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Guan H, Zhang W, Liu H, Jiang Y, Li F, Wang D, Liu Y, He F, Wu M, Ivan Neil Waterhouse G, Sun-Waterhouse D, Li D. Simultaneous binding of quercetin and catechin to FOXO3 enhances IKKα transcription inhibition and suppression of oxidative stress-induced acute alcoholic liver injury in rats. J Adv Res 2025; 67:71-92. [PMID: 38286301 PMCID: PMC11725110 DOI: 10.1016/j.jare.2024.01.030] [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: 11/29/2023] [Revised: 01/11/2024] [Accepted: 01/26/2024] [Indexed: 01/31/2024] Open
Abstract
INTRODUCTION Oxidative stress is one of the major contributors to acute alcoholic liver injury (AALI), which is a common alcoholic liver disease. Quercetin and catechin are flavonoid antioxidants present in plant foods and possess chemopreventive and chemotherapeutic activities. Quercetin and catechin are often included in the same meal and ingested together. While they show cooperative actions against oxidative damage, the underlying mechanisms behind their counteracting effects against oxidative stress-induced AALI remain poorly understood. OBJECTIVES The aim of this study was to understand the mechanism underlying the enhanced antioxidant effect of quercetin-catechin combination to alleviate AALI in rats. METHODS The ethanol (EtOH)-treated rats and H2O2-treated liver cells were used to demonstrate the enhanced antioxidant effect of quercetin and catechin. Then we used RNA-sequencing to compare quercetin alone, catechin alone and quercetin-catechin combination and then identified the critical role of IKKα combining with gene silencing and overexpression techniques. Its transcription factor, FOXO3 was found through yeast one-hybrid assay, luciferase reporter assay, EMSA and ChIP assay. Finally, the interaction between quercetin, catechin and FOXO3 was verified through molecular docking, UV-Vis absorption spectroscopy, fluorescence spectroscopy, and CD spectroscopy. RESULTS The study demonstrated the enhanced antioxidant effect of a quercetin-catechin combination in EtOH-treated rats and in H2O2-treated liver cells. Quercetin and catechin cooperatively inhibited IKKα/p53 pathway and activated Nrf2 signaling pathway. IKKα was a critical negative regulator in their joint action. FOXO3 bound to IKKα promoter to regulate IKKα transcription. Quercetin and catechin influenced FOXO3-IKKα binding through attaching directly to FOXO3 at different sites and altering FOXO3's secondary structures. CONCLUSION Our study revealed the mechanism of quercetin and catechin against oxidative stress-induced AALI through jointly interacting with transcription factor. This research opens new vistas for examining the joint effect of therapeutics towards functional proteins and confirms the chemopreventive effects of multiple flavonoids via co-regulation.
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Affiliation(s)
- Hui Guan
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China
| | - Wenyuan Zhang
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China
| | - Hui Liu
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China
| | - Yang Jiang
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China
| | - Feng Li
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China
| | - Dan Wang
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China
| | - Yang Liu
- College of Life Sciences, Shandong Agricultural University, State Key Laboratory of Crop Biology, Shandong Key Laboratory of Crop Biology, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China
| | - Fatao He
- Jinan Fruit Research Institute of All China Federation of Supply & Marketing Cooperatives, 16001 East Road Jingshi, Jinan 250220, Shandong, People's Republic of China
| | - Maoyu Wu
- Jinan Fruit Research Institute of All China Federation of Supply & Marketing Cooperatives, 16001 East Road Jingshi, Jinan 250220, Shandong, People's Republic of China
| | | | - Dongxiao Sun-Waterhouse
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China; School of Chemical Sciences, The University of Auckland, Auckland, New Zealand.
| | - Dapeng Li
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, 61 Dai Zong Street, Tai'an 271018, Shandong, People's Republic of China.
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Wu Q, Yang D, Liu C, Xu T. Alcohol Plus Additional Risk Factors: Rodent Model of Liver Injury. Semin Liver Dis 2024. [PMID: 39719149 DOI: 10.1055/a-2490-4278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2024]
Abstract
Alcohol-associated liver disease (ALD), primarily caused by chronic excessive alcohol consumption, is a leading cause of chronic liver disease worldwide. ALD includes alcohol-associated steatotic liver, alcohol-associated hepatitis (AH), fibrosis, cirrhosis, and can even progress to hepatocellular carcinoma (HCC). Existing research indicates that the risk factors of ALD are quite numerous. In addition to drinking patterns, factors such as aldehyde dehydrogenase 2 (ALDH2) deficiency, smoking, medication administration, high-fat diet (HFD), hepatitis virus infection, and disruption of circadian rhythms can also increase susceptibility to ALD. However, there is limited understanding regarding the exacerbation of liver injury by alcohol plus additional risk factors. This review presents rodent models of EtOH + "X," which simulate the synergistic effects of alcohol and additional risk factors in causing liver injury. These models offer a further exploration of the interactions between alcohol and additional risk factors, advancing the simulation of human ALD and providing a more reliable platform for studying disease mechanisms and exploring therapeutic interventions. We summarize the modeling methods, relevant indicators of liver injury, and focus on the targets of the synergistic effects as well as the associated mechanisms.
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Affiliation(s)
- Qixiang Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, P.R. China
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, P.R. China
| | - Dashuai Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, P.R. China
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, P.R. China
| | - Chixiang Liu
- Department of Blood Transfusion, Southern Medical University, Nanfang Hospital, Guangzhou, P.R. China
- School of Laboratory and Biotechnology, Institute of Antibody Engineering, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, P.R. China
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, P.R. China
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Peng J, Liang G, Li Y, Mao S, Zhang C, Wang Y, Li Z. Identification of a novel FOXO3 agonist that protects against alcohol induced liver injury. Biochem Biophys Res Commun 2024; 704:149690. [PMID: 38387326 DOI: 10.1016/j.bbrc.2024.149690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 02/24/2024]
Abstract
Alcohol-related liver disease (ALD) is a global healthcare concern which caused by excessive alcohol consumption with limited treatment options. The pathogenesis of ALD is complex and involves in hepatocyte damage, hepatic inflammation, increased gut permeability and microbiome dysbiosis. FOXO3 is a well-recognized transcription factor which associated with longevity via promoting antioxidant stress response, preventing senescence and cell death, and inhibiting inflammation. We and many others have reported that FOXO3-/- mice develop more severe liver injury in response to alcohol. In the present study, we aimed to develop compounds that activate FOXO3 and further investigate their effects in alcohol induced liver injury. Through virtual screening, we discovered series of small molecular compounds that showed high affinity to FOXO3. We confirmed effects of compounds on FOXO3 target gene expression, as well as antioxidant and anti-apoptotic effects in vitro. Subsequently we evaluated the protective efficacy of compounds in alcohol induced liver injury in vivo. As a result, the leading compound we identified, 214991, activated downstream target genes expression of FOXO3, inhibited intracellular ROS accumulation and cell apoptosis induced by H2O2 and sorafenib. By using Lieber-DeCarli alcohol feeding mouse model, 214991 showed protective effects against alcohol-induced liver inflammation, macrophage and neutrophil infiltration, and steatosis. These findings not only reinforce the potential of FOXO3 as a valuable target for therapeutic intervention of ALD, but also suggested that compound 214991 as a promising candidate for the development of innovative therapeutic strategies of ALD.
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Affiliation(s)
- Jinying Peng
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
| | - Gaoshuang Liang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
| | - Yaqi Li
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Hunan, 410081, China; Institute of Interdisciplinary Studies, Hunan Normal University, Hunan, 410081, China; Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Hunan, 410081, China
| | - Siyu Mao
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
| | - Chen Zhang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
| | - Ying Wang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Hunan, 410081, China; Institute of Interdisciplinary Studies, Hunan Normal University, Hunan, 410081, China; Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Hunan, 410081, China.
| | - Zhuan Li
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China.
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Zheng K, Chen S, Ren Z, Wang Y. Protein arginine methylation in viral infection and antiviral immunity. Int J Biol Sci 2023; 19:5292-5318. [PMID: 37928266 PMCID: PMC10620831 DOI: 10.7150/ijbs.89498] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/10/2023] [Indexed: 11/07/2023] Open
Abstract
Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes including epigenetic gene regulation, genome stability maintenance, RNA metabolism, and stress-responsive signal transduction. The varying substrates and biological functions of arginine methylation in cancer and neurological diseases have been extensively discussed, providing a rationale for targeting PRMTs in clinical applications. An increasing number of studies have demonstrated an interplay between arginine methylation and viral infections. PRMTs have been found to methylate and regulate several host cell proteins and different functional types of viral proteins, such as viral capsids, mRNA exporters, transcription factors, and latency regulators. This modulation affects their activity, subcellular localization, protein-nucleic acid and protein-protein interactions, ultimately impacting their roles in various virus-associated processes. In this review, we discuss the classification, structure, and regulation of PRMTs and their pleiotropic biological functions through the methylation of histones and non-histones. Additionally, we summarize the broad spectrum of PRMT substrates and explore their intricate effects on various viral infection processes and antiviral innate immunity. Thus, comprehending the regulation of arginine methylation provides a critical foundation for understanding the pathogenesis of viral diseases and uncovering opportunities for antiviral therapy.
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Affiliation(s)
- Kai Zheng
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Siyu Chen
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Zhe Ren
- Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou, 510632, China
| | - Yifei Wang
- Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou, 510632, China
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Zhang C, Zhao J, Zhao J, Liu B, Tang W, Liu Y, Huang W, Weinman SA, Li Z. CYP2E1-dependent upregulation of SIRT7 is response to alcohol mediated metastasis in hepatocellular carcinoma. Cancer Gene Ther 2022; 29:1961-1974. [PMID: 35902730 PMCID: PMC10832389 DOI: 10.1038/s41417-022-00512-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 06/22/2022] [Accepted: 07/13/2022] [Indexed: 02/02/2023]
Abstract
Long-term alcohol use is a confirmed risk factor of liver cancer tumorigenesis and metastasis. Multiple mechanisms responsible for alcohol related tumorigenesis have been proposed, including toxic reactive metabolite production, oxidative stress and fat accumulation. However, mechanisms underlying alcohol-mediated liver cancer metastasis remain largely unknown. We have previously demonstrated that SIRT7 regulates chemosensitivity by altering a p53-dependent pathway in human HCC. In the current study, we further revealed that SIRT7 is a critical factor in promoting liver cancer metastasis. SIRT7 expression is associated with disease stage and high SIRT7 predicts worse overall and disease-free survival. Overexpression of SIRT7 promotes HCC cell migration and EMT while knockdown of SIRT7 showed opposite effects. Mechanistically, we found that SIRT7 suppresses E-Cadherin expression through FOXO3-dependent promoter binding and H3K18 deacetylation. Knockdown of FOXO3 abolished the suppressive effect of SIRT7 on E-cadherin transcription. More importantly, we identified that alcohol treatment upregulates SIRT7 and suppresses E-cadherin expression via a CYP2E/ROS axis in hepatocytes both in vitro and in vivo. Antioxidant treatment in primary hepatocyte or CYP2E1-/- mice fed with alcohol impaired those effects. Reducing SIRT7 activity completely abolished alcohol-mediated promotion of liver cancer metastasis in vivo. Taken together, our data reveal that SIRT7 is a pivotal regulator of alcohol-mediated HCC metastasis.
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Affiliation(s)
- Chen Zhang
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, Hunan, China
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Hunan Normal University School of Medicine, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, Hunan, China
| | - Jinqiu Zhao
- Department of Infectious Disease, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Zhao
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Bohao Liu
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, Hunan, China
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Hunan Normal University School of Medicine, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, Hunan, China
| | - Wenbin Tang
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, Hunan, China
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Hunan Normal University School of Medicine, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, Hunan, China
| | - Yi Liu
- Department of General Surgery, People's Hospital of Hunan Province and Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Wenxiang Huang
- Department of Infectious Disease, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Steven A Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
- Liver Center, University of Kansas Medical Center, Kansas City, KS, USA
| | - Zhuan Li
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, Hunan, China.
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Hunan Normal University School of Medicine, Changsha, Hunan, China.
- Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, Hunan, China.
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Pan M, Liu J, Huang D, Guo Y, Luo K, Yang M, Gao W, Xu Q, Zhang W, Mai K. FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot ( Scophthalmus maximus L.). Front Immunol 2021; 12:679704. [PMID: 34276667 PMCID: PMC8281027 DOI: 10.3389/fimmu.2021.679704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
In mammals, forkhead box O3 (foxo3) plays important roles in liver immune system. The foxo3 can regulate cell cycle, DNA repair, hypoxia, apoptosis and so on. However, as such an important transcription factor, few studies on foxo3 in fish have been reported. The present study characterized the foxo3 in turbot (Scophthalmus maximus L.). Lipopolysaccharide (LPS) incubated in vitro (hepatocytes) and injected in vivo (turbot liver) were used to construct inflammatory models. The foxo3 was interfered and overexpressed to investigate its functions in liver inflammation. The open reading frame (ORF) of foxo3 was 1998 bp (base pair), encoding 665 amino acids. Sequence analysis showed that foxo3 of turbot was highly homologous to other fishes. Tissue distribution analysis revealed that the highest expression of foxo3 was in muscle. Immunofluorescence result showed that foxo3 was expressed in cytoplasm and nucleus. Knockdown of foxo3 significantly increased mRNA levels of tumor necrosis factor-α (tnf-α), interleukin-1β (il-1β), interleukin-6 (il-6), myeloid-differentiation factor 88 (myd88), cd83, toll-like receptor 2 (tlr-2) and protein level of c-Jun N-terminal kinase (JNK) in sifoxo3 + LPS (siRNA of foxo3+ LPS) group compared with NC + LPS (negative control + LPS) group in turbot hepatocytes. Overexpressed foxo3 significantly decreased mRNA levels of tnf-α, il-6, nuclear transcription factor-kappa B (nf-κb), cd83, tlr-2 and the protein level of JNK in vitro. In vivo analysis, foxo3 knockdown significantly increased levels of GOT in serum after LPS injection compared with NC+LPS group. Overexpressed foxo3 significantly decreased levels of GPT and GOT in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in vivo. Foxo3 knockdown significantly increased mRNA levels of tnf-α, il-1β, il-6, nf-κb, myd88 and protein level of JNK in vivo in sifoxo3+LPS group compared with NC+LPS group in turbot liver. Overexpressed foxo3 significantly decreased mRNA levels of il-1β, il-6, myd88, cd83, jnk and protein level of JNK in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in turbot liver. The results indicated that foxo3 might modulate LPS-activated hepatic inflammation in turbot by decreasing the proinflammatory cytokines, the levels of GOT and GPT as well as activating JNK/caspase-3 and tlr-2/myd88/nf-κb pathways. Taken together, these findings indicated that FoxO3 may play important roles in liver immune responses to LPS in turbot and the research of FoxO3 in liver immunity enriches the studies on immune regulation, and provides theoretical basis and molecular targets for solving liver inflammation and liver injury in fish.
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Affiliation(s)
- Mingzhu Pan
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Jiahuan Liu
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Dong Huang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Yanlin Guo
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Kai Luo
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Mengxi Yang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
| | - Weihua Gao
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Qiaoqing Xu
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Wenbing Zhang
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
| | - Kangsen Mai
- The Key Laboratory of Mariculture (Ministry of Education), The Key Laboratory of Aquaculture Nutrition and Feeds (Ministry of Agriculture and Rural Affairs), Fisheries College, Ocean University of China, Qingdao, China
- Department of Fisheries, College of Animal Science, Yangtze University, Jingzhou, China
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Yang L, Fan C, Shu T, Wang S. Punicalin alleviates TNF-α- and IL-1β-induced chondrocyte dysfunction and cartilage metabolism via mediating FOXO3 signaling axis. J Food Biochem 2021; 45:e13755. [PMID: 33974280 DOI: 10.1111/jfbc.13755] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 12/11/2022]
Abstract
Forkhead box O3 (FOXO3) transcription factor is involved in chondral homeostasis of normal, aging and osteoarthritis (OA) cartilage. At present, we aimed to investigate whether FOXO3 is a target of punicalin to prevent IL-1β- and TNF-α-induced chondrocyte dysfunction in vitro and in vivo models. Cell and mouse models of chondrocyte dysfunction were established to determine the pharmacological value of hydrolyzable tannin, punicalin, which was extracted from the pomegranate. FOXO3 protein levels in the nucleus and cytoplasm were analysed using western blot. Safranine O staining was performed to evaluate the expansion of growth plate and chondrocyte differentiation in IL-1β- and TNF-α-treated mice. In IL-1β- and TNF-α-treated chondrocytes and mice, IL-1β and TNF-α evoked phosphorylation and nucleocytoplasmic shuttling of FOXO3, as well as reduced FOXO3 expression levels in the nucleus. However, punicalin treatment repressed FOXO3 phosphorylation and cytoplasmic transfer. Punicalin treatment improved IL-1β and TNF-α-induced growth inhibition and apoptosis of chondrocyte and the abnormal expansion of growth plate and hypertrophic zone. Moreover, punicalin could maintain the normal phenotype of chondrocyte via mediating multiple gene expression. Punicalin showed a beneficial effect on IL-1β- and TNF-α-stimulated chondrocytes and cartilaginous metabolic disorders via preserving the transcriptional activity of FOXO3. PRACTICAL APPLICATIONS: Our study presents a prospective adjuvant therapeutic drug, punicalin, to prevent inflammation-related cartilage injury and chondrocyte dysfunction.
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Affiliation(s)
- Lin Yang
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, P.R. China
| | - Changdong Fan
- Department of Emergency Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, P.R. China
| | - Taipengfei Shu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, P.R. China
| | - Shujun Wang
- Department of Rheumatology, Zibo Central Hospital, Zibo, 255036, Shandong Province, P.R. China
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Murtagh R, Swan D, O'Connor E, McCombe G, Lambert JS, Avramovic G, Cullen W. Hepatitis C Prevalence and Management Among Patients Receiving Opioid Substitution Treatment in General Practice in Ireland: Baseline Data from a Feasibility Study. Interact J Med Res 2018; 7:e10313. [PMID: 30567692 PMCID: PMC6315251 DOI: 10.2196/10313] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 07/16/2018] [Accepted: 08/21/2018] [Indexed: 12/26/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and death. Injection drug use is now one of the main routes of transmission of HCV in Ireland and globally with an estimated 80% new infections occurring among people who inject drugs (PWID). Objective We aimed to examine whether patients receiving opioid substitution therapy in primary care practices in Ireland were receiving guideline-adherent care regarding HCV screening. Ireland has developed a model of care for delivering opioid substitution treatment in the primary care setting. We conducted this study given the shift of providing care for PWID from secondary to primary care settings, in light of current guidelines aimed at scaling up interventions to reduce chronic HCV infection and associated mortality. Methods We included baseline data from the Dublin site of the Heplink study, a feasibility study focusing on developing complex interventions to enhance community-based HCV treatment and improve the HCV care pathway between primary and secondary care. We recruited 14 opioid substitution treatment-prescribing general practices that employed the administration of opioid substitution therapy from the professional networks and databases of members of the research consortium. A standardized nonprobability sampling framework was used to identify 10 patients from each practice to participate in the study. Patients were eligible if aged ≥18 years, on opioid substitution treatment, and attending the practice for any reason during the recruitment period. The baseline data were collected from the clinical records of participating patients. We collected and analyzed data on demographic characteristics, care processes and outcomes regarding HCV and other blood-borne viruses, urinalysis test results, alcohol use disorders, chronic illness, and health service utilization. We examined whether patients received care concordant with guidelines related to HCV screening and care. Results The baseline data were collected from clinical records of 134 patients; 72.2% (96/134) were males; (mean age 43, SD 7.6; range 27-71 years); 94.8% (127/134) of patients had been tested for anti-HCV antibody in their lifetime; of those, 77.9% (99/127) tested positive. Then, 83.6% (112/134) of patients had received an HIV antibody test in their lifetime; of those, 6.3% (7/112) tested HIV positive. Moreover, 66.4% (89/134) of patients had been tested for hepatitis B virus in their lifetime and 8% (7/89) of those were positive. In the 12 months before the study, 30.6% (41/134) of patients were asked about their alcohol use by their general practitioner, 6.0% (8/134) received a brief intervention, and 2.2% (3/134) were referred to a specialist addiction or alcohol treatment service. Conclusions With general practice and primary care playing an increased role in HCV care, this study highlights the importance of prioritizing the development and evaluation of real-world clinical solutions that support patients from diagnosis to treatment completion.
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Affiliation(s)
| | | | | | | | - John S Lambert
- University College Dublin, Dublin, Ireland.,Mater Misericordiae University Hospital, Dublin, Ireland
| | - Gordana Avramovic
- University College Dublin, Dublin, Ireland.,Mater Misericordiae University Hospital, Dublin, Ireland
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9
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Liu S, Yuan J, Yue W, Bi Y, Shen X, Gao J, Xu X, Lu Z. GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3257-3267. [PMID: 30006154 DOI: 10.1016/j.bbadis.2018.07.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 06/27/2018] [Accepted: 07/09/2018] [Indexed: 02/05/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid deposition and oxidative stress. It has been demonstrated that general control nonderepressible 2 (GCN2) is required to maintain hepatic fatty acid homeostasis under conditions of amino acid deprivation. However, the impact of GCN2 on the development of NAFLD has not been investigated. In this study, we used Gcn2-/- mice to investigate the effect of GCN2 on high fat diet (HFD)-induced hepatic steatosis. After HFD feeding for 12 weeks, Gcn2-/- mice were less obese than wild-type (WT) mice, and Gcn2-/- significantly attenuated HFD-induced liver dysfunction, hepatic steatosis and insulin resistance. In the livers of the HFD-fed mice, GCN2 deficiency resulted in higher levels of lipolysis genes, lower expression of genes related to FA synthesis, transport and lipogenesis, and less induction of oxidative stress. Furthermore, we found that knockdown of GCN2 attenuated, whereas overexpression of GCN2 exacerbated, palmitic acid-induced steatosis, oxidative & ER stress, and changes of peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS) and metallothionein (MT) expression in HepG2 cells. Collectively, our data provide evidences that GCN2 deficiency protects against HFD-induced hepatic steatosis by inhibiting lipogenesis and reducing oxidative stress. Our findings suggest that strategies to inhibit GCN2 activity in the liver may provide a novel approach to attenuate NAFLD development.
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Affiliation(s)
- Shasha Liu
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Juntao Yuan
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenhui Yue
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China; Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Yanwei Bi
- Shantou University Medical College, Shantou 515041, China
| | - Xiyue Shen
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Junling Gao
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xin Xu
- Department of Exercise Rehabilitation, Shanghai University of Sport, Shanghai 200438, China.
| | - Zhongbing Lu
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China.
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10
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Li Z, Zhao J, Zhang S, Weinman SA. FOXO3-dependent apoptosis limits alcohol-induced liver inflammation by promoting infiltrating macrophage differentiation. Cell Death Discov 2018. [PMID: 29531813 PMCID: PMC5841311 DOI: 10.1038/s41420-017-0020-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Alcohol consumption is generally well tolerated by the liver but in some individuals it results in persistent inflammation and liver disease. The mechanisms that regulate alcohol-induced liver inflammation are poorly understood. The transcription factor FOXO3 has previously been shown to be involved in suppressing alcohol-induced liver injury. In this study we demonstrate that in response to alcohol, approximately 10% of mouse hepatic macrophages undergo FOXO3-dependent apoptosis. By 3 days of alcohol exposure total hepatic macrophage numbers declined by 30% but these were restored to normal after 10 days of continued exposure. Whole body or myeloid specific Foxo3-/- mice failed to show this apoptotic response. After 10 days of alcohol exposure, Foxo3−/− mice had an increased basal inflammatory phenotype and an increase in the proportion of pro-inflammatory CD11b+, Ly6C+ infiltrating macrophages (IMs) infiltrating. This led to marked sensitivity to LPS with a 5-fold ALT elevation and liver injury after LPS challenge in Foxo3−/− but not WT mice. Restoring the early macrophage apoptosis burst with a pulse of intravenous GdCl3 at day 2 had no effect on the day 10 phenotype of WT mice but it corrected the hyper-inflammatory phenotype in Foxo3−/− mice. In conclusion, FOXO3-dependent hepatic macrophage apoptosis in response to ethanol serves to promote differentiation of infiltrating macrophages thus limiting the magnitude of the inflammatory response to ethanol.
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Affiliation(s)
- Zhuan Li
- 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS USA
| | - Jie Zhao
- 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS USA
| | - Shujun Zhang
- 2Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Steven A Weinman
- 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS USA.,3Liver Center, University of Kansas Medical Center, Kansas City, KS USA
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11
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Thompson MG, Navarro F, Chitsike L, Ramirez L, Kovacs EJ, Watkins SK. Alcohol exposure differentially effects anti-tumor immunity in females by altering dendritic cell function. Alcohol 2016; 57:1-8. [PMID: 27916138 DOI: 10.1016/j.alcohol.2016.10.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 10/17/2016] [Accepted: 10/17/2016] [Indexed: 12/18/2022]
Abstract
Dendritic cells (DCs) are a critical component of anti-tumor immunity due to their ability to induce a robust immune response to antigen (Ag). Alcohol was previously shown to reduce DC ability to present foreign Ag and promote pro-inflammatory responses in situations of infection and trauma. However the impact of alcohol exposure on generation of an anti-tumor response, especially in the context of generation of an immune vaccine has not been examined. In the clinic, DC vaccines are typically generated from autologous blood, therefore prior exposure to substances such as alcohol may be a critical factor to consider regarding the effectiveness in generating an immune response. In this study, we demonstrate for the first time that ethanol differentially affects DC and tumor Ag-specific T cell responses depending on sex. Signaling pathways were found to be differentially regulated in DC in females compared to males and these differences were exacerbated by ethanol treatment. DC from female mice treated with ethanol were unable to activate Ag-specific cytotoxic T cells (CTL) as shown by reduced expression of CD44, CD69, and decreased production of granzyme B and IFNγ. Furthermore, although FOXO3, an immune suppressive mediator of DC function, was found to be upregulated in DC from female mice, ethanol related suppression was independent of FOXO3. These findings demonstrate for the first time differential impacts of alcohol on the immune system of females compared to males and may be a critical consideration for determining the effectiveness of an immune based therapy for cancer in patients that consume alcohol.
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Affiliation(s)
- Matthew G Thompson
- Loyola University Chicago, Department of Surgery, Cardinal Bernardin Cancer Center, Maywood, IL 60153, USA
| | - Flor Navarro
- Loyola University Chicago, Department of Surgery, Cardinal Bernardin Cancer Center, Maywood, IL 60153, USA
| | - Lennox Chitsike
- Loyola University Chicago, Department of Surgery, Cardinal Bernardin Cancer Center, Maywood, IL 60153, USA
| | - Luis Ramirez
- Loyola University Chicago, Department of Surgery, Cardinal Bernardin Cancer Center, Maywood, IL 60153, USA
| | - Elizabeth J Kovacs
- Loyola University Chicago, Department of Surgery, Cardinal Bernardin Cancer Center, Maywood, IL 60153, USA; University of Colorado Denver, Department of Surgery, Aurora, CO, USA
| | - Stephanie K Watkins
- Loyola University Chicago, Department of Surgery, Cardinal Bernardin Cancer Center, Maywood, IL 60153, USA.
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12
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Abstract
Alcoholic liver disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a complication of cirrhosis. The pathogenesis of alcoholic liver disease can be conceptually divided into (1) ethanol-mediated liver injury, (2) inflammatory immune response to injury, (3) intestinal permeability and microbiome changes. Corticosteroids may improve outcomes, but this is controversial and probably only impacts short-term survival. New pathophysiology-based therapies are under study, including antibiotics, caspase inhibition, interleukin-22, anakinra, FXR agonist and others. These studies provide hope for better future outcomes for this difficult disease.
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Affiliation(s)
- Winston Dunn
- Gastroenterology & Hepatology, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS USA
| | - Vijay H. Shah
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN USA
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13
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Abstract
Alcohol consumption is often a comorbid condition in other chronic liver diseases. It has been shown to act in synergy to increase liver injury in viral hepatitis, hereditary hemochromatosis, and nonalcoholic fatty liver disease (NAFLD), leading to an increased risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Data suggest that modest alcohol consumption may be inversely related to the risk of developing NAFLD and lower rates of progression of NAFLD to nonalcoholic steatohepatitis (NASH). This article reviews data on the relationship between alcohol consumption and other chronic liver diseases.
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Affiliation(s)
- Christine C Hsu
- Division of Gastroenterology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19146, USA
| | - Kris V Kowdley
- Swedish Liver Care Network, Swedish Medical Center, 1124 Columbia Street, Suite 600, Seattle, WA 98104, USA.
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14
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Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression. Cell Death Differ 2015; 23:583-95. [PMID: 26470730 DOI: 10.1038/cdd.2015.125] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 08/17/2015] [Accepted: 08/20/2015] [Indexed: 01/27/2023] Open
Abstract
Forkhead box O3 (FOXO3) is a multispecific transcription factor that is responsible for multiple and conflicting transcriptional programs such as cell survival and apoptosis. The protein is heavily post-translationally modified and there is considerable evidence that post-transcriptional modifications (PTMs) regulate protein stability and nuclear-cytosolic translocation. Much less is known about how FOXO3 PTMs determine the specificity of its transcriptional program. In this study we demonstrate that exposure of hepatocytes to ethanol or exposure of macrophages to lipopolysaccharide (LPS) induces the c-Jun N-terminal kinase (JNK)-dependent phosphorylation of FOXO3 at serine-574. Chromatin immunoprecipitation (ChIP), mRNA and protein measurements demonstrate that p-574-FOXO3 selectively binds to promoters of pro-apoptotic genes but not to other well-described FOXO3 targets. Both unphosphorylated and p-574-FOXO3 bound to the B-cell lymphoma 2 (Bcl-2) promoter, but the unphosphorylated form was a transcriptional activator, whereas p-574-FOXO3 was a transcriptional repressor. The combination of increased TRAIL (TNF-related apoptosis-inducing ligand) and decreased Bcl-2 was both necessary and sufficient to induce apoptosis. LPS treatment of a human monocyte cell line (THP-1) induced FOXO3 S-574 phosphorylation and apoptosis. LPS-induced apoptosis was prevented by knockdown of FOXO3. It was restored by overexpressing wild-type FOXO3 but not by overexpressing a nonphosphorylatable S-574A FOXO3. Expression of an S-574D phosphomimetic form of FOXO3 induced apoptosis even in the absence of LPS. A similar result was obtained with mouse peritoneal macrophages where LPS treatment increased TRAIL, decreased Bcl-2 and induced apoptosis in wild-type but not FOXO3(-/-) cells. This work thus demonstrates that S-574 phosphorylation generates a specifically apoptotic form of FOXO3 with decreased transcriptional activity for other well-described FOXO3 functions.
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15
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Leti F, Malenica I, Doshi M, Courtright A, Van Keuren-Jensen K, Legendre C, Still CD, Gerhard GS, DiStefano JK. High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis. Transl Res 2015; 166:304-14. [PMID: 26001595 PMCID: PMC4537840 DOI: 10.1016/j.trsl.2015.04.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 04/08/2015] [Accepted: 04/28/2015] [Indexed: 12/11/2022]
Abstract
Recent evidence suggests that microRNAs (miRNAs), small, noncoding RNA molecules that regulate gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 individuals with severe NAFLD fibrosis or cirrhosis (F3-F4), matched for age, sex, body mass index, type 2 diabetes status, hemoglobin A1c, and use of diabetes medications. We used DESeq2 and Kruskal-Wallis test to identify miRNAs that were differentially expressed between NAFLD patients with or without fibrosis, adjusting for multiple testing using Bonferroni correction. We identified a total of 75 miRNAs showing statistically significant evidence (adjusted P value <0.05) for differential expression between the 2 groups, including 30 upregulated and 45 downregulated miRNAs. Quantitative reverse-transcription polymerase chain reaction analysis of selected miRNAs identified by sequencing validated 9 of 11 of the top differentially expressed miRNAs. We performed functional enrichment analysis of dysregulated miRNAs and identified several potential gene targets related to NAFLD-related fibrosis including hepatic fibrosis, hepatic stellate cell activation, transforming growth factor beta signaling, and apoptosis signaling. We identified forkhead box O3 and F-box WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) as potential targets of miR-182, and found that levels of forkhead box O3, but not FBXW7, were significantly decreased in fibrotic samples. These findings support a role for hepatic miRNAs in the pathogenesis of NAFLD-related fibrosis and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis.
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Affiliation(s)
- Fatjon Leti
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Ivana Malenica
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Meera Doshi
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Amanda Courtright
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Kendall Van Keuren-Jensen
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Christophe Legendre
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz
| | - Christopher D Still
- Department of Gastroenterology and Nutrition, Geisinger Obesity Institute, Danville, PA
| | - Glenn S Gerhard
- Department of Biochemistry and Molecular Biology, Temple University School of Medicine, Philadelphia, PA
| | - Johanna K DiStefano
- Division of Diabetes, Cardiovascular and Metabolic Diseases, Translational Genomics Research Institute, Phoenix, Ariz.
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16
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Berard AR, Severini A, Coombs KM. Comparative proteomic analyses of two reovirus T3D subtypes and comparison to T1L identifies multiple novel proteins in key cellular pathogenic pathways. Proteomics 2015; 15:2113-35. [DOI: 10.1002/pmic.201400602] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 02/23/2015] [Accepted: 04/16/2015] [Indexed: 01/14/2023]
Affiliation(s)
- Alicia R. Berard
- Department of Medical Microbiology; Faculty of Medicine; University of Manitoba; Winnipeg Canada R3E 0J9
- Manitoba Center for Proteomics and Systems Biology; Room 799 John Buhler Research Centre University of Manitoba; Winnipeg Canada R3E 3P4
| | - Alberto Severini
- Department of Medical Microbiology; Faculty of Medicine; University of Manitoba; Winnipeg Canada R3E 0J9
- National Microbiology Laboratory; Public Health Agency of Canada; 1015 Arlington St. Winnipeg Canada R3E 3R2
| | - Kevin M. Coombs
- Department of Medical Microbiology; Faculty of Medicine; University of Manitoba; Winnipeg Canada R3E 0J9
- Manitoba Center for Proteomics and Systems Biology; Room 799 John Buhler Research Centre University of Manitoba; Winnipeg Canada R3E 3P4
- Manitoba Institute of Child Health; Room 641 John Buhler Research Center; University of Manitoba; Winnipeg Canada R3E 3P4
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17
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Manley S, Ding W. Role of farnesoid X receptor and bile acids in alcoholic liver disease. Acta Pharm Sin B 2015; 5:158-67. [PMID: 26579442 PMCID: PMC4629219 DOI: 10.1016/j.apsb.2014.12.011] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 12/20/2014] [Accepted: 12/29/2014] [Indexed: 02/07/2023] Open
Abstract
Alcoholic liver disease (ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a) and PPARα (peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.
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Key Words
- 6ECDCA, 6α-ethyl-chenodeoxycholic acid
- ADH, alcohol dehydrogenase
- AF, activation function
- AKT, protein kinase B
- ALD, alcoholic liver disease
- ALT, alanine aminotransferase
- ASBT, apical sodium dependent bile acid transporter
- Alcoholic liver disease
- Atg, autophagy-related
- Autophagy
- BAAT, bile acid CoA:amino acid N-acyltransferase
- BACS, bile acid CoA synthetase
- BSEP, bile salt export pump
- Bile acids
- CA, cholic acid
- CB1R, cannabinoid receptor type 1
- CDCA, chenodeoxycholic acid
- CREB, cAMP response element-binding protein
- CREBH, cAMP response element-binding protein, hepatocyte specific
- CRTC2, CREB regulated transcription coactivator 2
- CYP, cytochrome P450
- DCA, deoxycholic acid
- DR1, direct repeat 1
- FGF15/19, fibroblast growth factor 15/19
- FGFR4, fibroblast growth factor receptor 4
- FXR, farnesoid X receptor
- Farnesoid X receptor
- FoxO3
- FoxO3a, forkhead box-containing protein class O3a
- GGT, gamma-glutamyltranspeptidase
- HCC, hepatocellular carcinoma
- IR-1, inverted repeat-1
- KO, knockout
- LC3, light chain 3
- LRH-1, liver receptor homolog 1
- LXR, liver X receptor
- MRP4, multidrug resistance protein 4
- NAD+, nicotinamide adenine dinucleotide
- NTCP, sodium taurocholate cotransporting polypeptide
- OSTα/β, organic solute transporter α/β
- PE, phosphatidylethanolamine
- PPARα, peroxisome proliferator-activated receptor alpha
- ROS, reactive oxygen species
- RXRα, retinoid X receptor-alpha
- SHP, small heterodimer partner
- SQSTM, sequestome-1
- SREBP1, sterol regulatory element-binding protein 1
- Sirt1, sirtuin 1
- TCA, taurocholic acid
- TFEB, transcription factor EB
- TLR4, toll-like receptor 4
- TUDCA, tauro-ursodeoxycholic acid
- UDCA, ursodeoxycholic acid
- WAY, WAY-362450
- WT, wild type
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Affiliation(s)
| | - Wenxing Ding
- Corresponding author. Tel.: +1 913 5889813; fax: +1 913 5887501.
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18
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Ni HM, Bhakta A, Wang S, Li Z, Manley S, Huang H, Copple B, Ding WX. Role of hypoxia inducing factor-1β in alcohol-induced autophagy, steatosis and liver injury in mice. PLoS One 2014; 9:e115849. [PMID: 25536043 PMCID: PMC4275262 DOI: 10.1371/journal.pone.0115849] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 11/27/2014] [Indexed: 12/12/2022] Open
Abstract
Chronic alcohol causes liver hypoxia and steatosis, which eventually develops into alcoholic liver disease (ALD). While it has been known that alcohol consumption activates hepatic hypoxia inducing factor-1α (HIF-1α), conflicting results regarding the role of HIF-1α in alcohol-induced liver injury and steatosis in mice have been reported. In the present study, we aimed to use hepatocyte-specific HIF-1β knockout mice to eliminate the possible compensatory effects of the single knockout of the 1α subunit of HIF to study the role of HIFs in ALD. C57BL/6 wild type mice were treated with acute ethanol to mimic human binge drinking. Matched wild-type and hepatocyte specific HIF-1β knockout mice were also subjected to a recently established Gao-binge alcohol model to mimic chronic plus binge conditions, which is quite common in human alcoholics. We found that acute alcohol treatment increased BNIP3 and BNIP3L/NIX expression in primary cultured hepatocytes and in mouse livers, suggesting that HIF may be activated in these models. We further found that hepatocyte-specific HIF-1β knockout mice developed less steatosis and liver injury following the Gao-binge model or acute ethanol treatment compared with their matched wild type mice. Mechanistically, protection against Gao-binge treatment-induced steatosis and liver injury was likely associated with increased FoxO3a activation and subsequent induction of autophagy in hepatocyte-specific HIF-1β knockout mice.
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Affiliation(s)
- Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Amar Bhakta
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Zhenrui Li
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Sharon Manley
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Heqing Huang
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Bryan Copple
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
- * E-mail:
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19
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Williams JA, Manley S, Ding WX. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol 2014; 20:12908-12933. [PMID: 25278688 PMCID: PMC4177473 DOI: 10.3748/wjg.v20.i36.12908] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/07/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
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20
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Shoreibah M, Anand BS, Singal AK. Alcoholic hepatitis and concomitant hepatitis C virus infection. World J Gastroenterol 2014; 20:11929-11934. [PMID: 25232227 PMCID: PMC4161778 DOI: 10.3748/wjg.v20.i34.11929] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/25/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection and alcohol abuse are two most important causes of chronic liver disease in the United States. Alcoholic hepatitis is a unique clinical syndrome among patients with chronic and active alcohol abuse with a potential for high short-term mortality. About 20% of patients presenting with alcoholic hepatitis have concomitant HCV infection. Mortality from alcoholic hepatitis is increased in the presence of concomitant hepatitis C due to synergistic interaction between HCV and alcohol in causing hepatocellular damage. Large prospective randomized studies are needed to develop guidelines on the use of corticosteroids among patients with alcoholic hepatitis and concomitant HCV infection. The impact of antiviral therapy on mortality and outcome in the setting of alcoholic hepatitis remains a novel area for future research.
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Chen CL, Tsukamoto H, Machida K. Oncogenic signaling pathways and origins of tumor-initiating stem-like cells of hepatocellular carcinomas induced by hepatitis C virus, alcohol and/or obesity. Hepatol Int 2014; 8:330-8. [PMID: 26202636 PMCID: PMC10560513 DOI: 10.1007/s12072-014-9545-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 05/13/2014] [Indexed: 12/21/2022]
Abstract
This review article discusses the importance and oncogenic signaling pathways of tumor-initiating cells (TICs) in several etiologies of hepatocellular carcinomas (HCCs) induced by hepatitis C virus (HCV), alcohol, obesity and/or chemicals. Stem cells may be present in cancer tissue, and a hierarchy of cells is formed, as is the case for normal tissue. Tumor formation, growth and propagation are maintained by a small proportion of cells with stem cell-like properties. TICs are present in alcohol-fed HCV transgenic mice, diethylnitrosamine/phenobarbital-treated mice (chemical carcinogenesis) and Spnb2 +/- mice (defective TGF-β signal). Alcohol/obesity-associated endotoxemia induces the stem cell marker Nanog through TLR4 signaling to generate TICs and liver tumors in several HCC models. The oncogenic pathway (such as the STAT3 and TLR4-NANOG pathway) and mechanism of generation of TICs of HCCs associated with HCV, alcohol and obesity are discussed. Understanding the molecular stemness signaling and cellular hierarchy and defining key TIC-specific genes will accelerate the development of novel biomarkers and treatment strategies. This review highlights recent advances in understanding the pathogenesis of liver TICs and discusses unanswered questions about the concept of liver TICs. (This project was supported by NIH grants 1R01AA018857 and P50AA11999).
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Affiliation(s)
- Chia-Lin Chen
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
- Department of Pathology, University of Southern California, Los Angeles, CA, 90033, USA
| | - Keigo Machida
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, 90033, USA.
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.
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