|
1
|
Wang J, Qiu K, Zhou S, Gan Y, Jiang K, Wang D, Wang H. Risk factors for hepatocellular carcinoma: an umbrella review of systematic review and meta-analysis. Ann Med 2025; 57:2455539. [PMID: 39834076 PMCID: PMC11753015 DOI: 10.1080/07853890.2025.2455539] [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: 10/21/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Numerous meta-analyses have identified various risk factors for hepatocellular carcinoma (HCC), prompting a comprehensive study to synthesize evidence quality and strength. METHODS This umbrella review of meta-analyses was conducted throughout PubMed, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews. Evidence strength was evaluated according to the evidence categories criteria. RESULTS We identified 101 risk factors throughout 175 meta-analyses. 31 risk factors were classified as evidence levels of class I, II, or III. HBV and HCV infections increase HCC risk by 12.5-fold and 11.2-fold, respectively. These risks are moderated by antiviral treatments and virological responses but are exacerbated by higher HBsAg levels, anti-HBc positivity, and co-infection. Smoking, obesity, non-alcoholic fatty liver disease, diabetes, low platelet, elevated liver enzymes and liver fluke infection increase HCC risk, while coffee consumption, a healthy diet, and bariatric surgery lower it. Medications like metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), aspirin, statins, and selective serotonin reuptake inhibitors reduce HCC risk, while acid suppressive agents, particularly proton pump inhibitors, elevate it. Blood type O reduces the risk of HCC, while male gender and older age increase the risk. CONCLUSIONS HBV and HCV are major HCC risk factors, with risk mitigation through antiviral treatments. Lifestyle habits such as smoking and alcohol use significantly increase HCC risk, highlighting the importance of cessation. Certain drugs like aspirin, statins, GLP-1 RAs, and metformin may reduce HCC occurrence, but further research is needed to confirm these effects.
Collapse
Affiliation(s)
- Jie Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Kaijie Qiu
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Songsheng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Yichao Gan
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Keting Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Donghuan Wang
- Operations Department, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| | - Haibiao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China
| |
Collapse
|
|
2
|
Yeo YH, Abdelmalek M, Khan S, Moylan CA, Rodriquez L, Villanueva A, Yang JD. Current and emerging strategies for the prevention of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2025; 22:173-190. [PMID: 39653784 DOI: 10.1038/s41575-024-01021-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/07/2024] [Indexed: 01/05/2025]
Abstract
Liver cancer is the third leading cause of cancer-related deaths globally, with incident cases expected to rise from 905,700 in 2020 to 1.4 million by 2040. Hepatocellular carcinoma (HCC) accounts for about 80% of all primary liver cancers. Viral hepatitis and chronic excessive alcohol consumption are major risk factors for HCC, but metabolic dysfunction-associated steatotic liver disease is also becoming a dominant cause. The increasing numbers of cases of HCC and changes in risk factors highlight the urgent need for updated and targeted prevention strategies. Preventive interventions encompass strategies to decrease the burden of chronic liver diseases and their progression to HCC. These strategies include nutritional interventions and medications that have shown promise in preclinical models. Although prevailing approaches focus on treating chronic liver disease, leveraging a wider range of interventions represents a promising area to safeguard at-risk populations. In this Review, we explore existing evidence for preventive strategies by highlighting established and potential paths to reducing HCC risk effectively and safely, especially in individuals with chronic liver diseases. We categorize the preventive strategies by the mechanism of action, including anti-inflammatory, antihyperglycaemic, lipid-lowering, nutrition and dietary, antiviral, and antifibrotic pathways. For each category, we discuss the efficacy and safety information derived from mechanistic, translational, observational and clinical trial data, pinpointing knowledge gaps and directions for future research.
Collapse
Affiliation(s)
- Yee Hui Yeo
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Manal Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Seema Khan
- Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL, USA
| | - Cynthia A Moylan
- Division of Gastroenterology, Duke University Health System, Durham, NC, USA
| | - Luz Rodriquez
- Gastrointestinal & Other Cancers Research Group, NCI, Rockville, MD, USA
| | - Augusto Villanueva
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| |
Collapse
|
|
3
|
Bian W, Bian W, Li Q, Li Y. Aspirin in Patients with Viral Hepatitis: Systematic Review and Meta-Analysis of Observational Studies. J Gastrointest Cancer 2024; 55:638-651. [PMID: 38557825 DOI: 10.1007/s12029-024-01027-5] [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] [Accepted: 02/05/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a disease demonstrating increasing morbidity and mortality, especially in patients with chronic viral hepatitis. Studies have shown that aspirin can reduce the incidence of liver cancer; however, the degree of benefit in patients with viral hepatitis is unclear. This study focused on the association between aspirin use and HCC risk in patients with chronic viral hepatitis. METHODS A systematic search of the PubMed, Embase, Web of Science, and Cochrane Library databases was performed from the earliest available date to December 16, 2023. The primary outcome was HCC incidence, and the secondary outcome was gastrointestinal bleeding. The results were expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). Meta-analyses were performed by using random or fixed-effects models based on the heterogeneity assessed via the I2 statistic. RESULTS A total of 13 articles (303,414 participants and 14,423 HCC patients) were included in the analysis. The incidence of HCC in aspirin users was lower than that in non-aspirin users (HR 0.75; 95% CI, 0.68-0.83; P < 0.001; I2 = 90.0%). Subgroup analysis further showed that this effect may be more obvious in HCV patients, non-cirrhotic patients, patients with statins, and long-term aspirin users, but it may have the risk of gastrointestinal bleeding (HR 1.13; 95% CI, 1.07-1.20; P = 0.906; I2 = 0.0%). CONCLUSIONS Our meta-analysis shows that in patients with chronic viral hepatitis, aspirin use is associated with a significantly reduced risk of liver cancer, but attention should be paid to the possible risk of gastrointestinal bleeding, and this conclusion needs further validation in the future.
Collapse
Affiliation(s)
- Wentao Bian
- Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Wenkai Bian
- National Radio Spectrum Management Research Institute, Xi'an, China
| | - Qingyu Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yulian Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
4
|
Werz O, Stettler H, Theurer C, Seibel J. The 125th Anniversary of Aspirin-The Story Continues. Pharmaceuticals (Basel) 2024; 17:437. [PMID: 38675399 PMCID: PMC11054228 DOI: 10.3390/ph17040437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/25/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
The year 2024 marks the 125th anniversary of aspirin, still one of the most frequently used drugs worldwide. Despite its veritable age, it is still relevant in pharmacotherapy and its use has spread to new areas over time. Due to aspirin's multiple pharmacological actions unified in one single molecule (i.e., analgesic, antipyretic, anti-inflammatory, antithrombotic, and antiviral effects), it continues to attract considerable attention in the scientific community and is subject to intense basic and clinical research. In fact, recent results confirmed aspirin's potential role as an antiviral drug and as an agent that can block harmful platelet functions in inflammatory/immunological processes. These features may open up new horizons for this ancient drug. The future of aspirin looks, therefore, bright and promising. Aspirin is not yet ready for retirement; on the contrary, its success story continues. This 125th anniversary paper will concisely review the various therapeutic uses of aspirin with a particular emphasis on the latest research results and their implications (e.g., use as an antiviral agent). In addition, the reader is provided with future perspectives for this remarkable drug.
Collapse
Affiliation(s)
- Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany;
| | - Hans Stettler
- Bayer Consumer Care AG, Peter Merian-Strasse 84, 4002 Basel, Switzerland;
| | - Christoph Theurer
- Bayer Vital GmbH, Kaiser-Wilhelm-Allee 70, 51373 Leverkusen, Germany;
| | - Jens Seibel
- Bayer Vital GmbH, Kaiser-Wilhelm-Allee 70, 51373 Leverkusen, Germany;
| |
Collapse
|
|
5
|
Zhao W, Li Z, Yu ML, Liu Y, Liu CC, Jia XJ, Liu MQ, Li YG. Aspirin inhibits rotavirus replication and alters rat gut microbial composition. Virol J 2023; 20:237. [PMID: 37848986 PMCID: PMC10580602 DOI: 10.1186/s12985-023-02199-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/02/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Aspirin is widely used to treat various clinical symptoms. Evidence suggests that aspirin has antiviral properties, but little is known about its specific effect against rotavirus. METHODS MA104, Caco-2, and CV-1 cells were infected with rotavirus, and aspirin was added after 12 h. Viral mRNA and titer levels were measured by qRT-PCR and immunofluorescence assays. For in vivo validation, forty specific-pathogen-free SD rats were randomly divided into oral aspirin (ASP) groups and control (NC) groups. 16 S rRNA gene sequencing was performed to identify gut microbiota. After 6 months of continuous ASP/NC administration, the rats were infected with rotavirus. Fecal samples were collected over a 30-day time course, and viral levels were quantified. Proinflammatory cytokines/chemokine levels were measured by ELISA. RESULTS Aspirin inhibited rotavirus infection in cell lines and in rats. The effects of aspirin on viral replication were associated with the alteration of gut microbiota composition by aspirin, including increased abundance of Firmicutes and decreased abundance of Bacteroidetes after aspirin treatment. Mechanistically, aspirin reduced IL-2 and IL-10 levels, and increased IRF-1 and COX-2 levels. Aspirin blocked rotavirus replication in vitro and in vivo, which might be related to effects on IRF-1, COX-2, chemokines, and gut microbial composition. CONCLUSION These results indicate that long-term oral aspirin administration reduces rotavirus infection. Intestinal virus infection may be suppressed in elderly patients who take aspirin for a long time. The change of their Gut microbiota may lead to functional disorder of the intestinal tract, which may provide some reference for clinical adjuvant probiotics treatment.
Collapse
Affiliation(s)
- Wei Zhao
- College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, China
| | - ZhouPing Li
- The first affiliated hospital of Jinzhou Medical University, Jinzhou, China
| | - Mei Ling Yu
- College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, China
| | - Yang Liu
- College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, China
| | - Chang Cheng Liu
- College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, China
| | - Xue Jiao Jia
- College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, China
| | - Meng Qi Liu
- College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, China
| | - Yong Gang Li
- College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, China.
| |
Collapse
|
|
6
|
Fernández-Sánchez SY, Cerón-Carrasco JP, Risco C, Fernández de Castro I. Antiviral Activity of Acetylsalicylic Acid against Bunyamwera Virus in Cell Culture. Viruses 2023; 15:v15040948. [PMID: 37112928 PMCID: PMC10141918 DOI: 10.3390/v15040948] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
The Bunyavirales order is a large group of RNA viruses that includes important pathogens for humans, animals and plants. With high-throughput screening of clinically tested compounds we have looked for potential inhibitors of the endonuclease domain of a bunyavirus RNA polymerase. From a list of fifteen top candidates, five compounds were selected and their antiviral properties studied with Bunyamwera virus (BUNV), a prototypic bunyavirus widely used for studies about the biology of this group of viruses and to test antivirals. Four compounds (silibinin A, myricetin, L-phenylalanine and p-aminohippuric acid) showed no antiviral activity in BUNV-infected Vero cells. On the contrary, acetylsalicylic acid (ASA) efficiently inhibited BUNV infection with a half maximal inhibitory concentration (IC50) of 2.02 mM. In cell culture supernatants, ASA reduced viral titer up to three logarithmic units. A significant dose-dependent reduction of the expression levels of Gc and N viral proteins was also measured. Immunofluorescence and confocal microscopy showed that ASA protects the Golgi complex from the characteristic BUNV-induced fragmentation in Vero cells. Electron microscopy showed that ASA inhibits the assembly of Golgi-associated BUNV spherules that are the replication organelles of bunyaviruses. As a consequence, the assembly of new viral particles is also significantly reduced. Considering its availability and low cost, the potential usability of ASA to treat bunyavirus infections deserves further investigation.
Collapse
Affiliation(s)
| | - José P Cerón-Carrasco
- Centro Universitario de la Defensa, Universidad Politécnica de Cartagena, C/Coronel López Peña s/n, Base Aérea de San Javier, Santiago de la Ribera, 30720 Murcia, Spain
| | - Cristina Risco
- Cell Structure Laboratory, Centro Nacional de Biotecnología, CSIC, Campus de Cantoblanco, 28049 Madrid, Spain
| | - Isabel Fernández de Castro
- Cell Structure Laboratory, Centro Nacional de Biotecnología, CSIC, Campus de Cantoblanco, 28049 Madrid, Spain
| |
Collapse
|
|
7
|
Shah S, Valiani D, Balogun O, Zanoria MA, Jarrett S, Hiedra R, Patarroyo-Aponte G, Azmaiparashvili Z, Lo KB, Eiger G. Demographic and clinical profile of patients suffering prolonged severe hypoxia in COVID-19. Expert Rev Respir Med 2022; 16:1017-1021. [PMID: 36122195 DOI: 10.1080/17476348.2022.2126354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) may result in rapid onset of hypoxemic respiratory failure. This study aimed to characterize the factors and outcomes associated with prolonged hypoxia in patients with COVID-19. Prolonged severe hypoxia (PSH) was defined as hypoxia requiring ≥ 6 L/min of oxygen by nasal cannula or equivalent for more than 10 days. RESEARCH DESIGN AND METHODS This study was designed as a single-center retrospective analysis. Multivariable logistic regression was utilized to assess factors associated with PSH. RESULTS The final sample included 554 patients with 117 (21%) having PSH. Median length of stay of patients with PSH was significantly longer (median IQR: 18 days vs 6 days, p<0.0001). Patients with prolonged severe hypoxia had significantly higher rates of acute venous thromboembolism (p <0.0001) and major bleeding (p<0.004). The presence of cirrhosis (OR 3.32, 95% CI [1.02 to 10.83]) and hypertension (OR 1.99, 95% CI [1.12 to 3.53]) were independently associated with PSH, while outpatient use of anti-platelet agents had an inverse association (OR 0.57, 95% CI [0.36 to 0.91]. CONCLUSION PSH is associated with increased length of stay, morbidity, and mortality. Hypertension and liver cirrhosis were significantly associated with higher odds of PSH, while use of anti-platelet therapy had a protective effect.
Collapse
Affiliation(s)
- Samir Shah
- Albert Einstein Medical Center, Philadelphia, PA, USA
| | | | | | | | | | - Raul Hiedra
- Albert Einstein Medical Center, Philadelphia, PA, USA
| | | | | | | | - Glenn Eiger
- Albert Einstein Medical Center, Philadelphia, PA, USA
| |
Collapse
|
|
8
|
Wang Y, Wang M, Liu C, Wang W, Shi J, Dang S. Aspirin Use and the Risk of Hepatocellular Carcinoma: A Meta-analysis. J Clin Gastroenterol 2022; 56:e293-e302. [PMID: 35316225 DOI: 10.1097/mcg.0000000000001693] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/12/2022] [Indexed: 12/11/2022]
Abstract
INTRODUCTION AND AIM The use of aspirin is a potential protective factor against the development of hepatocellular carcinoma (HCC). Therefore, we conducted a meta-analysis to evaluate the contribution of aspirin to the risk of HCC. METHODS We searched for PubMed and EMBASE through September 2021. RESULTS Eighteen studies (16 cohort, 2 case-control) were included. Aspirin users were less likely to develop HCC than nonusers [adjusted odds ratio (OR), 0.54; 95% confidence interval (CI): 0.44-0.66]. Stratified analysis showed that aspirin reduced the risk of HCC in Asian and Western populations (OR, 0.59 vs. 0.67). Besides, aspirin has protective effects against HCC after hepatitis B virus (OR, 0.70; 95% CI: 0.52-0.93) and hepatitis C virus infections (OR, 0.41; 95% CI: 0.23-0.73). Aspirin has protective effects on people with chronic liver disease (OR, 0.46; 95% CI: 0.31-0.67) and on the general population (OR, 0.65; 95% CI: 0.54-0.79). In addition, confounding factors have an important impact on the results of aspirin prevention of liver cancer before (OR, 0.28; 95% CI: 0.06-1.27) and after (OR, 0.58; 95% CI: 0.47-0.71) adjustment. Further studies have shown that those in the long duration group do not experience better effects in preventing HCC (OR, 0.62 vs. 0.63). A further meta-analysis of 3 articles showed that the use of aspirin did not increase the risk of bleeding in patients with HCC (OR, 1.19; 95% CI: 0.87-1.64). CONCLUSION Our meta-analysis shows that the use of aspirin is associated with a lower risk of liver cancer.
Collapse
Affiliation(s)
- Yikai Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | | | | | | | | | | |
Collapse
|
|
9
|
Sodano F, Gazzano E, Fruttero R, Lazzarato L. NO in Viral Infections: Role and Development of Antiviral Therapies. Molecules 2022; 27:2337. [PMID: 35408735 PMCID: PMC9000700 DOI: 10.3390/molecules27072337] [Citation(s) in RCA: 10] [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: 03/06/2022] [Revised: 03/31/2022] [Accepted: 04/02/2022] [Indexed: 11/16/2022] Open
Abstract
Nitric oxide is a ubiquitous signaling radical that influences critical body functions. Its importance in the cardiovascular system and the innate immune response to bacterial and viral infections has been extensively investigated. The overproduction of NO is an early component of viral infections, including those affecting the respiratory tract. The production of high levels of NO is due to the overexpression of NO biosynthesis by inducible NO synthase (iNOS), which is involved in viral clearance. The development of NO-based antiviral therapies, particularly gaseous NO inhalation and NO-donors, has proven to be an excellent antiviral therapeutic strategy. The aim of this review is to systematically examine the multiple research studies that have been carried out to elucidate the role of NO in viral infections and to comprehensively describe the NO-based antiviral strategies that have been developed thus far. Particular attention has been paid to the potential mechanisms of NO and its clinical use in the prevention and therapy of COVID-19.
Collapse
Affiliation(s)
- Federica Sodano
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy; (R.F.); (L.L.)
- Department of Pharmacy, “Federico II” University of Naples, 80131 Naples, Italy
| | - Elena Gazzano
- Department of Life Sciences and Systems Biology, University of Torino, 10123 Torino, Italy
| | - Roberta Fruttero
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy; (R.F.); (L.L.)
| | - Loretta Lazzarato
- Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy; (R.F.); (L.L.)
| |
Collapse
|
|
10
|
Qiu X, Gao F, Wang K, Zhang Z, Shao C, Xu X. Aspirin in hepatocellular carcinoma: Is it an out-of-date or promising treatment? ILIVER 2022; 1:55-64. [DOI: 10.1016/j.iliver.2022.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
11
|
Cao M, Yang J, Wang X, Hu W, Xie X, Zhao Y, Liu M, Wei Y, Yu M, Hu T. Sophora subprostrate polysaccharide regulates histone acetylation to inhibit inflammation in PCV2-infected murine splenic lymphocytes in vitro and in vivo. Int J Biol Macromol 2021; 191:668-678. [PMID: 34560152 DOI: 10.1016/j.ijbiomac.2021.09.119] [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: 11/12/2020] [Revised: 09/10/2021] [Accepted: 09/18/2021] [Indexed: 11/26/2022]
Abstract
Porcine circovirus type 2 (PCV2) has caused large economic losses in the swine industry worldwide; therefore, research on relevant therapeutic medicines is still urgently needed. To define the relationship between histone acetylation and inflammation induced by PCV2, we investigated whether traditional Chinese medicinal polysaccharides could alleviate viral infection by regulating histone acetylation. In this study, Sophora subprostrate polysaccharide (SSP)-treated PCV2-infected murine splenic lymphocytes in vitro and murine spleen in vivo were used to explore the regulatory effects of SSP on inflammation and histone acetylation caused by PCV2. SSP at different concentrations significantly reduced the secretion levels of the proinflammatory cytokines TNF-α and IL-6, the activity of COX-2, the mRNA expression levels of TNF-α, IL-6, iNOS and COX-2 and the protein expression levels of iNOS and COX-2 but promoted the secretion and mRNA expression levels of IL-10. Furthermore, the different concentrations of SSP significantly regulated the activity of histone acetylase (HAT) and the mRNA expression of HAT1, increased the activity of histone deacetylase (HDAC) and the mRNA expression of HDAC1 and reduced the protein expression levels of Ac-H3 and Ac-H4. Overall, SSP inhibited inflammation in PCV2-infected murine splenic lymphocytes by regulating histone acetylation in vitro and in vivo, thus playing an important role in PCV2 infection.
Collapse
Affiliation(s)
- Mixia Cao
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China
| | - Jian Yang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China; College of Animal Science, Guizhou University, Guiyang 550025, PR China
| | - Xinrui Wang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China
| | - Wenyue Hu
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, PR China
| | - Xiaodong Xie
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China
| | - Yi Zhao
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China
| | - Mengqian Liu
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China
| | - Yingyi Wei
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China
| | - Meiling Yu
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China
| | - Tingjun Hu
- College of Animal Science and Technology, Guangxi University, Nanning 530004, PR China.
| |
Collapse
|
|
12
|
Biondo-Simões MDELP, Pessini VCDEA, Ichi CA, Robes RR, Ioshii S. Acetylsalicylic acid (Aspirin®) and liver regeneration: experimental study in rats. Rev Col Bras Cir 2021; 48:e20213164. [PMID: 34816883 PMCID: PMC10683428 DOI: 10.1590/0100-6991e-20213164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/06/2021] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE to evaluate the influence of acetylsalicylic acid (ASA) on cell proliferation after partial hepatectomy in rats. METHODS 40 male Wistar rats were separated into four groups of ten rats each. Groups 1 and 2 (controls): undergoing 30% partial hepatectomy and, after one day (group 1) and seven days (group 2), to euthanasia; daily administration of 0.9% saline solution (1mL per 200g of body weight). Groups 3 and 4 (experimental): undergoing 30% partial hepatectomy and, after one day (group 3) and seven days (group 4), to euthanasia; daily administration of ASA (40mg/mL, 1mL per 200g of body weight). The absolute number of cells stained with PCNA was counted in photomicrographs, in five fields, and it was calculated the mean of positive cells per animal and per group. RESULTS the final mean of PCNA+ cells per group was: in group 1, 17.57 ± 6.77; in group 2, 19.31 ± 5.30; in group 3, 27.46 ± 11.55; and, in group 4, 12.40 ± 5.23. There was no significant difference at the two evaluation times in the control group (p=0.491), but there was in the experimental group (p=0.020), with a lower number of PCNA+ cells on the seventh day. The comparison between the two groups, on the first day, showed more PCNA+ cells in the livers of the animals that received ASA (p=0.047), and on the seventh day the number was lower in the experimental group (p=0.007). CONCLUSION ASA induced greater hepatocyte proliferation.
Collapse
Affiliation(s)
| | | | | | - Rogério Ribeiro Robes
- - Universidade Federal do Paraná (UFPR), Departamento de Veterinária - Curitiba - PR - Brasil
| | - Sérgio Ioshii
- - Universidade Federal do Paraná (UFPR), Departamento de Anatomia Patológica - Curitiba - PR - Brasil
| |
Collapse
|
|
13
|
Xie L, Zhang Z, Wang Q, Chen Y, Lu D, Wu W. COVID-19 and Diabetes: A Comprehensive Review of Angiotensin Converting Enzyme 2, Mutual Effects and Pharmacotherapy. Front Endocrinol (Lausanne) 2021; 12:772865. [PMID: 34867819 PMCID: PMC8639866 DOI: 10.3389/fendo.2021.772865] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/29/2021] [Indexed: 01/08/2023] Open
Abstract
The potential relationship between diabetes and COVID-19 has been evaluated. However, new knowledge is rapidly emerging. In this study, we systematically reviewed the relationship between viral cell surface receptors (ACE2, AXL, CD147, DC-SIGN, L-SIGN and DPP4) and SARS-CoV-2 infection risk, and emphasized the implications of ACE2 on SARS-CoV-2 infection and COVID-19 pathogenesis. Besides, we updated on the two-way interactions between diabetes and COVID-19, as well as the treatment options for COVID-19 comorbid patients from the perspective of ACE2. The efficacies of various clinical chemotherapeutic options, including anti-diabetic drugs, renin-angiotensin-aldosterone system inhibitors, lipid-lowering drugs, anticoagulants, and glucocorticoids for COVID-19 positive diabetic patients were discussed. Moreover, we reviewed the significance of two different forms of ACE2 (mACE2 and sACE2) and gender on COVID-19 susceptibility and severity. This review summarizes COVID-19 pathophysiology and the best strategies for clinical management of diabetes patients with COVID-19.
Collapse
Affiliation(s)
| | | | | | | | | | - Weihua Wu
- Department of Endocrinology, The 3rd Affiliated Hospital of Shenzhen University, Shenzhen, China
| |
Collapse
|
|
14
|
Li X, Yu Y, Liu L. Influence of aspirin use on clinical outcomes of patients with hepatocellular carcinoma: a meta-analysis. Clin Res Hepatol Gastroenterol 2021; 45:101545. [PMID: 33067170 DOI: 10.1016/j.clinre.2020.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/10/2020] [Accepted: 09/19/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Aspirin use has been suggested to reduce cancer risk. However, previous studies showed inconsistent results as for the association between aspirin use and mortality in patients with hepatocellular carcinoma (HCC). The aim of the study was to evaluate the influence of aspirin use on clinical outcomes of patients with HCC in a meta-analysis. MATERIALS Studies were obtained via systematic search of PubMed, Cochrane's Library, and Embase databases. A random-effect model, which incorporated the potential heterogeneity, was used to pool the results. RESULTS Six retrospective cohort studies including 18,855 HCC patients that underwent liver resection or transarterial chemoembolization were included. Pooled results showed that compared to the non-users, aspirin users of HCC had significantly reduced risk of HCC recurrence (risk ratio [RR]: 0.74, 95% confidence interval [CI]: 0.59-0.93, p = 0.01; I2 = 34%) and all-cause mortality (RR: 0.59, 95% CI: 0.47-0.73, p < 0.001; I2 = 0%) after controlling of potential confounding factors. In addition, pooled results showed that aspirin use was not associated with a significantly increased risk of major bleeding events (RR: 1.42, 95% CI: 0.81-2.51, p = 0.22; I2 = 29%) in patients with HCC. CONCLUSIONS Evidence from retrospective studies suggests that aspirin use is associated with reduced recurrence and all-cause mortality of HCC. These results should be validated in prospective cohort studies and randomized controlled trials.
Collapse
Affiliation(s)
- Xiaofei Li
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu 322000, China.
| | - Yuexiao Yu
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu 322000, China
| | - Liwen Liu
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu 322000, China
| |
Collapse
|
|
15
|
Ricciotti E, Wangensteen KJ, FitzGerald GA. Aspirin in Hepatocellular Carcinoma. Cancer Res 2021; 81:3751-3761. [PMID: 33893087 DOI: 10.1158/0008-5472.can-21-0758] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 01/27/2023]
Abstract
Preclinical and clinical studies provide evidence for aspirin as a preventative agent for cancer. Compelling direct evidence supports a chemopreventive effect of aspirin in individuals at high risk of developing colorectal cancer due to Lynch syndrome, while indirect evidence indicates that aspirin may reduce the risk of and mortality from sporadic colorectal cancer. There is weaker evidence for a protective effect of aspirin against all cancers taken as a group. Nevertheless, the results of recent retrospective cohort studies consistently indicate a beneficial effect of aspirin as a chemopreventive or adjuvant chemotherapeutic agent in hepatocellular carcinoma (HCC). Epidemiologic studies conducted in the general population or in selected populations at higher risk for HCC reveal that regular aspirin use is associated with reduced HCC incidence. In addition, aspirin may act as an adjuvant to other therapies in reducing HCC recurrence. According to studies in animal models, the cancer-preventative effect of aspirin may be related to its antiplatelet and anti-inflammatory activities. Prospective studies are warranted to determine whether aspirin should be recommended to diverse populations of patients at risk for HCC.
Collapse
Affiliation(s)
- Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kirk J Wangensteen
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Garret A FitzGerald
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. .,Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| |
Collapse
|
|
16
|
Liu Q, Huang N, Li A, Zhou Y, Liang L, Song X, Yang Z, Zhou X. Effect of low-dose aspirin on mortality and viral duration of the hospitalized adults with COVID-19. Medicine (Baltimore) 2021; 100:e24544. [PMID: 33578548 PMCID: PMC7886487 DOI: 10.1097/md.0000000000024544] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 11/05/2020] [Accepted: 01/07/2021] [Indexed: 01/05/2023] Open
Abstract
To clarify the effect of aspirin on mortality and viral duration in adults infected with respiratory syndrome coronavirus 2 (SARS-Cov-2).After propensity score-matched (PSM) case-control analyses 24 pairs of patients were enrolled and followed up for 2 months. Both 30-day and 60-day mortality in the aspirin group were significantly lower than that in the non-aspirin group (P = .021 and P = .030, respectively). The viral duration time between the 2 groups was not significantly different (P = .942).Among adults (with hypertension, cardiovascular diseases) infected with SARS-Cov-2, low-dose aspirin medication (100 mg/day) was associated with lower risk of mortality compared with non-aspirin users.
Collapse
Affiliation(s)
- Qiang Liu
- Department of Infectious Disease, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang
| | - Na Huang
- Department of Infectious Disease, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang
| | - Anni Li
- Department of Infectious Disease, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang
| | - Yuanhong Zhou
- Department of Infectious Disease, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang
| | - Liang Liang
- Department of Infectious Disease, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang
| | - Xinyu Song
- Department of Infectious Disease, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang
| | - Zhanqiu Yang
- State Key Laboratory of Virology, Institute of Medical Virology, School of Medicine, Wuhan University, Wuhan, Hubei, China
| | - Xiaolin Zhou
- Department of Infectious Disease, Yichang Central People's Hospital, The First College of Clinical Medical Science, China Three Gorges University, Yichang
| |
Collapse
|
|
17
|
Li X, Wu S, Yu Y. Aspirin Use and the Incidence of Hepatocellular Carcinoma in Patients With Hepatitis B Virus or Hepatitis C Virus Infection: A Meta-Analysis of Cohort Studies. Front Med (Lausanne) 2021; 7:569759. [PMID: 33490093 PMCID: PMC7820703 DOI: 10.3389/fmed.2020.569759] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 11/23/2020] [Indexed: 12/17/2022] Open
Abstract
Background: The association between aspirin use and the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) or hepatitis C (HCV) virus infection remains not fully determined. A meta-analysis was performed to summarize the findings of cohort studies. Methods: Relevant cohort studies were retrieved via a search of PubMed Cochrane's Library and Embase databases. A random-effect model was used to pool the results. Subgroup analyses were performed to evaluate the influence of study characteristics on the association. Results: Seven cohort studies with 120,945 adult patients with HBV or HCV infection were included. Pooled results showed that aspirin use was independently associated with a reduced risk of HCC in these patients (risk ratio: 0.73, 95% confidence interval: 0.64 to 0.83, p < 0.001; I2 = 86%). Subgroup analyses showed that aspirin use was associated with a reduced HCC risk regardless of the viral type, age, sex, the diabetic, and cirrhotic status of the patients, and the follow-up durations. Moreover, consistent results were obtained in studies with and without adjustment of antiviral treatment and statin use. Pooled results of four studies showed that aspirin use was associated with an increased risk of gastrointestinal bleeding in these patients (risk ratio: 1.15, 95% confidence interval: 1.02 to 1.28, p = 0.02; I2 = 0%). Conclusions: Aspirin use was independently associated with a reduced risk of HCC in patients with HBV or HCV infection, whereas the risk of gastrointestinal bleeding may be increased. These results should be validated in clinical trials.
Collapse
Affiliation(s)
- Xiaofei Li
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China
| | - Shuang Wu
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China
| | - Yuexiao Yu
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China
| |
Collapse
|
|
18
|
Bagheri A, Moezzi SMI, Mosaddeghi P, Nadimi Parashkouhi S, Fazel Hoseini SM, Badakhshan F, Negahdaripour M. Interferon-inducer antivirals: Potential candidates to combat COVID-19. Int Immunopharmacol 2020; 91:107245. [PMID: 33348292 PMCID: PMC7705326 DOI: 10.1016/j.intimp.2020.107245] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/19/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022]
Abstract
Coronavirus disease 2019 (COVID-19) is an infective disease generated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the pandemic urgency and lack of an effective cure for this disease, drug repurposing could open the way for finding a solution. Lots of investigations are ongoing to test the compounds already identified as antivirals. On the other hand, induction of type I interferons are found to play an important role in the generation of immune responses against SARS-CoV-2. Therefore, it was opined that the antivirals capable of triggering the interferons and their signaling pathway, could rationally be beneficial for treating COVID-19. On this basis, using a database of antivirals, called drugvirus, some antiviral agents were derived, followed by searches on their relevance to interferon induction. The examined list included drugs from different categories such as antibiotics, immunosuppressants, anti-cancers, non-steroidal anti-inflammatory drugs (NSAID), calcium channel blocker compounds, and some others. The results as briefed here, could help in finding potential drug candidates for COVID-19 treatment. However, their advantages and risks should be taken into account through precise studies, considering a systemic approach. Even though the adverse effects of some of these drugs may overweight their benefits, considering their mechanisms and structures may give a clue for designing novel drugs in the future. Furthermore, the antiviral effect and IFN-modifying mechanisms possessed by some of these drugs might lead to a synergistic effect against SARS-CoV-2, which deserve to be evaluated in further investigations.
Collapse
Affiliation(s)
- Ashkan Bagheri
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Iman Moezzi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pouria Mosaddeghi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sadra Nadimi Parashkouhi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mostafa Fazel Hoseini
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Badakhshan
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Manica Negahdaripour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| |
Collapse
|
|
19
|
Lee TY, Hsu YC, Tseng HC, Lin JT, Wu MS, Wu CY. Association of Daily Aspirin Therapy With Hepatocellular Carcinoma Risk in Patients With Chronic Hepatitis C Virus Infection. Clin Gastroenterol Hepatol 2020; 18:2784-2792.e7. [PMID: 32360983 DOI: 10.1016/j.cgh.2020.04.036] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 03/30/2020] [Accepted: 04/10/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Aspirin therapy has been associated with reduced risk of colon cancer, but there is only limited evidence for its effects on risk of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We aimed to investigate the association of daily aspirin therapy with HCV-related HCC risk. METHODS In this cohort study, based on Taiwan's National Health Insurance Research Database, we screened 237,963 patients with chronic HCV infection for the period of 1997 through 2011. We excluded patients with confounding conditions and 2478 patients who continuously received daily aspirin therapy for 90 days or more (treated group) were randomly matched 1:2 with 4956 patients who had never received antiplatelet therapy (untreated group) by means of propensity scores. Cumulative incidence of, and hazard ratio (HR) for, HCC development were analyzed after we adjusted for patient mortality as a competing risk event. RESULTS The cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group over 5 years (4.67%; 95% CI, 3.74%-5.59% vs 7.32%; 95% CI, 6.33%-8.30%; P<.001). In the multivariable regression analysis, aspirin therapy was independently associated with a reduced HCC risk (HR, 0.78, 95% CI, 0.64-0.95; P = .011), after adjustment for age per year, male sex, cirrhosis, liver decompensation, hyperlipidemia, statin use, and interferon therapy. Sensitivity subgroup analyses also verified this association (all HRs<1.0). In addition, older age (HR, 1.03 per year; 95% CI, 1.02-1.04), male sex (HR, 1.46; 95% CI, 1.21-1.77), and cirrhosis (HR, 3.13; 95% CI, 2.55-3.84) were independently associated with an increased HCC risk. CONCLUSIONS In a nationwide cohort study in Taiwan, we found aspirin therapy to be significantly associated with a reduced risk of HCV-related HCC.
Collapse
Affiliation(s)
- Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung; Department of Medicine, Chung Shan Medical University, Taichung
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei; Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung; Graduate Institute of Clinical Medicine, China Medical University, Taichung
| | - Hsiao-Ching Tseng
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung
| | - Jaw-Town Lin
- Digestive Medicine Center, China Medical University Hospital, Taichung
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei
| | - Chun-Ying Wu
- Division of Translational Medicine and Excellence Cancer Research Center, Department of Medical Research, Taipei Veterans General Hospital, Taipei; Institute of Biomedical Informatics and Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei; College of Public Health, China Medical University, Taichung; National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
| |
Collapse
|
|
20
|
Abstract
Severe Acute Respiratory Syndrome-Coronavirus-2 is responsible for the current pandemic that has led to more than 10 million confirmed cases of Coronavirus Disease-19 (COVID-19) and over 500,000 deaths worldwide (4 July 2020). Virus-mediated injury to multiple organs, mainly the respiratory tract, activation of immune response with the release of pro-inflammatory cytokines, and overactivation of the coagulation cascade and platelet aggregation leading to micro- and macrovascular thrombosis are the main pathological features of COVID-19. Empirical multidrug therapeutic approaches to treat COVID-19 are currently used with extremely uncertain outcomes, and many others are being tested in clinical trials. Acetylsalicylic acid (ASA) has both anti-inflammatory and antithrombotic effects. In addition, a significant ASA-mediated antiviral activity against DNA and RNA viruses, including different human coronaviruses, has been documented. The use of ASA in patients with different types of infections has been associated with reduced thrombo-inflammation and lower rates of clinical complications and in-hospital mortality. However, safety issues related both to the risk of bleeding and to that of developing rare but serious liver and brain damage mostly among children (i.e., Reye's syndrome) should be considered. Hence, whether ASA might be a safe and reasonable therapeutic candidate to be tested in clinical trials involving adults with COVID-19 deserves further attention. In this review we provide a critical appraisal of current evidence on the anti-inflammatory, antithrombotic, and antiviral effects of ASA, from both a pre-clinical and a clinical perspective. In addition, the potential benefits and risks of use of ASA have been put in the context of the adult-restricted COVID-19 population.
Collapse
|
|
21
|
Begg DP, Sinclair AJ, Weisinger RS. Impaired Fluid Intake, but Not Sodium Appetite, in Aged Rats Is Mediated by the Cyclooxygenase-Prostaglandin E 2 Pathway. Front Aging Neurosci 2020; 12:19. [PMID: 32184716 PMCID: PMC7059018 DOI: 10.3389/fnagi.2020.00019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 01/20/2020] [Indexed: 01/22/2023] Open
Abstract
Aging results in decreased fluid intake following dehydration and other dipsogenic stimuli; similar reductions in sodium intake have also been observed with aging. Given that cyclooxygenase (COX)-derived prostanoids are elevated in aged rats in the midbrain and proinflammatory prostanoids are known to decrease fluid intake in dehydrated rats, the aim of this study was to determine if the reductions of fluid intake and sodium intake in aging are mediated by proinflammatory eicosanoid signaling. Therefore, we examined the effect of acute COX inhibition in adult (4 months-old) and aged (30 months-old) rats prior to ingestive behavior challenges. COX inhibition, using acetylsalicylic acid (ASA), increased fluid intake in aged, but not adult, rats in response to 24-h dehydration. ASA had no effect on salt intake following sodium depletion and ASA did not change basal fluid or sodium consumption in either age group. Hypothalamic COX-1 and -2, prostaglandin E synthase (PGES) and inducible nitric oxide synthase (iNOS) mRNA expression were all elevated in aged animals, leading to elevated PGE2 levels. COX expression in the hypothalamus was reduced by ASA treatment in rats of both ages resulting in reduced PGE2 levels in aged ASA treated animals. These data indicate that the reduced fluid intake that occurs in aging is due to increased COX-PGE2-mediated inflammation. However, the reduced sodium intake in these animals appears to occur via an alternate mechanism.
Collapse
Affiliation(s)
- Denovan P Begg
- School of Psychology, UNSW Sydney, Sydney, NSW, Australia
| | | | | |
Collapse
|
|
22
|
Rivas-Estilla AM, Lozano-Sepulveda SA. Where is the focus on hepatitis C research after the introduction of DAAs: To Understand, knowledge, prevent or cure hepatitis C? Ann Hepatol 2020; 19:119-120. [PMID: 32138868 DOI: 10.1016/j.aohep.2020.02.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 02/14/2020] [Indexed: 02/08/2023]
Affiliation(s)
- Ana M Rivas-Estilla
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autónoma de Nuevo León, Monterrey, NL, México.
| | - Sonia A Lozano-Sepulveda
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autónoma de Nuevo León, Monterrey, NL, México
| |
Collapse
|
|
23
|
Liao YH, Hsu RJ, Wang TH, Wu CT, Huang SY, Hsu CY, Su YC, Hsu WL, Liu DW. Aspirin decreases hepatocellular carcinoma risk in hepatitis C virus carriers: a nationwide cohort study. BMC Gastroenterol 2020; 20:6. [PMID: 31918672 PMCID: PMC6953130 DOI: 10.1186/s12876-020-1158-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 12/31/2019] [Indexed: 12/21/2022] Open
Abstract
Background Aspirin has been found to lower the occurrence rates of some cancers through the inhibition of the cyclooxygenase enzyme. For example, there is a well-known association between aspirin use and the occurrence of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers. However, the association, if any, between aspirin use and HCC in hepatitis C virus (HCV) carriers is unknown. Therefore, this study compared the occurrence rates of HCC in HCV carriers treated with or without aspirin. Methods The participants in this retrospective cohort study consisted of people newly diagnosed with HCV in Taiwan from 2000 to 2012. Those who were treated with aspirin were defined as the control group, whereas those not treated with aspirin were defined as the comparison cohort. We used a 1:1 propensity score matching by age, sex, comorbidities, drugs, diagnosis year, and index year with covariate assessment. Results Our study sample consisted of 2980 aspirin-treated HCV carriers and 7771 non-aspirin-treated HCV carriers. After propensity score matching, each cohort consisted of 1911 HCV carriers. The adjusted hazard ratio (aHR) of HCC incidence in the aspirin users (aHR = 0.56, 95% CI = 0.43–0.72, p < 0.001) was significantly lower than that in the non-aspirin users. A Kaplan-Meier analysis showed that among the HCV carriers, the aspirin users had a lower cumulative incidence rate of HCC over the first 10 years of aspirin treatment (p < 0.0001). Conclusions The HCC incidence rate was lower in the aspirin-using HCV carriers than in the non- aspirin-using HCV carriers, indicating that the effects of aspirin might occur through inhibition of the cyclooxygenase enzyme pathway. Moreover, protection from HCC was provided by less than a year of aspirin treatment, while treatment with aspirin for 1 to 2 years exhibited the greatest protective effect. We therefore encourage aspirin treatment to prevent HCC in HCV carriers.
Collapse
Affiliation(s)
- Yen-Hsiang Liao
- Department of Radiation Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Ren-Jun Hsu
- Department of Radiation Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Tzu-Hwei Wang
- Department of Radiation Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chen-Ta Wu
- Department of Radiation Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Sheng-Yao Huang
- Department of Radiation Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Chung-Y Hsu
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Yuan-Chih Su
- College of Medicine, China Medical University, Taichung, Taiwan.,Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Wen-Lin Hsu
- Department of Radiation Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.,School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Dai-Wei Liu
- Department of Radiation Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan. .,School of Medicine, Tzu Chi University, Hualien, Taiwan.
| |
Collapse
|
|
24
|
Lozano-Sepúlveda SA, Rincón-Sanchez AR, Rivas-Estilla AM. Antioxidants benefits in hepatitis C infection in the new DAAs era. Ann Hepatol 2019; 18:410-415. [PMID: 31122787 DOI: 10.1016/j.aohep.2019.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 02/25/2019] [Indexed: 02/04/2023]
Abstract
Some of the evidence on whether antioxidant supplements are effective in treatment of liver diseases is contradictory. Here we perform a descriptive analysis of the available data in vivo and in vitro of the possible antiviral action and controversy of several antioxidant molecules against HCV.
Collapse
Affiliation(s)
- Sonia A Lozano-Sepúlveda
- Universidad Autónoma de Nuevo León, Facultad de Medicina y Hospital Universitario "Dr. Jose Eluterio Gonzalez", Department of Biochemistry and Molecular Medicine, Monterrey, Nuevo Leon, Mexico
| | - Ana R Rincón-Sanchez
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco, Mexico
| | - Ana M Rivas-Estilla
- Universidad Autónoma de Nuevo León, Facultad de Medicina y Hospital Universitario "Dr. Jose Eluterio Gonzalez", Department of Biochemistry and Molecular Medicine, Monterrey, Nuevo Leon, Mexico.
| |
Collapse
|
|
25
|
Mahmoudvand S, Shokri S, Taherkhani R, Farshadpour F. Hepatitis C virus core protein modulates several signaling pathways involved in hepatocellular carcinoma. World J Gastroenterol 2019; 25:42-58. [PMID: 30643357 PMCID: PMC6328967 DOI: 10.3748/wjg.v25.i1.42] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/07/2018] [Accepted: 12/13/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and hepatitis C virus (HCV) infection plays a major role in HCC development. The molecular mechanisms by which HCV infection leads to HCC are varied. HCV core protein is an important risk factor in HCV-associated liver pathogenesis and can modulate several signaling pathways involved in cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress and lipid metabolism. The dysregulation of signaling pathways such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), Wnt/β-catenin (WNT), cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor α (PPARα) by HCV core protein is implicated in the development of HCC. Therefore, it has been suggested that this protein be considered a favorable target for further studies in the development of HCC. In addition, considering the axial role of these signaling pathways in HCC, they are considered druggable targets for cancer therapy. Therefore, using strategies to limit the dysregulation effects of core protein on these signaling pathways seems necessary to prevent HCV-related HCC.
Collapse
Affiliation(s)
- Shahab Mahmoudvand
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Somayeh Shokri
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Reza Taherkhani
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Fatemeh Farshadpour
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| |
Collapse
|
|
26
|
Rios-Ibarra CP, Torres-De La Cruz V, Ochoa-Ruiz AG, Rivas-Estilla AM. Quantification of nitric oxide by high-performance liquid chromatography-fluorometric method in subgenomic hepatitis C virus-replicon expressing Huh7 cells upon treatment with acetylsalicylic acid. Exp Ther Med 2018; 16:2621-2626. [PMID: 30186494 PMCID: PMC6122491 DOI: 10.3892/etm.2018.6515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 02/22/2018] [Indexed: 12/13/2022] Open
Abstract
As nitric oxide (NO) expression levels are lower in hepatocytes compared with other cell types, it is difficult to quantify this compound via Griess assay. The aim of the present study was to quantify NO concentration in the cell culture medium from a subgenomic hepatitis C virus (HCV)-replicon expressing Huh-7 cell system using a high-performance liquid chromatography (HPLC)-fluorescence detector in the presence or absence of acetylsalicylic acid (ASA) treatment. HCV-replicon cells were incubated with ASA (4 mM) for 24, 48 and 72 h. Thereafter, the medium was collected to measure nitrites (NO2-) as an indirect indicator of NO levels using diaminonaphtalene as a derivate agent. NO levels were significantly higher (1.7-fold) in Huh-7 replicon cells treated with ASA (72 h post-treatment) than untreated cells (P<0.05); NO inhibitor reduced ~30% the level of NO in Huh-7 replicon cells treated with ASA (48 h post-treatment; P<0.05). The findings suggested that the HPLC-fluorescence method provided an accurate and efficient measurement of NO production in Huh-7-HCV-replicon cells culture medium.
Collapse
Affiliation(s)
- Clara Patricia Rios-Ibarra
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, México
- Department of Bioengineering, Tecnologico de Monterrey, Campus Guadalajara, Zapopan, Jalisco 45138, México
| | - Victor Torres-De La Cruz
- Biomedical Research Center, Northeast Mexican Social Security Institute, Monterrey, Nuevo León 64720, México
| | - Andrea Gabriela Ochoa-Ruiz
- Department of Bioengineering, Tecnologico de Monterrey, Campus Guadalajara, Zapopan, Jalisco 45138, México
| | - Ana María Rivas-Estilla
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo León 64460, México
| |
Collapse
|
|
27
|
Role of mitogen-activated protein kinase signaling in the pathogenesis of dengue virus infection. Cell Signal 2018; 48:64-68. [PMID: 29753850 DOI: 10.1016/j.cellsig.2018.05.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 05/04/2018] [Accepted: 05/08/2018] [Indexed: 01/08/2023]
Abstract
Dengue virus (DENV) infection is a disease that is endemic to many parts of the world, and its increasing prevalence ranks it among the diseases considered to be a significant threat to public health. The clinical manifestations of DENV infection range from mild dengue fever (DF) to more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Increased proinflammatory cytokines and vascular permeability, both of which cause organ injury, are the hallmarks of severe dengue disease. Signs of liver injury were observed in studies using hepatic cell lines, mouse models, and autopsy specimens from DENV-infected patients, and these signs substantiated the effects of inflammatory responses and hepatic cell apoptosis. Mitogen-activated protein kinases (MAPK) are involved in inflammatory responses and cellular stress during viral infections. The roles of MAPK signaling in DENV infection were reviewed, and published data indicate MAPK signaling to be involved in inflammatory responses and hepatic cell apoptosis in both in vitro cultures and in vivo models. Modulation of MAPK signaling ameliorates the inflammatory responses and hepatic cell apoptosis in DENV infection. This accumulation of published data relative to the role of MAPK signaling in inflammatory responses and cell apoptosis in DENV infection is elucidatory, and may help to accelerate the development of novel or repositioned therapies to treat this unpredictable and often debilitating disease.
Collapse
|
|
28
|
Aeginetia indica Decoction Inhibits Hepatitis C Virus Life Cycle. Int J Mol Sci 2018; 19:ijms19010208. [PMID: 29315273 PMCID: PMC5796157 DOI: 10.3390/ijms19010208] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 01/03/2018] [Accepted: 01/05/2018] [Indexed: 12/16/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is still a global epidemic despite the introduction of several highly effective direct-acting antivirals that are tagged with sky-high prices. The present study aimed to identify an herbal decoction that ameliorates HCV infection. Among six herbal decoctions tested, the Aeginetia indica decoction had the most profound effect on the HCV reporter activity in infected Huh7.5.1 liver cells in a dose- and time-dependent manner. The Aeginetia indica decoction exerted multiple inhibitory effects on the HCV life cycle. Pretreatment of the cells with the Aeginetia indica decoction prior to HCV infection reduced the HCV RNA and non-structural protein 3 (NS3) protein levels in the infected cells. The Aeginetia indica decoction reduced HCV internal ribosome entry site-mediated protein translation activity. It also reduced the HCV RNA level in the infected cells in association with reduced NS5A phosphorylation at serine 235, a predominant phosphorylation event indispensable to HCV replication. Thus, the Aeginetia indica decoction inhibits HCV infection, translation, and replication. Mechanistically, the Aeginetia indica decoction probably reduced HCV replication via reducing NS5A phosphorylation at serine 235.
Collapse
|
|
29
|
Abstract
Antipyretics are some of the most commonly used drugs. Since they are often coadministered with antimicrobial therapy, it is important to understand the interactions between these two classes of drugs. Our review is the first to summarize the antimicrobial effects of antipyretic drugs and the underlying mechanisms involved. Antipyretics can inhibit virus replication, inhibit or promote bacterial or fungal growth, alter the expression of virulence factors, change the surface hydrophobicity of microbes, influence biofilm production, affect the motility, adherence, and metabolism of pathogens, interact with the transport and release of antibiotics by leukocytes, modify the susceptibility of bacteria to antibiotics, and induce or reduce the frequency of mutations leading to antimicrobial resistance. While antipyretics may compromise the efficacy of antimicrobial therapy, they can also be beneficial, for example, in the management of biofilm-associated infections, in reducing virulence factors, in therapy of resistant pathogens, and in inducing synergistic effects. In an era where it is becoming increasingly difficult to find new antimicrobial drugs, targeting virulence factors, enhancing the efficacy of antimicrobial therapy, and reducing resistance may be important strategies.
Collapse
|
|
30
|
Echeverría N, Moreno P, Cristina J. Molecular Evolution of Hepatitis C Virus: From Epidemiology to Antiviral Therapy (Current Research in Latin America). HUMAN VIROLOGY IN LATIN AMERICA 2017:333-359. [DOI: 10.1007/978-3-319-54567-7_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
31
|
Glatthaar-Saalmüller B, Mair KH, Saalmüller A. Antiviral activity of aspirin against RNA viruses of the respiratory tract-an in vitro study. Influenza Other Respir Viruses 2016; 11:85-92. [PMID: 27542891 PMCID: PMC5155651 DOI: 10.1111/irv.12421] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2016] [Indexed: 12/21/2022] Open
Abstract
AIM Aspirin (acetylsalicylic acid) has been used for more than 115 years in medicine. Research exists to show that aspirin has antiviral effects in vitro, for example, by blocking influenza virus propagation via NF-κB inhibition when used at high concentrations and short-term incubation steps. The aim of this study was to confirm the antiviral activity of aspirin against influenza virus and further elucidate the activity of aspirin against other respiratory viruses. METHODS Tests to detect antiviral activity were performed using plaque-reduction assays. Aspirin was administered to the virus-infected cell cultures one hour after infection. Prior to these assays, the non-cytotoxic concentrations of aspirin on cells used for propagation of the respective viruses were determined. RESULTS Aspirin was found to be highly effective against influenza A H1N1 virus. The antiviral activity against further respiratory RNA viruses was less distinct. Respiratory syncytial virus was minimally inhibited. However, the activity of aspirin against rhinoviruses was more pronounced. Aspirin demonstrated antiviral activity against all human rhinoviruses (HRV), but the effect on members of the "major group" viruses, namely HRV14 and HRV39, was greater than on those of the "minor group," HRV1A and HRV2. CONCLUSIONS These data demonstrate a specific antiviral activity of aspirin against influenza A virus and HRV. The mode of action against rhinoviruses is still unknown and requires further investigation, as does the possibility of aspirin being effective in vivo to treat the common cold.
Collapse
Affiliation(s)
- Bernadette Glatthaar-Saalmüller
- Labor Dr. Glatthaar, Ochsenhausen, Germany.,Department of Pathobiology, Institute of Immunology, University of Veterinary Medicine Vienna, Wien, Austria
| | - Kerstin H Mair
- Department of Pathobiology, Institute of Immunology, University of Veterinary Medicine Vienna, Wien, Austria
| | - Armin Saalmüller
- Department of Pathobiology, Institute of Immunology, University of Veterinary Medicine Vienna, Wien, Austria
| |
Collapse
|
|
32
|
Klessig DF, Tian M, Choi HW. Multiple Targets of Salicylic Acid and Its Derivatives in Plants and Animals. Front Immunol 2016; 7:206. [PMID: 27303403 PMCID: PMC4880560 DOI: 10.3389/fimmu.2016.00206] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 05/12/2016] [Indexed: 01/04/2023] Open
Abstract
Salicylic acid (SA) is a critical plant hormone that is involved in many processes, including seed germination, root initiation, stomatal closure, floral induction, thermogenesis, and response to abiotic and biotic stresses. Its central role in plant immunity, although extensively studied, is still only partially understood. Classical biochemical approaches and, more recently, genome-wide high-throughput screens have identified more than two dozen plant SA-binding proteins (SABPs), as well as multiple candidates that have yet to be characterized. Some of these proteins bind SA with high affinity, while the affinity of others exhibit is low. Given that SA levels vary greatly even within a particular plant species depending on subcellular location, tissue type, developmental stage, and with respect to both time and location after an environmental stimulus such as infection, the presence of SABPs exhibiting a wide range of affinities for SA may provide great flexibility and multiple mechanisms through which SA can act. SA and its derivatives, both natural and synthetic, also have multiple targets in animals/humans. Interestingly, many of these proteins, like their plant counterparts, are associated with immunity or disease development. Two recently identified SABPs, high mobility group box protein and glyceraldehyde 3-phosphate dehydrogenase, are critical proteins that not only serve key structural or metabolic functions but also play prominent roles in disease responses in both kingdoms.
Collapse
Affiliation(s)
| | - Miaoying Tian
- Department of Plant and Environmental Protection Sciences, University of Hawaii at Manoa , Honolulu, HI , USA
| | - Hyong Woo Choi
- Boyce Thompson Institute, Cornell University , Ithaca, NY , USA
| |
Collapse
|
|
33
|
Lozano-Sepulveda SA, Bautista-Osorio E, Merino-Mascorro JA, Varela-Rey M, Muñoz-Espinosa LE, Cordero-Perez P, Martinez-Chantar ML, Rivas-Estilla AM. S-adenosyl-L-methionine modifies antioxidant-enzymes, glutathione-biosynthesis and methionine adenosyltransferases-1/2 in hepatitis C virus-expressing cells. World J Gastroenterol 2016; 22:3746-3757. [PMID: 27076759 PMCID: PMC4814737 DOI: 10.3748/wjg.v22.i14.3746] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 02/14/2016] [Accepted: 03/01/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the mechanism(s) by which S-adenosyl-L-methionine (SAM) decreases hepatitis C virus (HCV) expression. METHODS We examined the effects of SAM on viral expression using an HCV subgenomic replicon cell culture system. Huh7 HCV-replicon cells were treated with 1 mmol/L SAM for different times (24-72 h), then total RNA and proteins were isolated. cDNA was synthesized and real time-PCR was achieved to quantify HCV-RNA, superoxide dismutase 1 and 2 (SOD-1, SOD-2) catalase, thioredoxin 1, methionine adenosyltransferase 1A and 2A (MAT1A, MAT2A) expression, and GAPDH and RPS18 as endogenous genes. Expression of cellular and viral protein was evaluated by western-blot analysis using antibodies vs HCV-NS5A, SOD-1, SOD-2, catalase, thioredoxin-1, MAT1A, MAT2A, GAPDH and actin. Total glutathione levels were measured at different times by Ellman's recycling method (0-24 h). Reactive oxidative species (ROS) levels were quantified by the dichlorofluorescein assay (0-48 h); Pyrrolidin dithiocarbamate (PDTC) was tested as an antioxidant control and H2O2 as a positive oxidant agent. RESULTS SAM exposition decreased HCV-RNA levels 50%-70% compared to non-treated controls (24-72 h). SAM induced a synergic antiviral effect with standard IFN treatment but it was independent of IFN signaling. In addition, 1 mmol/L SAM exposition did not modify viral RNA stability, but it needs cellular translation machinery in order to decrease HCV expression. Total glutathione levels increased upon SAM treatment in HCV-replicon cells. Transcriptional antioxidant enzyme expression (SOD-1, SOD-2 and thioredoxin-1) was increased at different times but interestingly, there was no significant change in ROS levels upon SAM treatment, contrary to what was detected with PDTC treatment, where an average 40% reduction was observed in exposed cells. There was a turnover from MAT1A/MAT2A, since MAT1A expression was increased (2.5 fold-times at 48 h) and MAT2A was diminished (from 24 h) upon SAM treatment at both the transcriptional and translational level. CONCLUSION A likely mechanism(s) by which SAM diminish HCV expression could involve modulating antioxidant enzymes, restoring biosynthesis of glutathione and switching MAT1/MAT2 turnover in HCV expressing cells.
Collapse
|
|
34
|
Yin P, Zhang L. Aspirin inhibits hepatitis C virus entry by downregulating claudin-1. J Viral Hepat 2016; 23:62-64. [PMID: 26289738 DOI: 10.1111/jvh.12446] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 07/16/2015] [Indexed: 12/09/2022]
Abstract
Aspirin has previously been reported to inhibit hepatitis C virus (HCV) replication. The aim of this study was to investigate whether aspirin is involved in blocking HCV entry. We found that aspirin inhibits the entry of HCVpp and infectious HCV. The level of claudin-1, an HCV receptor, is reduced by aspirin. Our results extend the anti-HCV effect of aspirin to the HCV entry step and further reinforce the anti-HCV role of aspirin.
Collapse
Affiliation(s)
- P Yin
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - L Zhang
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| |
Collapse
|
|
35
|
Lozano-Sepulveda SA, Bryan-Marrugo OL, Cordova-Fletes C, Gutierrez-Ruiz MC, Rivas-Estilla AM. Oxidative stress modulation in hepatitis C virus infected cells. World J Hepatol 2015; 7:2880-2889. [PMID: 26692473 PMCID: PMC4678374 DOI: 10.4254/wjh.v7.i29.2880] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 11/07/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) replication is associated with the endoplasmic reticulum, where the virus can induce cellular stress. Oxidative cell damage plays an important role in HCV physiopathology. Oxidative stress is triggered when the concentration of oxygen species in the extracellular or intracellular environment exceeds antioxidant defenses. Cells are protected and modulate oxidative stress through the interplay of intracellular antioxidant agents, mainly glutathione system (GSH) and thioredoxin; and antioxidant enzyme systems such as superoxide dismutase, catalase, GSH peroxidase, and heme oxygenase-1. Also, the use of natural and synthetic antioxidants (vitamin C and E, N-acetylcysteine, glycyrrhizin, polyenylphosphatidyl choline, mitoquinone, quercetin, S-adenosylmethionine and silymarin) has already shown promising results as co-adjuvants in HCV therapy. Despite all the available information, it is not known how different agents with antiviral activity can interfere with the modulation of the cell redox state induced by HCV and decrease viral replication. This review describes an evidence-based consensus on molecular mechanisms involved in HCV replication and their relationship with cell damage induced by oxidative stress generated by the virus itself and cell antiviral machinery. It also describes some molecules that modify the levels of oxidative stress in HCV-infected cells.
Collapse
Affiliation(s)
- Sonia A Lozano-Sepulveda
- Sonia A Lozano-Sepulveda, Owen L Bryan-Marrugo, Carlos Cordova-Fletes, Ana M Rivas-Estilla, Department of Biochemistry and Molecular Medicine, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Owen L Bryan-Marrugo
- Sonia A Lozano-Sepulveda, Owen L Bryan-Marrugo, Carlos Cordova-Fletes, Ana M Rivas-Estilla, Department of Biochemistry and Molecular Medicine, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Carlos Cordova-Fletes
- Sonia A Lozano-Sepulveda, Owen L Bryan-Marrugo, Carlos Cordova-Fletes, Ana M Rivas-Estilla, Department of Biochemistry and Molecular Medicine, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Maria C Gutierrez-Ruiz
- Sonia A Lozano-Sepulveda, Owen L Bryan-Marrugo, Carlos Cordova-Fletes, Ana M Rivas-Estilla, Department of Biochemistry and Molecular Medicine, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| | - Ana M Rivas-Estilla
- Sonia A Lozano-Sepulveda, Owen L Bryan-Marrugo, Carlos Cordova-Fletes, Ana M Rivas-Estilla, Department of Biochemistry and Molecular Medicine, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico
| |
Collapse
|
|
36
|
Govea-Salas M, Rivas-Estilla AM, Rodríguez-Herrera R, Lozano-Sepúlveda SA, Aguilar-Gonzalez CN, Zugasti-Cruz A, Salas-Villalobos TB, Morlett-Chávez JA. Gallic acid decreases hepatitis C virus expression through its antioxidant capacity. Exp Ther Med 2015; 11:619-624. [PMID: 26893656 DOI: 10.3892/etm.2015.2923] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 09/25/2015] [Indexed: 01/16/2023] Open
Abstract
Gallic acid (GA) is a natural phenolic compound that possesses various biological effects, including antioxidant, anti-inflammatory, antibiotic, anticancer, antiviral and cardiovascular protection activities. In addition, numerous studies have reported that antioxidants possess antiviral activities. Hepatitis C virus (HCV) is one of the most important causes of chronic liver diseases worldwide, but until recently, only a small number of antiviral agents had been developed against HCV. Therefore, the present study investigated whether GA exhibits an anti-HCV activity. The effects of GA on HCV expression were examined using a subgenomic HCV replicon cell culture system that expressed HCV nonstructural proteins (NSs). In addition, GA cytotoxicity was evaluated at concentrations between 100-600 mg/ml using an MTT assay. Huh-7 replicon cells were incubated with 300 mg/ml GA for different times, and the HCV-RNA and protein levels were measured by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Pyrrolidine dithiocarbamate (PDTC) was used as an antioxidant control and reactive oxygen species (ROS) production was measured during the exposure. The results indicated that GA did not produce a statistically significant cytotoxicity in parental and HCV replicon cells. Furthermore, GA downregulated the expression levels of NS5A-HCV protein (~55%) and HCV-RNA (~50%) in a time-dependent manner compared with the levels in untreated cells. Notably, GA treatment decreased ROS production at the early time points of exposure in cells expressing HCV proteins. Similar results were obtained upon PDTC exposure. These findings suggest that the antioxidant capacity of GA may be involved in the downregulation of HCV replication in hepatoma cells.
Collapse
Affiliation(s)
- Mayela Govea-Salas
- Food Research Department, School of Chemical Sciences, Autonomous University of Coahuila, Saltillo Unit, Saltillo, Coahuila 25260, México; Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 66450, México
| | - Ana Maria Rivas-Estilla
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 66450, México
| | - Raul Rodríguez-Herrera
- Food Research Department, School of Chemical Sciences, Autonomous University of Coahuila, Saltillo Unit, Saltillo, Coahuila 25260, México
| | - Sonia A Lozano-Sepúlveda
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 66450, México
| | - Cristobal N Aguilar-Gonzalez
- Food Research Department, School of Chemical Sciences, Autonomous University of Coahuila, Saltillo Unit, Saltillo, Coahuila 25260, México
| | - Alejandro Zugasti-Cruz
- Food Research Department, School of Chemical Sciences, Autonomous University of Coahuila, Saltillo Unit, Saltillo, Coahuila 25260, México
| | - Tanya B Salas-Villalobos
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon 66450, México
| | - Jesus Antonio Morlett-Chávez
- Food Research Department, School of Chemical Sciences, Autonomous University of Coahuila, Saltillo Unit, Saltillo, Coahuila 25260, México; Clinical Laboratory Department, General Hospital Zone No. 2, Mexican Social Security Institute, Saltillo, Coahuila 25017, México
| |
Collapse
|
|
37
|
Lin CK, Tseng CK, Chen KH, Wu SH, Liaw CC, Lee JC. Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-κB- and MAPK-ERK1/2-mediated COX-2 expression. Br J Pharmacol 2015; 172:4481-4492. [PMID: 26102077 DOI: 10.1111/bph.13233] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 06/08/2015] [Accepted: 06/15/2015] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND PURPOSE This study was designed to evaluate the effect of betulinic acid (BA), extracted from Avicennia marina, on the replication of hepatitis C virus (HCV) and to investigate the mechanism of this BA-mediated anti-HCV activity. EXPERIMENTAL APPROACH HCV replicon and infectious systems were used to evaluate the anti-HCV activity of BA. Exogenous COX-2 or knock-down of COX-2 expression was used to investigate the role of COX-2 in the anti-HCV activity of BA. The effects of BA on the phosphorylation of NF-κB and on kinases in the MAPK signalling pathway were determined. The anti-HCV activity of BA in combination with other HCV inhibitors was also determined to assess its use as an anti-HCV supplement. KEY RESULTS BA inhibited HCV replication in both Ava5 replicon cells and in a cell culture-derived infectious HCV particle system. Treatment with a combination of BA and IFN-α, the protease inhibitor telaprevir or the NS5B polymerase inhibitor sofosbuvir resulted in the synergistic suppression of HCV RNA replication. Exogenous overexpression of COX-2 gradually attenuated the inhibitory effect of BA on HCV replication, suggesting that BA reduces HCV replication by suppressing the expression of COX-2. In particular, BA down-regulated HCV-induced COX-2 expression by reducing the phosphorylation of NF-κB and ERK1/2 of the MAPK signalling pathway. CONCLUSIONS AND IMPLICATIONS BA inhibits HCV replication by suppressing the NF-κB- and ERK1/2-mediated COX-2 pathway and may serve as a promising compound for drug development or as a potential supplement for use in the treatment of HCV-infected patients.
Collapse
Affiliation(s)
- Chun-Kuang Lin
- Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chin-Kai Tseng
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kai-Hsun Chen
- Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Shih-Hsiung Wu
- Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Chih-Chuang Liaw
- Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.,Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Jin-Ching Lee
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| |
Collapse
|
|
38
|
Chen WC, Tseng CK, Chen YH, Lin CK, Hsu SH, Wang SN, Lee JC. HCV NS5A Up-Regulates COX-2 Expression via IL-8-Mediated Activation of the ERK/JNK MAPK Pathway. PLoS One 2015; 10:e0133264. [PMID: 26231035 PMCID: PMC4521820 DOI: 10.1371/journal.pone.0133264] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Accepted: 06/24/2015] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection leads to intrahepatic inflammation and liver cell injury, which are considered a risk factor for virus-associated hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. Inflammatory cytokines are critical components of the immune system and influence cellular signaling, and genetic imbalances. In this study, we found that cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) were significantly induced by HCV infection and HCV NS5A expression, and induction of COX-2 correlated with HCV-induced IL-8 production. We also found that the ERK and JNK signaling pathways were involved in the regulation of IL-8-mediated COX-2 induction in response to HCV infection. Using a promoter-linked reporter assay, we identified that the C/EBP regulatory element within the COX-2 promoter was the dominant factor responsible for the induction of COX-2 by HCV. Silencing C/EBP attenuated HCV-induced COX-2 expression. Our results revealed that HCV-induced inflammation promotes viral replication, providing new insights into the involvement of IL-8-mediated COX-2 induction in HCV replication.
Collapse
Affiliation(s)
- Wei-Chun Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chin-Kai Tseng
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Hsu Chen
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center for Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan
| | - Chun-Kuang Lin
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Shih-hsien Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shen-Nien Wang
- Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jin-Ching Lee
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail:
| |
Collapse
|
|
39
|
Manvar D, Pelliccia S, La Regina G, Famiglini V, Coluccia A, Ruggieri A, Anticoli S, Lee JC, Basu A, Cevik O, Nencioni L, Palamara AT, Zamperini C, Botta M, Neyts J, Leyssen P, Kaushik-Basu N, Silvestri R. New 1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides inhibit hepatitis C virus replication via suppression of cyclooxygenase-2. Eur J Med Chem 2014; 90:497-506. [PMID: 25483263 DOI: 10.1016/j.ejmech.2014.11.042] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 11/15/2014] [Accepted: 11/21/2014] [Indexed: 12/18/2022]
Abstract
We report here the synthesis and mechanism of inhibition of pyrazolecarboxamide derivatives as a new class of HCV inhibitors. Compounds 6, 7, 8 and 16 inhibited the subgenomic HCV replicon 1b genotype at EC50 values between 5 and 8 μM and displayed an even higher potency against the infectious Jc1 HCV 2a genotype. Compound 6 exhibited an EC50 of 6.7 μM and selectivity index of 23 against HCV 1b, and reduced the RNA copies of the infectious Jc1 chimeric 2a clone by 82% at 7 μM. Evaluation of the mode of anti-HCV activity of 6 revealed that it suppressed HCV-induced COX-2 mRNA and protein expression, displaying an IC50 of 3.2 μM in COX-2 promoter-linked luciferase reporter assay. Conversely, the anti-HCV activity of 6 was abrogated upon over-expression of COX-2. These findings suggest that 6 as a representative of these pyrazolecarboxamides function as anti-HCV agents via targeting COX-2 at both the transcription and translation levels.
Collapse
Affiliation(s)
- Dinesh Manvar
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, New Jersey 07103, United States
| | - Sveva Pelliccia
- Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Giuseppe La Regina
- Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Valeria Famiglini
- Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Antonio Coluccia
- Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Anna Ruggieri
- Istituto Superiore di Sanità, Department of Infectious Parasitic and Immune Mediated Diseases, Viale Regina Elena 299, I-00161 Roma, Italy
| | - Simona Anticoli
- Department of Public Health and Infectious Diseases, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Jin-Ching Lee
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China
| | - Amartya Basu
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, New Jersey 07103, United States
| | - Ozge Cevik
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, New Jersey 07103, United States
| | - Lucia Nencioni
- Department of Public Health and Infectious Diseases, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy
| | - Anna Teresa Palamara
- Department of Public Health and Infectious Diseases, Istituto Pasteur - Fondazione Cenci Bolognetti, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy; San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care, 00166 Rome, Italy
| | - Claudio Zamperini
- Dipartimento di Biotecnologia Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy
| | - Maurizio Botta
- Dipartimento di Biotecnologia Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy
| | - Johan Neyts
- Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
| | - Pieter Leyssen
- Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
| | - Neerja Kaushik-Basu
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, New Jersey 07103, United States
| | - Romano Silvestri
- Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
| |
Collapse
|
|
40
|
Demetz E, Schroll A, Auer K, Heim C, Patsch JR, Eller P, Theurl M, Theurl I, Theurl M, Seifert M, Lener D, Stanzl U, Haschka D, Asshoff M, Dichtl S, Nairz M, Huber E, Stadlinger M, Moschen AR, Li X, Pallweber P, Scharnagl H, Stojakovic T, März W, Kleber ME, Garlaschelli K, Uboldi P, Catapano AL, Stellaard F, Rudling M, Kuba K, Imai Y, Arita M, Schuetz JD, Pramstaller PP, Tietge UJF, Trauner M, Norata GD, Claudel T, Hicks AA, Weiss G, Tancevski I. The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism. Cell Metab 2014; 20:787-798. [PMID: 25444678 PMCID: PMC4232508 DOI: 10.1016/j.cmet.2014.09.004] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 08/10/2014] [Accepted: 09/08/2014] [Indexed: 12/12/2022]
Abstract
Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolomeasconserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.
Collapse
Affiliation(s)
- Egon Demetz
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Andrea Schroll
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Kristina Auer
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Christiane Heim
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Josef R Patsch
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Philipp Eller
- Department of Internal Medicine, Angiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
| | - Markus Theurl
- Department of Internal Medicine III, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Igor Theurl
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Milan Theurl
- Department of Ophthalmology and Optometry, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Markus Seifert
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Daniela Lener
- Department of Internal Medicine III, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Ursula Stanzl
- Department of Internal Medicine III, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - David Haschka
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Malte Asshoff
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Stefanie Dichtl
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Eva Huber
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Martin Stadlinger
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Alexander R Moschen
- Department of Internal Medicine I, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Xiaorong Li
- Department of Pharmacology, Capital Medical University, Number 10 Xitoutiao, You An Men, 100069 Beijing, China
| | - Petra Pallweber
- Department of Pediatrics II, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
| | - Winfried März
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Department of Internal Medicine, Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; Synlab Academy, Harrlachweg 1, 68163 Mannheim, Germany
| | - Marcus E Kleber
- Department of Internal Medicine, Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
| | - Katia Garlaschelli
- Center for the Study of Atherosclerosis, Bassini Hospital, via Gorki 50, 20092 Cinisello Balsamo Milan, Italy
| | - Patrizia Uboldi
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy
| | - Alberico L Catapano
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy; IRCCS Multimedica, via Milanese 300, 20099 Sesto San Giovanni Milan, Italy
| | - Frans Stellaard
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Mats Rudling
- Department of Medicine and Department of Biosciences and Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden
| | - Keiji Kuba
- Department of Biological Informatics and Experimental Therapeutics, Graduate School of Medicine, Akita University, 1-1 Tegata Gakuen-machi, 010-8502 Akita City, Japan
| | - Yumiko Imai
- Department of Biological Informatics and Experimental Therapeutics, Graduate School of Medicine, Akita University, 1-1 Tegata Gakuen-machi, 010-8502 Akita City, Japan
| | - Makoto Arita
- Department of Health Chemistry, University of Tokyo, 7-3-1 Hongo, Bunkyo, 113-8654 Tokyo, Japan
| | - John D Schuetz
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS313, Memphis, TN 38105, USA
| | - Peter P Pramstaller
- Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Drususallee 1, 39100 Bolzano, Italy-Affiliated Institute of the University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany
| | - Uwe J F Tietge
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Giuseppe D Norata
- Center for the Study of Atherosclerosis, Bassini Hospital, via Gorki 50, 20092 Cinisello Balsamo Milan, Italy; Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy; The Blizard Institute, Centre for Diabetes, Barts and The London School of Medicine & Dentistry, Queen Mary University, 4 Newark Street, E1 2AT London, UK
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Andrew A Hicks
- Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Drususallee 1, 39100 Bolzano, Italy-Affiliated Institute of the University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany
| | - Guenter Weiss
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
| | - Ivan Tancevski
- Department of Internal Medicine VI, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
| |
Collapse
|
|
41
|
Downregulation of inducible nitric oxide synthase (iNOS) expression is implicated in the antiviral activity of acetylsalicylic acid in HCV-expressing cells. Arch Virol 2014; 159:3321-8. [PMID: 25106115 DOI: 10.1007/s00705-014-2201-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 07/30/2014] [Indexed: 12/30/2022]
Abstract
Previously, we described that acetylsalicylic acid (ASA) decreases HCV expression, but the mechanisms involved have not been clearly established. We evaluated the participation of inducible nitric oxide synthase (iNOS) in the regulation of HCV-RNA induced by ASA. Huh7 cells expressing non-structural HCV proteins were exposed to 4 mM ASA and incubated at the same times we reported HCV downregulation (24-72 h), and iNOS mRNA and protein levels were then measured by real-time PCR and Western blot, respectively. Nitric oxide levels were measured at the same time. Inhibition of iNOS mRNA by small interfering RNAs (siRNA) and activation of the iNOS gene promoter by ASA treatment were evaluated. In Huh7 replicon cells treated with ASA, we found decreased levels of iNOS mRNA, iNOS protein and nitrosylated protein levels at 48-72 h. ASA exposure also reduced the transactivation of the iNOS promoter in HCV replicon cells at 48 h, and this was partly due to the decrease in the affinity of transcription factor C/EBP-β for its binding site in the iNOS promoter. siRNA silencing of iNOS decreased HCV-RNA expression (65 %) and potentiated the antiviral effect (80 %) of ASA compared with control cells. ASA reduces iNOS expression by downregulating promoter activity, mRNA and protein levels at the same time that it decreases HCV expression. These findings suggest that the antiviral activity of ASA is mediated partially through the modulation of iNOS.
Collapse
|
|
42
|
Sánchez-García A, Ríos-Ibarra CP, Rincón-Sánchez AR, Ortiz-López R, Garza-Juárez A, Morlett-Chávez J, Martínez-Rodríguez H, Rivas-Estilla AM. Use of proteomic analysis tools to identify HCV-proteins down-regulated by acetylsalicylic acid. Ann Hepatol 2013; 12:725-732. [DOI: 10.1016/s1665-2681(19)31313-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
|
|
43
|
Kagawa T, Kojima SI, Shiraishi K, Hirose S, Arase Y, Takashimizu S, Watanabe N, Nagata N, Numata M, Shiozawa H, Nishizaki Y, Toki M, Sugita T, Nomura K, Sakaguchi T, Atsukawa K, Tajima H, Tei Y, Inomoto T, Mine T. Meloxicam as an adjuvant to peginterferon-α-2a and ribavirin treatment for genotype 1 chronic hepatitis C: A randomized trial. Hepatol Res 2013; 43:925-932. [PMID: 23356876 DOI: 10.1111/hepr.12046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 12/03/2012] [Accepted: 12/16/2012] [Indexed: 02/08/2023]
Abstract
AIM In this multicenter, randomized trial, we evaluated the effectiveness of meloxicam - a non-steroidal anti-inflammatory drug - as an adjuvant for enhancing antiviral efficacy and preventing neutropenia during the treatment of patients with genotype 1 chronic hepatitis C using peginterferon and ribavirin. METHODS A total of 60 patients were randomly assigned, in a 1:1 ratio, to either the meloxicam or the control group after stratification by neutrophil count. Both groups received weekly peginterferon-α-2a (180 μg) and a weight-based dose of ribavirin for 48 weeks. The meloxicam group received meloxicam (10 mg/day) for the first 8 weeks after initiation of treatment. RESULTS Through intent-to-treat analysis, we found that the sustained virological response rate in the meloxicam group (19/30, 63.3%) was significantly higher than in the control group (11/30, 36.7%, P < 0.05). The relapse rate was more than twice as high (45%) in the control group than in the meloxicam group (19.0%); however, this difference was not statistically significant. The rate of neutrophil decrease, calculated by dividing the lowest value observed during the first 8 weeks by pretreatment count, was significantly smaller in the meloxicam group (55.1 ± 14.3%) than in the control group (62.3 ± 9.6%, P < 0.05). CONCLUSION Meloxicam enhanced antiviral efficacy and reduced the decline in neutrophil counts for the peginterferon and ribavirin treatment of genotype 1 chronic hepatitis C. This drug could be a reasonable adjuvant for the treatment of patients with chronic hepatitis C. The present study including a small number of patients warrants larger clinical trials.
Collapse
Affiliation(s)
- Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Kim AK, Dziura J, Strazzabosco M. Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma: the egg of columbus or another illusion? Hepatology 2013; 58:819-21. [PMID: 23703812 DOI: 10.1002/hep.26498] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 04/23/2013] [Indexed: 12/07/2022]
Affiliation(s)
- Amy K Kim
- Yale University Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | | | | |
Collapse
|
|
45
|
Chen KJ, Tseng CK, Chang FR, Yang JI, Yeh CC, Chen WC, Wu SF, Chang HW, Lee JC. Aqueous extract of the edible Gracilaria tenuistipitata inhibits hepatitis C viral replication via cyclooxygenase-2 suppression and reduces virus-induced inflammation. PLoS One 2013; 8:e57704. [PMID: 23469054 PMCID: PMC3585194 DOI: 10.1371/journal.pone.0057704] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 01/23/2013] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) is an important human pathogen leading to hepatocellular carcinoma. Using an in vitro cell-based HCV replicon and JFH-1 infection system, we demonstrated that an aqueous extract of the seaweed Gracilaria tenuistipitata (AEGT) concentration-dependently inhibited HCV replication at nontoxic concentrations. AEGT synergistically enhanced interferon-α (IFN-α) anti-HCV activity in a combination treatment. We found that AEGT also significantly suppressed virus-induced cyclooxygenase-2 (COX-2) expression at promoter transactivation and protein levels. Notably, addition of exogenous COX-2 expression in AEGT-treated HCV replicon cells gradually abolished AEGT anti-HCV activity, suggesting that COX-2 down-regulation was responsible for AEGT antiviral effects. Furthermore, we highlighted the inhibitory effect of AEGT in HCV-induced pro-inflammatory gene expression such as the expression of tumour necrosis factor-α, interleukin-1β, inducible nitrite oxide synthase and COX-2 in a concentration-dependent manner to evaluate the potential therapeutic supplement in the management of patients with chronic HCV infections.
Collapse
Affiliation(s)
- Kuan-Jen Chen
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Lin YT, Wu YH, Tseng CK, Lin CK, Chen WC, Hsu YC, Lee JC. Green tea phenolic epicatechins inhibit hepatitis C virus replication via cycloxygenase-2 and attenuate virus-induced inflammation. PLoS One 2013; 8:e54466. [PMID: 23365670 PMCID: PMC3554764 DOI: 10.1371/journal.pone.0054466] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 12/11/2012] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is the leading risk factor for hepatocellular carcinoma (HCC) and chronic liver disease worldwide. Green tea, in addition to being consumed as a healthy beverage, contains phenolic catechins that have been used as medicinal substances. In the present study, we illustrated that the epicatechin isomers (+)-epicatechin and (−)-epicatechin concentration-dependently inhibited HCV replication at nontoxic concentrations by using in vitro cell-based HCV replicon and JFH-1 infectious systems. In addition to significantly suppressing virus-induced cyclooxygenase-2 (COX-2) expression, our results revealed that the anti-HCV activity of the epicatechin isomers occurred through the down-regulation of COX-2. Furthermore, both the epicatechin isomers additively inhibited HCV replication in combination with either interferon-α or viral enzyme inhibitors [2′-C-methylcytidine (NM-107) or telaprevir]. They also had prominent anti-inflammatory effects by inhibiting the gene expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and inducible nitrite oxide synthase as well as the COX-2 in viral protein-expressing hepatoma Huh-7 cells. Collectively, (+)-epicatechin and (−)-epicatechin may serve as therapeutic supplements for treating HCV-related diseases.
Collapse
MESH Headings
- Antiviral Agents/pharmacology
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Catechin/pharmacology
- Cell Line, Tumor
- Cyclooxygenase 2/genetics
- Cyclooxygenase 2/metabolism
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- Gene Expression/drug effects
- Hepacivirus/drug effects
- Hepacivirus/physiology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/virology
- Humans
- Inflammation/prevention & control
- Interferon-alpha/pharmacology
- Interleukin-1beta/antagonists & inhibitors
- Interleukin-1beta/genetics
- Nitric Oxide Synthase Type II/antagonists & inhibitors
- Nitric Oxide Synthase Type II/genetics
- Oligopeptides/pharmacology
- RNA, Viral/antagonists & inhibitors
- Stereoisomerism
- Tea/chemistry
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Tumor Necrosis Factor-alpha/genetics
- Virus Replication/drug effects
Collapse
Affiliation(s)
- Ying-Ting Lin
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Hsuan Wu
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chin-Kai Tseng
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chun-Kuang Lin
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Chun Chen
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yao-Chin Hsu
- Department of Chinese Medicine, ChiMei Medical Center, Tainan, Taiwan
- * E-mail: (YCH); (JCL)
| | - Jin-Ching Lee
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail: (YCH); (JCL)
| |
Collapse
|
|
47
|
Rau SJ, Hildt E, Himmelsbach K, Thimme R, Wakita T, Blum HE, Fischer R. CD40 inhibits replication of hepatitis C virus in primary human hepatocytes by c-Jun N terminal kinase activation independent from the interferon pathway. Hepatology 2013; 57:23-36. [PMID: 22814930 DOI: 10.1002/hep.25966] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 07/01/2012] [Indexed: 12/27/2022]
Abstract
UNLABELLED CD40, a member of the tumor necrosis factor receptor family, and its ligand, CD40L (CD154), are important regulators of the antiviral immune response. CD40L is up-regulated on lymphocytes and CD40 on hepatocytes during infection with hepatitis C virus (HCV); we investigated the role of CD40 signaling during HCV replication in hepatocytes. Viral replication was studied in primary human hepatocytes (PHH) and Huh7.5 cells using the infectious HCV Japanese fulminate hepatitis 1 isolate (JFH1) culture system, and in coculture with HCV antigen-specific CD8+ T cells. CD40L rapidly and transiently inhibits expression of the HCV nonstructural proteins NS3 and NS5A as well as HCV structural proteins core and E2 in Huh7.5 cells. Similarly, CD40L prevented replication of HCV in PHH, in synergy with interferon (IFN)-alpha. In Huh7.5 cells with replicating HCV, CD40L prevented production of infectious viral particles. When HCV antigen-specific CD8+ T cells were cocultured with HLA-A2-expressing Huh7 cells that had replicating virus, the T cells became activated, up-regulated CD40L, and inhibited HCV replication. Inhibition of CD40L partially prevented the antiviral activity of the CD8+ T cells. The antiviral effect of CD40L required activation of c-Jun N terminal kinases (JNK)1/2, but not induction of apoptosis or the JAK/STAT pathway that is necessary for the antiviral effects of IFNs. CONCLUSION CD40 inhibits HCV replication by a novel, innate immune mechanism. This pathway might mediate viral clearance, and disruptions might be involved in the pathogenesis of HCV infection.
Collapse
Affiliation(s)
- Sibylle J Rau
- Department of Medicine II, University of Freiburg, Germany
| | | | | | | | | | | | | |
Collapse
|
|
48
|
Regulation of hepatitis C virus replication and gene expression by the MAPK-ERK pathway. Virol Sin 2012; 27:278-85. [PMID: 23001481 DOI: 10.1007/s12250-012-3257-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 08/17/2012] [Indexed: 12/12/2022] Open
Abstract
The mitogen activated protein kinases-extracellular signal regulated kinases (MAPK-ERK) pathway is involved in regulation of multiple cellular processes including the cell cycle. In the present study using a Huh7 cell line Con1 with an HCV replicon, we have shown that the MAPK-ERK pathway plays a significant role in the modulation of HCV replication and protein expression and might influence IFN-α signalling. Epithelial growth factor (EGF) was able to stimulate ERK activation and decreased HCV RNA load while a MAPK-ERK pathway inhibitor U0126 led to an elevated HCV RNA load and higher NS5A protein amounts in Con1 cells. It could be further demonstrated that the inhibition of the MAPK-ERK pathway facilitated the translation directed by the HCV internal ribosome entry site. Consistently, a U0126 treatment enhanced activity of the HCV reporter replicon in transient transfection assays. Thus, the MAPK-ERK pathway plays an important role in the regulation of HCV gene expression and replication. In addition, cyclin-dependent kinases (CDKs) downstream of ERK may also be involved in the modulation of HCV replication since roscovitine, an inhibitor of CDKs had a similar effect to that of U0126. Modulation of the cell cycle progression by cell cycle inhibitor or RNAi resulted consistently in changes of HCV RNA levels. Further, the replication of HCV replicon in Con1 cells was inhibited by IFN-α. The inhibitory effect of IFN-α could be partly reversed by pre-incubation of Con-1 cells with inhibitors of the MAPK-ERK pathway and CDKs. It could be shown that the MAPK-ERK inhibitors are able to partially modulate the expression of interferon-stimulated genes.
Collapse
|
|
49
|
Rivas-Estilla AM, Bryan-Marrugo OL, Trujillo-Murillo K, Pérez-Ibave D, Charles-Niño C, Pedroza-Roldan C, Ríos-Ibarra C, Ramírez-Valles E, Ortiz-López R, Islas-Carbajal MC, Nieto N, Rincón-Sánchez AR. Cu/Zn superoxide dismutase (SOD1) induction is implicated in the antioxidative and antiviral activity of acetylsalicylic acid in HCV-expressing cells. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1264-G1273. [PMID: 22442156 DOI: 10.1152/ajpgi.00237.2011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We evaluated the participation of oxidative stress in the negative regulation of hepatitis C virus (HCV)-RNA induced by acetylsalicylic acid (ASA). We used the HCV subgenomic replicon cell system that stably expresses HCV-nonstructural proteins (Huh7 HCV replicon cells) and the parental cell line. Cells were exposed to 4 mM ASA at different times (12-72 h), and pyrrolidine dithiocarbamate (PDTC) was used as an antioxidant control. Reactive oxygen species (ROS) production, oxidized protein levels, cytosolic superoxide dismutase (Cu/Zn-SOD), and glutathione peroxidase (GPx) activity were measured to evaluate oxidative stress. In addition, viral RNA and prostaglandin (PGE(2)) levels were determined. We observed that ASA treatment decreased ROS production and oxidized protein levels in a time-dependent fashion in both parental and HCV replicon cells with a greater extent in the latter. Similar results were found with PDTC exposure. Average GPx activity was decreased, whereas a striking increase was observed in average cytosolic SOD activity at 48 and 72 h in both cells exposed to ASA, compared with untreated cells. HCV replicon cells showed higher levels of Cu/Zn-SOD expression (mRNA and protein) with ASA treatment (48 and 72 h), whereas NS5A protein levels showed decreased expression. In addition, we found that inhibition of SOD1 expression reversed the effect of ASA. Interestingly, PDTC downregulated HCV-RNA expression (55%) and PGE(2) (60%) levels, imitating ASA exposure. These results suggest that ASA treatment could reduce cellular oxidative stress markers and modify Cu/Zn-SOD expression, a phenomenon that may contribute to the mechanisms involved in HCV downregulation.
Collapse
Affiliation(s)
- Ana María Rivas-Estilla
- Department of Biochemistry and Molecular Medicine, School of Medicine, Autonomous University of Nuevo León, México.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Lee J, Tseng C, Wu S, Chang F, Chiu C, Wu Y. San-Huang-Xie-Xin-Tang extract suppresses hepatitis C virus replication and virus-induced cyclooxygenase-2 expression. J Viral Hepat 2011; 18:e315-24. [PMID: 21692943 PMCID: PMC7185454 DOI: 10.1111/j.1365-2893.2010.01424.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is associated with chronic inflammation of liver, which leads to the development of cirrhosis and hepatocellular carcinoma (HCC). Because of severe side effects and only a 50-70% cure rate in genotype 1 HCV-infected patients upon current standard treatment with pegylated interferon-α plus ribavirin, new therapeutic regimens are still needed. San-Huang-Xie-Xin-Tang (SHXT) is a transitional Chinese herbal formula, composed of Rhei rhizoma, Scutellaria radix and Coptidis rhizome, and possesses anti-inflammatory effect. Here, we describe a (+)-catechin-containing fraction extracted from SHXT, referred as SHXT-frC, exhibited effective inhibition of HCV replication, with selectivity index value (SI; CC50 /EC50) of 84, and displayed synergistic anti-HCV effects when combined with interferon-α, HCV protease inhibitor telaprevir or polymerase inhibitor 2'-C-methylcytidine. The activation of factor-κB (NF-κB) and cyclooxygenase-2 (COX-2) signalling pathway has particular relevance to HCV-associated HCC. SHXT-frC treatment also caused a concentration-dependent decrease in the induction of COX-2 and NF-κB expression caused by either HCV replication or HCV NS5A protein. Collectively, SHXT-frC could be an adjuvant treatment for patients with HCV-induced liver diseases.
Collapse
Affiliation(s)
- J.‐C. Lee
- Department of Biotechnology, College of Life Science,Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung
| | - C.‐k. Tseng
- Department of Biotechnology, College of Life Science
| | - S.‐F. Wu
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung
| | - F.‐R. Chang
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung
| | - C.‐C. Chiu
- Department of Biotechnology, College of Life Science
| | - Y.‐C. Wu
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung,Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University,Natural Medicinal Products Research Center, China Medical University Hospital, Taichung, Taiwan, China
| |
Collapse
|