression and release of VEGF. CONCLUSION OSM is overexpressed in experimental and human progressive NAFLD and can act as a profibrogenic factor by directly stimulating migration of hepatic MFs.
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Zhang Z, Guo M, Shen M, Li Y, Tan S, Shao J, Zhang F, Chen A, Wang S, Zheng S. Oroxylin A regulates the turnover of lipid droplet via downregulating adipose triglyceride lipase (ATGL) in hepatic stellate cells. Life Sci 2019; 238:116934. [PMID: 31610205 DOI: 10.1016/j.lfs.2019.116934] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/26/2019] [Accepted: 10/03/2019] [Indexed: 02/07/2023]
Abstract
Proliferation and differentiation of hepatic stellate cells (HSCs) are the most noticeable events in hepatic fibrosis, in which the loss of lipid droplets (LDs) is the most important feature. However, the complex mechanisms of LD disappearance have not been fully elucidated. In the current study, we investigated whether oroxylin A has the pharmacological activity of reversing LDs in activated HSCs, and further examined its potential molecular mechanisms. Using genetic, pharmacological, and molecular biological measure, we found that LD content significantly decreased during HSC activation, whereas oroxylin A markedly reversed LD content in activated HSCs. Interestingly, oroxylin A treatment observably decreased the expression of adipose triglyceride lipase (ATGL) without large differences in classical LD synthesis pathway, LD-related transcription factors, and autophagy pathway. ATGL overexpression could completely impair the effect of oroxylin A on reversing LD content. Importantly, reactive oxygen species (ROS) signaling pathway mediated oroxylin A-induced ATGL downregulation and LD revision in activated HSCs. ROS specific stimulant buthionine sulfoximine (BSO) could dramatically diminish the antioxidant effect of oroxylin A, and in turn, abolish reversal effect of oroxylin A on LD content. Conversely, ROS specific scavenger N-acetyl cystenine (NAC) can significantly enhance the pharmacological effect of oroxylin A on LD revision. Taken together, our study reveals the important molecular mechanism of anti-fibrosis effect of oroxylin A, and also suggests that ROS-ATGL pathway is a potential target for reversing LDs.
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Affiliation(s)
- Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Mei Guo
- Department of Pathogenic biology and Immunology, Medical School, Southeast University, Nanjing, 210009, China
| | - Min Shen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yujia Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Shanzhong Tan
- Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, 63104, USA
| | - Shijun Wang
- Shandong co-innovation center of TCM formula, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Latief U, Umar MF, Ahmad R. Nrf2 protein as a therapeutic target during diethylnitrosamine-induced liver injury ameliorated by β-carotene-reduced graphene oxide (βC-rGO) nanocomposite. Int J Biol Macromol 2019; 137:346-357. [DOI: 10.1016/j.ijbiomac.2019.06.219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/26/2019] [Accepted: 06/27/2019] [Indexed: 12/31/2022]
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The role of oxidative stress in ovarian toxicity induced by haloperidol and clozapine—a histological and biochemical study in albino rats. Cell Tissue Res 2019; 378:371-383. [DOI: 10.1007/s00441-019-03067-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 07/01/2019] [Indexed: 12/20/2022]
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Vásquez-Garzón VR, Ramírez-Cosmes A, Reyes-Jiménez E, Carrasco-Torres G, Hernández-García S, Aguilar-Ruiz SR, Torres-Aguilar H, Alpuche J, Pérez-Campos Mayoral L, Pina-Canseco S, Arellanes-Robledo J, Villa-Treviño S, Baltiérrez-Hoyos R. Liver damage in bleomycin-induced pulmonary fibrosis in mice. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:1503-1513. [PMID: 31312848 DOI: 10.1007/s00210-019-01690-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/03/2019] [Indexed: 12/12/2022]
Abstract
Pulmonary fibrosis is an emerging disease with a poor prognosis and high mortality rate that is even surpassing some types of cancer. This disease has been linked to the concomitant appearance of liver cirrhosis. Bleomycin-induced pulmonary fibrosis is a widely used mouse model that mimics the histopathological and biochemical features of human systemic sclerosis, an autoimmune disease that is associated with inflammation and expressed in several corporal systems as fibrosis or other alterations. To determine the effects on proliferation, redox and inflammation protein expression markers were analyzed by immunohistochemistry. Analyses showed a significant increase in protein oxidation levels by lipoperoxidation bio-products and in proliferation and inflammation processes. These phenomena were associated with the induction of the redox status in mice subjected to 100 U/kg bleomycin. These findings clearly show that the bleomycin model induces histopathological alterations in the liver and partially reproduces the complexity of systemic sclerosis. Our results using the bleomycin-induced pulmonary fibrosis model provide a protocol to investigate the mechanism underlying the molecular alteration found in the liver linked to systemic sclerosis.
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Affiliation(s)
- V R Vásquez-Garzón
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - A Ramírez-Cosmes
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - E Reyes-Jiménez
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - G Carrasco-Torres
- CINVESTAV, Programa de Nanociencias y Nanotecnología, Ciudad de México, Mexico
| | | | - S R Aguilar-Ruiz
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - H Torres-Aguilar
- Facultad de Ciencias Químicas, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - J Alpuche
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | | | - S Pina-Canseco
- Centro de Investigación Facultad de Medicina, UNAM-UABJO, Oaxaca, Oax, Mexico
| | | | - S Villa-Treviño
- CINVESTAV, Departamento de Biología Celular, Ciudad de México, Mexico
| | - R Baltiérrez-Hoyos
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico.
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Synergistic Role of Oxidative Stress and Blood-Brain Barrier Permeability as Injury Mechanisms in the Acute Pathophysiology of Blast-induced Neurotrauma. Sci Rep 2019; 9:7717. [PMID: 31118451 PMCID: PMC6531444 DOI: 10.1038/s41598-019-44147-w] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 05/07/2019] [Indexed: 12/24/2022] Open
Abstract
Blast-induced traumatic brain injury (bTBI) has been recognized as the common mode of neurotrauma amongst military and civilian personnel due to an increased insurgent activity domestically and abroad. Previous studies from our laboratory have identified enhanced blood-brain barrier (BBB) permeability as a significant, sub-acute (four hours post-blast) pathological change in bTBI. We also found that NADPH oxidase (NOX)-mediated oxidative stress occurs at the same time post-blast when the BBB permeability changes. We therefore hypothesized that oxidative stress is a major causative factor in the BBB breakdown in the sub-acute stages. This work therefore examined the role of NOX1 and its downstream effects on BBB permeability in the frontal cortex (a region previously shown to be the most vulnerable) immediately and four hours post-blast exposure. Rats were injured by primary blast waves in a compressed gas-driven shock tube at 180 kPa and the BBB integrity was assessed by extravasation of Evans blue and changes in tight junction proteins (TJPs) as well as translocation of macromolecules from blood to brain and vice versa. NOX1 abundance was also assessed in neurovascular endothelial cells. Blast injury resulted in increased extravasation and reduced levels of TJPs in tissues consistent with our previous observations. NOX1 levels were significantly increased in endothelial cells followed by increased superoxide production within 4 hours of blast. Blast injury also increased the levels/activation of matrix metalloproteinase 3 and 9. To test the role of oxidative stress, rats were administered apocynin, which is known to inhibit the assembly of NOX subunits and arrests its function. We found apocynin completely inhibited dye extravasation as well as restored TJP levels to that of controls and reduced matrix metalloproteinase activation in the sub-acute stages following blast. Together these data strongly suggest that NOX-mediated oxidative stress contributes to enhanced BBB permeability in bTBI through a pathway involving increased matrix metalloproteinase activation.
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Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019; 76:99-128. [PMID: 30343320 PMCID: PMC11105781 DOI: 10.1007/s00018-018-2947-0] [Citation(s) in RCA: 394] [Impact Index Per Article: 65.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the "first hit" for NAFLD development. NAFLD progression seems to involve the occurrence of "parallel, multiple-hit" injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina.
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Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH. Transplantation 2019; 103:e1-e13. [DOI: 10.1097/tp.0000000000002480] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism. J Transl Med 2019; 99:17-36. [PMID: 30315255 DOI: 10.1038/s41374-018-0133-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 07/25/2018] [Accepted: 08/11/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatic stellate cells (HSCs) are key effectors during the development of liver fibrosis. Septin 6 (SEPT6) is a highly evolutionarily conserved GTP-binding protein that regulates various cell biological behaviors. The expression and function of SEPT6 in HSCs remain unknown. Here we demonstrate that SEPT6 expression is significantly elevated following the activation of primary rat HSCs, the human hepatic stellate cell line LX-2 and the rat hepatic stellate cell line HSC-T6, as well as in both human and rat fibrotic liver tissue. In vitro, the overexpression of SEPT6 promoted HSCs activation, proliferation, cell cycle progression and migration and inhibited HSCs apoptosis. In contrast, knockdown of SEPT6 exerted the opposite effects on HSCs. Mechanistically, SEPT6 exerted its pro-fibrogenic effect by promoting the expression of TGF-β1 and the phosphorylation of Smad2, Smad3, extracellular-signal-regulated kinase, c-Jun NH2-terminal kinase, stress-activated protein kinase-2, and protein kinase B. However, in HSC-T6 cells, blockade of the TGF-β1/Smad signaling pathway by SB431542 significantly decreased the expression of α-smooth muscle actin, cyclin D1, BCL2, and matrix metalloproteinase-2 and -9, which had been enhanced by SEPT6 overexpression. In vivo, adenovirus-mediated SEPT6 inhibition attenuated thioacetamide (TAA)-induced liver fibrosis in rats by decreasing the deposition of the extracellular matrix (ECM). SEPT6 inhibition decreased the proliferation capacity of HSCs and induced apoptosis of HSCs. Collectively, our results reveal that SEPT6 regulates various biological behaviors in HSCs through TGF-β1/Smad, mitogen-activated protein kinases and phosphatidylinositol-3-kinase/protein kinase B signaling pathways, thus promoting liver fibrosis.
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Abdel-Hamid M, Nada OH, Ellakwa DES, Ahmed LK. Role of Myeloperoxidase in hepatitis C virus related hepatocellular carcinoma. Meta Gene 2018. [DOI: 10.1016/j.mgene.2018.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Bessone F, Dirchwolf M, Rodil MA, Razori MV, Roma MG. Review article: drug-induced liver injury in the context of nonalcoholic fatty liver disease - a physiopathological and clinical integrated view. Aliment Pharmacol Ther 2018; 48:892-913. [PMID: 30194708 DOI: 10.1111/apt.14952] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/25/2018] [Accepted: 07/30/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Nonalcoholic fatty disease (NAFLD) is the most common liver disease, since it is strongly associated with obesity and metabolic syndrome pandemics. NAFLD may affect drug disposal and has common pathophysiological mechanisms with drug-induced liver injury (DILI); this may predispose to hepatoxicity induced by certain drugs that share these pathophysiological mechanisms. In addition, drugs may trigger fatty liver and inflammation per se by mimicking NAFLD pathophysiological mechanisms. AIMS To provide a comprehensive update on (a) potential mechanisms whereby certain drugs can be more hepatotoxic in NAFLD patients, (b) the steatogenic effects of drugs, and (c) the mechanism involved in drug-induced steatohepatitis (DISH). METHODS A language- and date-unrestricted Medline literature search was conducted to identify pertinent basic and clinical studies on the topic. RESULTS Drugs can induce macrovesicular steatosis by mimicking NAFLD pathogenic factors, including insulin resistance and imbalance between fat gain and loss. Other forms of hepatic fat accumulation exist, such as microvesicular steatosis and phospholipidosis, and are mostly associated with acute mitochondrial dysfunction and defective lipophagy, respectively. Drug-induced mitochondrial dysfunction is also commonly involved in DISH. Patients with pre-existing NAFLD may be at higher risk of DILI induced by certain drugs, and polypharmacy in obese individuals to treat their comorbidities may be a contributing factor. CONCLUSIONS The relationship between DILI and NAFLD may be reciprocal: drugs can cause NAFLD by acting as steatogenic factors, and pre-existing NAFLD could be a predisposing condition for certain drugs to cause DILI. Polypharmacy associated with obesity might potentiate the association between this condition and DILI.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Melisa Dirchwolf
- Unidad de Transplante Hepático, Servicio de Hepatología, Hospital Privado de Rosario, Rosario, Argentina
| | - María Agustina Rodil
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
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Wu JC, Luo SZ, Liu T, Lu LG, Xu MY. linc-SCRG1 accelerates liver fibrosis by decreasing RNA-binding protein tristetraprolin. FASEB J 2018; 33:2105-2115. [PMID: 30226813 DOI: 10.1096/fj.201800098rr] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The biologic roles of long noncoding RNAs (lncRNAs) in liver fibrosis remained unknown. Through microarray analysis, linc-SCRG1 (a lncRNA with transcript length 3118 bp) was found up-regulated 13.62-fold in human cirrhotic tissues. Quantitative PCR verified that linc-SCRG1 increased along with liver fibrosis progression in human tissues and in activated LX2 cells induced by TGF-β1. Knockdown of linc-SCRG1 significantly reversed the effects of TGF-β1 on LX2, including inhibiting activation, promoting apoptosis, reducing proliferation, lessening invasion, and down-regulating genes [fibrosis-related mRNA: α-smooth muscle actin ( α-SMA), type I collagen, and B-cell lymphoma-2; invasion-related mRNA: matrix metallopeptidase-2 ( MMP-2), MMP-9, and MMP-13; inflammation-related mRNA: TNF-α, IL-6, and IL-10]. linc-SCRG1 had binding sites with tristetraprolin (TTP), a kind of RNA-binding protein, and specifically combined to TTP proteins. Overexpression of linc-SCRG1 would cause TTP mRNA unstably and proteins decreasing. TTP mRNA was proved having negative relevance with linc-SCRG1 and was gradually reduced during human liver fibrosis progression. Overexpressing TTP resulted in knockdown of lincSCRG1 and degraded downstream target genes ( MMP-2 and TNF-α) in activated LX2. Overexpressing TTP had the same effects as small interfering RNA-lincSCRG1 (si- lincSCRG1), whereas knockdown of TTP had reversal effects on si- lincSCRG1 in activated LX2. In summary, linc-SCRG1 reduced TTP and restricted its degradation of target genes TNF-α and MMP-2. Therefore, linc-SCRG1 had a repressing TTP-elicited inactivation effect on hepatic stellate cell (HSC) phenotypes. Inhibition of linc-SCRG1 may be a novel therapeutic approach to inactivate HSCs and extenuate human liver fibrosis.-Wu, J.-C., Luo, S.-Z., Liu, T., Lu, L.-G., Xu, M.-Y. linc-SCRG1 accelerates liver fibrosis by decreasing RNA-binding protein tristetraprolin.
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Affiliation(s)
- Jun-Cheng Wu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sheng-Zheng Luo
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Liu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming-Yi Xu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Asiatic acid attenuates CCl 4 -induced liver fibrosis in rats by regulating the PI3K/AKT/mTOR and Bcl-2/Bax signaling pathways. Int Immunopharmacol 2018; 60:1-8. [DOI: 10.1016/j.intimp.2018.04.016] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 03/21/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
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Ezhilarasan D. Oxidative stress is bane in chronic liver diseases: Clinical and experimental perspective. Arab J Gastroenterol 2018; 19:56-64. [PMID: 29853428 DOI: 10.1016/j.ajg.2018.03.002] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 12/09/2016] [Accepted: 03/08/2018] [Indexed: 02/06/2023]
Abstract
Oxidative stress plays an important role in the pathogenesis of various chronic liver diseases (CLD) and increasing evidence have confirmed the contributory role of oxidative stress in the pathogenesis of drugs and chemical-induced CLD. Chronic liver injury is manifested as necrosis, cholestasis, fibrosis, and cirrhosis. Chronic administration of anti-tubercular, anti-retroviral, immunosuppressive drugs is reported to induce free radical generation during their biotransformation in the liver. Further, these reactive intermediates are said to induce profibrogenic cytokines, several inflammatory markers, collagen synthesis during the progression of hepatic fibrosis. Oxidative stress and free radicals are reported to induce activation and proliferation of hepatic stellate cells in the injured liver leading to the progression of CLD. Hence, to counteract or to scavenge these reactive intermediates, several plant-derived antioxidant principles have been effectively employed against oxidative stress and came out with promising results in human and experimental models of CLD. This review summarizes the relationships between oxidative stress and different liver pathogenesis induced by drugs and xenobiotics, focusing upon different chronic liver injury induced by alcohol, antitubercular drugs and hyperactivity of antiretroviral drugs in HIV patients, viral hepatitis infection induced oxidative stress.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Saveetha Dental College, Saveetha Institue of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu-600 077, India.
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Mani SKK, Andrisani O. Hepatitis B Virus-Associated Hepatocellular Carcinoma and Hepatic Cancer Stem Cells. Genes (Basel) 2018; 9:genes9030137. [PMID: 29498629 PMCID: PMC5867858 DOI: 10.3390/genes9030137] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 02/23/2018] [Accepted: 02/23/2018] [Indexed: 02/06/2023] Open
Abstract
Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, destined to develop liver cancer. Thus, new therapeutic approaches are needed to target essential pathways involved in HCC pathogenesis. Accumulating evidence supports existence of hepatic cancer stem cells (hCSCs), which contribute to chemotherapy resistance and cancer recurrence after treatment or surgery. Understanding how hCSCs form will enable development of therapeutic strategies to prevent their formation. Recent studies have identified an epigenetic mechanism involving the downregulation of the chromatin modifying Polycomb Repressive Complex 2 (PRC2) during HBV infection, which results in re-expression of hCSC marker genes in infected hepatocytes and HBV-associated liver tumors. However, the genesis of hCSCs requires, in addition to the expression of hCSC markers cellular changes, rewiring of metabolism, cell survival, escape from programmed cell death, and immune evasion. How these changes occur in chronically HBV-infected hepatocytes is not yet understood. In this review, we will present the basics about HBV infection and hepatocarcinogenesis. Next, we will discuss studies describing the mutational landscape of liver cancers and how epigenetic mechanisms likely orchestrate cellular reprograming of hepatocytes to enable formation of hCSCs.
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Affiliation(s)
- Saravana Kumar Kailasam Mani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
| | - Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
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Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Fatty Liver Disease. ZAKIM AND BOYER'S HEPATOLOGY 2018:369-390.e14. [DOI: 10.1016/b978-0-323-37591-7.00025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Li J, Hu R, Xu S, Li Y, Qin Y, Wu Q, Xiao Z. Xiaochaihutang attenuates liver fibrosis by activation of Nrf2 pathway in rats. Biomed Pharmacother 2017; 96:847-853. [DOI: 10.1016/j.biopha.2017.10.065] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/09/2017] [Accepted: 10/14/2017] [Indexed: 12/11/2022] Open
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Brar TS, Hilgenfeldt E, Soldevila-Pico C. Etiology and Pathogenesis of Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/978-3-319-68082-8_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Paired related homeobox protein 1 regulates PDGF-induced chemotaxis of hepatic stellate cells in liver fibrosis. J Transl Med 2017; 97:1020-1032. [PMID: 28737764 DOI: 10.1038/labinvest.2017.65] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/16/2017] [Accepted: 05/03/2017] [Indexed: 01/27/2023] Open
Abstract
Activation of the platelet-derived growth factor (PDGF)/PDGF beta receptor (PDGFβR) axis has a critical role in liver fibrosis. However, the mechanisms that regulate the PDGF signaling are yet to be elucidated. The present study demonstrates that paired related homeobox protein 1 (Prrx1) is involved in PDGF-dependent hepatic stellate cell (HSCs) migration via modulation of the expression of metalloproteinases MMP2 and MMP9. PDGF elevated the level of Prrx1 through the activation of ERK/Sp1 and PI3K/Akt/Ets1 pathways. In vivo, an adenoviral-mediated Prrx1 shRNA administration attenuated liver fibrosis in thioacetamide-induced fibrotic models. These studies reveal a role of Prrx1 as a modulator of PDGF-dependent signaling in HSCs, and inhibiting its expression may offer a therapeutic approach for hepatic fibrosis.
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Casas-Grajales S, Vázquez-Flores LF, Ramos-Tovar E, Hernández-Aquino E, Flores-Beltrán RE, Cerda-García-Rojas CM, Camacho J, Shibayama M, Tsutsumi V, Muriel P. Quercetin reverses experimental cirrhosis by immunomodulation of the proinflammatory and profibrotic processes. Fundam Clin Pharmacol 2017; 31:610-624. [PMID: 28802065 DOI: 10.1111/fcp.12315] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 07/07/2017] [Accepted: 08/09/2017] [Indexed: 12/14/2022]
Abstract
The ability of quercetin to reverse an established cirrhosis has not yet been investigated. Therefore, the aim of this study was to examine the efficacy of this flavonoid in reversing experimental cirrhosis. Cirrhosis was induced by intraperitoneal administration of TAA (200 mg/kg of body weight) three times per week for 8 weeks or by intraperitoneal petrolatum-CCl4 (400 mg/kg of body weight) administration three times per week for 8 weeks. To determine the capacity of quercetin to prevent liver fibrosis, the flavonoid (50 mg/kg of body weight, p.o.) was administered daily to rats during the CCl4 or TAA treatment. To evaluate the ability of quercetin to reverse the previously induced cirrhosis, we first treated rats with CCl4 for 8 weeks, as previously described and then the flavonoid was administered for four more weeks. We found that the liver anti-inflammatory and antinecrotic effects of quercetin are associated with its antioxidant properties, to the ability of the flavonoid to block NF-κB activation and in consequence to reduce cytokine IL-1. The ability of quercetin to reverse fibrosis may be associated with the capacity of the flavonoid to decrease TGF-β levels, hepatic stellate cell activation, and to promote degradation of the ECM by increasing metalloproteinases. The main conclusion is that quercetin, in addition to its liver protective activity against TAA chronic intoxication, is also capable of reversing a well-stablished cirrhosis by blocking the prooxidant processes and by downregulating the inflammatory and profibrotic responses.
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Affiliation(s)
- Sael Casas-Grajales
- Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Luis F Vázquez-Flores
- Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Erika Ramos-Tovar
- Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Erika Hernández-Aquino
- Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Rosa E Flores-Beltrán
- Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Carlos M Cerda-García-Rojas
- Department of Chemistry, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Javier Camacho
- Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Mineko Shibayama
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Víctor Tsutsumi
- Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
| | - Pablo Muriel
- Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado postal 14-740, Mexico City, Mexico
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Effect of Nitric Oxide on Human Corneal Epithelial Cell Viability and Corneal Wound Healing. Sci Rep 2017; 7:8093. [PMID: 28808342 PMCID: PMC5556055 DOI: 10.1038/s41598-017-08576-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 07/14/2017] [Indexed: 01/05/2023] Open
Abstract
Although the wound healing effects of nitric oxide (NO) are known, the mechanism by which NO modulates corneal wound healing remains unclear. In this study, we investigated the effect of exogenous NO donor (NaNO2) on corneal wound healing. We found that NaNO2 (0.1 μM to 100 μM) increased human corneal epithelial cell (HCEC) viability and migration. It also modulated the phosphorylation of mitogen-activated protein kinases (MAPKs) in a time- dependent manner in those HCECs. Further, p38 MAPK phosphorylation increased at 6 h and normalized at 24 h, while the phosphorylation of extracellular signal regulated kinase (ERK) was increased both at 6 h and 24 h. Topical treatment with NaNO2 (10 μM) enhanced corneal epithelial healing and decreased corneal opacity in murine corneal alkali burn model by modulating inflammatory cytokines. Our findings suggest that NO increased HCEC proliferation and migration via time-dependent MAPK activation and eventually enhanced corneal recovery from the alkali burn.
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El-Tanbouly DM, Wadie W, Sayed RH. Modulation of TGF-β/Smad and ERK signaling pathways mediates the anti-fibrotic effect of mirtazapine in mice. Toxicol Appl Pharmacol 2017. [DOI: 10.1016/j.taap.2017.06.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Li L, Bao X, Zhang QY, Negishi M, Ding X. Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice. Drug Metab Dispos 2017; 45:977-981. [PMID: 28546505 PMCID: PMC5518717 DOI: 10.1124/dmd.117.076406] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 05/23/2017] [Indexed: 11/22/2022] Open
Abstract
Phenobarbital (PB) promotes liver tumorigenesis in rodents, in part through activation of the constitutive androstane receptor (CAR) and the consequent changes in hepatic gene expression and increases in hepatocyte proliferation. A typical effect of CAR activation by PB is a marked induction of Cyp2b10 expression in the liver; the latter has been suspected to be vital for PB-induced hepatocellular proliferation. This hypothesis was tested here by using a Cyp2a(4/5)bgs-null (null) mouse model in which all Cyp2b genes are deleted. Adult male and female wild-type (WT) and null mice were treated intraperitoneally with PB at 50 mg/kg once daily for 5 successive days and tested on day 6. The liver-to-body weight ratio, an indicator of liver hypertrophy, was increased by 47% in male WT mice, but by only 22% in male Cyp2a(4/5)bgs-null mice, by the PB treatment. The fractions of bromodeoxyuridine-positive hepatocyte nuclei, assessed as a measure of the rate of hepatocyte proliferation, were also significantly lower in PB-treated male null mice compared with PB-treated male WT mice. However, whereas few proliferating hepatocytes were detected in saline-treated mice, many proliferating hepatocytes were still detected in PB-treated male null mice. In contrast, female WT mice were much less sensitive than male WT mice to PB-induced hepatocyte proliferation, and PB-treated female WT and PB-treated female null mice did not show significant difference in rates of hepatocyte proliferation. These results indicate that CYP2B induction plays a significant, but partial, role in PB-induced hepatocyte proliferation in male mice.
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Affiliation(s)
- Lei Li
- College of Nanoscale Science, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.); Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (L.L., X.B., Q.Z., X.D.); and National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (M.N.)
| | - Xiaochen Bao
- College of Nanoscale Science, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.); Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (L.L., X.B., Q.Z., X.D.); and National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (M.N.)
| | - Qing-Yu Zhang
- College of Nanoscale Science, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.); Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (L.L., X.B., Q.Z., X.D.); and National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (M.N.)
| | - Masahiko Negishi
- College of Nanoscale Science, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.); Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (L.L., X.B., Q.Z., X.D.); and National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (M.N.)
| | - Xinxin Ding
- College of Nanoscale Science, SUNY Polytechnic Institute, Albany, New York (L.L., X.D.); Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (L.L., X.B., Q.Z., X.D.); and National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (M.N.)
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Rubio-Araiz A, Porcu F, Pérez-Hernández M, García-Gutiérrez MS, Aracil-Fernández MA, Gutierrez-López MD, Guerri C, Manzanares J, O'Shea E, Colado MI. Disruption of blood-brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model. Addict Biol 2017; 22:1103-1116. [PMID: 26949123 DOI: 10.1111/adb.12376] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 01/12/2016] [Accepted: 01/13/2016] [Indexed: 01/16/2023]
Abstract
Inflammatory cytokines and reactive oxygen species are reported to be involved in blood-brain barrier (BBB) disruption. Because there is evidence that ethanol (EtOH) induces release of free radicals, cytokines and inflammatory mediators we examined BBB integrity and matrix metalloproteinase (MMP) activity in postmortem human alcoholic brain and investigated the role of TLR4 signaling in BBB permeability in TLR4-knockout mice under a binge-like EtOH drinking protocol. Immunohistochemical studies showed reduced immunoreactivity of the basal lamina protein, collagen-IV and of the tight junction protein, claudin-5 in dorsolateral prefrontal cortex of alcoholics. There was also increased MMP-9 activity and expression of phosphorylated ERK1/2 and p-38. Greater number of CD45+ IR cells were observed associated with an enhanced neuroinflammatory response reflected by increased GFAP and Iba-1 immunostaining. To further explore effects of high EtOH consumption on BBB integrity we studied TLR4-knockout mice exposed to the drinking in the dark paradigm. Repetitive EtOH exposure in wild-type mice decreased hippocampal expression of laminin and collagen-IV and increased IgG immunoreactivity, indicating IgG extravasation. Western blot analysis also revealed increased MyD88 and p-ERK1/2 levels. None of these changes was observed in TLR4-knockout mice. Collectively, these findings indicate that chronic EtOH increases degradation of tight junctions and extracellular matrix in postmortem human brain and induces a neuroinflammatory response associated with activation of ERK1/2 and p-38 and greater MMP-9 activity. The EtOH-induced effects on BBB impairment are not evident in the hippocampus of TLR4-knockout mice, suggesting the involvement of TLR4 signaling in the underlying mechanism leading to BBB disruption in mice.
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Affiliation(s)
- Ana Rubio-Araiz
- Departamento de Farmacología, Facultad de Medicina; Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - Francesca Porcu
- Departamento de Farmacología, Facultad de Medicina; Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - Mercedes Pérez-Hernández
- Departamento de Farmacología, Facultad de Medicina; Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - Mª Salud García-Gutiérrez
- Instituto de Neurociencias, Campus de San Juan; Universidad Miguel Hernández-CSIC; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - María Auxiliadora Aracil-Fernández
- Instituto de Neurociencias, Campus de San Juan; Universidad Miguel Hernández-CSIC; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - María Dolores Gutierrez-López
- Departamento de Farmacología, Facultad de Medicina; Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - Consuelo Guerri
- Departamento de Patología Celular; Centro de Investigación Príncipe Felipe; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - Jorge Manzanares
- Instituto de Neurociencias, Campus de San Juan; Universidad Miguel Hernández-CSIC; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - Esther O'Shea
- Departamento de Farmacología, Facultad de Medicina; Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
| | - María Isabel Colado
- Departamento de Farmacología, Facultad de Medicina; Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre; Spain
- Red de Trastornos Adictivos del Instituto de Salud Carlos III; Spain
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Hasan HF, Abdel-Rafei MK, Galal SM. Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-γ expression and hampering miR-17-5p-activated canonical Wnt-β-catenin signaling. Biochem Cell Biol 2016; 95:400-414. [PMID: 28177765 DOI: 10.1139/bcb-2016-0142] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Liver fibrosis is one of the major complications from upper right quadrant radiotherapy. MicroRNA-17-5p (miR-17-5p) is hypothesized to act as a regulator of hepatic stellate cell (HSCs) activation by activation of the canonical Wnt-β-catenin pathway. Diosmin (Dios), a citrus bioflavonoid, is known to possess potent antioxidant, anti-inflammatory, and anti-apoptotic properties. PURPOSE To explore the molecular mechanisms that underlie radiation-induced liver fibrosis, and to evaluate the possible influence of Dios on the miR-17-5p-Wnt-β-catenin signaling axis during fibrogenesis provoked by irradiation (IRR) in rats. Also, the effect of Dios on hepatic peroxisome proliferator activated receptor-γ (PPAR-γ) expression as a regulator for HSC activation was considered. METHODS We administered 100 mg·(kg body mass)-1·day-1 (per oral) of Dios were administered to IRR-exposed rats (overall dose of 12 Gy on 6 fractions of 2 Gy each) for 6 successive weeks. RESULTS Data analysis revealed that Dios treatment mitigated oxidative stress, enhanced antioxidant defenses, alleviated hepatic inflammatory responses, abrogated pro-fibrogenic cytokines, and stimulated PPAR-γ expression. Dios treatment repressed the miR-17-5p activated Wnt-β-catenin signaling induced by IRR. Moreover, Dios treatment restored the normal hepatic architecture and reversed pathological alterations induced by IRR. CONCLUSION We hypothesize that the stimulation of PPAR-γ expression and interference with miR-17-5p activated Wnt-β-catenin signaling mediates the antifibrotic properties of Dios.
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Affiliation(s)
- Hesham Farouk Hasan
- a Radiation Biology Department, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, PO Box 29, Nasr City, Cairo, Egypt
| | - Mohamed Khairy Abdel-Rafei
- a Radiation Biology Department, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, PO Box 29, Nasr City, Cairo, Egypt
| | - Shereen Mohamed Galal
- b Health Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Atomic Energy Authority, PO Box 29, Nasr City, Cairo, Egypt
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Elsakkar MG, Eissa MM, Hewedy WA, Nassra RM, Elatrebi SF. Sodium valproate, a histone deacetylase inhibitor, with praziquantel ameliorates Schistosoma mansoni-induced liver fibrosis in mice. Life Sci 2016; 162:95-101. [PMID: 27528511 DOI: 10.1016/j.lfs.2016.08.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 08/07/2016] [Accepted: 08/10/2016] [Indexed: 11/17/2022]
Abstract
AIMS This study explores the potential antifibrotic effect of sodium valproate (SV), an inhibitor of class I histone deacetylase (HDAC) enzymes, and/or praziquantel (PZQ) on Schistosoma mansoni (S. mansoni)-induced liver fibrosis in mice. MAIN METHODS Male Swiss albino mice were divided into nine groups: group I- normal control (NC); group II- uninfected gum mucilage (GM) treated; group III- uninfected PZQ- treated; group IV- uninfected SV-treated; group V- control S. mansoni infected mice; group VI- infected GM-treated; group VII- infected PZQ-treated; group VIII- infected SV-treated; group IX- infected PZQ+SV treated. All SV administrations were 300mg/kg/day orally and administered for five weeks beginning on the 5th week post infection (WPI). All PZQ administrations were 500mg/kg/day orally and administered for 2 consecutive days beginning on the 7th WPI. Serum transforming growth factor-beta 1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), hepatic hydroxyproline (Hyp) content, and liver function tests (AST and ALT) were determined. Specimens of the hepatic tissues were examined histologically. KEY FINDINGS Treatment of S. mansoni-infected mice with SV significantly decreased the serum levels of ALT, TGF-β1 and TNF-α, and the liver tissue hydroxyproline content compared with the S. mansoni infected untreated groups. Histologically, treatment with SV revealed regression of the granulomatous inflammatory reaction. Combined treatment with PZQ and SV produces more favorable biochemical results, and aborted granulomatous reaction compared with either drug alone. SIGNIFICANCE Sodium valproate is a promising anti-fibrotic agent. It demonstrated an anti-fibrotic effect in early stages of S. mansoni infection through downregulation of profibrogenic cytokines, and collagen deposition.
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Affiliation(s)
- Mohamed G Elsakkar
- Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Maha M Eissa
- Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Wafaa A Hewedy
- Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Rasha M Nassra
- Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Soha F Elatrebi
- Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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50
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Silymarin preconditioning protected insulin resistant rats from liver ischemia-reperfusion injury: role of endogenous H2S. J Surg Res 2016; 204:398-409. [DOI: 10.1016/j.jss.2016.04.069] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 04/21/2016] [Accepted: 04/28/2016] [Indexed: 12/26/2022]
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