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Liu Y, Yuan J, Xi W, Wang Z, Liu H, Zhang K, Zhao J, Wang Y. Lactiplantibacillus plantarum Ameliorated Morphological Damage and Barrier Dysfunction and Reduced Apoptosis and Ferroptosis in the Jejunum of Oxidatively Stressed Piglets. Animals (Basel) 2024; 14:3335. [PMID: 39595387 PMCID: PMC11591186 DOI: 10.3390/ani14223335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/15/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024] Open
Abstract
Oxidative stress induces apoptosis and ferroptosis, leading to intestinal injury of piglets. Lactiplantibacillus plantarum P8 (P8) has antioxidant capacity, but its roles in intestinal apoptosis and ferroptosis remain unclear. Here, 24 weaned piglets were assigned to three treatments: control (Con), diquat injection (DQ), and P8 supplementation + DQ injection (DQ + P8). The results showed that the increased jejunal oxidative stress, jejunal morphology impairment, and barrier dysfunction in the DQ-treated piglets were decreased by P8 supplementation. TUNEL and apoptosis-related gene expressions showed increased jejunal apoptosis of DQ-treated piglets; however, reduced apoptosis was observed in the DQ + P8 group. In addition, the mitochondrial morphology and ferroptosis-related gene expressions indicated elevated jejunal ferroptosis in the DQ-treated piglets, and the DQ + P8 treatment attenuated the ferroptosis. Transcriptome identified various differentially expressed genes (DEGs) between different treatments. KEGG analysis indicated that the DEGs were enriched in the PI3K-AKT, NF-κB, and apoptosis pathways. The expressions of key DEGs and key proteins in the PI3K-AKT and NF-κB pathways were further verified. In summary, our results indicate that P8 supplementation ameliorated jejunal oxidative stress, morphological damage, barrier dysfunction, apoptosis, and ferroptosis in the DQ-treated piglets. Moreover, the beneficial effect of P8 may be related to the regulation of PI3K/AKT and NF-κB pathways.
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Affiliation(s)
| | | | | | | | | | | | | | - Yang Wang
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China; (Y.L.); (J.Y.); (W.X.); (Z.W.); (H.L.); (K.Z.); (J.Z.)
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Danielpour D. Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective. Pharmaceuticals (Basel) 2024; 17:533. [PMID: 38675493 PMCID: PMC11054419 DOI: 10.3390/ph17040533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/11/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
The TGF-β family is a group of 25 kDa secretory cytokines, in mammals consisting of three dimeric isoforms (TGF-βs 1, 2, and 3), each encoded on a separate gene with unique regulatory elements. Each isoform plays unique, diverse, and pivotal roles in cell growth, survival, immune response, and differentiation. However, many researchers in the TGF-β field often mistakenly assume a uniform functionality among all three isoforms. Although TGF-βs are essential for normal development and many cellular and physiological processes, their dysregulated expression contributes significantly to various diseases. Notably, they drive conditions like fibrosis and tumor metastasis/progression. To counter these pathologies, extensive efforts have been directed towards targeting TGF-βs, resulting in the development of a range of TGF-β inhibitors. Despite some clinical success, these agents have yet to reach their full potential in the treatment of cancers. A significant challenge rests in effectively targeting TGF-βs' pathological functions while preserving their physiological roles. Many existing approaches collectively target all three isoforms, failing to target just the specific deregulated ones. Additionally, most strategies tackle the entire TGF-β signaling pathway instead of focusing on disease-specific components or preferentially targeting tumors. This review gives a unique historical overview of the TGF-β field often missed in other reviews and provides a current landscape of TGF-β research, emphasizing isoform-specific functions and disease implications. The review then delves into ongoing therapeutic strategies in cancer, stressing the need for more tools that target specific isoforms and disease-related pathway components, advocating mechanism-based and refined approaches to enhance the effectiveness of TGF-β-targeted cancer therapies.
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Affiliation(s)
- David Danielpour
- Case Comprehensive Cancer Center Research Laboratories, The Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, OH 44106, USA; ; Tel.: +1-216-368-5670; Fax: +1-216-368-8919
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA
- Institute of Urology, University Hospitals, Cleveland, OH 44106, USA
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Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther 2024; 9:61. [PMID: 38514615 PMCID: PMC10958066 DOI: 10.1038/s41392-024-01764-w] [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: 12/07/2022] [Revised: 08/31/2023] [Accepted: 01/31/2024] [Indexed: 03/23/2024] Open
Abstract
Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses and is particularly critical to embryonic development, wound healing, tissue homeostasis, and immune homeostasis in health. The dysfunction of TGF-β can play key roles in many diseases, and numerous targeted therapies have been developed to rectify its pathogenic activity. In the past decades, a large number of studies on TGF-β signaling have been carried out, covering a broad spectrum of topics in health, disease, and therapeutics. Thus, a comprehensive overview of TGF-β signaling is required for a general picture of the studies in this field. In this review, we retrace the research history of TGF-β and introduce the molecular mechanisms regarding its biosynthesis, activation, and signal transduction. We also provide deep insights into the functions of TGF-β signaling in physiological conditions as well as in pathological processes. TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted. Through the summary of previous knowledge and recent updates, this review aims to provide a systematic understanding of TGF-β signaling and to attract more attention and interest to this research area.
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Affiliation(s)
- Ziqin Deng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chu Xiao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yujia Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Medina Pizaño MY, Loera Arias MDJ, Montes de Oca Luna R, Saucedo Cárdenas O, Ventura Juárez J, Muñoz Ortega MH. Neuroimmunomodulation of adrenoblockers during liver cirrhosis: modulation of hepatic stellate cell activity. Ann Med 2023; 55:543-557. [PMID: 36826975 PMCID: PMC9970206 DOI: 10.1080/07853890.2022.2164047] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
The sympathetic nervous system and the immune system are responsible for producing neurotransmitters and cytokines that interact by binding to receptors; due to this, there is communication between these systems. Liver immune cells and nerve fibres are systematically distributed in the liver, and the partial overlap of both patterns may favour interactions between certain elements. Dendritic cells are attached to fibroblasts, and nerve fibres are connected via the dendritic cell-fibroblast complex. Receptors for most neuroactive substances, such as catecholamines, have been discovered on dendritic cells. The sympathetic nervous system regulates hepatic fibrosis through sympathetic fibres and adrenaline from the adrenal glands through the blood. When there is liver damage, the sympathetic nervous system is activated locally and systemically through proinflammatory cytokines that induce the production of epinephrine and norepinephrine. These neurotransmitters bind to cells through α-adrenergic receptors, triggering a cellular response that secretes inflammatory factors that stimulate and activate hepatic stellate cells. Hepatic stellate cells are key in the fibrotic process. They initiate the overproduction of extracellular matrix components in an active state that progresses from fibrosis to liver cirrhosis. It has also been shown that they can be directly activated by norepinephrine. Alpha and beta adrenoblockers, such as carvedilol, prazosin, and doxazosin, have recently been used to reverse CCl4-induced liver cirrhosis in rodent and murine models.KEY MESSAGESNeurotransmitters from the sympathetic nervous system activate and increase the proliferation of hepatic stellate cells.Hepatic fibrosis and cirrhosis treatment might depend on neurotransmitter and hepatic nervous system regulation.Strategies to reduce hepatic stellate cell activation and fibrosis are based on experimentation with α-adrenoblockers.
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Affiliation(s)
| | | | | | - Odila Saucedo Cárdenas
- Histology Department, Faculty of Medicine, Autonomous University of Nuevo León, Monterrey, México
| | - Javier Ventura Juárez
- Department of Morphology, Autonomous University of Aguascalientes, Aguascalientes, México
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Sharma A, Wang J, Gandhi CR. CD14 is not required for carbon tetrachloride-induced hepatic inflammation and fibrosis with or without lipopolysaccharide challenge. J Cell Physiol 2023; 238:1530-1541. [PMID: 37098757 DOI: 10.1002/jcp.31030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 04/05/2023] [Accepted: 04/11/2023] [Indexed: 04/27/2023]
Abstract
Binding of lipopolysaccharide (LPS) to CD14 is required for its cellular effects via TLR4. A role of LPS/TLR4-mediated signaling in activated hepatic stellate cells (aHSCs), the major fibrogenic cells, in liver fibrosis has been reported. We investigated effects of LPS on carbon tetrachloride (CCl4)-induced fibrosis in CD14-knockout (KO) mice in vivo, and culture-activated HSCs in vitro. CCl4 (biweekly; 4 weeks)-treated wild type (WT) and CD14-KO mice were challenged with single LPS administration for 24 h. Liver injury, inflammation and fibrosis were determined. Culture-activated HSCs from WT or CD14-KO mice were stimulated with LPS. Parameters of fibrogenic activity (expression of collagen1a1 [Col1a1], α-smooth muscle actin [αSMA] and TGFβ1) and inflammatory cytokines/chemokines were measured. CCl4 treatment caused similar liver injury and fibrosis in WT and CD14-KO mice. LPS increased liver injury and inflammation similarly in CCl4-treated WT and CD14-KO mice, but downregulated Timp1 and upregulated Mmp13. LPS elicited similar NFκB activation and inflammatory response in WT and CD14-KO aHSCs. LPS similarly downregulated Acta2 (encodes αSMA), Pdgfrb, Col1a1 and Mmp13 expression but did not affect Timp1 expression in WT and CD14-KO aHSCs. LPS did not alter Tgfb1 but increased expression of decorin (Dcn) (inhibitor of TGFβ1) expression in WT and CD14-KO aHSCs. The results indicate that the effects of LPS on HSCs are CD14-independent, and CD14 is not required for hepatic fibrosis. LPS-induced down-modulation of fibrogenic markers in aHSCs is also CD14-independent.
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Affiliation(s)
- Akanksha Sharma
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jiang Wang
- Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Chandrashekhar R Gandhi
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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Wan G, Chen Z, Lei L, Geng X, Zhang Y, Yang C, Cao W, Pan Z. The total polyphenolic glycoside extract of Lamiophlomis rotata ameliorates hepatic fibrosis through apoptosis by TGF-β/Smad signaling pathway. Chin Med 2023; 18:20. [PMID: 36829153 PMCID: PMC9951520 DOI: 10.1186/s13020-023-00723-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 02/07/2023] [Indexed: 02/26/2023] Open
Abstract
BACKGROUND Hepatic fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) which is mainly secreted by activated hepatic stellate cells (HSCs). Lamiophlomis rotata (L. rotata) was recorded to treat jaundice in the traditional Tibetan medical system with the potential of hepatoprotection. However, the bioactivities and the possible mechanism of L. rotata on hepatic fibrosis is still largely unknown. AIM OF THE STUDY To investigate the anti-hepatic fibrosis effects of bioactivities in L. rotata and the probable mechanism of action. MATERIALS AND METHODS Herein, total polyphenolic glycosides of L. rotata (TPLR) was purified with the selectivity adsorption resin and was analyzed by ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-Q/TOF/MSn). The anti-hepatic fibrosis effect of TPLR was evaluated by carbon tetrachloride (CCl4)-induced liver fibrosis, and was evaluated with the apoptosis of activated HSCs. RESULTS In total, sixteen compounds, including nine phenylpropanoids and six flavonoids, were identified in the UPLC-TOF-MSn profile of the extracts. TPLR significantly ameliorated hepatic fibrosis in CCl4-induced mice and inhibited HSCs proliferation, Moreover, TPLR notably increased the apoptosis of activated HSCs along with up-regulated caspase-3, -8, -9, and -10. Furthermore, TPLR inhibited TGF-β/Smad pathway ameliorating hepatic fibrosis though downregulation the expression of Smad2/3, Smad4, and upregulation the expression of Smad7 in vivo and in vitro. Simultaneously, the expression of fibronectin (FN), α-smooth muscle actin (α-SMA), and Collagen I (Col1α1) were decreased in tissues and in cells with TPLR administration. CONCLUSION These results initially demonstrated that TPLR has the potential to ameliorate hepatic fibrosis through an apoptosis mechanism via TGF-β/Smad signaling pathway.
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Affiliation(s)
- Guoguo Wan
- grid.203458.80000 0000 8653 0555Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Zhiwei Chen
- grid.203458.80000 0000 8653 0555Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Lei Lei
- grid.203458.80000 0000 8653 0555Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Xiaoyu Geng
- grid.203458.80000 0000 8653 0555Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Yi Zhang
- grid.411304.30000 0001 0376 205XCentre for Academic Inheritance and Innovation of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130 China
| | - Congwen Yang
- grid.203458.80000 0000 8653 0555Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Wenfu Cao
- grid.203458.80000 0000 8653 0555Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016 People’s Republic of China
| | - Zheng Pan
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People's Republic of China.
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Kharbanda KK, Chokshi S, Tikhanovich I, Weinman SA, New-Aaron M, Ganesan M, Osna NA. A Pathogenic Role of Non-Parenchymal Liver Cells in Alcohol-Associated Liver Disease of Infectious and Non-Infectious Origin. BIOLOGY 2023; 12:255. [PMID: 36829532 PMCID: PMC9953685 DOI: 10.3390/biology12020255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023]
Abstract
Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on the activity and properties of liver non-parenchymal cells (NPCs), which are either residential or infiltrated into the liver from the general circulation. NPCs play a pivotal role in the regulation of organ inflammation and fibrosis, both in the context of hepatotropic infections and in non-infectious settings. Here, we overview how NPC functions in ALD are regulated by second hits, such as gender and the exposure to bacterial or viral infections. As an example of the virus-mediated trigger of liver injury, we focused on HIV infections potentiated by alcohol exposure, since this combination was only limitedly studied in relation to the role of hepatic stellate cells (HSCs) in the development of liver fibrosis. The review specifically focusses on liver macrophages, HSC, and T-lymphocytes and their regulation of ALD pathogenesis and outcomes. It also illustrates the activation of NPCs by the engulfment of apoptotic bodies, a frequent event observed when hepatocytes are exposed to ethanol metabolites and infections. As an example of such a double-hit-induced apoptotic hepatocyte death, we deliberate on the hepatotoxic accumulation of HIV proteins, which in combination with ethanol metabolites, causes intensive hepatic cell death and pro-fibrotic activation of HSCs engulfing these HIV- and malondialdehyde-expressing apoptotic hepatocytes.
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Affiliation(s)
- Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Shilpa Chokshi
- Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King’s College London, London SE5 8AF, UK
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO 66160, USA
| | - Steven A. Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO 66160, USA
- Research Service, Kansas City Veterans Administration Medical Center, Kansas City, MO 64128, USA
| | - Moses New-Aaron
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Mostafa-Hedeab G, Ewaiss Hassan M, F. Halawa T, Ahmed Wani ِF. Epigallocatechin gallate ameliorates tetrahydrochloride-induced liver toxicity in rats via inhibition of TGFβ / p-ERK/p-Smad1/2 signaling, antioxidant, anti-inflammatory activity. Saudi Pharm J 2022; 30:1293-1300. [PMID: 36249942 PMCID: PMC9563045 DOI: 10.1016/j.jsps.2022.06.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 06/17/2022] [Indexed: 11/25/2022] Open
Abstract
Chronic liver disease is a worldwide health problem. Carbon tetra hydrochloride is an environmental toxin which is regarded as highly toxic and a potential human carcinogen. It can cause liver damage through the generation of metabolites and production of free radicals. Green tea contains catechins such as Epigallocatechin gallate which has been found to reduce the inflammation, oxidative stress, and fibrosis in experimental animal models. Hence, it represents a good source to prevent or ameliorate several chronic diseases. Silymarin is extracted from milk thistle seeds and has been found to be an effective agent to reduce the oxidative stress and free radical production and thereby exert protective effects in chronic liver conditions. The present study was planned to keep in view the above-mentioned facts. We included thirty rats in our study and divided them into five groups, each having six rats and the study continued for 8 weeks. Group I received normal saline; Group 2 received i.p. CCl4 injections; Group 3 received CCl4 i.p. injection and Epigallocatechin gallate (EGCG) oral gavage, Group 4 received CCl4 i.p. injection and silymarin by oral gavage; and Group 5 received CCl4 i.p. injection and combined EGCG + silymarin by oral gavage. The study found that in group 2, CCl4 induced significant elevation of ALT and MDA and reduced GSH thereby signifying increased oxidative stress. CCl4 also significantly increased inflammatory (TNFα, NFκB, IL1β, and TGFβ) as well as fibrotic markers (p-ERK and p-Smad1/2 protein expression). EGCG and silymarin significantly reversed the previously mentioned parameters either alone or in combination; however, the effect was more pronounced in case of EGCG. We conclude that EGCG and silymarin possess liver protective effects through their antioxidant, anti-inflammatory, and antifibrotic action.
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Liu ZW, Zhang YM, Zhang LY, Zhou T, Li YY, Zhou GC, Miao ZM, Shang M, He JP, Ding N, Liu YQ. Duality of Interactions Between TGF-β and TNF-α During Tumor Formation. Front Immunol 2022; 12:810286. [PMID: 35069596 PMCID: PMC8766837 DOI: 10.3389/fimmu.2021.810286] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 12/09/2021] [Indexed: 12/14/2022] Open
Abstract
The tumor microenvironment is essential for the formation and development of tumors. Cytokines in the microenvironment may affect the growth, metastasis and prognosis of tumors, and play different roles in different stages of tumors, of which transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α) are critical. The two have synergistic and antagonistic effect on tumor regulation. The inhibition of TGF-β can promote the formation rate of tumor, while TGF-β can promote the malignancy of tumor. TNF-α was initially determined to be a natural immune serum mediator that can induce tumor hemorrhagic necrosis, it has a wide range of biological activities and can be used clinically as a target to immune diseases as well as tumors. However, there are few reports on the interaction between the two in the tumor microenvironment. This paper combs the biological effect of the two in different aspects of different tumors. We summarized the changes and clinical medication rules of the two in different tissue cells, hoping to provide a new idea for the clinical application of the two cytokines.
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Affiliation(s)
- Zhi-Wei Liu
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yi-Ming Zhang
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China
| | - Li-Ying Zhang
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China.,Gansu Institute of Cardiovascular Diseases, The First People's Hospital of Lanzhou City, Lanzhou, China
| | - Ting Zhou
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yang-Yang Li
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China
| | - Gu-Cheng Zhou
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China
| | - Zhi-Ming Miao
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China
| | - Ming Shang
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jin-Peng He
- Key Laboratory of Space Radiobiology of Gansu Province & Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Nan- Ding
- Key Laboratory of Space Radiobiology of Gansu Province & Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Yong-Qi Liu
- Provincial-Level Key Laboratory for Molecular Medicine of Major Diseases and The Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and Universities, Gansu University of Chinese Medicine, Lanzhou, China.,Key Laboratory of Dunhuang Medicine and Transformation at Provincial and Ministerial Level, Gansu University of Chinese Medicine, Lanzhou, China
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The Effects of Freshwater Clam ( Corbicula fluminea) Extract on Activated Hepatic Stellate Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6065168. [PMID: 34804181 PMCID: PMC8604581 DOI: 10.1155/2021/6065168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/16/2021] [Accepted: 10/20/2021] [Indexed: 11/22/2022]
Abstract
Background The extract of freshwater clams has been used to protect the body against liver diseases in traditional folk medicine. This study aims at investigating the effects of freshwater clam extract on activated hepatic stellate cells (aHSCs), which are critical contributors to liver fibrosis. Methods The aHSCs used in this study were derived from hepatic stellate cells that were isolated and purified from the livers of male Wistar rats and then transformed into the activated phenotype by culturing on uncoated plastic dishes. Freshwater clam extract (CE) was collected after the outflow from the live freshwater clams in a water bath at 100°C for 60 min. The effects of CE on aHSCs were analyzed by MTT assay, flow cytometry, Oil Red O (ORO) staining, western blot, and real-time RT-PCR. Results The results indicated that CE suppressed the proliferation of aHSCs through G0/G1 cell cycle arrest by downregulating cyclin D1 and upregulating p27. The expression levels of a-SMA, collagen I, TGF-β, and TNF-α were inhibited in the CE-treated aHSCs. In addition, the CE treatment increased the lipid contents in aHSCs by promoting PPARγ expression. Furthermore, CE modulated the expression of ECM-related genes, i.e., by upregulating MMP-9 and downregulating TIMP-II. Conclusions These data revealed that CE could induce the deactivation of aHSCs. We therefore suggest that CE has potential as an adjuvant therapeutic agent against hepatic fibrosis.
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11
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Jia F, Hu X, Kimura T, Tanaka N. Impact of Dietary Fat on the Progression of Liver Fibrosis: Lessons from Animal and Cell Studies. Int J Mol Sci 2021; 22:10303. [PMID: 34638640 PMCID: PMC8508674 DOI: 10.3390/ijms221910303] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023] Open
Abstract
Previous studies have revealed that a high-fat diet is one of the key contributors to the progression of liver fibrosis, and increasing studies are devoted to analyzing the different influences of diverse fat sources on the progression of non-alcoholic steatohepatitis. When we treated three types of isocaloric diets that are rich in cholesterol, saturated fatty acid (SFA) and trans fatty acid (TFA) with hepatitis C virus core gene transgenic mice that spontaneously developed hepatic steatosis without apparent fibrosis, TFA and cholesterol-rich diet, but not SFA-rich diet, displayed distinct hepatic fibrosis. This review summarizes the recent advances in animal and cell studies regarding the effects of these three types of fat on liver fibrogenesis.
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Affiliation(s)
- Fangping Jia
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
| | - Xiao Hu
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang 050017, China;
| | - Takefumi Kimura
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
- International Relations Office, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Research Center for Social Systems, Shinshu University, Matsumoto 390-8621, Japan
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12
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Peterson LS, Hedou J, Ganio EA, Stelzer IA, Feyaerts D, Harbert E, Adusumelli Y, Ando K, Tsai ES, Tsai AS, Han X, Ringle M, Houghteling P, Reiss JD, Lewis DB, Winn VD, Angst MS, Aghaeepour N, Stevenson DK, Gaudilliere B. Single-Cell Analysis of the Neonatal Immune System Across the Gestational Age Continuum. Front Immunol 2021; 12:714090. [PMID: 34497610 PMCID: PMC8420969 DOI: 10.3389/fimmu.2021.714090] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/02/2021] [Indexed: 12/21/2022] Open
Abstract
Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8+CD161+ T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections.
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Affiliation(s)
- Laura S Peterson
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Julien Hedou
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Edward A Ganio
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Ina A Stelzer
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Dorien Feyaerts
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Eliza Harbert
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Yamini Adusumelli
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Kazuo Ando
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Eileen S Tsai
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Amy S Tsai
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Xiaoyuan Han
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Megan Ringle
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Pearl Houghteling
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Jonathan D Reiss
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - David B Lewis
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Virginia D Winn
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, United States
| | - Martin S Angst
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Nima Aghaeepour
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States.,Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States.,Department of Biomedical Data Sciences, Stanford University School of Medicine, Stanford, CA, United States
| | - David K Stevenson
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
| | - Brice Gaudilliere
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States.,Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
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13
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Liu YL, Yang WH, Chen BY, Nie J, Su ZR, Zheng JN, Gong ST, Chen JN, Jiang D, Li Y. miR‑29b suppresses proliferation and induces apoptosis of hepatocellular carcinoma ascites H22 cells via regulating TGF‑β1 and p53 signaling pathway. Int J Mol Med 2021; 48:157. [PMID: 34184070 PMCID: PMC8249050 DOI: 10.3892/ijmm.2021.4990] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/11/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNA (miR)‑29b is a key tumor regulator. It can inhibit tumor cell proliferation, induce apoptosis, suppress tumor invasion and migration, thus delaying tumor progression. Our previous studies revealed an increased level of miR‑29b in hepatoma 22 (H22) cells in ascites tumor‑bearing mice. The present study investigated the effect of miR‑29b on proliferation and apoptosis of hepatocellular carcinoma ascites H22 cells and its association with the transforming growth factor‑β1 (TGF‑β1) signaling pathway and p53‑mediated apoptotic pathway. Briefly, H22 cells were transfected with miR‑29b‑3p (hereinafter referred to as miR‑29b) mimic or miR‑29b inhibitor. MTS cell proliferation assay and flow cytometry were used to analyze cell viability and apoptosis. The expression change of the TGF‑β1 signaling pathway and p53‑mediated apoptotic pathway were detected by reverse transcription‑quantitative PCR, western blotting and immunofluorescence. Furthermore, cells were treated with exogenous TGF‑β1 and TGF‑β1 small interfering RNA to evaluate the crosstalk between TGF‑β1 and p53 under miR‑29b regulation. The overexpression of miR‑29b decreased cell viability, increased cell apoptosis, activated the TGF‑β1 signaling pathway and p53‑mediated apoptotic pathway. Conversely, these effects were reversed by the miR‑29b inhibitor. Moreover, the effect of miR‑29b mimic was further increased after treating cells with exogenous TGF‑β1. The activation of the TGF‑β1 signaling pathway and p53‑mediated apoptotic pathway induced by miR‑29b overexpression were reversed by TGF‑β1 inhibition. In summary, these data indicated that miR‑29b has an important role in proliferation and apoptosis of H22 cells by regulating the TGF‑β1 signaling pathway, the p53‑dependent apoptotic pathway, and the crosstalk between TGF‑β1 and p53.
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Affiliation(s)
- Yan-Lu Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Wen-Hao Yang
- School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510006, P.R. China
- School of Medicine and Health, Shunde Polytechnic, Foshan, Guangdong 528300, P.R. China
| | - Bao-Yi Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Juan Nie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Zi-Ren Su
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Jing-Na Zheng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Shi-Ting Gong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Jian-Nan Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Dongbo Jiang
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524000, P.R. China
| | - Yucui Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
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14
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Yue Z, Jiang Z, Ruan B, Duan J, Song P, Liu J, Han H, Wang L. Disruption of myofibroblastic Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression. Int J Biol Sci 2021; 17:2135-2146. [PMID: 34239344 PMCID: PMC8241719 DOI: 10.7150/ijbs.60056] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 05/08/2021] [Indexed: 01/15/2023] Open
Abstract
The phenotypic transformation of hepatic myofibroblasts (MFs) is involved in the whole process of the progression and regression of liver fibrosis. Notch signaling has been demonstrated to modulate the fibrosis. In this study, we found that Notch signaling in MFs was overactivated and suppressed with the progression and regression of hepatic fibrosis respectively, by detecting Notch signaling readouts in MFs. Moreover, we inactivated Notch signaling specifically in MFs with Sm22αCreER-RBPjflox/flox mice (RBPjMF-KO), and identified that MFs-specific down-regulation of Notch signaling significantly alleviated CCl4-induced liver fibrosis during the progression and regression. During the progression of liver fibrosis, MFs-specific blockade of Notch signaling inhibited the activation of HSCs to MFs and increases the expression of MMPs to reduce the deposition of ECM. During the regression of fibrosis, blocking Notch signaling in MFs increased the expression of HGF to promote proliferation in hepatocytes and up-regulated the expression of pro-apoptotic factors, Ngfr and Septin4, to induce apoptosis of MFs, thereby accelerating the reversal of fibrosis. Collectively, the MFs-specific disruption of Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression, which suggests a promising therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Zhensheng Yue
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China.,Department of Ophthalmology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Zijian Jiang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Bai Ruan
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China.,Aerospace Clinical Medical Center, School of Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Juanli Duan
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Ping Song
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Jingjing Liu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Hua Han
- State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.,Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
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15
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Tamura Y, Morikawa M, Tanabe R, Miyazono K, Koinuma D. Anti-pyroptotic function of TGF-β is suppressed by a synthetic dsRNA analogue in triple negative breast cancer cells. Mol Oncol 2021; 15:1289-1307. [PMID: 33342034 PMCID: PMC8096786 DOI: 10.1002/1878-0261.12890] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/27/2020] [Accepted: 12/17/2020] [Indexed: 12/11/2022] Open
Abstract
Development of innovative therapeutic modalities would address an unmet clinical need in the treatment of triple negative breast cancer (TNBC). Activation of retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) such as melanoma differentiation-associated gene 5 (MDA5) and RIG-I in cancer cells is suggested to suppress tumor progression by inducing cell death. Transfection of polyI:C, a conventionally used synthetic double-stranded RNA (dsRNA) analogue that activates RLRs, has been evaluated in clinical trials. However, detailed mechanisms of tumor suppression by RLRs, especially interactions with other signaling pathways, remain elusive. Here, we showed that transfection of polyI:C suppressed transforming growth factor-β (TGF-β) signaling in a MDA5- and RIG-I-dependent manner. We found that suppression of TGF-β signaling by polyI:C promoted cancer cell death, which was attenuated by forced expression of constitutively active Smad3. More detailed analysis suggested that cell death by polyI:C transfection exhibited characteristics of pyroptosis, which is distinct from apoptosis. Therapeutic efficacy of polyI:C transfection was also demonstrated using a mouse model. These results indicated that intratumor administration of polyI:C and related dsRNA analogues may be promising treatments for TNBC through inhibition of the anti-pyroptotic function of TGF-β.
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Affiliation(s)
- Yusuke Tamura
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
| | - Masato Morikawa
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
| | - Ryo Tanabe
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
| | - Kohei Miyazono
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
| | - Daizo Koinuma
- Department of Molecular PathologyGraduate School of MedicineThe University of TokyoJapan
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16
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Wu N, Xu X, Xin J, Fan J, Wei Y, Peng Q, Duan L, Wang W, Zhang H. The effects of nuclear factor-kappa B in pancreatic stellate cells on inflammation and fibrosis of chronic pancreatitis. J Cell Mol Med 2021; 25:2213-2227. [PMID: 33377616 PMCID: PMC7882951 DOI: 10.1111/jcmm.16213] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 11/13/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023] Open
Abstract
The activation of pancreatic stellate cells (PSCs) plays a critical role in the progression of pancreatic fibrosis. Nuclear factor-kappa B (NF-κB) is associated with chronic pancreatitis (CP). Previous evidence indicated that NF-κB in acinar cells played a double-edged role upon pancreatic injury, whereas NF-κB in inflammatory cells promoted the progression of CP. However, the effects of NF-κB in PSCs have not been studied. In the present study, using two CP models and RNAi strategy of p65 in cultured PSCs, we found that the macrophage infiltration and MCP-1 expression were increased, and the NF-κBp65 protein level was elevated. NF-κBp65 was co-expressed with PSCs. In vitro, TGF-β1 induced overexpression of the TGF-β receptor 1, phosphorylated TGF-β1-activated kinase 1 (p-TAK1) and NF-κB in the PSCs. Moreover, the concentration of MCP-1 in the supernatant of activated PSCs was elevated. The migration of BMDMs was promoted by the supernatant of activated PSCs. Further knockdown of NF-κBp65 in PSCs resulted in a decline of BMDM migration, accompanied by a lower production of MCP-1. These findings indicate that TGF-β1 can induce the activation of NF-κB pathway in PSCs by regulating p-TAK1, and the NF-κB pathway in PSCs may be a target of chronic inflammation and fibrosis.
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Affiliation(s)
- Nan Wu
- Department of PathophysiologyShaanxi University of Chinese MedicineXi'anChina
| | - Xiao‐Fan Xu
- Medical Experiment CenterShaanxi University of Chinese MedicineXi'anChina
- Ningxia Medical UniversityYinchuanChina
| | - Jia‐Qi Xin
- Department of PathophysiologyShaanxi University of Chinese MedicineXi'anChina
| | - Jian‐Wei Fan
- Department of PathophysiologyShaanxi University of Chinese MedicineXi'anChina
| | - Yuan‐Yuan Wei
- Department of PathophysiologyShaanxi University of Chinese MedicineXi'anChina
| | - Qing‐Xia Peng
- Department of PathophysiologyShaanxi University of Chinese MedicineXi'anChina
| | - Li‐Fang Duan
- Department of PathophysiologyShaanxi University of Chinese MedicineXi'anChina
| | - Wei Wang
- Department of General Surgery & Research Institute of Pancreatic DiseaseRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Hong Zhang
- Department of PathophysiologyShaanxi University of Chinese MedicineXi'anChina
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17
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He JY, Li PH, Huang X, Sun YH, He XP, Huang W, Yu ZH, Sun HY. Molecular cloning, expression and functional analysis of NF-kB1 p105 from sea cucumber Holothuria leucospilota. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 114:103801. [PMID: 32739504 DOI: 10.1016/j.dci.2020.103801] [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: 05/28/2020] [Revised: 07/12/2020] [Accepted: 07/13/2020] [Indexed: 06/11/2023]
Abstract
The nuclear factor-κB (NF-κB) family is evolutionary conserved and plays key roles in the regulation of numerous basic cellular processes. In this study, a sea cucumber Holothuria leucospilota NF-κB1 p105 named HLp105 was first obtained. The full-length cDNA of HLp105 is 6564 bp long, with a 219 bp 5' untranslated region (UTR), a 2979 bp 3' UTR, and a 3366 bp open reading frame (ORF) encoding for 1121 amino acids with a deduced molecular weight of 123.92 kDa and an estimated pI of 5.31. HLp105 protein contains the conserved domain RHD, IPT, ANK and DEATH. HLp105 mRNA can be detected in all tissues examined, with the highest level in the intestine, followed by the transverse vessel, rete mirabile, coelomocytes, respiratory tree, bolishiti, cuvierian tubules, body wall, oesophagus and muscle. Challenged by LPS or poly (I:C), the transcription level of HLp105 was apparently up-regulated in the tissues examined. Besides, Over-expression of HLp105 in HEK293T cells, the apoptosis was inhibited, and the cytokines IL-1β and TNF-α were activated. The results are important for better understanding the function of NF-κB1 p105 in sea cucumber and reveal its involvement in immunoreaction.
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Affiliation(s)
- Jia-Yang He
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Pin-Hong Li
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Xi Huang
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Yue-Hong Sun
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Xiao-Peng He
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Wei Huang
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Zong-He Yu
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China.
| | - Hong-Yan Sun
- Joint Laboratory of Guangdong Province and Hong Kong Regions on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China.
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18
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Kikuchi A, Singh S, Poddar M, Nakao T, Schmidt HM, Gayden JD, Sato T, Arteel GE, Monga SP. Hepatic Stellate Cell-Specific Platelet-Derived Growth Factor Receptor-α Loss Reduces Fibrosis and Promotes Repair after Hepatocellular Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:2080-2094. [PMID: 32615075 PMCID: PMC7527859 DOI: 10.1016/j.ajpath.2020.06.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 06/01/2020] [Accepted: 06/05/2020] [Indexed: 01/06/2023]
Abstract
Platelet-derived growth factor receptor (PDGFR)-α plays roles in cell survival, proliferation, and differentiation; however, its function in chronic liver injury sequelae, such as fibrosis, is unknown. Hepatic stellate cells (HSCs), the primary mediators of fibrosis, undergo activation, which entails differentiation to myofibroblasts, proliferation, migration, and collagen deposition, partially in response to PDGFs. To examine the role of PDGFR-α in HSCs, Lrat-Cre recombinase and Pdgfra-floxed mice were bred to generate Lrat-CrePdgfra-/- (knockout) animals, which were subjected to chronic liver injury through carbon tetrachloride treatment, bile duct ligation, and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Although no major difference was observed after other types of liver injury, PDGFR-α loss in HSCs led to a significant albeit transient reduction in fibrosis after carbon tetrachloride injury, associated with increased HSC death and reduced migration. There was continued alleviation of hepatocellular injury in knockout mice despite ongoing carbon tetrachloride insult, associated with increased numbers of CD68 and F480 macrophages and increased clearance of damaged hepatocytes. Altogether our findings support a profibrotic role of PDGFR-α in HSCs during chronic liver injury in vivo via regulation of HSC survival and migration and affect the immune microenvironment, especially macrophages in clearing dying hepatocytes. Thus, our study provides a preclinical foundation for the future testing of therapeutic PDGFR-α inhibition in hepatic fibrosis, especially in combination with other therapies.
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Affiliation(s)
- Alexander Kikuchi
- Department of Pathology, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Sucha Singh
- Department of Pathology, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Minakshi Poddar
- Department of Pathology, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Toshimasa Nakao
- Department of Surgery, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Heidi Marie Schmidt
- Department of Pathology, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Jenesis D Gayden
- Department of Pathology, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Toshifumi Sato
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Gavin E Arteel
- Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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19
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Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development. Cells 2020; 9:cells9020461. [PMID: 32085494 PMCID: PMC7072785 DOI: 10.3390/cells9020461] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/10/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammation has been known to be an important driver of fibrogenesis in the liver and onset of hepatic fibrosis. It starts off as a process meant to protect the liver from further damage, but it can become the main promoter of liver fibrosis. There are many inflammation-related pathways activated during liver fibrosis that lead to hepatic stellate cells (HSCs) activation and collagen-deposition in the liver. Such events are mostly modulated upstream of HSCs and involve signals from hepatocytes and innate immune cells. One particular event is represented by cell death during liver injury that generates multiple inflammatory signals that further trigger sterile inflammation and enhancement of inflammatory response. The assembly of inflammasome that responds to danger-associated molecular patterns (DAMPs) stimulates the release of pro-inflammatory cytokines and at the same time, initiates programmed cell death called pyroptosis. This review focuses on cellular and molecular mechanisms responsible for initiation and progress of inflammation in the liver.
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20
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Zhou J, Li Z, Huang Y, Ju W, Wang D, Zhu X, He X. MicroRNA-26a targets the mdm2/p53 loop directly in response to liver regeneration. Int J Mol Med 2019; 44:1505-1514. [PMID: 31364731 DOI: 10.3892/ijmm.2019.4282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 05/07/2019] [Indexed: 11/06/2022] Open
Abstract
Liver regeneration (LR) is the result of a dynamic balance between the increased proliferation and decreased apoptosis of hepatocytes. However, the role of microRNA (miR)‑26a in regulating complex signalling networks involving E3 ubiquitin‑protein ligase Mdm2 (mdm2), p53, p21 and p27 in the process of LR is currently unclear. In the present study, it was hypothesized that miR‑26a may negatively regulate the mdm2/p53 signalling loop in response to LR. In vitro experiments were performed, whereby mouse liver cells were transfected with an miR‑26a vector or an anti/miR‑26a vector. Cell proliferation was analysed using an MTS assay and cell apoptosis, and cell cycle progression were analysed by flow cytometry. In addition, the expression of mdm2, p53, p21 and p27 were assessed using western blotting and reverse transcription‑quantitative polymerase chain reaction analyses. Dual‑luciferase reporter assays were also used to examine the association between mdm2 and miR‑26a. A 70% partial hepatectomy in C57BL/6J mice was then performed, which was followed by injection with an mdm2‑cDNA vector or an mdm2‑small interfering RNA vector. The liver‑to‑body weight ratio and liver function of mice were measured at 72 h following vector administration. The results demonstrated an increase in hepatocyte proliferation accompanied by decreased hepatocyte apoptosis levels. In addition, inhibition of miR‑26a expression was associated with a marked increase in mdm2 expression, while the expression of p53, p21 and p27 was decreased when compared with negative controls. The opposite effects were observed when miR‑26a was overexpressed. Notably, miR‑26a was demonstrated to target the 3'‑untranslated region of mdm2 directly. The results of the present study are the first to demonstrate as far as the authors are aware that the mdm2/p53 negative feedback loop may be targeted by miR‑26a directly in response to LR, and that mdm2 negatively regulates p53, p21 and p27 but not miR‑26a. miR‑26a may therefore function as an important factor that regulates the interaction between mdm2 and p53.
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Affiliation(s)
- Jian Zhou
- Organ Transplant Centre, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zhuoyuan Li
- Organ Transplant Centre, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yingbin Huang
- Organ Transplant Centre, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Weiqiang Ju
- Organ Transplant Centre, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Dongping Wang
- Organ Transplant Centre, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiaofeng Zhu
- Organ Transplant Centre, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiaoshun He
- Organ Transplant Centre, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
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Wang L, Yang G, Yuan L, Yang Y, Zhao H, Ho CT, Li S. Green Tea Catechins Effectively Altered Hepatic Fibrogenesis in Rats by Inhibiting ERK and Smad1/2 Phosphorylation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:5437-5445. [PMID: 30424599 DOI: 10.1021/acs.jafc.8b05179] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Polyphenols derived from green tea have been reported to have a wide range of profound functions. Tea catechins, including epicatechin, epigallocatechin (EGC), epicatechin-3- O-gallate (ECG), and epigallocatechin-3- O-gallate (EGCG), are considered as the major bioactive polyphenols in tea. The present study was designed to elucidate the potential antifibrogenic role of three abundant tea catechins (ECG, EGC, and EGCG) in a CCl4-induced fibrotic rat and their underlying molecular mechanisms. Tea catechins, especially groups of ECG, EGC, and EGCG, effectively induced several beneficial alterations of liver injury markers, oxidative status, and liver histology. Furthermore, catechins ameliorated liver fibrosis, as evidenced by the reduced expression of desmin, α-smooth muscle actin, transforming growth factor β (TGF-β), and downstream ERK1/2 and Smad1/2 phosphorylation. The most significant inhibitory effect on those proteins was observed in ECG (300 mg/kg) and EGCG (300 mg/kg) groups. In addition, catechins conferred their protective role by downregulating the proinflammation cytokines TGF-β, tumor necrosis factor α, and interleukin 17. It is postulated that tea catechins, particularly ECG and EGCG, are potential therapeutic candidates in antifibrotic therapy.
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Affiliation(s)
- Liwen Wang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
- Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science , Tianjin University of Commerce , Tianjin 300134 , People's Republic of China
| | - Guliang Yang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Li Yuan
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Yiwen Yang
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
| | - Hui Zhao
- Tianjin Key Laboratory of Food and Biotechnology, School of Biotechnology and Food Science , Tianjin University of Commerce , Tianjin 300134 , People's Republic of China
| | - Chi-Tang Ho
- Department of Food Science , Rutgers, The State University of New Jersey , New Brunswick , New Jersey 08901 , United States
| | - Shiming Li
- Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources , Huanggang Normal University , Huanggang , Hubei 438000 , People's Republic of China
- Department of Food Science , Rutgers, The State University of New Jersey , New Brunswick , New Jersey 08901 , United States
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22
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Ulmasov B, Noritake H, Carmichael P, Oshima K, Griggs DW, Neuschwander‐Tetri BA. An Inhibitor of Arginine-Glycine-Aspartate-Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis. Hepatol Commun 2019; 3:246-261. [PMID: 30766962 PMCID: PMC6357833 DOI: 10.1002/hep4.1298] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 11/27/2018] [Indexed: 12/25/2022] Open
Abstract
The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine-glycine-aspartic acid tripeptide (RGD)-binding, integrin antagonist (3S)-3-(3-bromo-5-(tert-butyl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]-12). We hypothesized that RGD-binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM-12 in a choline deficient, amino-acid defined, high-fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM-12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM-12. Fibrosis measured by analysis of liver collagen was reduced by CWHM-12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM-12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD-binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.
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Affiliation(s)
- Barbara Ulmasov
- Division of Gastroenterology and HepatologySaint Louis UniversitySt. LouisMO
| | - Hidenao Noritake
- Division of Gastroenterology and HepatologySaint Louis UniversitySt. LouisMO
| | - Peter Carmichael
- Division of Gastroenterology and HepatologySaint Louis UniversitySt. LouisMO
| | - Kiyoko Oshima
- Department of PathologyJohns Hopkins University School of MedicineBaltimoreMD
| | - David W. Griggs
- Department of Molecular Microbiology and ImmunologySaint Louis UniversitySt. LouisMO
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23
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Jin XH, Jia YS, Shi YH, Li QY, Bao SQ, Lu WP, Tong ZS. ACT001 can prevent and reverse tamoxifen resistance in human breast cancer cell lines by inhibiting NF-κB activation. J Cell Biochem 2019; 120:1386-1397. [PMID: 30450651 DOI: 10.1002/jcb.27146] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/18/2018] [Indexed: 01/24/2023]
Abstract
Endocrine therapy is one of the main treatments for estrogen receptor-positive breast cancers. Tamoxifen is the most commonly used drug for endocrine therapy. However, primary or acquired tamoxifen resistance occurs in a large proportion of breast cancer patients, leading to therapeutic failure. We found that the combination of tamoxifen and ACT001, a nuclear factor-κB (NF-κB) signaling pathway inhibitor, effectively inhibited the proliferation of both tamoxifen-sensitive and tamoxifen-resistant cells. The tamoxifen-resistant cell line MCF7R/LCC9 showed active NF-κB signaling and high apoptosis-related gene transcription, especially for antiapoptotic genes, which could be diminished by treatment with ACT001. These results demonstrate that ACT001 can prevent and reverse tamoxifen resistance by inhibiting NF-κB activation.
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Affiliation(s)
- Xiao-Han Jin
- Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Ministry of Education, Tianjin Medical University, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yong-Sheng Jia
- Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Ministry of Education, Tianjin Medical University, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ye-Hui Shi
- Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Ministry of Education, Tianjin Medical University, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Qiu-Ying Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | | | - Wen-Ping Lu
- Oncology Department, Guang'anmen Hospital, Beijing, China
| | - Zhong-Sheng Tong
- Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Ministry of Education, Tianjin Medical University, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China
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24
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High Risk of Hepatocellular Carcinoma Development in Fibrotic Liver: Role of the Hippo-YAP/TAZ Signaling Pathway. Int J Mol Sci 2019; 20:ijms20030581. [PMID: 30700007 PMCID: PMC6387126 DOI: 10.3390/ijms20030581] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 01/24/2019] [Accepted: 01/28/2019] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, making up about 80% of cases. Liver fibrosis and its end-stage disease, cirrhosis, are major risk factors for HCC. A fibrotic liver typically shows persistent hepatocyte death and compensatory regeneration, chronic inflammation, and an increase in reactive oxygen species, which collaboratively create a tumor-promoting microenvironment via inducing genetic alterations and chromosomal instability, and activating various oncogenic molecular signaling pathways. In this article, we review recent advances in fields of liver fibrosis and carcinogenesis, and consider several molecular signaling pathways that promote hepato-carcinogenesis under the microenvironment of liver fibrosis. In particular, we pay attention to emerging roles of the Hippo-YAP/TAZ signaling pathway in stromal activation, hepatic fibrosis, and liver cancer.
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25
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Xu Z, Li T, Li M, Yang L, Xiao R, Liu L, Chi X, Liu D. eRF3b-37 inhibits the TGF-β1-induced activation of hepatic stellate cells by regulating cell proliferation, G0/G1 arrest, apoptosis and migration. Int J Mol Med 2018; 42:3602-3612. [PMID: 30272252 DOI: 10.3892/ijmm.2018.3900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 09/20/2018] [Indexed: 11/05/2022] Open
Abstract
The therapeutic management of liver fibrosis remains an unresolved clinical problem. The activation of hepatic stellate cells (HSCs) serves a pivotal role in the formation of liver fibrosis. In our previous study, matrix‑assisted laser desorption/ionization time‑of‑flight mass spectrometry (MALDI‑TOF MS) was employed to identify potential serum markers for liver cirrhosis, such as eukaryotic peptide chain releasing factor 3b polypeptide (eRF3b‑37), which was initially confirmed by our group to serve a protective role in liver tissues in a C‑C motif chemokine ligand 4‑induced liver cirrhosis mouse model. Therefore, eRF3b‑37 was hypothesized to affect the activation state of HSCs, which was determined by the expression of pro‑fibrogenic associated factors in HSCs. In the present study, peptide synthesis technology was employed to elucidate the role of eRF3b‑37 in the expression of pro‑fibrogenic factors induced by transforming growth factor‑β1 (TGF‑β1) in LX‑2 cells that were treated with either control, TGF‑β1 and TGF‑β1+eRF3b‑37. 3‑(4,5‑Dimethyl‑2‑thiazolyl)‑2,5‑diphenyltetrazolium bromide and flow cytometric assays, and fluorescent microscope examinations were performed to evaluate the effects of eRF3b‑37 on proliferation viability, G0/G1 arrest, apoptosis and cell migration. The results of the present study indicated that eRF3b‑37 inhibited the activation of HSCs. The increased mRNA and protein expression of the pro‑fibrogenic factors collagen I, connective tissue growth factor and α‑smooth muscle actin (SMA) stimulated by TGF‑β1 were reduced by eRF3b‑37 via the following mechanisms: i) Inhibiting LX‑2 cell proliferation, leading to G0/G1 cell cycle arrest and inhibition of DNA synthesis by downregulating the mRNA expressions of Cyclin D1 and cyclin dependent kinase‑4, and upregulating the levels of P21; ii) increasing cell apoptosis by upregulating the mRNA level of B‑cell lymphoma-2 (Bcl‑2)‑associated X protein (Bax) and Fas, and downregulating the expression of Bcl‑2; and iii) reducing cell migration by downregulating the mRNA and protein expression of α‑SMA. In addition, eRF3b‑37 is thought to serve a role in HSCs by inhibiting TGF‑β signaling. Therefore, eRF3b‑37 may be a novel therapeutic agent for targeting HSCs for hepatic fibrosis.
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Affiliation(s)
- Zhengrong Xu
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Tao Li
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Man Li
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Lei Yang
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Rudan Xiao
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Li Liu
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Xin Chi
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Dianwu Liu
- Department of Epidemiology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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26
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Alhusseiny SM, El-Beshbishi SN, Abu Hashim MM, El-nemr HEDE, Handoussa AE. Effectiveness of vinpocetine and isosorbide-5-mononitrate on experimental schistosomiasis mansoni: Biochemical and immunohistochemical study. Acta Trop 2018; 186:16-23. [PMID: 29963994 DOI: 10.1016/j.actatropica.2018.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 06/08/2018] [Accepted: 06/11/2018] [Indexed: 02/06/2023]
Abstract
Schistosomiasis is one of the most important tropical and subtropical devastating diseases, where praziquantel is the sole drug of choice. Praziquantel effectively kills the adult worms, however, drug resistance has been repeatedly reported. Moreover, there is currently no efficient anti-fibrotic therapy available for chronic schistosomiasis. So, novel drugs which exert anti-fibrotic efficacy are urgently needed. This research is complementary to our previous work that evaluated the anti-schistosomal effects of the anti-inflammatory vinpocetine, as well as the vasodilator and the anti-oxidant isosorbide-5-mononitrate. In the present study, we assessed the therapeutic efficacies of drugs in Swiss albino female mice experimentally infected with an Egyptian strain of Schistosoma mansoni, using some biochemical and immunohistochemical parameters. Our results revealed that both vinpocetine and isosorbide-5-mononitrate monotherapy significantly decreased hepatic nuclear factor-kappaB, 10 weeks post infection. The best effects were seen in mice administered praziquantel combined with isosorbide-5-mononitrate, as detected by reduction in hydroxyproline and collagen contents of the liver, and significant increase in the hepatic nitric oxide content. The data provides insight into the potential effects of the assessed drugs with isosorbide-5-mononitrate being more superior to vinpocetine, hence it can be used as novel adjuvant to praziquantel to alleviate schistosomal hepatic fibrosis. However, molecular mechanism/s and clinical trials are worthy to be scrutinized.
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27
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Reis MVP, de Souza GL, Moura CCG, da Silva MV, Souza MA, Soares PBF, Soares CJ. Effects of Lectin (ScLL) on osteoclast-like multinucleated giant cells' maturation-A preliminary in vitro study. Dent Traumatol 2018; 34:329-335. [PMID: 29856524 DOI: 10.1111/edt.12412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2018] [Indexed: 11/30/2022]
Abstract
BACKGROUND/AIM Lectin (ScLL) has been recently evaluated in the oral cavity due to its anti-inflammatory activities. ScLL could be a promising agent for blocking osteoclast activity and preventing root resorption. The aim of this study was to evaluate the effect of ScLL on the viability of the RAW 264.7 macrophage lineage, osteoclast-like maturation and the release of TNF-α and nitric oxide (NO). MATERIALS AND METHODS The viability of RAW 264.7 cells was determined by MTT and Alamar Blue assays after ScLL treatment for 24 hours. ScLL effects on RANKL-induced osteoclast-like maturation were assessed by tartrate-resistant acid phosphatase (TRAP) staining and F-actin ring formation. The supernatant was collected to detect the release of TNF-α using ELISA and NO using a nitrite assay. RESULTS ScLL suppressed osteoclast-like maturation by decreasing TRAP activity as well as F-actin ring formation. ScLL at 10 μg/mL showed the highest values of NO release compared with all other groups (P < .05). Lower levels of TNF-α were found for the negative control. CONCLUSIONS ScLL at 5 μg/mL suppressed osteoclast-like maturation in vitro and had no cytotoxic effect on RAW cell cultures.
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Affiliation(s)
- Manuella V P Reis
- Biomechanics Research Group, Department of Operative Dentistry and Dental Materials, Federal University of Uberlândia, Uberlândia, Brazil
| | - Gabriela L de Souza
- Biomechanics Research Group, Department of Endodontics, Federal University of Uberlândia, Uberlândia, Brazil
| | - Camilla C G Moura
- Department of Endodontics, School of Dentistry, Federal University of Uberlândia, Uberlândia, Brazil
| | - Marcus V da Silva
- Department of Immunology, Institute of Biomedical Sciences, Federal University of Triângulo Mineiro, Uberaba, Brazil
| | - Maria A Souza
- Department of Immunology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil
| | - Priscilla B F Soares
- Department of Oral and Maxillofacial Surgery and Implantology, School of Dentistry, Federal University of Uberlândia, Uberlândia, Brazil
| | - Carlos J Soares
- Biomechanics Research Group, Department of Operative Dentistry and Dental Materials, Federal University of Uberlândia, Uberlândia, Brazil
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28
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Wu YHS, Tseng JK, Chou CH, Chiu CH, Lin YL, Chen YC. Preventive effects of Ophiocordyceps sinensis mycelium on the liver fibrosis induced by thioacetamide. ENVIRONMENTAL TOXICOLOGY 2017; 32:1792-1800. [PMID: 28181416 DOI: 10.1002/tox.22402] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 01/05/2017] [Accepted: 01/15/2017] [Indexed: 06/06/2023]
Abstract
Thioacetamide (TAA), usually used as a fungicide to control the decay of citrus products, itself is not toxic to the liver, but its intermediates are able to increase oxidative stress in livers and further cause fibrosis. Ophiocordyceps sinensis mycelium (OSM) which contains 10% polysaccharides and 0.25% adenosine decreased (P < 0.05) the lipid accumulation and increased (P < 0.05) antioxidative capacity in livers of thioacetamide (TAA) injected rats. Meanwhile, the increased (P < 0.05) liver sizes, serum alanine transaminase (AST) and aspartate transaminase (ALT) values in thioacetamide (TAA)-injected rats were ameliorated (P < 0.05) by OSM supplementation. Moreover, the levels of proinflammatory cytokines, such as the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were also reduced (P < 0.05). The fibrosis phenomena in pathological (Masson's trichrome and H&E stainings) and immunohistochemical [α-smooth actin (αSMA) and CD86/ED1] observations in TAA-treated rats were reduced (P < 0.05) by OSM cotreatment. The protective effect of OSM against TAA-induced liver inflammation/fibrosis may be via downregulations (P < 0.05) of TGF-β pathways and NFκB which further influenced (P < 0.05) the expressions of fibrotic and inflammatory genes (i. e., αSMA, Col1α, COX2). Therefore, OSM shows preventive effects on the development of TAA-induced hepatic fibrosis.
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Affiliation(s)
- Yi-Hsieng Samuel Wu
- Department of Animal Science and Technology, National Taiwan University, Taipei, 106, Taiwan
| | - Jung-Kai Tseng
- Department of Optometry, Asia University, Taichung, 413, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404, Taiwan
| | - Chung-Hsi Chou
- School of Veterinary Medicine, National Taiwan University, Taipei, 106, Taiwan
- Zoonoses Research Center, National Taiwan University, Taipei, 106, Taiwan
| | - Chih-Hsien Chiu
- Department of Animal Science and Technology, National Taiwan University, Taipei, 106, Taiwan
| | - Yi-Ling Lin
- Department of Animal Science and Technology, National Taiwan University, Taipei, 106, Taiwan
| | - Yi-Chen Chen
- Department of Animal Science and Technology, National Taiwan University, Taipei, 106, Taiwan
- Zoonoses Research Center, National Taiwan University, Taipei, 106, Taiwan
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29
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Fernández-Iglesias A, Gracia-Sancho J. How to Face Chronic Liver Disease: The Sinusoidal Perspective. Front Med (Lausanne) 2017; 4:7. [PMID: 28239607 PMCID: PMC5300981 DOI: 10.3389/fmed.2017.00007] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 01/19/2017] [Indexed: 12/20/2022] Open
Abstract
Liver microcirculation plays an essential role in the progression and aggravation of chronic liver disease. Hepatic sinusoid environment, mainly composed by hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, intimately cooperate to maintain global liver function and specific phenotype of each cell type. However, continuous liver injury significantly deregulates liver cells protective phenotype, leading to parenchymal and non-parenchymal dysfunction. Recent data have enlightened the molecular processes that mediate hepatic microcirculatory injury, and consequently, opened the possibility to develop new therapeutic strategies to ameliorate liver circulation and viability. The present review summarizes the main cellular components of the hepatic sinusoid, to afterward focus on non-parenchymal cells phenotype deregulation due to chronic injury, in the specific clinical context of liver cirrhosis and derived portal hypertension. Finally, we herein detail new therapies developed at the bench-side with high potential to be translated to the bedside.
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Affiliation(s)
- Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute – CIBEREHD, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute – CIBEREHD, Barcelona, Spain
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30
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Ezhilarasan D, Evraerts J, Sid B, Calderon PB, Karthikeyan S, Sokal E, Najimi M. Silibinin induces hepatic stellate cell cycle arrest via enhancing p53/p27 and inhibiting Akt downstream signaling protein expression. Hepatobiliary Pancreat Dis Int 2017; 16:80-87. [PMID: 28119262 DOI: 10.1016/s1499-3872(16)60166-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Proliferation of hepatic stellate cells (HSCs) plays a pivotal role in the progression of liver fibrosis consequent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess anti-fibrogenic effects in animal models of liver fibrosis. This was attributed to an inhibition of cell proliferation of activated HSCs. The present study was to gain insight into the molecular pathways involved in silibinin anti-fibrogenic effect. METHODS The study was conducted on LX-2 human stellate cells treated with three concentrations of silibinin (10, 50 and 100 μmol/L) for 24 and 96 hours. At the end of the treatment cell viability and proliferation were evaluated. Protein expression of p27, p21, p53, Akt and phosphorylated-Akt was evaluated by Western blotting analysis and Ki-67 protein expression was by immunocytochemistry. Sirtuin activity was evaluated by chemiluminescence based assay. RESULTS Silibinin inhibits LX-2 cell proliferation in dose- and time-dependent manner; we showed that silibinin upregulated the protein expressions of p27 and p53. Such regulation was correlated to an inhibition of both downstream Akt and phosphorylated-Akt protein signaling and Ki-67 protein expression. Sirtuin activity also was correlated to silibinin-inhibited proliferation of LX-2 cells. CONCLUSION The anti-proliferative effect of silibinin on LX-2 human stellate cells is via the inhibition of the expressions of various cell cycle targets including p27, Akt and sirtuin signaling.
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Affiliation(s)
- Devaraj Ezhilarasan
- Institut de Recherche Experimentale et Clinique (IREC), Laboratory of Pediatric Hepatology and Cell Therapy, Universite Catholique de Louvain, 1200, Brussels, Belgium.
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Bettermann K. NF-κB and Its Implication in Liver Health and Cancer Development. MECHANISMS OF MOLECULAR CARCINOGENESIS – VOLUME 1 2017:87-114. [DOI: 10.1007/978-3-319-53659-0_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Fullár A, Firneisz G, Regős E, Dudás J, Szarvas T, Baghy K, Ramadori G, Kovalszky I. Response of Hepatic Stellate Cells to TGFB1 Differs from the Response of Myofibroblasts. Decorin Protects against the Action of Growth Factor. Pathol Oncol Res 2016; 23:287-294. [PMID: 27495255 DOI: 10.1007/s12253-016-0095-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 07/27/2016] [Indexed: 12/15/2022]
Abstract
Regardless to the exact nature of damage, hepatic stellate cells (HSCs) and other non-parenchymal liver cells transform to activated myofibroblasts, synthesizing the accumulating extracellular matrix (ECM) proteins, and transforming growth factor-β1 (TGF-β1) plays a crucial role in this process. Later it was discovered that decorin, member of the small leucin rich proteoglycan family is able to inhibit this action of TGF-β1. The aim of our present study was to clarify whether HSCs and activated myofibroblasts of portal region exert identical or different response to TGF-β1 exposure, and the inhibitory action of decorin against the growth factor is a generalized phenomenon on myofibroblast of different origin? To this end we measured mRNA expression and production of major collagen components (collagen type I, III and IV) of the liver after stimulation and co-stimulation with TGF-β1 and decorin in primary cell cultures of HSCs and myofibroblasts (MFs). Production of matrix proteins, decorin and members of the TGF-β1 signaling pathways were assessed on Western blots. Messenger RNA expression of collagens and TIEG was quantified by real-time RT-PCR. HSCs and MFs responded differently to TGF-β1 exposure. In contrast to HSCs in which TGF-β1 stimulated the synthesis of collagen type I, type III, and type IV, only the increase of collagen type IV was detected in portal MFs. However, in a combined treatment, decorin seemed to interfere with TGF-β1 and its stimulatory effect was abolished. The different mode of TGF-β1 action is mirrored by the different activation of signaling pathways in activated HSCs and portal fibroblasts. In HSCs the activation of pSMAD2 whereas in myofibroblasts the activation of MAPK pathway was detected. The inhibitory effect of decorin was neither related to the Smad-dependent nor to the Smad-independent signaling pathways.
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Affiliation(s)
- Alexandra Fullár
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary
| | - Gábor Firneisz
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Eszter Regős
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary
| | - József Dudás
- Department of Otorhinolaryngology, Medical University Innsbruck, Innsbruck, Austria
- Department of Gastroenterology and Endocrinology, George August University, Göttingen, Germany
| | - Tibor Szarvas
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary
| | - Kornélia Baghy
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary
| | - Giuliano Ramadori
- Department of Gastroenterology and Endocrinology, George August University, Göttingen, Germany
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary.
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Mandal S, Chatterjee NS. Vibrio cholerae GbpA elicits necrotic cell death in intestinal cells. J Med Microbiol 2016; 65:837-847. [PMID: 27324251 DOI: 10.1099/jmm.0.000298] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Vibrio choleraeN-acetylglucosamine-binding protein GbpA is a secretory protein that facilitates the initial adherence of bacteria in the human intestine. Until now, considerable progress in the characterization of GbpA has been done, yet little is known about its role in host response. Our present studies demonstrated that GbpA at the amount secreted in the intestine resulted in decreased cell viability, altered cell morphology, disruption of cell membrane integrity and damage of cellular DNA indicating necrotic cell death. We observed that GbpA exposure leads to mitochondrial dysfunction, characterized by accumulation of reactive oxygen species (ROS), depolarization of mitochondrial membrane potential and depletion of ATP pool in host cells. Additionally, the intra-cellular ROS, accumulated in response to GbpA, were found to induce the migration of NF-κB from cytoplasm into nucleus in host cells. Taken together, these results prompted us to conclude that GbpA orchestrates a necrotic response in host cells which may have implications in immune response.
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Affiliation(s)
- Sudipto Mandal
- Division of Biochemistry, National Institute of Cholera and Enteric Diseases, Kolkata 700010, India
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Shahzad M, Small DM, Morais C, Wojcikowski K, Shabbir A, Gobe GC. Protection against oxidative stress-induced apoptosis in kidney epithelium by Angelica and Astragalus. JOURNAL OF ETHNOPHARMACOLOGY 2016; 179:412-419. [PMID: 26719285 DOI: 10.1016/j.jep.2015.12.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 12/06/2015] [Accepted: 12/20/2015] [Indexed: 05/21/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Astragalus membranaceus either alone or in combination with Angelica sinensis has been used traditionally for kidney disease in East Asia and China for thousands of years. Previous studies using in vivo animal models have shown the benefits of these medicinal herbs in kidney diseases that involve oxidative stress. However, the mechanisms by which these medicinal herbs protect kidney cells remain largely unknown. AIM OF THE STUDY To investigate the mechanisms by which ethanol, methanol and aqueous crude extracts of roots of A. membranaceus and A. sinensis afford protection to human kidney proximal tubular epithelial cells, using an in vitro model of oxidative stress. MATERIALS AND METHODS Ethanol, methanol and aqueous extracts of roots of A. membranaceus and A. sinensis were prepared by a three-solvent sequential process. HK2 human kidney proximal tubular epithelial cells were treated with H2O2 alone (0.5mM) or in combination with different concentrations of extracts. Cell mitosis and death (microscopy) and cell viability (MTT assay) were compared. Western immunoblot was used to study expression of apoptosis-related proteins (pro-apoptotic Bax andanti-apoptotic Bcl-XL), and cell survival (NFκB subunits p65 and p50), pro-inflammatory (TNF-α) and protective (TGFβ1) proteins. RESULTS H2O2-induced oxidative stress significantly increased apoptosis and reduced cell survival; upregulated pro-apoptotic and down-regulated Bcl-XL; increased NFκB (p65, p50); increased TNFα and decreased TGFβ1. All changes indicated kidney damage and dysfunction. All were modulated by all extracts of both plant species, except for NFκB which was only modulated by extracts of A. membranaceus. CONCLUSIONS In conclusion, in a model of oxidative stress that might occur after nephrotoxicity, the plant extracts were protective via anti-apoptotic and anti-inflammatory mechanisms.
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Affiliation(s)
- Muhammad Shahzad
- Centre for Kidney Disease Research, School of Medicine, University of Queensland, Translational Research Institute, Brisbane, Australia; Department of Pharmacology, University of Health Sciences, Lahore, Pakistan
| | - David M Small
- Centre for Kidney Disease Research, School of Medicine, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Christudas Morais
- Centre for Kidney Disease Research, School of Medicine, University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Ken Wojcikowski
- Department of Natural and Complementary Medicine, Southern Cross University, Lismore, Australia
| | - Arham Shabbir
- Department of Pharmacology, University of Health Sciences, Lahore, Pakistan
| | - Glenda C Gobe
- Centre for Kidney Disease Research, School of Medicine, University of Queensland, Translational Research Institute, Brisbane, Australia.
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Nakhaei-Rad S, Nakhaeizadeh H, Götze S, Kordes C, Sawitza I, Hoffmann MJ, Franke M, Schulz WA, Scheller J, Piekorz RP, Häussinger D, Ahmadian MR. The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells. J Biol Chem 2016; 291:8399-413. [PMID: 26884329 DOI: 10.1074/jbc.m115.700088] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Indexed: 12/11/2022] Open
Abstract
Hepatic stellate cells (HSCs) were recently identified as liver-resident mesenchymal stem cells. HSCs are activated after liver injury and involved in pivotal processes, such as liver development, immunoregulation, regeneration, and also fibrogenesis. To date, several studies have reported candidate pathways that regulate the plasticity of HSCs during physiological and pathophysiological processes. Here we analyzed the expression changes and activity of the RAS family GTPases and thereby investigated the signaling networks of quiescent HSCs versus activated HSCs. For the first time, we report that embryonic stem cell-expressed RAS (ERAS) is specifically expressed in quiescent HSCs and down-regulated during HSC activation via promoter DNA methylation. Notably, in quiescent HSCs, the high level of ERAS protein correlates with the activation of AKT, STAT3, mTORC2, and HIPPO signaling pathways and inactivation of FOXO1 and YAP. Our data strongly indicate that in quiescent HSCs, ERAS targets AKT via two distinct pathways driven by PI3Kα/δ and mTORC2, whereas in activated HSCs, RAS signaling shifts to RAF-MEK-ERK. Thus, in contrast to the reported role of ERAS in tumor cells associated with cell proliferation, our findings indicate that ERAS is important to maintain quiescence in HSCs.
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Affiliation(s)
- Saeideh Nakhaei-Rad
- From the Institute of Biochemistry and Molecular Biology II, Medical Faculty
| | | | - Silke Götze
- the Clinic of Gastroenterology, Hepatology, and Infectious Diseases, and
| | - Claus Kordes
- the Clinic of Gastroenterology, Hepatology, and Infectious Diseases, and
| | - Iris Sawitza
- the Clinic of Gastroenterology, Hepatology, and Infectious Diseases, and
| | - Michèle J Hoffmann
- the Department of Urology, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany
| | - Manuel Franke
- From the Institute of Biochemistry and Molecular Biology II, Medical Faculty
| | - Wolfgang A Schulz
- the Department of Urology, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany
| | - Jürgen Scheller
- From the Institute of Biochemistry and Molecular Biology II, Medical Faculty
| | - Roland P Piekorz
- From the Institute of Biochemistry and Molecular Biology II, Medical Faculty
| | - Dieter Häussinger
- the Clinic of Gastroenterology, Hepatology, and Infectious Diseases, and
| | - Mohammad R Ahmadian
- From the Institute of Biochemistry and Molecular Biology II, Medical Faculty,
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Yang N, Zhang Y, Guo J. Preventive effect of total glycosides from Ligustri Lucidi Fructus against nonalcoholic fatty liver in mice. ACTA ACUST UNITED AC 2015; 70:237-41. [PMID: 26501160 DOI: 10.1515/znc-2015-4161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 09/21/2015] [Indexed: 11/15/2022]
Abstract
Abstract
The protective effects of the total glycosides from Ligustri Lucidi Fructus against nonalcoholic fatty liver (NAFL) in mice were investigated. Liver injury was induced by the administration of high fat diet for 60 days. During this period, the model group received high fat diet only; the treatment groups received various drugs plus high fat diet. Compared with the model group, the total glycosides significantly decreased the contents of triglyceride (TG) and cholesterol (TC), as well as the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum. Moreover, the contents of TG and TC in liver tissue and the liver index were reduced. Histological findings also confirmed antisteatosis. Compared with the model group, total glycosides significantly reduced the levels of the sterol regulatory element binding protein-1c (SREBP-1c) and liver X receptor-a (LXR-α) protein, and down-regulated the expression of SREBP-1c, LXR-α and interleukin-6 (IL-6) mRNA in the liver. These results suggest that the total glycosides are effective in the treatment of NAFL of mice. Their mode of action is associated with inhibiting SREBP-1c, LXR-α and IL-6 mRNA, reducing lipid synthesis factor SREBP-1c and LXR-α protein and gene expression, suppressing inflammatory responses, then decreasing serum lipid and hepatic lipid.
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Affiliation(s)
- Nianyun Yang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yiwen Zhang
- The 306th Hospital of PLA, Beijing 100101, China
| | - Jianming Guo
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
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Zhou H, Rigoutsos I. The emerging roles of GPRC5A in diseases. Oncoscience 2014; 1:765-76. [PMID: 25621293 PMCID: PMC4303886 DOI: 10.18632/oncoscience.104] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 11/24/2014] [Indexed: 12/14/2022] Open
Abstract
The ‘Retinoic Acid-Inducible G-protein-coupled receptors’ or RAIG are a group comprising the four orphan receptors GPRC5A, GPRC5B, GPRC5C and GPRC5D. As the name implies, their expression is induced by retinoic acid but beyond that very little is known about their function. In recent years, one member, GPRC5A, has been receiving increasing attention as it was shown to play important roles in human cancers. As a matter of fact, dysregulation of GPRC5A has been associated with several cancers including lung cancer, breast cancer, colorectal cancer, and pancreatic cancer. Here we review the current state of knowledge about the heterogeneity and evolution of GPRC5A, its regulation, its molecular functions, and its involvement in human disease.
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Affiliation(s)
- Honglei Zhou
- Computational Medicine Center, Jefferson Alumni Hall, Thomas Jefferson University, Philadelphia, PA
| | - Isidore Rigoutsos
- Computational Medicine Center, Jefferson Alumni Hall, Thomas Jefferson University, Philadelphia, PA
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38
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Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20:7312-7324. [PMID: 24966602 PMCID: PMC4064077 DOI: 10.3748/wjg.v20.i23.7312] [Citation(s) in RCA: 380] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/16/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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Krithika R, Jyothilakshmi V, Verma RJ. Phyllanthin inhibits CCl4-mediated oxidative stress and hepatic fibrosis by down-regulating TNF-α/NF-κB, and pro-fibrotic factor TGF-β1 mediating inflammatory signaling. Toxicol Ind Health 2014; 32:953-60. [PMID: 24817434 DOI: 10.1177/0748233714532996] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Hepatic fibrosis is an important outcome of chronic liver injury and results in excess synthesis and accumulation of extracellular matrix (ECM) components. Phyllanthin (PLN) isolated from Phyllanthus amarus exhibits strong antioxidative property and protects HepG2 cells from carbon tetrachloride (CCl4)-induced experimental toxicity. The present study reports the antifibrotic potential of PLN. The in vivo inhibitory effect of PLN on CCl4-mediated lipid peroxidation and important profibrotic mediator transforming growth factor β1 and on predominant ECM components collagen and fibronectin were also studied. The results show that PLN acts by suppressing the expression of inflammatory cytokine tumor necrosis factor-α and prevents activation of nuclear factor-κB in hepatic tissue. Our study highlights the molecular mechanism responsible for the antifibrotic efficacy of PLN.
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Affiliation(s)
- Rajesh Krithika
- Department of Zoology, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Vasavan Jyothilakshmi
- Department of Medical Biochemistry, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai, Tamil Nadu, India
| | - Ramtej Jayaram Verma
- Department of Zoology, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
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Obesity and the Endometrium: Adipocyte-Secreted Proinflammatory TNF α Cytokine Enhances the Proliferation of Human Endometrial Glandular Cells. Obstet Gynecol Int 2013; 2013:368543. [PMID: 24288542 PMCID: PMC3832969 DOI: 10.1155/2013/368543] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Accepted: 09/22/2013] [Indexed: 11/18/2022] Open
Abstract
Obesity, a state of chronic inflammation, is associated with poor fertility and low implantation rates and is a well-documented risk factor for endometrial cancer. Adipokines, such as tumor necrosis factor alpha, play an important role in initiation of endometrial cancer. The aim of this study is to evaluate in vitro effects of human adipocyte cells (SW872) on growth of endometrial glandular epithelial cells (EGE). Methods. We measured cell proliferation and expression of cell-growth proteins—proliferating cell nuclear antigen, cyclin D1, cyclin-dependent kinase-1, and apoptotic markers (BCL-2 and BAK) in human EGE cells cocultured with SW872 cells. EGE cells were also evaluated in SW872-conditioned media neutralized with anti-TNFα antibody. Results. A significant increase in EGE cell proliferation was observed in both SW872-conditioned media and in coculture (P < 0.05). We observed an upregulation of proliferation markers PCNA, cyclin D1, CDK-1, and BCL-2 and decrease in BAK (P < 0.05). Neutralization of SW872-conditioned media using anti-TNFα antibodies reversed EGE cell proliferation as indicated by BCL-2 expression. Conclusions. Adipocytes have potent proliferative paracrine effect on EGE cells which may be, in part, mediated via TNFα. Further understanding of the role of obesity in endometrial carcinogenesis should lead to better preventative and therapeutic strategies.
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Bittnerová L, Jiroutová A, Rudolf E, Rezácová M, Kanta J. Effect of collagen I gel on apoptosis of rat hepatic stellate cells. ACTA MEDICA (HRADEC KRÁLOVÉ) 2013; 56:73-9. [PMID: 24069661 DOI: 10.14712/18059694.2014.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Activated hepatic stellate cells (HSC) are a major source offibrous proteins in cirrhotic liver. Inducing or accelerating their apoptosis is a potential way of liver fibrosis treatment. Extracellular matrix (ECM) surrounding cells in tissue affects their differentiation, migration, proliferation and function. Type I collagen is the main ECM component in fibrotic liver. We have examined how this protein modifies apoptosis of normal rat HSC induced by gliotoxin, cycloheximide and cytochalasin D in vitro and spontaneous apoptosis of HSC isolated from CCl4-damaged liver. We have found that type I collagen gel enhances HSC apoptosis regardless of the agent triggering this process.
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Affiliation(s)
- Lenka Bittnerová
- Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine, Hradec Králové, Czech Republic
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42
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Aldaba-Muruato LR, Moreno MG, Shibayama M, Tsutsumi V, Muriel P. Allopurinol reverses liver damage induced by chronic carbon tetrachloride treatment by decreasing oxidative stress, TGF-β production and NF-κB nuclear translocation. Pharmacology 2013; 92:138-49. [PMID: 24008378 DOI: 10.1159/000339078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 04/13/2012] [Indexed: 12/22/2022]
Abstract
Allopurinol is an inhibitor of xanthine oxidase. The aim of this work was to evaluate the efficacy of allopurinol to reverse the experimental cirrhosis induced by CCl4. Rats received CCl4 for 8 weeks, and immediately after allopurinol was administered for 4 weeks more. Allopurinol reversed all markers of liver damage and oxidative stress to normal values, restoring the metabolic capacity of the liver. Chronic injury by CCl4 induced significant overexpression of profibrogenic cytokine TGF-β, while allopurinol decreased this production and consequently decreased the collagen content. Moreover, allopurinol is capable of partially inhibiting NF-κB. These findings suggest that allopurinol is capable of reversing the cirrhosis induced by CCl4, modulating oxidative stress, TGF-β expression and NF-κB nuclear translocation.
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Surachetpong S, Jiranantasak T, Rungsipipat A, Orton EC. Apoptosis and abundance of Bcl-2 family and transforming growth factor β1 signaling proteins in canine myxomatous mitral valves. J Vet Cardiol 2013; 15:171-80. [DOI: 10.1016/j.jvc.2013.02.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Revised: 02/12/2013] [Accepted: 02/18/2013] [Indexed: 01/05/2023]
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Yoshida K, Hashiramoto A, Okano T, Yamane T, Shibanuma N, Shiozawa S. TNF-α modulates expression of the circadian clock genePer2in rheumatoid synovial cells. Scand J Rheumatol 2013; 42:276-80. [DOI: 10.3109/03009742.2013.765031] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Shimizu F, Sano Y, Tominaga O, Maeda T, Abe MA, Kanda T. Advanced glycation end-products disrupt the blood-brain barrier by stimulating the release of transforming growth factor-β by pericytes and vascular endothelial growth factor and matrix metalloproteinase-2 by endothelial cells in vitro. Neurobiol Aging 2013; 34:1902-12. [PMID: 23428182 DOI: 10.1016/j.neurobiolaging.2013.01.012] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 01/14/2013] [Accepted: 01/20/2013] [Indexed: 01/31/2023]
Abstract
Diabetic encephalopathy is now accepted as an important complication of diabetes. The breakdown of the blood-brain barrier (BBB) is associated with dementia in patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to identify the possible mechanisms responsible for the disruption of the BBB after exposure to advanced glycation end-products (AGEs). We investigated the effect of AGEs on the basement membrane and the barrier property of the BBB by Western blot analysis, using our newly established lines of human brain microvascular endothelial cell (BMEC), pericytes, and astrocytes. AGEs reduced the expression of claudin-5 in BMECs by increasing the autocrine signaling through vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) secreted by the BMECs themselves. Furthermore, AGEs increased the amount of fibronectin in the pericytes through a similar up-regulation of the autocrine transforming growth factor (TGF)-β released by pericytes. These results indicated that AGEs induce basement membrane hypertrophy of the BBB by increasing the degree of autocrine TGF-β signaling by pericytes, and thereby disrupt the BBB through the up-regulation of VEGF and MMP-2 in BMECs under diabetic conditions.
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Affiliation(s)
- Fumitaka Shimizu
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
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46
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Chhunchha B, Fatma N, Kubo E, Rai P, Singh SP, Singh DP. Curcumin abates hypoxia-induced oxidative stress based-ER stress-mediated cell death in mouse hippocampal cells (HT22) by controlling Prdx6 and NF-κB regulation. Am J Physiol Cell Physiol 2013; 304:C636-55. [PMID: 23364261 DOI: 10.1152/ajpcell.00345.2012] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Oxidative stress and endoplasmic reticulum (ER) stress are emerging as crucial events in the etiopathology of many neurodegenerative diseases. While the neuroprotective contributions of the dietary compound curcumin has been recognized, the molecular mechanisms underlying curcumin's neuroprotection under oxidative and ER stresses remains elusive. Herein, we show that curcumin protects HT22 from oxidative and ER stresses evoked by the hypoxia (1% O(2) or CoCl(2) treatment) by enhancing peroxiredoxin 6 (Prdx6) expression. Cells exposed to CoCl(2) displayed reduced expression of Prdx6 with higher reactive oxygen species (ROS) expression and activation of NF-κB with IκB phosphorylation. When NF-κB activity was blocked by using SN50, an inhibitor of NF-κB, or cells treated with curcumin, the repression of Prdx6 expression was restored, suggesting the involvement of NF-κB in modulating Prdx6 expression. These cells were enriched with an accumulation of ER stress proteins, C/EBP homologous protein (CHOP), GRP/78, and calreticulin, and had activated states of caspases 12, 9, and 3. Reinforced expression of Prdx6 in HT22 cells by curcumin reestablished survival signaling by reducing propagation of ROS and blunting ER stress signaling. Intriguingly, knockdown of Prdx6 by antisense revealed that loss of Prdx6 contributed to cell death by sustaining enhanced levels of ER stress-responsive proapoptotic proteins, which was due to elevated ROS production, suggesting that Prdx6 deficiency is a cause of initiation of ROS-mediated ER stress-induced apoptosis. We propose that using curcumin to reinforce the naturally occurring Prdx6 expression and attenuate ROS-based ER stress and NF-κB-mediated aberrant signaling improves cell survival and may provide an avenue to treat and/or postpone diseases associated with ROS or ER stress.
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Affiliation(s)
- Bhavana Chhunchha
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
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47
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Danielpour D. Transforming Growth Factor-Beta in Prostate Cancer. Prostate Cancer 2013. [DOI: 10.1007/978-1-4614-6828-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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48
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De Minicis S, Candelaresi C, Agostinelli L, Taffetani S, Saccomanno S, Rychlicki C, Trozzi L, Marzioni M, Benedetti A, Svegliati-Baroni G. Endoplasmic Reticulum stress induces hepatic stellate cell apoptosis and contributes to fibrosis resolution. Liver Int 2012; 32:1574-84. [PMID: 22938186 DOI: 10.1111/j.1478-3231.2012.02860.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Accepted: 07/07/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Survival of hepatic stellate cells (HSCs) is a hallmark of liver fibrosis, while the induction of HSC apoptosis may induce recovery. Activated HSC are resistant to many pro-apoptotic stimuli. To this issue, the role of Endoplasmic Reticulum (ER) stress in promoting apoptosis of HSCs and consequently fibrosis resolution is still debated. AIM To evaluate the potential ER stress-mediated apoptosis of HSCs and fibrosis resolution METHODS HSCs were incubated with the ER stress agonists, tunicamycin or thapsigargin. In vivo, HSC were isolated from normal, bile duct-ligated (BDL) and bile duct-diverted (BDD) rats. RESULTS In activated HSC, the specific inhibitor of ER stress-induced apoptosis, calpastatin, is significantly increased vs. quiescent HSCs. Calpain is conversely reduced in activated HSCs. This pattern of protein expression provides HSCs resistance to the ER stress signals of apoptosis (apoptosis-resistant phenotype). However, both tunicamycin and thapsigargin are able to induce apoptosis in HSCs in vitro, completely reversing the calpain/calpastatin pattern expression. Furthermore, in vivo, the fibrosis resolution observed in rat livers subjected to bile duct ligation (BDL) and subsequent bile duct diversion (BDD), leads to fibrosis resolution through a mechanism of HSCs apoptosis, potentially associated with ER stress: in fact, BDD rat liver shows an increased number of apoptotic HSCs associated with reduced calapstatin and increased calpain protein expression, leading to an apoptosis-sensible phenotype. CONCLUSIONS ER stress sensitizes HSC to apoptosis both in vitro and in vivo. Thus, ER stress represents a key target to trigger cell death in activated HSC and promotes fibrosis resolution.
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Affiliation(s)
- Samuele De Minicis
- Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy
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Llorente-Cortes V, Barbarigo V, Badimon L. Low density lipoprotein receptor-related protein 1 modulates the proliferation and migration of human hepatic stellate cells. J Cell Physiol 2012; 227:3528-33. [PMID: 22392894 DOI: 10.1002/jcp.24080] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Human hepatic stellate cells (HHSCs) proliferation and migration play a key role in the pathogenesis of liver inflammation and fibrogenesis. Low density lipoprotein receptor-related protein (LRP1) is an endocytic receptor involved in intracellular signal transduction. The aim of this work was to analyse the role of low density lipoprotein receptor-related protein (LRP1) in HHSCs proliferation and migration and the mechanisms involved. Human LRP1 deficient-HHSCs were generated by nucleofecting the line HHSCs with siRNA anti-LRP1. HHSCs DNA synthesis was measured by [(3) H]-thymidine incorporation and cell cycle progression by flow cytometry after annexin V and iodure propidium staining. Cell migration was assessed using a wound repair model system. LRP1 expression and extracellular matrix-regulated kinase (ERK1,2) phosphorylation were analysed by Western blot analysis. Transforming growth factor-β (TGF-β) extracellular levels were analysed by ELISA. siRNA-antiLRP1 treatment almost completely inhibited LRP1 mRNA and protein expression. LRP1 deficient HHSCs showed higher proliferative response (172 ± 19 vs. 93 ± 8 [(3) H]-thymidine incorporation; 78.68% vs. 82.69% in G0/G1, 21.32% vs. 17.30% in G2/S) and higher migration rates than control HHSCs. LRP1 deficient cells showed higher levels of phosphorylated ERK1,2. TGF-β extracellular levels were threefold higher in LRP1-deficient than in control HHSCs cells. These results demonstrate that LRP1 regulates HHSCs proliferation and migration through modulation of ERK1,2 phosphorylation and TGF-β extracellular levels. These results suggest that HHSCs-LRP1 may play a key role in the modulation of factors determining hepatic fibrosis.
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Affiliation(s)
- V Llorente-Cortes
- Cardiovascular Research Center of Barcelona, CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
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Kim IH, Kim SW, Kim SH, Lee SO, Lee ST, Kim DG, Lee MJ, Park WH. Parthenolide-induced apoptosis of hepatic stellate cells and anti-fibrotic effects in an in vivo rat model. Exp Mol Med 2012; 44:448-456. [PMID: 22581380 PMCID: PMC3406290 DOI: 10.3858/emm.2012.44.7.051] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2012] [Indexed: 01/18/2023] Open
Abstract
Parthenolide (PT), a sesquiterpene lactone derived from the plant feverfew, has pro-apoptotic activity in a number of cancer cell types. We assessed whether PT induces the apoptosis of hepatic stellate cells (HCSs) and examined its effects on hepatic fibrosis in an in vivo model. The effects of PT on rat HSCs were investigated in relation to cell growth inhibition, apoptosis, NF-κB binding activity, intracellular reactive oxygen species (ROS) generation, and glutathione (GSH) levels. In addition, the anti-fibrotic effects of PT were investigated in a thioacetamide-treated rat model. PT induced growth inhibition and apoptosis in HSCs, as evidenced by cell growth inhibition and apoptosis assays. PT increased the expression of Bax proteins during apoptosis, but decreased the expression of Bcl-2 and Bcl-X(L) proteins. PT also induced a reduction in mitochondrial membrane potential, poly(ADP-ribose) polymerase cleavage, and caspase-3 activation. PT inhibited TNF-α-stimulated NF-κB binding activity in HSCs. The pro-apoptotic activity of PT in HSCs was associated with increased intracellular oxidative stress as evidenced by increased intracellular ROS levels and depleted intracellular GSH levels. Furthermore, PT ameliorated hepatic fibrosis significantly in a thioacetamide- treated rat model. In conclusion, PT exhibited pro-apoptotic effects in rat HSCs and ameliorated hepatic fibrosis in a thioacetamide-induced rat model.
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Affiliation(s)
- In Hee Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju 561-712, Korea
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