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Yang Y, Ge F, Luo C, Chen Y, Deng J, Yang Y, Guo X, Zhang S, Bai Z, Xiao X, Tang C. Inhibition of hepatitis B virus through PPAR-JAK/STAT pathway modulation by electroacupuncture and tenofovir disoproxil fumarate combination therapy. Int Immunopharmacol 2024; 143:113304. [PMID: 39369463 DOI: 10.1016/j.intimp.2024.113304] [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: 07/02/2024] [Revised: 09/21/2024] [Accepted: 09/29/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Acupuncture combined with nucleos(t)ide analogues (NAs) has shown promise in treating chronic hepatitis B (CHB), though mechanisms remain unclear. This study evaluates the antiviral effects of combining acupuncture with NAs against hepatitis B virus (HBV) and explores underlying mechanisms. METHODS The HBV-infected mouse model, established using the high-pressure hydrodynamic method, was divided into three groups: normal saline (NS), tenofovir disoproxil fumarate (TF), and electroacupuncture combined with TF (E_T), n = 6. Antiviral effects were assessed by monitoring HBV DNA, HBsAg, and HBeAg levels weekly. Mechanistic insights were gained via transcriptomics, metabolomics, and 16S rDNA sequencing, validated by WB, PCR, and flow cytometry. RESULTS Serum HBV DNA levels decreased by 1.98 log10 IU/mL in TF and 2.2 log10 IU/mL in E_T groups compared to NS. Serum HBeAg decreased by 10.61 % in TF and 35.75 % in E_T, while HBsAg decreased by 7.38 % and 37.58 %, respectively. Multi-omics indicated E_T modulates the PPAR pathway, upregulates taurine and all-trans-retinoic acid, and increases gut microbiota like Bacteroides and Blautia. E_T also enhanced tight junction proteins (ZO-1, Occludin, Claudin-4), improving intestinal barrier integrity. Mechanistically, E_T inhibited the PGC-1α/PPAR-α/SIRT1 pathway, reducing PGC-1α, PPAR-α, SIRT1, RXRα, and HNF4α, while promoting JAK/STAT signaling via IFN-γ, p-JAK1, p-JAK2, p-STAT1, IRF8, and suppressing SOCS-1. CONCLUSION E_T more effectively inhibited HBV replication, showing superior antigen inhibition, particularly HBsAg, than TF alone. This may be due to PPAR-JAK/STAT pathway regulation, suggesting E_T as a potential adjuvant therapy for CHB, especially in achieving a functional cure.
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Affiliation(s)
- Yan Yang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400010, China; College of Acupuncture and Tuina, Chongqing College of Traditional Chinese Medicine, Chongqing 402760, China
| | - Feilin Ge
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Chen Luo
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400010, China
| | - Yang Chen
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400010, China; College of Acupuncture and Tuina, Chongqing College of Traditional Chinese Medicine, Chongqing 402760, China
| | - Junyuan Deng
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400010, China
| | - Yunhao Yang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400010, China
| | - Xiao Guo
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400010, China
| | - Shanshan Zhang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400010, China
| | - Zhaofang Bai
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
| | - Xiaohe Xiao
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
| | - Chenglin Tang
- College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400010, China; College of Acupuncture and Tuina, Chongqing College of Traditional Chinese Medicine, Chongqing 402760, China.
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Quan J, Wen X, Su G, Zhong Y, Huang T, Xiong Z, Huang J, Lv Y, Li S, Luo S, Luo C, Cai X, Lai X, Xiang Y, Zheng SG, Shao Y, Lin H, Gao X, Tang J, Lai T. Epithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling. Nat Commun 2023; 14:8525. [PMID: 38135684 PMCID: PMC10746710 DOI: 10.1038/s41467-023-44179-x] [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: 02/13/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
Dysregulation of IL-17A is closely associated with airway inflammation and remodeling in severe asthma. However, the molecular mechanisms by which IL-17A is regulated remain unclear. Here we identify epithelial sirtuin 6 (SIRT6) as an epigenetic regulator that governs IL-17A pathogenicity in severe asthma. Mice with airway epithelial cell-specific deletion of Sirt6 are protected against allergen-induced airway inflammation and remodeling via inhibiting IL-17A-mediated inflammatory chemokines and mesenchymal reprogramming. Mechanistically, SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via its PPXY motifs. SIRT6 promotes RORγt recruitment to the IL-17A gene promoter and enhances its transcription. In severe asthma patients, high expression of SIRT6 positively correlates with airway remodeling and disease severity. SIRT6 inhibitor (OSS_128167) treatment significantly attenuates airway inflammation and remodeling in mice. Collectively, these results uncover a function for SIRT6 in regulating IL-17A pathogenicity in severe asthma, implicating SIRT6 as a potential therapeutic target for severe asthma.
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Affiliation(s)
- Jingyun Quan
- Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China
- Department of Health Management & Physical Examination Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xiaoxia Wen
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Guomei Su
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yu Zhong
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Tong Huang
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Zhilin Xiong
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Jiewen Huang
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yingying Lv
- Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China
| | - Shihai Li
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Shuhua Luo
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Chaole Luo
- Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China
| | - Xin Cai
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xianwen Lai
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yuanyuan Xiang
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Song Guo Zheng
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China
| | - Yiming Shao
- Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China
| | - Haitao Lin
- Department of Health Management & Physical Examination Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xiao Gao
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Jing Tang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Tianwen Lai
- Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523710, China.
- Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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Abounouh K, Tanouti IA, Ouladlahsen A, Tahiri M, Badre W, Dehbi H, Sarih M, Benjelloun S, Pineau P, Ezzikouri S. The peroxisome proliferator-activated receptor γ coactivator-1 alpha rs8192678 (Gly482Ser) variant and hepatitis B virus clearance. Infect Dis (Lond) 2023; 55:614-624. [PMID: 37376899 DOI: 10.1080/23744235.2023.2228403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 06/06/2023] [Accepted: 06/18/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (CHB) infection is still incurable a major public health problem. It is yet unclear how host genetic factors influence the development of HBV infection. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) has been shown to regulate hepatitis B virus (HBV). Several reports found that PPARGC1A variants are involved in a number of distinct liver diseases. Here we investigate whether the PPARGC1A rs8192678 (Gly482Ser) variant is involved in the spontaneous clearance of acute HBV infection and if it participates in chronic disease progression in Moroccan patients. METHODS Our study included 292 chronic hepatitis B (CHB) patients and 181 individuals who spontaneously cleared-HBV infection. We genotyped the rs8192678 SNP using a TaqMan allelic discrimination assay and then explored its association with spontaneous HBV clearance and CHB progression. RESULTS Our data showed that individuals carrying CT and TT genotypes were more likely to achieve spontaneous clearance (OR = 0.48, 95% CI (0.32-0.73), p = 0.00047; OR = 0.28, 95% CI (0.15-0.53), p = 0.00005, respectively). Subjects carrying the mutant allele T were more likely to achieve spontaneous clearance (OR = 0.51, 95% CI (0.38-0.67), P = 2.68E-06). However, when we investigated the impact of rs8192678 on the progression of liver diseases, we neither observe any influence (p > 0.05) nor found any significant association between ALT, AST, HBV viral loads, and the PPARGC1A rs8192678 genotypes in patients with CHB (p > 0.05). CONCLUSION Our result suggests that PPARGC1A rs8192678 may modulate acute HBV infection, and could therefore represent a potential predictive marker in the Moroccan population.
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Affiliation(s)
- Karima Abounouh
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
- Laboratory of Cellular and Molecular Pathology, Medical School, University Hassan II
| | - Ikram-Allah Tanouti
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Ahd Ouladlahsen
- Faculté de médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Mohamed Tahiri
- Faculté de médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Wafaa Badre
- Faculté de médecine de Casablanca, CHU Ibn Rochd, Casablanca, Morocco
| | - Hind Dehbi
- Laboratory of Cellular and Molecular Pathology, Medical School, University Hassan II
| | - M'hammed Sarih
- Service de Parasitologie et des Maladies Vectorielles, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
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Abstract
Liver fibrosis has a high incidence worldwide and is the common pathological basis of many chronic liver diseases. Liver fibrosis is caused by the excessive deposition of extracellular matrix and concomitant collagen accumulation in livers and can lead to the development of liver cirrhosis and even liver cancer. A large number of studies have provided evidence that liver fibrosis can be blocked or even reversed by appropriate medical interventions. However, the antifibrosis drugs with ideal clinical efficacy are still insufficient. The edible plant-derived natural compounds have been reported to exert effective antifibrotic effects with few side-effects, representing a kind of promising source for the treatment of liver fibrosis. In this article, we reviewed the current progress of the natural compounds derived from dietary plants in the treatment of liver fibrosis, including phenolic compounds (capsaicin, chlorogenic acid, curcumin, ellagic acid, epigallocatechin-3-gallate, resveratrol, sinapic acid, syringic acid, vanillic acid and vitamin E), flavonoid compounds (genistein, hesperidin, hesperetin, naringenin, naringin and quercetin), sulfur-containing compounds (S-allylcysteine, ergothioneine, lipoic acid and sulforaphane) and other compounds (betaine, caffeine, cucurbitacin B, lycopene, α-mangostin, γ-mangostin, ursolic acid, vitamin C and yangonin). The pharmacological effects and related mechanisms of these compounds in in-vivo and in-vitro models of liver fibrosis are focused.
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Okudaira N, Ishizaka Y, Tamamori-Adachi M. Resveratrol blocks retrotransposition of LINE-1 through PPAR α and sirtuin-6. Sci Rep 2022; 12:7772. [PMID: 35546166 PMCID: PMC9095727 DOI: 10.1038/s41598-022-11761-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 04/26/2022] [Indexed: 11/09/2022] Open
Abstract
The retroelement long interspersed element-1 (LINE-1 or L1) comprises about 17% of the human genome. L1 retrotransposition is known to cause genomic instability and related disorders, and resveratrol suppresses this retrotransposition; however, the underlying mechanism is still not elucidated. Recent observations showed that low-molecular-weight compounds might induce L1 retrotransposition through unknown mechanisms. This study aimed to determine polyphenol resveratrol (RV)'s effect on L1-RTP (retrotransposition) in somatic cells. Surprisingly, RV completely blocked L1-RTP. Experiments using the PPARα inhibitor GW6471 or siRNA-mediated PPARα depletion showed that RV-mediated L1-RTP's inhibition depended on peroxisome proliferator-activated receptor α (PPARα). We demonstrated that RV inhibits p38 and cAMP response element binding protein phosphorylation, which are involved in MAPK signaling, and the L1-ORF1 protein's chromatin recruitment. Furthermore, RV increased the expression of sirtuin-6 (SIRT6), which inhibited the activation of L1. The sirtuins family, SIRT1, SIRT6, and SIRT7, but not SIRT3, are involved in RV-mediated inhibition of L1-RTP. Overall, our findings suggest that RV directly modulates PPARα-mediated L1-RTP in somatic cells and that MAPK signaling interacts with SIRT6 closely and may play a role in preventing human diseases such as cancer.
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Affiliation(s)
- Noriyuki Okudaira
- Department of Biochemistry, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
| | - Yukihito Ishizaka
- Department of Intractable Diseases, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Mimi Tamamori-Adachi
- Department of Biochemistry, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
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Lan W, Wang Y, Zhou Z, Sun X, Zhang Y, Zhang F. Metabolic Regulation of Hepatitis B Virus Infection in HBV-Transgenic Mice. Metabolites 2022; 12:287. [PMID: 35448475 PMCID: PMC9031567 DOI: 10.3390/metabo12040287] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/17/2022] [Accepted: 03/23/2022] [Indexed: 11/20/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a worldwide health burden. Metabolomics analysis has revealed HBV-induced metabolism dysregulation in liver tissues and hepatocytes. However, as an infectious disease, the tissue-specific landscape of metabolic profiles of HBV infection remains unclear. To fill this gap, we applied untargeted nuclear magnetic resonance (NMR) metabolomic analysis of the heart, liver, spleen, lung, kidney, pancreas, and intestine (duodenum, jejunum, ileum) in HBV-transgenic mice and their wild-type littermates. Strikingly, we found systemic metabolic alterations induced by HBV in liver and extrahepatic organs. Significant changes in metabolites have been observed in most tissues of HBV-transgenic mice, except for ileum. The metabolic changes may provide novel therapeutic targets for the treatment of HBV infection. Moreover, tissue-specific metabolic profiles could speed up the study of HBV induced systemic metabolic reprogramming, which could help follow the progression of HBV infection and explain the underlying pathogenesis.
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Affiliation(s)
- Wenning Lan
- Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
- Ganjiang Innovation Academy, Chinese Academy of Sciences, Ganzhou 341001, China
| | - Yang Wang
- Institute of Immunotherapy, Fujian Medical University, Fuzhou 350122, China;
| | - Zixiong Zhou
- Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
| | - Xia Sun
- Fujian Science and Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, China;
| | - Yun Zhang
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
- Fujian Science and Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, China;
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
| | - Fangrong Zhang
- Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou 350122, China
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Linn YH, Ei WW, Myint LMM, Lwin KM. Anti-hepatitis B activities of Myanmar medicinal plants: a narrative review of current evidence. Virusdisease 2021; 32:446-466. [PMID: 34631974 DOI: 10.1007/s13337-021-00714-2] [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: 12/18/2020] [Accepted: 06/12/2021] [Indexed: 11/28/2022] Open
Abstract
Hepatitis B is one of the major burdens for health services and is the leading cause of morbidity and mortality from cirrhosis of liver and hepatocellular carcinoma. Current treatment strategies using nucleos(t)ide analogue reverse-transcriptase inhibitors or interferons are targeted for the long-term suppression of hepatitis B DNA. However, functional cure of hepatitis B infection (HBsAg clearance) was difficult to attain with such treatments. Therefore, new treatment strategies or innovative treatments are urgently needed. The new treatments should focus on the potential therapeutic targets such as covalently closed circular DNA which may be important for the HBsAg clearance. Plant based medicines have been used in different traditional medicine practices and these natural products/compounds serve as a good source of information or clues for use in drug discovery and design. Many natural products were found to be effective against hepatitis B virus and some even have better therapeutic activities than currently used compounds. This review summarizes the current evidence of Myanmar medicinal plants in basic and clinical research which shows promising potential for the development of novel therapeutic agents for the treatment of hepatitis B.
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Affiliation(s)
- Ye Htut Linn
- FAME Pharmaceuticals Industry Co., Ltd., No. 20, Mingyi Mahar Min Gaung Road, Industrial Zone (3), Hlaing Thar Yar City of Industry, Yangon, 11401 Myanmar
| | - Win Win Ei
- FAME Pharmaceuticals Industry Co., Ltd., No. 20, Mingyi Mahar Min Gaung Road, Industrial Zone (3), Hlaing Thar Yar City of Industry, Yangon, 11401 Myanmar
| | - Lwin Mon Mon Myint
- FAME Pharmaceuticals Industry Co., Ltd., No. 20, Mingyi Mahar Min Gaung Road, Industrial Zone (3), Hlaing Thar Yar City of Industry, Yangon, 11401 Myanmar
| | - Khin Maung Lwin
- FAME Pharmaceuticals Industry Co., Ltd., No. 20, Mingyi Mahar Min Gaung Road, Industrial Zone (3), Hlaing Thar Yar City of Industry, Yangon, 11401 Myanmar
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Kong F, Li Q, Zhang F, Li X, You H, Pan X, Zheng K, Tang R. Sirtuins as Potential Therapeutic Targets for Hepatitis B Virus Infection. Front Med (Lausanne) 2021; 8:751516. [PMID: 34708060 PMCID: PMC8542665 DOI: 10.3389/fmed.2021.751516] [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: 08/01/2021] [Accepted: 09/15/2021] [Indexed: 01/15/2023] Open
Abstract
Sirtuins (SIRTs) are well-known histone deacetylases that are capable of modulating various cellular processes in numerous diseases, including the infection of hepatitis B virus (HBV), which is one of the primary pathogenic drivers of liver cirrhosis and hepatocellular carcinoma. Mounting evidence reveals that HBV can alter the expression levels of all SIRT proteins. In turn, all SIRTs regulate HBV replication via a cascade of molecular mechanisms. Furthermore, several studies suggest that targeting SIRTs using suitable drugs is a potential treatment strategy for HBV infection. Here, we discuss the molecular mechanisms associated with SIRT-mediated upregulation of viral propagation and the recent advances in SIRT-targeted therapy as potential therapeutic modalities against HBV infection.
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Affiliation(s)
- Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Qi Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- Laboratory Department, The People's Hospital of Funing, Yancheng, China
| | - Fulong Zhang
- Imaging Department, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Xiucheng Pan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
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Chojnacka K, Skrzypczak D, Izydorczyk G, Mikula K, Szopa D, Witek-Krowiak A. Antiviral Properties of Polyphenols from Plants. Foods 2021; 10:foods10102277. [PMID: 34681326 PMCID: PMC8534698 DOI: 10.3390/foods10102277] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/03/2021] [Accepted: 09/21/2021] [Indexed: 02/06/2023] Open
Abstract
Polyphenols are active substances against various types of viral infections. Researchers have characterized methods of how to isolate polyphenols without losing their potential to formulate pharmaceutical products. Researchers have also described mechanisms against common viral infections (i.e., influenza, herpes, hepatitis, rotavirus, coronavirus). Particular compounds have been discussed together with the plants in the biomass in which they occur. Quercetin, gallic acid and epigallocatechin are exemplary compounds that inhibit the growth cycle of viruses. Special attention has been paid to identify plants and polyphenols that can be efficient against coronavirus infections. It has been proven that polyphenols present in the diet and in pharmaceuticals protect us from viral infections and, in case of infection, support the healing process by various mechanisms, i.e., they block the entry into the host cells, inhibit the multiplication of the virus, seal blood vessels and protect against superinfection.
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Monroy-Ramirez HC, Galicia-Moreno M, Sandoval-Rodriguez A, Meza-Rios A, Santos A, Armendariz-Borunda J. PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases. Int J Mol Sci 2021; 22:ijms22158298. [PMID: 34361064 PMCID: PMC8347792 DOI: 10.3390/ijms22158298] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.
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Affiliation(s)
- Hugo Christian Monroy-Ramirez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Marina Galicia-Moreno
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Ana Sandoval-Rodriguez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Alejandra Meza-Rios
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Juan Armendariz-Borunda
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
- Correspondence:
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Jhanji M, Rao CN, Sajish M. Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation. GeroScience 2021; 43:1171-1200. [PMID: 33244652 PMCID: PMC7690980 DOI: 10.1007/s11357-020-00295-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/28/2020] [Indexed: 02/07/2023] Open
Abstract
Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADP-ribose polymerase 1 (PARP1), a major determinant of cellular NAD+-dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the auto-poly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1-mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention.
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Affiliation(s)
- Megha Jhanji
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA
| | - Chintada Nageswara Rao
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA
| | - Mathew Sajish
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
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Tang Y, Ma N, Luo H, Chen S, Yu F. Downregulated long non-coding RNA LINC01093 in liver fibrosis promotes hepatocyte apoptosis via increasing ubiquitination of SIRT1. J Biochem 2021; 167:525-534. [PMID: 32044992 DOI: 10.1093/jb/mvaa013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 12/25/2019] [Indexed: 02/07/2023] Open
Abstract
The apoptosis of hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thus promoting the accumulation of extracellular matrix proteins and aggravating liver fibrosis. Silent information regulator 1 (SIRT1) is an anti-fibrotic protein whose downregulation induces hepatocyte apoptosis. This study aims to identify whether SIRT1 is regulated by long non-coding RNA LINC01093 and explore its underlying mechanisms. Liver fibrosis was induced in mice using CCl4, and the differential expressions of several fibrosis-related long noncoding RNAs were detected in liver tissues. The effect of LINC01093 on cell apoptosis and viability of hepatocytes were investigated after LINC01093 overexpression or knockdown using flow cytometry and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The anti-fibrotic effect of LINC01093 overexpression was observed in vivo. LncRNA LINC01093 is downregulated in CCl4-induced liver tissues and TGF-β1-stimulated hepatocytes. Downregulated LINC01093 promoted cell apoptosis and inhibited cell viability of hepatocytes. The co-culture between LINC01093-knockdown hepatocytes and HSCs increased the expressions of pro-fibrotic proteins. Downregulated LINC01093 promoted hepatocyte apoptosis via promoting degradation and ubiquitination of SIRT1 under TGF-β1 stimulation. The injection of LINC01093-overexpressing vectors alleviated liver fibrosis in vivo. In liver fibrosis, the downregulated LINC01093 promoted hepatocyte apoptosis, which is mediated by increasing the degradation and ubiquitination of SIRT1.
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Affiliation(s)
- Yinhe Tang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical University, 205 Wenrui Avenue, Wenzhou 325000, People's Republic of China
| | - Naijing Ma
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical University, 205 Wenrui Avenue, Wenzhou 325000, People's Republic of China
| | - Hao Luo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical University, 205 Wenrui Avenue, Wenzhou 325000, People's Republic of China
| | - Shizuan Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical University, 205 Wenrui Avenue, Wenzhou 325000, People's Republic of China
| | - Fuxiang Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical University, 205 Wenrui Avenue, Wenzhou 325000, People's Republic of China
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Wu J, Li Y, Yu J, Gan Z, Wei W, Wang C, Zhang L, Wang T, Zhong X. Resveratrol Attenuates High-Fat Diet Induced Hepatic Lipid Homeostasis Disorder and Decreases m 6A RNA Methylation. Front Pharmacol 2020; 11:568006. [PMID: 33519432 PMCID: PMC7845411 DOI: 10.3389/fphar.2020.568006] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 10/13/2020] [Indexed: 12/31/2022] Open
Abstract
Purpose: N 6-methyladenosine (m6A) mRNA methylation is affected by dietary factors and associated with lipid metabolism; however, whether the regulatory role of resveratrol in lipid metabolism is involved in m6A mRNA methylation remains unknown. Here, the objective of this study was to investigate the effect of resveratrol on hepatic lipid metabolism and m6A RNA methylation in the liver of mice. Methods: A total of 24 male mice were randomly allocated to LFD (low-fat diet), LFDR (low-fat diet + resveratrol), HFD (high-fat diet), and HFDR (high-fat diet + resveratrol) groups for 12 weeks (n = 6/group). Final body weight of mice was measured before sacrificing. Perirhemtric fat, abdominal and epididymal fat, liver tissues, and serum were collected at sacrifice and analyzed. Briefly, mice phenotype, lipid metabolic index, and m6A modification in the liver were assessed. Results: Compared to the HFD group, dietary resveratrol supplementation reduced the body weight and relative abdominal, epididymal, and perirhemtric fat weight in high-fat-exposed mice; however, resveratrol significantly increased average daily feed intake in mice given HFD. The amounts of serum low-density lipoprotein cholesterol (LDL), liver total cholesterol (TC), and triacylglycerol (TAG) were significantly decreased by resveratrol supplementation. In addition, resveratrol significantly enhanced the levels of peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), cytochrome P450, family 4, subfamily a, polypeptide 10/14 (CYP4A10/14), acyl-CoA oxidase 1 (ACOX1), and fatty acid-binding protein 4 (FABP4) mRNA and inhibited acyl-CoA carboxylase (ACC) mRNA levels in the liver. Furthermore, the resveratrol in HFD increased the transcript levels of methyltransferase like 3 (METTL3), alkB homolog 5 (ALKBH5), fat mass and obesity associated protein (FTO), and YTH domain family 2 (YTHDF2), whereas it decreased the level of YTH domain family 3 (YTHDF3) and m6A abundance in mice liver. Conclusion: The beneficial effect of resveratrol on lipid metabolism disorder under HFD may be due to decrease of m6A RNA methylation and increase of PPARα mRNA, providing mechanistic insights into the function of resveratrol in alleviating the disturbance of lipid metabolism in mice.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Xiang Zhong
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
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14
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Zeng Z, Cao Z, Tang Y. Identification of diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus-associated early stage hepatocellular carcinoma based on RNA-sequencing data. Oncol Lett 2020; 20:231. [PMID: 32968453 PMCID: PMC7499982 DOI: 10.3892/ol.2020.12094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 07/15/2020] [Indexed: 02/07/2023] Open
Abstract
Primary liver cancer is a rapidly progressing neoplasm with high morbidity and mortality rates. The present study aimed to identify potential diagnostic and prognostic biomarkers, and candidate targeted agents for hepatitis B virus (HBV)-associated early stage hepatocellular carcinoma (HCC). The gene expression profiles were extracted from the Gene Expression Omnibus database. Differentially expressed genes (DEGs), hub genes and the enrichment of signaling pathways were filtered out via a high-throughput sequencing method. The association between hub genes and the effects of the abnormal expression of hub genes on the rate of genetic variation, overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS) and disease-free survival (DSS) of patients with HCC, as well as pathological stage and grade, were analyzed using different databases. A total of 1,582 DEGs were identified. Gene Ontology analysis revealed that the DEGs were mainly involved in the ‘oxidation-reduction process’, ‘steroid metabolic process’, ‘metabolic process’ and ‘fatty acid beta-oxidation’. Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways revealed that the DEGs were mainly associated with ‘metabolic pathways’, ‘PPAR signaling pathway’, ‘fatty acid degradation’ and the ‘cell cycle’. A total of 8 hub genes were extracted. Additionally, the abnormal expression levels of hub genes were closely associated with the OS, RFS, PFS and DSS of patients, the pathological stage and the grade. Furthermore, abnormal expression levels of the 8 hub genes were found in >30% of all samples. Several small molecular compounds that may reverse the altered DEGs were identified based on Connectivity Map analysis, including phenoxybenzamine, GW-8510, resveratrol, 0175029-0000 and daunorubicin. In conclusion, the dysfunction of fat metabolic pathways, the cell cycle, oxidation-reduction processes and viral carcinogenesis may serve critical roles in the occurrence of HBV-associated early stage HCC. The identified 8 hub genes may act as robust biomarkers for diagnosis and prognosis. Some small molecular compounds may be promising targeted agents against HBV-associated early stage HCC.
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Affiliation(s)
- Zhili Zeng
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Zebiao Cao
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Ying Tang
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.,Department of Oncology, Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
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Yang Y, Ying G, Wu S, Wu F, Chen Z. In vitro inhibition effects of hepatitis B virus by dandelion and taraxasterol. Infect Agent Cancer 2020; 15:44. [PMID: 32647534 PMCID: PMC7336670 DOI: 10.1186/s13027-020-00309-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/23/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV) causes hepatitis, which progresses to fatal liver diseases and remains a global health problem. Current treatments for chronic hepatitis B are unable to cure hepatitis. Thus, new antiviral drugs must be developed. In this study, the viral inhibition effects of dandelion and taraxasterol were assessed in HepG2.2.15 cell line. Taraxacum officinale F.H.Wigg. (compositae) with English name dandelion is used as a traditional herb for liver disorders and as a common antiviral agent. Taraxasterol is one of the active compounds of dandelion. The secretion of HBV DNA and HBV surface antigen (HBsAg) and HBeAg was detected using fluorescence quantitative PCR (qPCR) and ELISA, respectively. Intracellular HBsAg was detected by immunofluorescence. In order to demonstrate the potential mechanism of anti-viral activity, the expression levels of host factors polypyrimidine tract binding protein 1 (PTBP1) and sirtuin 1 (SIRT1) were detected with Western blotting and qPCR. Dandelion and taraxasterol effectively reduced the secretion of HBsAg, HBeAg and the HBV DNA in cell supernatants, and significantly reduced the intracellular HBsAg as indicated by immunofluorescence results. Taraxasterol may be one of the main effective components of dandelion. It significantly decreased the protein expression levels of PTBP1 and SIRT1. The present study revealed that dandelion and its component taraxasterol could inhibit HBV and may be a potential anti-HBV drug, whose potential targets were the host factors PTBP1 and SIRT1.
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Affiliation(s)
- Ying Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China
| | - Gaoxiang Ying
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China
| | - Shanshan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China
| | - Fengtian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China
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3,4,5-Tri-O-caffeoylquinic acid methyl ester isolated from Lonicera japonica Thunb. Flower buds facilitates hepatitis B virus replication in HepG2.2.15 cells. Food Chem Toxicol 2020; 138:111250. [PMID: 32156566 DOI: 10.1016/j.fct.2020.111250] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 02/05/2020] [Accepted: 03/06/2020] [Indexed: 12/26/2022]
Abstract
Caffeoylquinic acids are well known for their prominent antiviral activities. Beyond our expectations, we initially found 3,4,5-Tri-O-caffeoylquinic acid methyl ester (3,4,5-CQME) from L. japonica can facilitate HBV DNA and antigens secretion. This study aimed to investigate its underlying molecular mechanism. The results indicate that 3,4,5-CQME signally increased intracellular and secreted HBsAg levels by more than two times in HepG2.2.15 cells and HepAD38 cells. Furthermore, levels of HBeAg, HBV DNA and RNA were significantly enhanced by 3-day 3,4,5-CQME treatment; it didn't directly affect intracellular cccDNA amount, although it slightly increased cccDNA accumulation as a HBV DNA replication feedback. In addition, treatment with 3,4,5-CQME significantly induced HBx protein expression for viral replication. We utilized a phospho-antibody assay to profile the signal transduction change by 3,4,5-CQME to illuminate its molecular mechanism. The results indicate that treatment with 3,4,5-CQME activated AKT/mTOR, MAPK and NF-κB pathways verified by immunoblot. Moreover, 3,4,5-CQME upregulated the expression of nuclear transcriptional factors PGC1α and PPARα. In short, 3,4,5-CQME promotes HBV transcription and replication by upregulating HBx expression and activating HBV transcriptional regulation-related signals. As caffeoylquinic acids are widely present in traditional Chinese medicines, the risk of intaking caffeoylquinic acids-containing herbs for hepatitis B treatment requires more evaluation and further research.
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17
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Host Transcription Factors in Hepatitis B Virus RNA Synthesis. Viruses 2020; 12:v12020160. [PMID: 32019103 PMCID: PMC7077322 DOI: 10.3390/v12020160] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/27/2020] [Accepted: 01/28/2020] [Indexed: 02/06/2023] Open
Abstract
The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA (cccDNA) that resides in the nucleus. As HBV replication requires the help of host transcription factors to replicate, focusing on host protein–HBV genome interactions may reveal insights into new drug targets against cccDNA. The structural details on such complexes, however, remain poorly defined. In this review, the current literature regarding host transcription factors’ interactions with HBV cccDNA is discussed.
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Khorolskaya VG, Gureev AP, Shaforostova EA, Laver DA, Popov VN. The Fenofibrate Effect on Genotoxicity in Brain and Liver and on the Expression of Genes Regulating Fatty Acids Metabolism of Mice. BIOCHEMISTRY (MOSCOW), SUPPLEMENT SERIES B: BIOMEDICAL CHEMISTRY 2020. [DOI: 10.1134/s1990750820010084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Wang Q, Cheng ST, Chen J. HBx mediated Increase of SIRT1 Contributes to HBV-related Hepatocellular Carcinoma Tumorigenesis. Int J Med Sci 2020; 17:1783-1794. [PMID: 32714081 PMCID: PMC7378664 DOI: 10.7150/ijms.43491] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 05/26/2020] [Indexed: 12/16/2022] Open
Abstract
Objective: Hepatocellular carcinoma (HCC) is one of the main causes of cancer-related deaths worldwide, and chronic hepatitis B virus (HBV) infection is strongly associated with HCC development, but the pathogenesis of HBV-related HCC remains obscure. Sirtuin 1 (SIRT1) has been implicated to enhance the replication of HBV and to promote the tumorigenesis of HCC. In this study, we aim to investigate the functional role of SIRT1 on HBV viral protein and HBV-induced HCC. Methods: Tumorous liver tissues from patient diagnosed with HBV-related HCC were collected and further divided into two groups (with or without metastasis). Then, the mRNA and protein level of SIRT1 in those tissues were detected by real time PCR and Western blot, respectively. Meanwhile, the protein level of epithelial-mesenchymal transition (EMT) relative markers in those tissues was determined by Western blot. Furthermore, the expression of SIRT1 in HBV-expressing HCC cells was examined. Next, the relationship between viral proteins and SIRT1 expression were determined by real time PCR and Western blot. In addition, the potential role of HBx-upregulated SIRT1 in HCC proliferation, migration and invasion were analyzed by cell viability assays, cell proliferation assay, wound healing assay, transwell assay and Western blot. Results: In this study, we found that the expression of SIRT1 was obviously increased in patients with metastasis compared to the patients without metastasis. Consistently, the expression of SIRT1 was also upregulated in HBV-expressing HCC cells compared to the controls. Further investigation showed that viral protein HBx was responsible for the elevated SIRT1 in HBV-expressing HCC cells. Meanwhile, the expression of HBx could be upregulated by SIRT1. Additionally, functional studies showed that HBx-elevated SIRT1 could promote HCC cell proliferation, migration and invasion. Importantly, HBx induced HCC proliferation and migration could be suppressed by Nicotinamide in a dose dependent manner. Conclusions: Our findings uncovered the positive role of SIRT1 in HBx-mediated tumorigenesis which implicated the potential role of SIRT1 in HBV-related HCC treatment.
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Affiliation(s)
- Qing Wang
- Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Sheng-Tao Cheng
- Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Juan Chen
- Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
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Khorolskaya VG, Gureev AP, Shaforostova EA, Laver DA, Popov VN. [The fenofibrate effect on genotoxicity in brain and liver and on the expression of genes regulating fatty acids metabolism of mice]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2019; 65:388-397. [PMID: 31666411 DOI: 10.18097/pbmc20196505388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Fibrates are well-known agonists of the PPAR family (peroxisome proliferator-activated receptors). This class of drugs is used for the treatment of dyslipidemia and atherosclerosis. Fenofibrate is one of the members of this class of synthetic PPARα receptor ligands. The oral administration of 0.3% fenofibrate caused a decrease in strength due to loss of body weight in laboratory animals when improving behavioural features. Analysis of the mitochondrial DNA of liver cells showed a genotoxic effect of fenofibrate, due to accumulation of reactive oxygen species, which could be attributed to activation of peroxisomal β-oxidation processes, as well as to the lack of increase in the expression of genes encoding antioxidant defense proteins. Treatment with fenofibrate did not cause brain mtDNA damage. It has been shown that fenofibrate induced mitochondrial β-oxidation in the brain, as indicated by the increased expression of the Acadm and Cpt1a and Ppargc1a and Ppara. The study found no effect of fenofibrate on the increase of mitochondrial biogenesis in brain and liver cells. Thus, we can conclude that fenofibrate significantly affects lipid metabolism in the liver and brain, but in the liver it is associated with an increase of oxidative stress, resulting in mtDNA oxidative damage. However, fenofibrate-induced increase in the expression of Ppargc1a is not associated with an increase of mitochondrial biogenesis. This is consistent with the recent suggestion that PGC-1α might not be a master regulator of mitochondrial biogenesis.
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Affiliation(s)
| | - A P Gureev
- Voronezh State University, Voronezh, Russia
| | | | - D A Laver
- Voronezh State University, Voronezh, Russia
| | - V N Popov
- Voronezh State University, Voronezh, Russia; Voronezh State University of Engineering Technologies, Voronezh, Russia
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21
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Chen W, Zhu X, Ma J, Zhang M, Wu H. Structural Elucidation of a Novel Pectin-Polysaccharide from the Petal of Saussurea laniceps and the Mechanism of its Anti-HBV Activity. Carbohydr Polym 2019; 223:115077. [DOI: 10.1016/j.carbpol.2019.115077] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/09/2019] [Accepted: 07/09/2019] [Indexed: 12/30/2022]
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A Yeast Suppressor Screen Used To Identify Mammalian SIRT1 as a Proviral Factor for Middle East Respiratory Syndrome Coronavirus Replication. J Virol 2019; 93:JVI.00197-19. [PMID: 31142674 PMCID: PMC6675885 DOI: 10.1128/jvi.00197-19] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 05/21/2019] [Indexed: 02/08/2023] Open
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) initially emerged in 2012 and has since been responsible for over 2,300 infections, with a case fatality ratio of approximately 35%. We have used the highly characterized model system of Saccharomyces cerevisiae to investigate novel functional interactions between viral proteins and eukaryotic cells that may provide new avenues for antiviral intervention. We identify a functional link between the MERS-CoV ORF4a proteins and the YDL042C/SIR2 yeast gene. The mammalian homologue of SIR2 is SIRT1, an NAD-dependent histone deacetylase. We demonstrate for the first time that SIRT1 is a proviral factor for MERS-CoV replication and that ORF4a has a role in modulating its activity in mammalian cells. Viral proteins must intimately interact with the host cell machinery during virus replication. Here, we used the yeast Saccharomyces cerevisiae as a system to identify novel functional interactions between viral proteins and eukaryotic cells. Our work demonstrates that when the Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a accessory gene is expressed in yeast it causes a slow-growth phenotype. ORF4a has been characterized as an interferon antagonist in mammalian cells, and yet yeast lack an interferon system, suggesting further interactions between ORF4a and eukaryotic cells. Using the slow-growth phenotype as a reporter of ORF4a function, we utilized the yeast knockout library collection to perform a suppressor screen where we identified the YDL042C/SIR2 yeast gene as a suppressor of ORF4a function. The mammalian homologue of SIR2 is SIRT1, an NAD-dependent histone deacetylase. We found that when SIRT1 was inhibited by either chemical or genetic manipulation, there was reduced MERS-CoV replication, suggesting that SIRT1 is a proviral factor for MERS-CoV. Moreover, ORF4a inhibited SIRT1-mediated modulation of NF-κB signaling, demonstrating a functional link between ORF4a and SIRT1 in mammalian cells. Overall, the data presented here demonstrate the utility of yeast studies for identifying genetic interactions between viral proteins and eukaryotic cells. We also demonstrate for the first time that SIRT1 is a proviral factor for MERS-CoV replication and that ORF4a has a role in modulating its activity in cells. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) initially emerged in 2012 and has since been responsible for over 2,300 infections, with a case fatality ratio of approximately 35%. We have used the highly characterized model system of Saccharomyces cerevisiae to investigate novel functional interactions between viral proteins and eukaryotic cells that may provide new avenues for antiviral intervention. We identify a functional link between the MERS-CoV ORF4a proteins and the YDL042C/SIR2 yeast gene. The mammalian homologue of SIR2 is SIRT1, an NAD-dependent histone deacetylase. We demonstrate for the first time that SIRT1 is a proviral factor for MERS-CoV replication and that ORF4a has a role in modulating its activity in mammalian cells.
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Du N, Li XH, Bao WG, Wang B, Xu G, Wang F. Resveratrol‑loaded nanoparticles inhibit enterovirus 71 replication through the oxidative stress‑mediated ERS/autophagy pathway. Int J Mol Med 2019; 44:737-749. [PMID: 31173159 DOI: 10.3892/ijmm.2019.4211] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 05/23/2019] [Indexed: 11/05/2022] Open
Abstract
A number of studies have demonstrated that resveratrol (RES) has a variety of biological functions, including cardiovascular protective effects, treatment of mutations, and anti‑inflammatory, anti‑tumor and antiviral effects. In the present study, RES‑loaded nanoparticles (RES‑NPs) were used to protect rhabdosarcoma (RD) cells from enterovirus 71 (EV71) infection, and the relevant mechanisms were also explored. An amphiphilic copolymer, monomethoxy poly (ethylene glycol)‑b‑poly (D,L‑lactide), was used as vehicle material, and RES‑NPs with necessitated drug‑loading content and suitable sizes were prepared under optimized conditions. RES‑NPs exhibited the ability to inhibit the increase of intracellular oxidative stress. The prospective mechanism for the function of RES‑NPs suggested was that RES‑NPs may inhibit the oxidative stress‑mediated PERK/eIF2α/ATF4 signaling pathway, downregulate the autophagy pathway and resist EV71‑induced RD cells injury. Furthermore, RES‑NPs treatment markedly inhibited the secretion of inflammatory factors, including interleukin (IL)‑6, IL‑8 and tumor necrosis factor‑α elicited by EV71 infection. Concomitantly, inhibitors of oxidative stress, endoplasmic reticulum stress (ERS) or autophagy were demonstrated to negate the anti‑inflammatory and antiviral effects of RES‑NPs on EV71‑infected RD cells. These results demonstrated that RES‑NPs attenuated EV71‑induced viral replication and inflammatory effects by inhibiting the oxidative stress‑mediated ERS/autophagy signaling pathway. In view of their safety and efficiency, these RES‑NPs have potential applications in protecting RD cells from EV71 injury.
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Affiliation(s)
- Na Du
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xiao-Hua Li
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wan-Guo Bao
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Bin Wang
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Guang Xu
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Feng Wang
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Mello T, Simeone I, Galli A. Mito-Nuclear Communication in Hepatocellular Carcinoma Metabolic Rewiring. Cells 2019; 8:cells8050417. [PMID: 31060333 PMCID: PMC6562577 DOI: 10.3390/cells8050417] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/29/2019] [Accepted: 05/01/2019] [Indexed: 12/24/2022] Open
Abstract
As the main metabolic and detoxification organ, the liver constantly adapts its activity to fulfill the energy requirements of the whole body. Despite the remarkable adaptive capacity of the liver, prolonged exposure to noxious stimuli such as alcohol, viruses and metabolic disorders results in the development of chronic liver disease that can progress to hepatocellular carcinoma (HCC), which is currently the second leading cause of cancer-related death worldwide. Metabolic rewiring is a common feature of cancers, including HCC. Altered mito-nuclear communication is emerging as a driving force in the metabolic reprogramming of cancer cells, affecting all aspects of cancer biology from neoplastic transformation to acquired drug resistance. Here, we explore relevant aspects (and discuss recent findings) of mito-nuclear crosstalk in the metabolic reprogramming of hepatocellular carcinoma.
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Affiliation(s)
- Tommaso Mello
- Clinical Gastroenterology Unit, Department of Biomedical Clinical and Experimental Sciences "Mario Serio", University of Florence, V.le Pieraccini 6, Florence 50129, Italy.
| | - Irene Simeone
- Clinical Gastroenterology Unit, Department of Biomedical Clinical and Experimental Sciences "Mario Serio", University of Florence, V.le Pieraccini 6, Florence 50129, Italy.
- University of Siena, 53100 Siena, Italy.
| | - Andrea Galli
- Clinical Gastroenterology Unit, Department of Biomedical Clinical and Experimental Sciences "Mario Serio", University of Florence, V.le Pieraccini 6, Florence 50129, Italy.
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25
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Pant K, Mishra AK, Pradhan SM, Nayak B, Das P, Shalimar D, Saraya A, Venugopal SK. Butyrate inhibits HBV replication and HBV-induced hepatoma cell proliferation via modulating SIRT-1/Ac-p53 regulatory axis. Mol Carcinog 2018; 58:524-532. [PMID: 30501014 DOI: 10.1002/mc.22946] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 10/11/2018] [Accepted: 11/22/2018] [Indexed: 02/01/2023]
Abstract
Butyrate, a histone deacetylase inhibitor, has several therapeutic applications, including cancer. However, the effect of butyrate in HBV replication is not known so far. It was hypothesized that butyrate might inhibit HBV replication and host cell proliferation via SIRT-1. It was found that the increased expression of SIRT-1 in Hep G2.2.15 cells (HBV expressing cells) than Hep G2 cells. Next the expression of SIRT-1 and Acetylated p53 (Ac-p53) were measured in the liver biopsy samples of chronic hepatitis B (CHB) patients with high viral load and compared to CHB patients with low viral load and found that there was a high SIRT-1 expression and a low Ac-p53 levels in CHB patients with high viral load compared to CHB patients with low viral load. Incubation of butyrate inhibited SIRT-1 expression and cell proliferation. Inhibition of SIRT-1 by butyrate or SIRT-1 siRNA increased the levels of Ac-p53. The elevated Ac-p53 decreased p-akt, cyclin D1, and thereby inhibited cell proliferation. Incubation of butyrate with Hep G2.2.15 cells also inhibited HBx protein expression, HBV-DNA and hepatitis B surface antigen (HBsAg). Taken together, the data showed that butyrate inhibited HBV replication and cell proliferation by inhibiting SIRT-1 expression in hepatoma cells.
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Affiliation(s)
- Kishor Pant
- Molecular Medicine Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Amit K Mishra
- Molecular Medicine Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Saman Man Pradhan
- Molecular Medicine Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Dr Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Senthil K Venugopal
- Molecular Medicine Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, India
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26
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Pan J, Tong S, Tang J. LncRNA expression profiles in HBV-transformed human hepatocellular carcinoma cells treated with a novel inhibitor of human La protein. J Viral Hepat 2018; 25:391-400. [PMID: 29091324 DOI: 10.1111/jvh.12821] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/19/2017] [Indexed: 12/21/2022]
Abstract
We previously identified a novel inhibitor of La protein, H11, which inhibited hepatitis B virus (HBV) replication by inhibiting the interaction between La protein and HBV RNA. However, the other cellular factors involved in this process remain unclear. To investigate the mechanism of H11-mediated inhibition of HBV infection, a lncRNA microarray analysis was performed using H11-treated and untreated stable HBV-expressing human hepatoblastoma HepG2.2.15 cells. The profiles of differentially expressed lncRNAs and mRNAs were generated and analysed using Gene Ontology (GO) and pathway analyses. The microarray data showed that 61 lncRNAs were upregulated, 74 lncRNAs were downregulated, 43 mRNAs were upregulated, and 44 mRNAs were downregulated in H11 treatment group when compared with the control group, and these results were consistent with qRT-PCR expression data. Bioinformatic analysis indicated that the differentially expressed lncRNAs were involved in RNA-mediated post-transcriptional gene silencing, regulation of viral genome replication and Jak-STAT signalling and apoptosis pathways. GO analysis showed that differentially expressed mRNAs were enriched in negative regulation of the Wnt signalling pathway and negative regulation of growth. Pathways analysis indicated that the differentially expressed mRNAs were involved in regulation of nuclear β-catenin signalling and target gene transcription, as direct p53 effectors, and in the peroxisome proliferator-activated receptors signalling and peroxisome pathways. Microarray data and qRT-PCR results indicated that H11 mediates inhibition of HBV replication by regulating the Wnt, β-catenin and PPAR signalling pathways.
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Affiliation(s)
- J Pan
- Department of Pharmacy, The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China.,Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - S Tong
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - J Tang
- Department of Pharmacy, The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China.,Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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MERS-CoV: Understanding the Latest Human Coronavirus Threat. Viruses 2018; 10:v10020093. [PMID: 29495250 PMCID: PMC5850400 DOI: 10.3390/v10020093] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 01/28/2018] [Accepted: 02/02/2018] [Indexed: 12/19/2022] Open
Abstract
Human coronaviruses cause both upper and lower respiratory tract infections in humans. In 2012, a sixth human coronavirus (hCoV) was isolated from a patient presenting with severe respiratory illness. The 60-year-old man died as a result of renal and respiratory failure after admission to a hospital in Jeddah, Saudi Arabia. The aetiological agent was eventually identified as a coronavirus and designated Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV has now been reported in more than 27 countries across the Middle East, Europe, North Africa and Asia. As of July 2017, 2040 MERS-CoV laboratory confirmed cases, resulting in 712 deaths, were reported globally, with a majority of these cases from the Arabian Peninsula. This review summarises the current understanding of MERS-CoV, with special reference to the (i) genome structure; (ii) clinical features; (iii) diagnosis of infection; and (iv) treatment and vaccine development.
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28
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Mulberry leaf alleviates streptozotocin-induced diabetic rats by attenuating NEFA signaling and modulating intestinal microflora. Sci Rep 2017; 7:12041. [PMID: 28935866 PMCID: PMC5608946 DOI: 10.1038/s41598-017-12245-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 09/06/2017] [Indexed: 02/06/2023] Open
Abstract
Improvement of hyperglycemia through dietotherapy/herbal remedy is an effective approach to treating diabetes. In this study, mulberry leaf, famous for silkworm’s special food and therapeutic value without any side effects, alleviated diabetes by attenuating NEFA signaling and modulating intestinal microflora. Mulberry leaf treatment significantly reduce fasting blood-glucose and HbA1c, ameliorate the blood lipid profile and improve insulin resistance in streptozotocin-induced diabetic rats. Mechanistically, we found that mulberry leaf inhibited NEFA signaling by reducing downstream signaling in the NEFA pathway, further verified by reduced PKC and improved cellular energy homeostasis based on restored expression of PGC-1α, AK2, OXPHOS and adiponectin. Mulberry leaf treatment also restored the phyla Bacteroidetes and Proteobacteria and class Clostridia, which were associated with insulin resistance and diabetes. Our findings reveal that mulberry leaf is an edible with therapeutic potential for diabetes and may provide a novel dietotherapy/herbal remedy to the treatment of diabetes.
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29
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Zeng X, Pan X, Xu X, Lin J, Que F, Tian Y, Li L, Liu S. Resveratrol Reactivates Latent HIV through Increasing Histone Acetylation and Activating Heat Shock Factor 1. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:4384-4394. [PMID: 28471170 DOI: 10.1021/acs.jafc.7b00418] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on "shock and kill" strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC). However, latent HIV was reactivated by resveratrol mediated through increasing histone acetylation and activation of heat shock factor 1 (HSF1). Additionally, synergistic activation of the latent HIV reservoirs was observed under cotreatment with resveratrol and conventional LRAs. Collectively, this research reveals that resveratrol is a natural LRA and shows promise for HIV therapy.
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Affiliation(s)
- Xiaoyun Zeng
- Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China
| | - Xiaoyan Pan
- Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science , Wuhan 430071, China
| | - Xinfeng Xu
- Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China
| | - Jian Lin
- Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China
| | - Fuchang Que
- Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China
| | - Yuanxin Tian
- Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China
| | - Lin Li
- Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China
| | - Shuwen Liu
- Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University , Guangzhou 510515, China
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30
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Zhang P, Li Y, Du Y, Li G, Wang L, Zhou F. Resveratrol Ameliorated Vascular Calcification by Regulating Sirt-1 and Nrf2. Transplant Proc 2017; 48:3378-3386. [PMID: 27931585 DOI: 10.1016/j.transproceed.2016.10.023] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 10/27/2016] [Indexed: 02/08/2023]
Abstract
Pathologic vascular calcification is a significant reason for mortality and morbidity in patients who suffer from end-stage renal disease (ESRD). Resveratrol, a scavenger for many free radicals, is a crucial compound for biomedicine. However, the role and mechanism of resveratrol in vascular calcification is still unknown. In this study, to mimic vascular calcification in ESRD, we used β-glyceophosphate to stimulate the rat vascular smooth muscle cells (RASMCs). We investigate the therapeutic role of resveratrol pretreatment in vascular calcification. In the current in vitro study, we observe the effects of resveratrol on improving intracellular calcium deposition and protecting against mitochondria dysfunction in calcific RASMCs. Resveratrol decreased the mRNA level of fibroblast growth factor-23, then increased the mRNA level of klotho and the nuclear transcription factor NF-E2-related factor 2 (nuclear factor-erythroid 2-related factor 2 [Nrf2]) in RASMCs after calcification. Further, resveratrol activated the expression of sirtuin-1 and Nrf2, and inhibited the expression of osteopontin, runt-related transcription factor 2, and heme oxygenase-1. Our study shows that resveratrol could ameliorate oxidative injury of RASMCs by preventing vascular calcification-induced calcium deposition and mitochondria dysfunction through involving sirtuin-1 and Nrf2. These results might indicate a novel role for resveratrol in resistance to oxidative stress for ESRD patients suffering from vascular calcification.
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Affiliation(s)
- P Zhang
- Chongqing Medical University, The First College of Clinical Medicine, Clinical Medicine of Grade 2012, Chongqing, China; Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Science & Sichuan Provincial People's Hospital, Chengdu, China
| | - Y Li
- Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Science & Sichuan Provincial People's Hospital, Chengdu, China
| | - Y Du
- Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Science & Sichuan Provincial People's Hospital, Chengdu, China
| | - G Li
- Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Science & Sichuan Provincial People's Hospital, Chengdu, China
| | - L Wang
- Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Science & Sichuan Provincial People's Hospital, Chengdu, China.
| | - F Zhou
- Chongqing Medical University, The First College of Clinical Medicine, Clinical Medicine of Grade 2012, Chongqing, China; Department of Emergency, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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31
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Deng JJ, Kong KYE, Gao WW, Tang HMV, Chaudhary V, Cheng Y, Zhou J, Chan CP, Wong DKH, Yuen MF, Jin DY. Interplay between SIRT1 and hepatitis B virus X protein in the activation of viral transcription. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2017; 1860:491-501. [PMID: 28242208 DOI: 10.1016/j.bbagrm.2017.02.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/13/2017] [Accepted: 02/20/2017] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) genome is organized into a minichromosome known as covalently closed circular DNA (cccDNA), which serves as the template for all viral transcripts. SIRT1 is an NAD+-dependent protein deacetylase which activates HBV transcription by promoting the activity of cellular transcription factors and coactivators. How SIRT1 and viral transactivator X protein (HBx) might affect each other remains to be clarified. In this study we show synergy and mutual dependence between SIRT1 and HBx in the activation of HBV transcription. All human sirtuins SIRT1 through SIRT7 activated HBV gene expression. The steady-state levels of SIRT1 protein were elevated in HBV-infected liver tissues and HBV-replicating hepatoma cells. SIRT1 interacted with HBx and potentiated HBx transcriptional activity on precore promoter and covalently closed circular DNA (cccDNA) likely through a deacetylase-independent mechanism, leading to more robust production of cccDNA, pregenomic RNA and surface antigen. SIRT1 and HBx proteins were more abundant when both were expressed. SIRT1 promoted the recruitment of HBx as well as cellular transcriptional factors and coactivators such as PGC-1α and FXRα to cccDNA. Depletion of SIRT1 suppressed HBx recruitment. On the other hand, SIRT1 recruitment to cccDNA was compromised when HBx was deficient. Whereas pharmaceutical agonists of SIRT1 such as resveratrol activated HBV transcription, small-molecule inhibitors of SIRT1 including sirtinol and Ex527 exhibited anti-HBV activity. Taken together, our findings revealed not only the interplay between SIRT1 and HBx in the activation of HBV transcription but also new strategies and compounds for developing antivirals against HBV.
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Affiliation(s)
- Jian-Jun Deng
- School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; Shaanxi Key Laboratory of Biodegradable Materials, College of Chemical Engineering, Northwest University, 229 Taibai Road North, Xi'an 710069, China; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong
| | - Ka-Yiu Edwin Kong
- School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong
| | - Wei-Wei Gao
- School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong
| | - Hei-Man Vincent Tang
- School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong
| | - Vidyanath Chaudhary
- School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong
| | - Yun Cheng
- School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong
| | - Jie Zhou
- Department of Microbiology, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong
| | - Chi-Ping Chan
- School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong
| | - Danny Ka-Ho Wong
- State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong; Department of Medicine, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong
| | - Man-Fung Yuen
- State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong; Department of Medicine, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong
| | - Dong-Yan Jin
- School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
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Ajami M, Pazoki-Toroudi H, Amani H, Nabavi SF, Braidy N, Vacca RA, Atanasov AG, Mocan A, Nabavi SM. Therapeutic role of sirtuins in neurodegenerative disease and their modulation by polyphenols. Neurosci Biobehav Rev 2016; 73:39-47. [PMID: 27914941 DOI: 10.1016/j.neubiorev.2016.11.022] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Revised: 10/26/2016] [Accepted: 11/26/2016] [Indexed: 12/15/2022]
Abstract
Searching for effective therapeutic agents to prevent neurodegeneration is a challenging task due to the growing list of neurodegenerative disorders associated with a multitude of inter-related pathways. The induction and inhibition of several different signaling pathways has been shown to slow down and/or attenuate neurodegeneration and decline in cognition and locomotor function. Among these signaling pathways, a new class of enzymes known as sirtuins or silent information regulators of gene transcription has been shown to play important regulatory roles in the ageing process. SIRT1, a nuclear sirtuin, has received particular interest due to its role as a deacetylase for several metabolic and signaling proteins involved in stress response, apoptosis, mitochondrial function, self-renewal, and neuroprotection. A new strategy to treat neurodegenerative diseases is targeted therapy. In this paper, we reviewed up-to-date findings regarding the targeting of SIRT1 by polyphenolic compounds, as a new approach in the search for novel, safe and effective treatments for neurodegenerative diseases. .
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Affiliation(s)
- Marjan Ajami
- National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Pazoki-Toroudi
- Physiology Research Center and Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Amani
- Physiology Research Center and Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Fazel Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Australia.
| | - Rosa Anna Vacca
- Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
| | - Atanas Georgiev Atanasov
- Department of Pharmacognosy, University of Vienna, 1090 Vienna, Austria; Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland
| | - Andrei Mocan
- Department of Pharmaceutical Botany, Iuliu Hațieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Shi YX, Huang CJ, Yang ZG. Impact of hepatitis B virus infection on hepatic metabolic signaling pathway. World J Gastroenterol 2016; 22:8161-8167. [PMID: 27688657 PMCID: PMC5037084 DOI: 10.3748/wjg.v22.i36.8161] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 08/01/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023] Open
Abstract
A growing body of epidemiologic research has demonstrated that metabolic derangement exists in patients with hepatitis B virus (HBV) infection, indicating that there are clinical associations between HBV infection and host metabolism. In order to understand the complex interplay between HBV and hepatic metabolism in greater depth, we systematically reviewed these alterations in different metabolic signaling pathways due to HBV infection. HBV infection interfered with most aspects of hepatic metabolic responses, including glucose, lipid, nucleic acid, bile acid and vitamin metabolism. Glucose and lipid metabolism is a particular focus due to the significant promotion of gluconeogenesis, glucose aerobic oxidation, the pentose phosphate pathway, fatty acid synthesis or oxidation, phospholipid and cholesterol biosynthesis affected by HBV. These altered metabolic pathways are involved in the pathological process of not only hepatitis B, but also metabolic disorders, increasing the occurrence of complications, such as hepatocellular carcinoma and liver steatosis. Thus, a clearer understanding of the hepatic metabolic pathways affected by HBV and its pathogenesis is necessary to develop more novel therapeutic strategies targeting viral eradication.
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Huffman DM, Schafer MJ, LeBrasseur NK. Energetic interventions for healthspan and resiliency with aging. Exp Gerontol 2016; 86:73-83. [PMID: 27260561 DOI: 10.1016/j.exger.2016.05.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 05/03/2016] [Accepted: 05/24/2016] [Indexed: 12/16/2022]
Abstract
Several behavioral and pharmacological strategies improve longevity, which is indicative of delayed organismal aging, with the most effective interventions extending both life- and healthspan. In free living creatures, maintaining health and function into old age requires resilience against a multitude of stressors. Conversely, in experimental settings, conventional housing of rodents limits exposure to such challenges, thereby obscuring an accurate assessment of resilience. Caloric restriction (CR) and exercise, as well as pharmacologic strategies (resveratrol, rapamycin, metformin, senolytics), are well established to improve indices of health and aging, but some paradoxical effects have been observed on resilience. For instance, CR potently retards the onset of age-related diseases, and improves lifespan to a greater extent than exercise in a variety of models. However, exercise has proven more consistently beneficial to organismal resilience against a broad array of stressors, including infections, surgery, wound healing and frailty. CR can improve cellular stress defenses and protect from frailty, but also impairs the response to infections, bed rest and healing. How an intervention will impact not only longevity, health and function, but also resiliency, is critical to better understanding translational implications. Thus, organismal robustness represents a critical, albeit understudied aspect of aging, which needs more careful attention in order to better inform on how putative age-delaying strategies will impact preservation of health and function in response to stressors with aging in humans.
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Affiliation(s)
- Derek M Huffman
- Department of Molecular Pharmacology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Marissa J Schafer
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
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