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Erguven P, Tanrikulu-Kucuk S, Sevgin K, Degirmencioglu S, Cetinalp P, Aksu S, Gun-Atak P, Sogut I. Protective effects of boric acid on HBV-transgenic mice with chronic alcohol consumption: An experimental study. Biochem Biophys Res Commun 2025; 768:151956. [PMID: 40345014 DOI: 10.1016/j.bbrc.2025.151956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/18/2025] [Accepted: 05/05/2025] [Indexed: 05/11/2025]
Abstract
This study aimed to investigate the protective effect of boric acid supplementation against liver damage in chronic alcohol-dependent HBV transgenic mice. The HBV transgenic mice were divided into four groups: control(C), boric acid(B), alcohol(A), and alcohol + boric acid(A + B). Blood alcohol concentration (BAC), alanine aminotransferase (ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), malondialdehyde(MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), total antioxidant capacity (TAS), total oxidant capacity (TOS) levels, and oxidative stress index (OSI) were examined biochemically. H&E, PAS, Masson trichrome, and TUNEL staining were performed. Caspase 3, cytochrome c, and APAF-1 expression levels were determined by qRT-PCR. The alcohol group exhibited significantly higher levels of ROS, MDA, TOS, OSI, and mRNA expressions of Cytochrome c, caspase 3, and APAF-1, while TAS level and CAT activity were significantly lower compared to the boric acid group. Compared to the control group, the alcohol group exhibited significantly increased TOS, OSI, AST levels, APAF-1 mRNA expression, and the number of TUNEL-positive cells, along with a reduction in GPx activity (p < 0.05). However, in the alcohol + boric acid group, TOS and AST levels were significantly higher compared to the control group (p < 0.05), and TOS was higher compared to the boric acid group (p < 0.01). Among the boron-treated groups, only the TOS level was lower in the boric acid group compared to the alcohol + boric acid group (p < 0.01). Histopathological examination revealed reduced sinusoidal dilatation and connective tissue distribution in the boric acid-supplemented groups. These findings suggest that boric acid supplementation may mitigate oxidative damage and histopathological alterations associated with chronic alcohol consumption in HBV-transgenic mice.
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Affiliation(s)
- Pelin Erguven
- Department of Histology and Embryology, International Faculty of Medicine, University of Health Sciences, Istanbul, 34668, Turkiye
| | - Sevda Tanrikulu-Kucuk
- Department of Biochemistry, Faculty of Medicine, Demiroglu Bilim University, Istanbul, 34394, Turkiye
| | - Kubra Sevgin
- Department of Histology and Embryology, International Faculty of Medicine, University of Health Sciences, Istanbul, 34668, Turkiye
| | - Sevgin Degirmencioglu
- Department of Biochemistry, Faculty of Medicine, Kirklareli University, Kirklareli, Turkiye
| | - Pinar Cetinalp
- Department of Biochemistry, Faculty of Medicine, Demiroglu Bilim University, Istanbul, 34394, Turkiye
| | - Soner Aksu
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Istanbul Health and Technology University, Istanbul, 34275, Turkiye
| | - Palmet Gun-Atak
- Medical Biochemistry Laboratory, Liv Hospital, Istanbul, Turkiye
| | - Ibrahim Sogut
- Department of Biochemistry, Faculty of Medicine, Demiroglu Bilim University, Istanbul, 34394, Turkiye.
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Salami AT, Orji JC, Akpamu U, Iyiola TO, Olaleye SB. Attenuation of Experimental Cholesterol Gallstone Formation by Manganese Chloride in Mice: Role of NF-κβ Pathways. Biol Trace Elem Res 2024:10.1007/s12011-024-04467-z. [PMID: 39715976 DOI: 10.1007/s12011-024-04467-z] [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: 07/20/2024] [Accepted: 11/24/2024] [Indexed: 12/25/2024]
Abstract
Manganese (Mn), a trace element, has been documented to exert an important role in the metabolism of cholesterol. Cholesterol gallstone (CG) pathogenesis is directly linked to biliary cholesterol imbalance which could be due to diabetes complications or mismanagement. NF-κβ pathway, an inflammatory regulator, has been implicated in metabolic disease especially in the context of diabetes and gallstone formation. However, the management of cholesterol gallstones due to diabetes with trace elements is vague. This study investigates the probable role of manganese during CG formation due to diabetes complications. Eighty female Swiss mice were grouped: I (control), II (untreated CG), III and IV (normal mice treated 0.37 mg/kg and 0.74 mg/kg Mn, respectively), V and VI (CG treated 0.37 mg/kg and 0.74 mg/kg Mn, respectively), and VII and VIII (CG treated 75 mg/7 kg and 350 mg/kg aspirin, respectively). Experimental CG was induced with cholesterol-rich diets after alloxan-induced diabetes. On sacrifice, blood collected was evaluated for complete hematological analysis and biochemistry while the excised liver was assayed for biochemical variables. Results were subjected to one-way ANOVA values were expressed as Mean ± SEM and significant at p ≤ 0.05. Manganese treatment significantly increased packed cell volume, RBC count, and hemoglobin with decreased platelet and leukocyte counts, liver enzymes (AST, ALT, and ALP), BUN, and creatinine levels in CG groups compared with untreated CG. Blood glucose, plasma low-density lipoproteins, and liver malodialdehyde levels were significantly reduced while liver nitric-oxide, sulfhydryl, and glutathione levels increased significantly in manganese-treated groups compared with untreated CG. Manganese significantly increased fecal iron contents in normal mice by the 2nd week. Hepatocytes and gallbladder histology appear normal in manganese-treated groups. Liver NF-Kβ immunoreactivity was downregulated in manganese-treated CG groups. Manganese attenuated experimental hyperglycemia-induced cholesterol gallstone by ameliorating liver oxidative stress and NF-Kβ inflammatory pathway.
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Affiliation(s)
| | - J C Orji
- University of Ibadan, Ibadan, Nigeria
| | - U Akpamu
- Federal University Oye-Ekiti, Oye, Nigeria
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Petrović A, Štancl P, Gršković P, Hančić S, Karlić R, Gašparov S, Korać P. Gene Expression Aberrations in Alcohol-Associated Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:10558. [PMID: 39408891 PMCID: PMC11476681 DOI: 10.3390/ijms251910558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, ranking as the sixth most common cancer worldwide and the fourth leading cause of cancer-related deaths. Most HCC cases originate from cirrhotic livers, typically due to chronic liver diseases, such as hepatitis B (HBV) and hepatitis C (HCV) infections, and alcoholism. HCC cells often harbor numerous somatic mutations that are implicated in HCC development, but epigenetic factors, such as miRNA interference, can also affect HCC initiation and progress. miRNA-221 has been explored as a factor affecting HCC development in HCC of viral etiology, but little is known about its effects on gene expression in alcohol-associated HCC. This study aimed to explore potentially similar gene expression aberrations underlying viral and alcohol-induced HCC. We analyzed available transcriptome data from non-tumor hepatocytes and viral-induced HCC tissues. The most notable differences in gene expression associated with miRNA-221 between non-tumor hepatocytes and viral-induced HCC involved NTF-3 and MYBL1 genes. To assess these data in alcohol-induced HCC, we examined 111 tissue samples: tumor tissue and cirrhotic tissue samples from 37 HCC patients and 37 samples from non-tumor liver tissue using RT-Q PCR. We found no significant difference in NTF-3 expression, but MYBL1 expression was significantly lower in HCC tissue compared to non-tumor hepatocytes and cirrhotic tissue. Our findings highlight the importance of the MYBL1 gene in HCC development and emphasize the need for diverse approaches in evaluating tumor mechanisms.
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Affiliation(s)
- Andreja Petrović
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia; (A.P.); (P.Š.); (R.K.)
- Institute of Clinical Pathology and Cytology, Merkur University Hospital, 10000 Zagreb, Croatia; (S.H.); (S.G.)
| | - Paula Štancl
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia; (A.P.); (P.Š.); (R.K.)
| | - Paula Gršković
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia; (A.P.); (P.Š.); (R.K.)
| | - Suzana Hančić
- Institute of Clinical Pathology and Cytology, Merkur University Hospital, 10000 Zagreb, Croatia; (S.H.); (S.G.)
| | - Rosa Karlić
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia; (A.P.); (P.Š.); (R.K.)
| | - Slavko Gašparov
- Institute of Clinical Pathology and Cytology, Merkur University Hospital, 10000 Zagreb, Croatia; (S.H.); (S.G.)
- Department of Pathology, Medical School Zagreb, University of Zagreb, 10000 Zagreb, Croatia
| | - Petra Korać
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia; (A.P.); (P.Š.); (R.K.)
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Li L, Xie D, Yu S, Ma M, Fan K, Chen J, Xiu M, Xie K, Li Y, Gao Y. WNK1 Interaction with KEAP1 Promotes NRF2 Stabilization to Enhance the Oxidative Stress Response in Hepatocellular Carcinoma. Cancer Res 2024; 84:2776-2791. [PMID: 38885324 DOI: 10.1158/0008-5472.can-23-1167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 01/30/2024] [Accepted: 06/12/2024] [Indexed: 06/20/2024]
Abstract
Cellular oxidative stress plays a key role in the development and progression of hepatocellular carcinoma (HCC). A better understanding of the processes that regulate reactive oxygen species (ROS) homeostasis could uncover improved strategies for treating HCC. Herein, we identified protein kinase with-no-lysine kinase 1 (WNK1) as an antioxidative factor and therapeutic target in HCC. In human HCC, WNK1 expression was increased and correlated with poor patient prognosis. WNK1 knockdown significantly inhibited cell proliferation and xenograft tumor growth. Mechanistically, WNK1 competed with nuclear factor erythroid 2-related factor 2 (NRF2) for binding with the partial Kelch domain of Kelch-like ECH-associated protein 1 (KEAP1), reducing NRF2 ubiquitination and promoting NRF2 accumulation and nuclear translocation to increase antioxidant response. WNK1 silencing increased H2O2-induced apoptosis and inhibited cell growth by elevating ROS levels, which could be rescued by treatment with the antioxidant N-acetylcysteine and NRF2 activator tert-butylhydroquinone. Liver-specific WNK1 knockout mouse models of HCC substantiated that WNK1 promoted HCC development by regulating ROS levels. WNK463, an inhibitor of the WNK kinase family, suppressed HCC progression and altered the redox status. These findings suggest that WNK1 plays a critical role in HCC development and progression and that the WNK1-oxidative stress axis may be a promising therapeutic target for HCC. Significance: Inhibiting WNK1 induces NRF2 degradation and reduces the oxidative stress response to suppress hepatocellular carcinoma growth, indicating that targeting the WNK1-KEAP1-NRF2 axis is a potential strategy to treat liver cancer.
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Affiliation(s)
- Li Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dacheng Xie
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Shijun Yu
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Muyuan Ma
- Center for Pancreatic Cancer Research, The South China University of Technology, Guangzhou, China
| | - Kailing Fan
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jingde Chen
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Mengxi Xiu
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Keping Xie
- Center for Pancreatic Cancer Research, The South China University of Technology, Guangzhou, China
| | - Yandong Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yong Gao
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Huang XW, Li Y, Jiang LN, Zhao BK, Liu YS, Chen C, Zhao D, Zhang XL, Li ML, Jiang YY, Liu SH, Zhu L, Zhao JM. Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma. Open Med (Wars) 2024; 19:20240982. [PMID: 38883336 PMCID: PMC11179385 DOI: 10.1515/med-2024-0982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 06/18/2024] Open
Abstract
Carnosine dipeptidase 1 (CNDP1), an enzyme integral to the hydrolysis of dipeptides containing histidine, plays an indispensable role in myriad physiological processes, including hydrolysis of proteins, maturation of specific biochemical functionalities within proteins, tissue regeneration, and regulation of cell cycle. However, the implications of CNDP1 in oncogenesis and its prognostic value are not yet fully elucidated. Initially, we procured the GSE40367 dataset from the Gene Expression Omnibus and established a protein-protein interaction network. Thereafter, we conducted functional and pathway enrichment analyses utilizing GO, KEGG, and GSEA. Moreover, we undertook an association analysis concerning the expression of CNDP1 with immune infiltration, along with survival analysis across various cancers and specifically in hepatocellular carcinoma (HCC). Our study uncovered a total of 2,248 differentially expressed genes, with a down-regulation of CNDP1 in HCC and other cancers. Our explorations into the relationship between CNDP1 and immune infiltration disclosed a negative correlation between CNDP1 expression and the presence of immune cells in HCC. Survival analyses revealed that diminished expression of CNDP1 correlates with an adverse prognosis in HCC and several other types of cancer. These observations intimate that CNDP1 holds promise as a novel prognostic biomarker for both pan-cancer and HCC.
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Affiliation(s)
- Xiao-Wen Huang
- Medical School of Chinese PLA, Beijing, China
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Yan Li
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Li-Na Jiang
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Bo-Kang Zhao
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
| | - Yi-Si Liu
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Chun Chen
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Dan Zhao
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Xue-Li Zhang
- Medical School of Chinese PLA, Beijing, China
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Mei-Ling Li
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Yi-Yun Jiang
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Shu-Hong Liu
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Li Zhu
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Jing-Min Zhao
- Medical School of Chinese PLA, Beijing, China
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
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Elmoslemany AM, Elzallat M, Abd-Elfatah MH, Mohammed DM, Elhady EE. Possible therapeutic effect of frankincense (Gum olibanum) and myrrh (Commiphora myrrha) resins extracts on DEN/CCL4 induced hepatocellular carcinoma in rats. PHYTOMEDICINE PLUS 2024; 4:100517. [DOI: 10.1016/j.phyplu.2023.100517] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
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Park JS, Rustamov N, Roh YS. The Roles of NFR2-Regulated Oxidative Stress and Mitochondrial Quality Control in Chronic Liver Diseases. Antioxidants (Basel) 2023; 12:1928. [PMID: 38001781 PMCID: PMC10669501 DOI: 10.3390/antiox12111928] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Chronic liver disease (CLD) affects a significant portion of the global population, leading to a substantial number of deaths each year. Distinct forms like non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (ALD), though they have different etiologies, highlight shared pathologies rooted in oxidative stress. Central to liver metabolism, mitochondria are essential for ATP production, gluconeogenesis, fatty acid oxidation, and heme synthesis. However, in diseases like NAFLD, ALD, and liver fibrosis, mitochondrial function is compromised by inflammatory cytokines, hepatotoxins, and metabolic irregularities. This dysfunction, especially electron leakage, exacerbates the production of reactive oxygen species (ROS), augmenting liver damage. Amidst this, nuclear factor erythroid 2-related factor 2 (NRF2) emerges as a cellular protector. It not only counters oxidative stress by regulating antioxidant genes but also maintains mitochondrial health by overseeing autophagy and biogenesis. The synergy between NRF2 modulation and mitochondrial function introduces new therapeutic potentials for CLD, focusing on preserving mitochondrial integrity against oxidative threats. This review delves into the intricate role of oxidative stress in CLD, shedding light on innovative strategies for its prevention and treatment, especially through the modulation of the NRF2 and mitochondrial pathways.
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Affiliation(s)
| | | | - Yoon-Seok Roh
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, Republic of Korea; (J.-S.P.); (N.R.)
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Abdal TA, Al-Naemi RS. Osteopontin (SPP1) expression on gallstone formation in rabbits fed with a lithogenic diet. J Adv Vet Anim Res 2023; 10:301-307. [PMID: 37534080 PMCID: PMC10390682 DOI: 10.5455/javar.2023.j682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/18/2023] [Accepted: 03/19/2023] [Indexed: 08/04/2023] Open
Abstract
Objective This research was designed to assess the influence of the administration of a lithogenic diet, hydrogen peroxide, and vitamin AD3E on rabbits' gallstone formation and to envisage the expression of osteopontin (OPN) in their hepatic tissues. Materials and Methods Twenty-four healthy local mature rabbits of both genders were divided into four equal groups. At the end of the feeding period, samples of blood were taken from all rabbits after they had fasted overnight to estimate the serum lipid profile. And some of the hepatic tissue has been preserved at -28°C for molecular analysis and gene expression. Results The gallstones were formed 100% in the GIII and 50% in the GIV. The mRNA OPN expression showed a significant increase in the GIII when compared with other groups. In Groups III and II, the serum levels of total cholesterol, Triglyceride, L-C, low-density lipoprotein-choles, and VLDL-C were significantly increased when compared with GI, while in GIII, the serum level of high-density lipoprotein-cholesterol was significantly decreased when compared with GI. Conclusion It was concluded that the expression of the mRNA OPN was increased in the hepatic tissue of gallstone-formed rabbits.
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Affiliation(s)
- Tareek Abdulqadir Abdal
- Department of Theriogenology, Physiology, and Anatomy, College of Veterinary Medicine, University of Duhok, Duhok, Iraq
| | - Raed Salim Al-Naemi
- Department of Physiology, College of Medicine, University of Duhok, Duhok, Iraq
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Vanekova L, Polidarova M, Charvat V, Vavrina Z, Veverka V, Birkus G, Brazdova A. Development and characterization of a chronic hepatitis B murine model with a mutation in the START codon of an HBV polymerase. Physiol Res 2023; 72:37-47. [PMID: 36545874 PMCID: PMC10069812 DOI: 10.33549/physiolres.934979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023] Open
Abstract
Chronic hepatitis B (CHB) is caused by the Hepatitis B virus (HBV) and affects millions of people worldwide. Developing an effective CHB therapy requires using in vivo screening methods, such as mouse models reflecting CHB based on hydrodynamic delivery of plasmid vectors containing a replication-competent HBV genome. However, long-term expression of HBV proteins is accompanied by production of progeny virions, thereby requiring a Biosafety Level (BSL) 3 animal facility. In the present study, we introduced a point mutation in the START codon of the HBV polymerase to develop a mouse model reflecting chronic hepatitis B infection without formation of viral progeny. We induced the mouse model by hydrodynamic injection of adeno-associated virus plasmid vector (pAAV) and minicircle plasmid (pMC) constructs into C57Bl/6 and C3H/HeN mouse strains, monitoring HBV antigens and antibodies in blood by enzyme-linked immunosorbent assay and analyzing liver expression of HBV core antigen by immunohistology. Persisting expression of viral antigens over 140 days (study endpoint) was observed only in the C3H/HeN mouse strain when using pAAV/1.2HBV-A and pMC/1.0HBV-D with pre-C and pre-S recombination sites. In addition, pAAV/1.2HBV-A in C3H/HeN sustained HBV core antigen positivity up to the study endpoint in C3H/HeN mice. Moreover, introducing the point mutation in the START codon of polymerase effectively prevented the formation of viral progeny. Our study establishes an accessible and affordable experimental paradigm for developing a robust mouse model reflecting CHB suitable for preclinical testing of anti-HBV therapeutics in a BSL2 animal facility.
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Affiliation(s)
- L Vanekova
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
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Bae SJ, Bak SB, Kim YW. Coordination of AMPK and YAP by Spatholobi Caulis and Procyanidin B2 Provides Antioxidant Effects In Vitro and In Vivo. Int J Mol Sci 2022; 23:ijms232213730. [PMID: 36430207 PMCID: PMC9694094 DOI: 10.3390/ijms232213730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/01/2022] [Accepted: 11/06/2022] [Indexed: 11/09/2022] Open
Abstract
The liver is vulnerable to oxidative attacks from heavy metals, such as iron, as well as some drugs, including acetaminophen. It has been shown that enhanced oxidative stress in the liver leads to excessive ROS production and mitochondrial dysfunction, resulting in organ injury. The beneficial effects of Spatholobi Caulis (SC), a natural herbal medicine, include treating ischemic stroke, inhibiting tumor cell invasion, pro-angiogenic activities, and anti-inflammatory properties. Scientific studies on its effects against hepatotoxic reagents (e.g., iron and acetaminophen), as well as their underlying mechanisms, are insufficient. This study examined the antioxidant effects and mechanisms of SC in vitro and in vivo. In cells, the proinflammatory mediator, arachidonic acid (AA), plus iron, significantly induced an increase in ROS generation, the damage in mitochondrial membrane potential, and the resulting apoptosis, which were markedly blocked by SC. More importantly, SC affected the activation of AMP-activated protein kinase (AMPK)-related proteins, which were vital to regulating oxidative stress in cells. In addition, SC mediated the expression of Yes-associated protein (YAP)-related proteins. Among the active compounds in SC, the procyanidin B2, but not liquiritigenin, daidzein, and genistein, significantly inhibited the cytotoxicity induced by AA + iron, and activated the LKB1-AMPK pathway. In mice, the oral administration of SC alleviated the elevations of ALT and histological changes by the acetaminophen-induced liver injury. These results reveal the potential of SC and a key bioactive component, procyanidin B2, as antioxidant candidates for hepatoprotection.
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Huang W, Liu WY, Chen LY, Ni L, Zou XX, Ye M, Zhang ZY, Zou SQ. Flavonoid and chromone-rich extract from Euscaphis Konishii Hayata leaf attenuated alcoholic liver injury in mice. JOURNAL OF ETHNOPHARMACOLOGY 2022; 295:115455. [PMID: 35697192 DOI: 10.1016/j.jep.2022.115455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 06/06/2022] [Accepted: 06/08/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Euscaphis konishii Hayata is a traditional medicinal plant in China, and its leaves are usually used to make dishes for hepatic or gastrointestinal issues by Chinese She nationality. Pharmacological analysis showed that E. konishii leaves contain high levels of flavonoids and chromones with favorable anti-hepatoma effect. AIM OF THE STUDY The extract from E. konishii leaves was detected to evaluate its chemical composition, and the alcoholic liver injury mice model was adopted to elucidate its hepatoprotective effects. MATERIALS AND METHODS The total leaf extract from E. konishii was separated by polyamide column to get the flavonoid and chromone-rich extract (FCE). Single compounds from FCE was purified by gel and Sephadex LH-20 chromatography and analyzed by nuclear magnetic resonance (NMR). The chemical component of FCE was confirmed and quantified by HPLC-MS. The OH·, O2-, DPPH and ABTS + free radical assays were adopted to estimate the antioxidant activity of FCE in vitro. The alcohol-fed model mice were established to assess the hepatoprotective capacity of FCE in vivo, through biochemical determination, histopathological analysis, mitochondrial function measurement, quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) detection and Western blot determination. RESULTS 8 flavonoids and 2 chromones were recognized in the FCEextract by both NMR and HPLC-MS. FCE represented strong free radicals scavenging activity in vitro. With oral administration, FCE (50, 100 and 200 mg/kg) dose-dependently decreased the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) in alcohol-fed mice. FCE gradually reduced the malondialdehyde (MDA) content, increased the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the alcohol-treated liver tissues. FCE also alleviated the hepatic inflammation, inhibited the hepatocyte apoptosis and lessened the alcohol-induced histological alteration and lipid accumulation in the liver tissues. FCE administration inhibited the overexpression of endoplasmic reticulum (ER) chaperones signaling and unfolded protein response (UPR) pathways to defense the ER-induced apoptosis. Pretreatment with FCE also restored the mitochondrial membrane potentials andadenosine triphosphate (ATP) levels, which in turn suppressed the Cytochrome C release and mitochondria-induced apoptosis. CONCLUSIONS FCE conferred great protection against alcoholic liver injury, which might be associated with its viability through suppressing reactive oxygen species (ROS) stress and hepatocyte apoptosis.
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Affiliation(s)
- Wei Huang
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China; Engineering Research Institute of Conservation, Utilization of Natural Bioresources, Fujian Agriculture and Forestry University, Fuzhou, 350002, China; College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
| | - Wan-Yi Liu
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Lu-Yao Chen
- Engineering Research Institute of Conservation, Utilization of Natural Bioresources, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Lin Ni
- Engineering Research Institute of Conservation, Utilization of Natural Bioresources, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Xiao-Xing Zou
- Engineering Research Institute of Conservation, Utilization of Natural Bioresources, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Min Ye
- Fujian Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, 350004, China
| | - Zhong-Yi Zhang
- College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
| | - Shuang-Quan Zou
- Engineering Research Institute of Conservation, Utilization of Natural Bioresources, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
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Sun L, Zhang Y, Wen S, Li Q, Chen R, Lai X, Zhang Z, Zhou Z, Xie Y, Zheng X, Zhang K, Li D, Sun S. Extract of Jasminum grandiflorum L. alleviates CCl 4-induced liver injury by decreasing inflammation, oxidative stress and hepatic CYP2E1 expression in mice. Biomed Pharmacother 2022; 152:113255. [PMID: 35689859 DOI: 10.1016/j.biopha.2022.113255] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 11/02/2022] Open
Abstract
Jasminum grandiflorum L. (JG) is a medicinal plant containing many bioactive ingredients. Herein, we analyzed the effects of four different extracts and two compounds of JG on acute liver injury caused by carbon tetrachloride (CCl4) and underlying molecular mechanisms. 7 weeks old C57BL/6 male mice were used to establish a liver injury model by injecting with 1% CCl4, 10 mL/kg ip. Four different extracts and two compounds of JG were given to mice by gavage for 3 days. Clinical and histological chemistry assays were performed to assess liver injury. Moreover, hepatic oxidative stress and inflammation related markers were determined by immunohistochemistry and western blotting. As a result, JG extracts and two functional components showed different degree of protect effects against CCl4-induced liver injury by the decrease of elevated serum transaminases and liver index, and the attenuation of histopathological changes in mice, among which JG extracted with petroleum ether (PET) had the most significant effect. In addition, PET remarkably alleviated hepatic oxidative stress and inflammation. Further studies revealed that PET significantly inhibited the TNF-α expression, signal pathway expression, NF-κB p65 and inflammatory factors IL-1β and IL-6 expression in CCl4-induced liver injury mice. Nevertheless, hydroxytyrosol (HT) alleviated liver injury by reducing oxidative stress. Apart from PET extract, other extracts of JG can inhibit cytochrome CYP2E1 expression to protect liver tissue. These findings suggest that the extracts and its components of JG possesses the potential protective effects against CCl4-induced liver injury in mice by exerting antioxidative stress and anti-inflammation.
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Affiliation(s)
- Lingli Sun
- Tea Research Institute, Guangdong Academy of Agricultural Sciences / Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Yizi Zhang
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Shuai Wen
- Tea Research Institute, Guangdong Academy of Agricultural Sciences / Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Qiuhua Li
- Tea Research Institute, Guangdong Academy of Agricultural Sciences / Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Ruohong Chen
- Tea Research Institute, Guangdong Academy of Agricultural Sciences / Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Xingfei Lai
- Tea Research Institute, Guangdong Academy of Agricultural Sciences / Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Zhenbiao Zhang
- Tea Research Institute, Guangdong Academy of Agricultural Sciences / Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China
| | - Zhiyan Zhou
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Yinzheng Xie
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Xi Zheng
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
| | - Kun Zhang
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
| | - Dongli Li
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China.
| | - Shili Sun
- Tea Research Institute, Guangdong Academy of Agricultural Sciences / Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou 510640, China.
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Samuvel DJ, Nguyen NT, Jaeschke H, Lemasters JJ, Wang X, Choo YM, Hamann MT, Zhong Z. Platanosides, a Potential Botanical Drug Combination, Decrease Liver Injury Caused by Acetaminophen Overdose in Mice. JOURNAL OF NATURAL PRODUCTS 2022; 85:1779-1788. [PMID: 35815804 PMCID: PMC9788857 DOI: 10.1021/acs.jnatprod.2c00324] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. Platanosides (PTSs) isolated from the American sycamore tree (Platanus occidentalis) represent a potential new four-molecule botanical drug class of antibiotics active against drug-resistant infectious disease. Preliminary studies have suggested that PTSs are safe and well tolerated and have antioxidant properties. The potential utility of PTSs in decreasing APAP hepatotoxicity in mice in addition to an assessment of their potential with APAP for the control of infectious diseases along with pain and pyrexia associated with a bacterial infection was investigated. On PTS treatment in mice, serum alanine aminotransferase (ALT) release, hepatic centrilobular necrosis, and 4-hydroxynonenal (4-HNE) were markedly decreased. In addition, inducible nitric oxide synthase (iNOS) expression and c-Jun-N-terminal kinase (JNK) activation decreased when mice overdosed with APAP were treated with PTSs. Computational studies suggested that PTSs may act as JNK-1/2 and Keap1-Nrf2 inhibitors and that the isomeric mixture could provide greater efficacy than the individual molecules. Overall, PTSs represent promising botanical drugs for hepatoprotection and drug-resistant bacterial infections and are effective in protecting against APAP-related hepatotoxicity, which decreases liver necrosis and inflammation, iNOS expression, and oxidative and nitrative stresses, possibly by preventing persistent JNK activation.
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Affiliation(s)
- Devadoss J. Samuvel
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Nga T. Nguyen
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
| | - John J. Lemasters
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States
- Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Xiaojuan Wang
- School of Pharmacy, Lanzhou University, Lanzhou, Gansu, People Republic of China
| | - Yeun-Mun Choo
- Chemistry Department, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
| | - Mark T. Hamann
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Zhi Zhong
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States
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Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study. Pharmaceuticals (Basel) 2022; 15:ph15070832. [PMID: 35890131 PMCID: PMC9319470 DOI: 10.3390/ph15070832] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/26/2022] [Accepted: 07/01/2022] [Indexed: 02/01/2023] Open
Abstract
Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia–reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (−14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.
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Rattanasupar A, Chang A, Prateepchaiboon T, Pungpipattrakul N, Akarapatima K, Songjamrat A, Pakdeejit S, Prachayakul V, Piratvisuth T. Impact of alcohol consumption on treatment outcome of hepatocellular carcinoma patients with viral hepatitis who underwent transarterial chemoembolization. World J Hepatol 2022; 14:1162-1172. [PMID: 35978671 PMCID: PMC9258258 DOI: 10.4254/wjh.v14.i6.1162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/24/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alcohol consumption increases the risk of hepatocellular carcinoma (HCC) in patients with pre-existing liver disease, including viral hepatitis. However, studies on the impact of alcohol consumption on the outcomes of HCC are limited. We hypothesized that alcohol had an additional effect with chronic viral hepatitis infection on treatment outcomes after transarterial chemoembolization (TACE) in patients with intermediate-stage HCC (Barcelona Clinical Liver Cancer [BCLC] -B). AIM To evaluate the additional effect of alcohol on treatment outcomes of TACE among HCC patients with viral hepatitis. METHODS This study, conducted at Hatyai Hospital in Thailand, included HCC patients over 18 years of age with chronic viral hepatitis. Records of HCC patients with viral hepatitis classified as BCLC-B who underwent TACE as the first treatment modality between 2014 and 2019 were retrospectively reviewed. Patients with chronic viral hepatitis only were categorized under group A, and those with chronic viral hepatitis and concurrent alcohol consumption were categorized under group B. Both groups were compared, and the Cox proportional-hazards model was used to identify the survival-influencing variables. RESULTS Of the 69 patients, 53 were categorized in group A and 16 in group B. There were no statistically significant differences in tumor characteristics between the two patient groups. However, Group A had a statistically significantly higher proportion of complete response (24.5% vs 0%, P = 0.030) and a higher median survival rate (26.2 mo vs 8.4 mo; log-rank P = 0.012) compared to group B. Factors associated with decreased survival in the proportional-hazards model included alcohol consumption (hazards ratio [HR], 2.377; 95% confidence interval [CI], 1.109-5.095; P = 0.026), presence of portal hypertension (HR, 2.578; 95%CI, 1.320-5.037; P = 0.006), largest tumor size > 5 cm (HR, 3.558; 95%CI, 1.824-6.939; P < 0.001), and serum alpha-fetoprotein level > 100 ng/mL (HR, 2.536; 95%CI, 1.377-4.670; P = 0.003). CONCLUSION In HCC BCLC B patients with chronic viral hepatitis, alcohol consumption is an independent risk factor for increased mortality and decreases the rate of complete response and survival after TACE.
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Affiliation(s)
- Attapon Rattanasupar
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Arunchai Chang
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand.
| | | | | | - Keerati Akarapatima
- Division of Gastroenterology, Department of Internal Medicine, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Apiradee Songjamrat
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Songklod Pakdeejit
- Division of Intervention Radiology, Department of Radiology, Hatyai Hospital, Hatyai 90110, Songkhla, Thailand
| | - Varayu Prachayakul
- Siriraj Gastrointestinal Endoscopy Center, Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkoknoi 10700, Bangkok, Thailand
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Hatyai 90110, Songkhla, Thailand
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16
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Zhang H, Jiang PJ, Lv MY, Zhao YH, Cui J, Chen J. OGG1 contributes to hepatocellular carcinoma by promoting cell cycle-related protein expression and enhancing DNA oxidative damage repair in tumor cells. J Clin Lab Anal 2022; 36:e24561. [PMID: 35723423 PMCID: PMC9279955 DOI: 10.1002/jcla.24561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/08/2022] [Accepted: 05/26/2022] [Indexed: 02/05/2023] Open
Abstract
Background This study aimed to analyze the expression of 8‐oxoguanine DNA glycosylase (OGG1) in patients with hepatocellular carcinoma (HCC) and its effect on prognosis by bioinformatics techniques and to determine its possible carcinogenic mechanism through data mining. Methods The difference in OGG1 expression between healthy people and HCC patients was searched and analyzed by TCGA and GEO databases, and the effect of OGG1 on prognosis was judged by survival analysis. Meanwhile, the possible molecular mechanism of OGG1 in the tumorigenesis and development of HCC was explored by GO analysis, KEGG analysis, immune infiltration analysis, protein–protein interaction network, promoter methylation analysis, and so forth. Quantitative polymerase chain reaction (qPCR) was used to examine the gene expression in 36 pairs of HCC tissues and adjacent tissues. Results The expression of OGG1 in HCC patients was higher than that in healthy people, and the overexpression of OGG1 might stimulate cell proliferation by increasing the activity of cell cycle‐related proteins. Conclusion The alteration of OGG1 was significantly correlated with the tumorigenesis and development of HCC. OGG1 is expected to be a new biomarker for evaluating the prognosis of HCC and a new target for the treatment of HCC.
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Affiliation(s)
- He Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng-Jun Jiang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Meng-Yuan Lv
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yan-Hua Zhao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Ju Cui
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jie Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
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17
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Zhen X, Moya EA, Gautane M, Zhao H, Lawrence ES, Gu W, Barnes LA, Yuan JXJ, Jain PP, Xiong M, Catalan Serra P, Pham LV, Malhotra A, Simonson TS, Mesarwi OA. Combined intermittent and sustained hypoxia is a novel and deleterious cardio-metabolic phenotype. Sleep 2022; 45:zsab290. [PMID: 34893914 PMCID: PMC9189937 DOI: 10.1093/sleep/zsab290] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 12/01/2021] [Indexed: 11/14/2022] Open
Abstract
STUDY OBJECTIVES Chronic obstructive pulmonary disease and obstructive sleep apnea overlap syndrome is associated with excess mortality, and outcomes are related to the degree of hypoxemia. People at high altitudes are susceptible to periodic breathing, and hypoxia at altitude is associated with cardio-metabolic dysfunction. Hypoxemia in these scenarios may be described as superimposed sustained hypoxia (SH) plus intermittent hypoxia (IH), or overlap hypoxia (OH), the effects of which have not been investigated. We aimed to characterize the cardio-metabolic consequences of OH in mice. METHODS C57BL/6J mice were subjected to either SH (FiO2 = 0.10), IH (FiO2 = 0.21 for 12 h, and FiO2 oscillating between 0.21 and 0.06, 60 times/hour, for 12 h), OH (FiO2 = 0.13 for 12 h, and FiO2 oscillating between 0.13 and 0.06, 60 times/hour, for 12 h), or room air (RA), n = 8/group. Blood pressure and intraperitoneal glucose tolerance test were measured serially, and right ventricular systolic pressure (RVSP) was assessed. RESULTS Systolic blood pressure transiently increased in IH and OH relative to SH and RA. RVSP did not increase in IH, but increased in SH and OH by 52% (p < .001) and 20% (p = .001). Glucose disposal worsened in IH and improved in SH, with no change in OH. Serum low- and very-low-density lipoproteins increased in OH and SH, but not in IH. Hepatic oxidative stress increased in all hypoxic groups, with the highest increase in OH. CONCLUSIONS OH may represent a unique and deleterious cardio-metabolic stimulus, causing systemic and pulmonary hypertension, and without protective metabolic effects characteristic of SH.
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Affiliation(s)
- Xin Zhen
- University of California, San Diego, La Jolla, CA, USA
| | - Esteban A Moya
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | - Mary Gautane
- University of California, San Diego, La Jolla, CA, USA
| | - Huayi Zhao
- University of California, San Diego, La Jolla, CA, USA
| | - Elijah S Lawrence
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | - Wanjun Gu
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | - Laura A Barnes
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | - Jason X-J Yuan
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | - Pritesh P Jain
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Mingmei Xiong
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | | | - Luu V Pham
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD,USA
| | - Atul Malhotra
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
- Center for Physiological Genomics of Low Oxygen, University of California, San Diego, CA, USA
| | - Tatum S Simonson
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
- Center for Physiological Genomics of Low Oxygen, University of California, San Diego, CA, USA
| | - Omar A Mesarwi
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
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18
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Gümüş H, Erat T, Öztürk İ, Demir A, Koyuncu I. Oxidative stress and decreased Nrf2 level in pediatric patients with COVID-19. J Med Virol 2022; 94:2259-2264. [PMID: 35128704 PMCID: PMC9088523 DOI: 10.1002/jmv.27640] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/06/2022] [Accepted: 01/30/2022] [Indexed: 11/11/2022]
Abstract
The aim of this study was to investigate the change in nuclear factor erythroid 2-related factor (Nrf2), which plays a critical role in cytoprotection against oxidative stress, in pediatric patients with coronavirus disease 2019 (COVID-19) infection positivity, and to evaluate the relationship between Nrf2 and oxidative balance. The study included 40 children with confirmed COVID-19 infection and 35 healthy children. The groups were compared in respect of Nrf2, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI), in addition to clinical findings of fever, cough, shortness of breath, contact history, and demographic data of age and gender. The mean Nrf2 values and TAS levels were determined to be statistically significantly low (p < 0.001) and the TOS level and OSI were statistically significantly high in the children with COVID-19 compared to the control group. A significant positive correlation was determined between Nrf2 and TAS (p < 0.01); as the Nrf2 value increased, so the TAS value increased. A significant negative correlation was determined between Nrf2 and TOS and OSI (p < 0.01); as the Nrf2 value increased, there was determined to be a significant decrease in the TOS and OSI values. COVID-19 infection in pediatric patients causes a decrease in the Nrf2 level. By causing a decrease in the TAS level and an increase in the TOS and OSI levels, the decrease in Nrf2 may explain the tissue damage which can be caused by COVID-19.
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Affiliation(s)
- Hüseyin Gümüş
- Department of Pediatrics, Faculty of MedicineHarran UniversityŞanlıurfaTurkey
| | - Tuğba Erat
- Department of Pediatric Infectious DiseasesSanliurfa Training and Research HospitalŞanlıurfaTurkey
| | - İrfan Öztürk
- Department of Animal Science, Biometry Genetics Unit, Agricultural FacultyHarran UniversityŞanlıurfaTurkey
| | - Abit Demir
- Department of Pediatrics, Faculty of Medicine, Harran UniversityHarran UniversityŞanlıurfaTurkey
| | - Ismail Koyuncu
- Department of Medical BiochemistryFaculty of Medicine, Harran UniversityŞanlıurfaTurkey
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Mao J, Zhan H, Meng F, Wang G, Huang D, Liao Z, Chen M. Costunolide protects against alcohol-induced liver injury by regulating gut microbiota, oxidative stress and attenuating inflammation in vivo and in vitro. Phytother Res 2022; 36:1268-1283. [PMID: 35084790 DOI: 10.1002/ptr.7383] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 12/14/2021] [Accepted: 12/29/2021] [Indexed: 12/17/2022]
Abstract
Costunolide (cos) derived from the roots of Dolomiaea souliei (Franch.), which belongs to the Dolomiaea genus in the family Compositae, exert the anti-inebriation effect mainly by inhibiting the absorption of alcohol in the gastrointestinal tract. However, the protective effect of cos against alcohol-induced liver injury (ALI) remains obscure. The present study was aimed to evaluate the hepatoprotective effects of cos (silymarin was used as positive control) against ALI and its potential mechanisms. MTT was used to examine the effect of cos on the cell viability of L-02 cells. Plasma was separated from blood that used to test the levels of TNF-α, IL-6 and IL-12, and LPS while serum separated from blood which used to detect the level of ALT and AST. Liver tissues were obtained for histopathological examination and western blot analysis. Fresh mice feces samples were collected for the detection of bacterial composition. Cos exhibited protective effect against alcoholic-induced liver injury by regulating gut microbiota capacities (higher relative abundance of Firmicutes and Actinobacteria while lower in Bacteroidetes and Proteobacteria), adjusting oxidative stress (reduced the activities of MDA and ROS while promoted SOD, GSH and GSH-PX in L-02 cells) and attenuating inflammation (decreased the levels of ALT, AST, LPS, IL-6, IL-12 and TNF-α) via LPS-TLR4-NF-κB p65 signaling pathway, which might be an active therapeutic agent for treatment of ALI.
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Affiliation(s)
- Jingxin Mao
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Honghong Zhan
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Fancheng Meng
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Guowei Wang
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Dan Huang
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Zhihua Liao
- School of Life Sciences, Southwest University, Chongqing, China
| | - Min Chen
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
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20
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Mabrouk AA, Eltablawy NA, El-Allawy RM, Abdel Maksoud H, Elsenosi YA. The ameliorating effect of Terminalia muelleri extract on oxidative stress–related factors in induced hepatocellular carcinoma rat model. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2021.101482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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21
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Barré T, Fontaine H, Pol S, Ramier C, Di Beo V, Protopopescu C, Marcellin F, Bureau M, Bourlière M, Dorival C, Petrov-Sanchez V, Asselah T, Delarocque-Astagneau E, Larrey D, Duclos-Vallée JC, Carrat F, Carrieri P, on behalf of the ANRS/AFEF Hepather Study Group. Metabolic Disorders in Patients with Chronic Hepatitis B Virus Infection: Coffee as a Panacea? (ANRS CO22 Hepather Cohort). Antioxidants (Basel) 2022; 11:antiox11020379. [PMID: 35204261 PMCID: PMC8869416 DOI: 10.3390/antiox11020379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/10/2022] [Accepted: 02/11/2022] [Indexed: 12/04/2022] Open
Abstract
People living with chronic hepatitis B virus (HBV) infection are at high risk of liver disease progression, which is positively associated with metabolic disorders, but inversely associated with dyslipidemia. Diet, including dietary antioxidants, is a lever of metabolic disorder management. In particular, elevated coffee consumption is associated with different metabolic outcomes in the general population. We aimed to test whether such associations occur in HBV-infected people. Based on cross-sectional data from the ANRS CO22 Hepather cohort, we performed logistic regression models with (i) dyslipidemia, (ii) hypertension, and (iii) diabetes as outcomes, and with demographic, clinical, and socio-behavioral (including coffee consumption) data as explanatory variables. Among 4746 HBV-infected patients, drinking ≥3 cups of coffee per day was associated with a higher risk of dyslipidemia (adjusted odds ratio [95% confidence interval] 1.49 [1.10–2.00], p = 0.009) and a lower risk of hypertension (0.64 [0.50–0.82], p = 0.001). It was not associated with diabetes. Elevated coffee consumption was associated with a higher risk of dyslipidemia and a lower risk of hypertension in HBV-infected patients, two effects expected to be associated with favorable clinical outcomes. Further studies should test whether such metabolic benefits translate into reduced mortality risk in this population.
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Affiliation(s)
- Tangui Barré
- Aix Marseille Univ. Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, 13005 Marseille, France; (T.B.); (C.R.); (V.D.B.); (C.P.); (F.M.); (M.B.); (M.B.)
| | - Hélène Fontaine
- Université de Paris, AP-HP, Hôpital Cochin, Département d’Hépatologie/Addictologie, 75014 Paris, France; (H.F.); (S.P.)
| | - Stanislas Pol
- Université de Paris, AP-HP, Hôpital Cochin, Département d’Hépatologie/Addictologie, 75014 Paris, France; (H.F.); (S.P.)
| | - Clémence Ramier
- Aix Marseille Univ. Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, 13005 Marseille, France; (T.B.); (C.R.); (V.D.B.); (C.P.); (F.M.); (M.B.); (M.B.)
| | - Vincent Di Beo
- Aix Marseille Univ. Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, 13005 Marseille, France; (T.B.); (C.R.); (V.D.B.); (C.P.); (F.M.); (M.B.); (M.B.)
| | - Camelia Protopopescu
- Aix Marseille Univ. Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, 13005 Marseille, France; (T.B.); (C.R.); (V.D.B.); (C.P.); (F.M.); (M.B.); (M.B.)
| | - Fabienne Marcellin
- Aix Marseille Univ. Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, 13005 Marseille, France; (T.B.); (C.R.); (V.D.B.); (C.P.); (F.M.); (M.B.); (M.B.)
| | - Morgane Bureau
- Aix Marseille Univ. Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, 13005 Marseille, France; (T.B.); (C.R.); (V.D.B.); (C.P.); (F.M.); (M.B.); (M.B.)
| | - Marc Bourlière
- Aix Marseille Univ. Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, 13005 Marseille, France; (T.B.); (C.R.); (V.D.B.); (C.P.); (F.M.); (M.B.); (M.B.)
- Hôpital St. Joseph, Service d’Hépato-Gastroentérologie, 13008 Marseille, France
| | - Céline Dorival
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d’Epidémiologie et de Santé Publique, Sorbonne Université, 75646 Paris, France;
| | - Ventzislava Petrov-Sanchez
- ANRS MIE (France Recherche Nord & Sud Sida-HIV Hépatites|Maladies Infectieuses Emergentes), Unit for Basic and Clinical Research on Viral Hepatitis, 73013 Paris, France;
| | - Tarik Asselah
- Université de Paris, Centre de Recherche sur L’inflammation, INSERM UMR1149, 75018 Paris, France;
- Department of Hepatology, AP-HP, Hôpital Beaujon, 92110 Clichy, France
| | - Elisabeth Delarocque-Astagneau
- Université Paris-Saclay, UVSQ, Inserm, CESP, Team Anti-Infective Evasion and Pharmacoepidemiology, 78180 Montigny, France;
- AP-HP, GHU Paris Saclay University, Raymond Poincaré Hospital, Epidemiology and Public Health Department, 92380 Garches, France
| | - Dominique Larrey
- Liver Unit-IRB-INSERM 1183, Hôpital Saint Eloi, 34090 Montpellier, France;
| | - Jean-Charles Duclos-Vallée
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, UMR-S 1193, Université Paris-Saclay, FHU HEPATINOV, 94800 Villejuif, France;
| | - Fabrice Carrat
- Hôpital Saint-Antoine, Unité de Santé Publique, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012 Paris, France;
| | - Patrizia Carrieri
- Aix Marseille Univ. Inserm, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, ISSPAM, 13005 Marseille, France; (T.B.); (C.R.); (V.D.B.); (C.P.); (F.M.); (M.B.); (M.B.)
- Correspondence:
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22
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Cioarca-Nedelcu R, Atanasiu V, Stoian I. Alcoholic liver disease-from steatosis to cirrhosis - a biochemistry approach. J Med Life 2022; 14:594-599. [PMID: 35027961 PMCID: PMC8742892 DOI: 10.25122/jml-2021-0081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 10/07/2021] [Indexed: 12/20/2022] Open
Abstract
Nowadays, chronic alcoholism and its health implications represent a global concern. Over three million deaths are linked to chronic alcohol intake every year. This article aims to spread awareness about the negative impact ethanol can have on almost every organ in the body, especially the liver. Understanding ethanol metabolism and the cellular pathways through which alcohol increases liver oxidative stress may prevent a broad spectrum of hepatic lesions such as steatosis, steatohepatitis, and, ultimately, cirrhosis. After a short review of ethanol metabolism and liver oxidative stress, each hepatic lesion will be individually discussed regarding the mechanism of apparition, treatment, and future targeted therapies.
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Affiliation(s)
| | - Valeriu Atanasiu
- Biochemistry Department, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
| | - Irina Stoian
- Biochemistry Department, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
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23
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Liu GZ, Xu XW, Tao SH, Gao MJ, Hou ZH. HBx facilitates ferroptosis in acute liver failure via EZH2 mediated SLC7A11 suppression. J Biomed Sci 2021; 28:67. [PMID: 34615538 PMCID: PMC8495979 DOI: 10.1186/s12929-021-00762-2] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022] Open
Abstract
Background Acute liver failure (ALF) is a syndrome of severe hepatocyte injury with high rate of mortality. Hepatitis B virus (HBV) infection is the major cause of ALF worldwide, however, the underlying mechanism by which HBV infection leads to ALF has not been fully disclosed. Methods D-GalN-induced hepatocyte injury model and LPS/D-GalN-induced ALF mice model were used to investigate the effects of HBV X protein (HBx) in vitro and in vivo, respectively. Cell viability and the levels of Glutathione (GSH), malondialdehyde (MDA) and iron were measured using commercial kits. The expression of ferroptosis-related molecules were detected by qRT-PCR and western blotting. Epigenetic modification and protein interaction were detected by chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (co-IP), respectively. Mouse liver function was assessed by measuring aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The histological changes in liver tissues were monitored by hematoxylin and eosin (H&E) staining, and SLC7A11 immunoreactivity was assessed by immunohistochemistry (IHC) analysis. Results D-GalN triggered ferroptosis in primary hepatocytes. HBx potentiated D-GalN-induced hepatotoxicity and ferroptosis in vitro, and it suppressed SLC7A11 expression through H3K27me3 modification by EZH2. In addition, EZH2 inhibition or SLC7A11 overexpression attenuated the effects of HBx on D-GalN-induced ferroptosis in primary hepatocytes. The ferroptosis inhibitor ferrostatin-1 (Fer-1) protected against ALF and ferroptosis in vivo. By contrast, HBx exacerbates LPS/D-GalN-induced ALF and ferroptosis in HBx transgenic (HBx-Tg) mice. Conclusion HBx facilitates ferroptosis in ALF via EZH2/H3K27me3-mediated SLC7A11 suppression.
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Affiliation(s)
- Guo-Zhen Liu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, No.87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, China
| | - Xu-Wen Xu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Shu-Hui Tao
- Department of Liver Diseases, Shenzhen Hospital, Southern Medical University, Shenzhen, 518100, Guangdong, China
| | - Ming-Jian Gao
- Department of Infectious Diseases, Xiangya Hospital, Central South University, No.87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, China
| | - Zhou-Hua Hou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, No.87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, China.
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24
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Abstract
Significance: As the central metabolic organ, the liver is exposed to a variety of potentially cytotoxic, proinflammatory, profibrotic, and carcinogenic stimuli. To protect the organism from these deleterious effects, the liver has evolved a number of defense systems, which include antioxidant substrates and enzymes, anti-inflammatory tools, enzymatic biotransformation systems, and metabolic pathways. Recent Advances: One of the pivotal systems that evolved during phylogenesis was the heme catabolic pathway. Comprising the important enzymes heme oxygenase and biliverdin reductase, this complex pathway has a number of key functions including enzymatic activities, but also cell signaling, and DNA transcription. It further generates two important bile pigments, biliverdin and bilirubin, as well as the gaseous molecule carbon monoxide. These heme degradation products have potent antioxidant, immunosuppressive, and cytoprotective effects. Recent data suggest that the pathway participates in the regulation of metabolic and hormonal processes implicated in the pathogenesis of hepatic and other diseases. Critical Issues: This review discusses the impact of the heme catabolic pathway on major liver diseases, with particular focus on the involvement of cellular targeting and signaling in the pathogenesis of these conditions. Future Directions: To utilize the biological consequences of the heme catabolic pathway, several unique therapeutic strategies have been developed. Research indicates that pharmaceutical, nutraceutical, and lifestyle modifications positively affect the pathway, delivering potentially long-term clinical benefits. However, further well-designed studies are needed to confirm the clinical benefits of these approaches. Antioxid. Redox Signal. 35, 734-752.
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Affiliation(s)
- Libor Vítek
- Fourth Department of Internal Medicine, and Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic
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25
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Aykac K, Ozsurekci Y, Yayla BCC, Gurlevik SL, Oygar PD, Bolu NB, Tasar MA, Erdinc FS, Ertem GT, Neselioglu S, Erel O, Cengiz AB, Ceyhan M. Oxidant and antioxidant balance in patients with COVID-19. Pediatr Pulmonol 2021; 56:2803-2810. [PMID: 34265172 PMCID: PMC8441878 DOI: 10.1002/ppul.25549] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/30/2021] [Accepted: 06/08/2021] [Indexed: 01/11/2023]
Abstract
BACKGROUND A crucial balance exists between oxidant and antioxidant mechanisms in the functional immune system. We aimed to evaluate the contributions of balance between these systems to coronavirus disease 2019 (COVID-19), a devastating pandemic caused by viral infection. METHOD We analyzed serum oxidant and antioxidant stress parameters according to the clinical and demographic characteristics of children and adults with COVID-19 and compared them against the values of healthy controls. Serum native thiol (NT), total thiol (TT), disulfide, total antioxidant status, total oxidant status, and ischemia-modified albumin levels were evaluated and compared between groups. RESULTS A total of 79 children and 74 adults were evaluated in the present study, including 46 children and 40 adults with COVID-19, 33 healthy children, and 34 healthy adults. TT, NT, and disulfide levels were significantly lower in the adult COVID-19 group than in all other groups (p = .001, p = .001, and p = .005, respectively). Additionally, TT and NT levels were significantly lower in both pediatric and adult COVID-19 cases with severe disease course than mild/moderate course. TT and NT levels were identified as predictors for the diagnosis of the adult COVID-19 cases and as independent predictors for disease severity in both children and adults with COVID-19. CONCLUSION Parameters that reveal the oxidant and antioxidant capacity, including TT and NT, appear to be good candidates for the accurate prediction of the clinical course among patients with COVID-19.
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Affiliation(s)
- Kubra Aykac
- Department of Pediatric Infectious Diseases, Ankara Training and Research Hospital, University of Health Science, Ankara, Turkey
| | - Yasemin Ozsurekci
- Department of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Burcu Ceylan Cura Yayla
- Department of Pediatric Infectious Diseases, Ankara Training and Research Hospital, University of Health Science, Ankara, Turkey
| | - Sibel Lacinel Gurlevik
- Department of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Pembe Derin Oygar
- Department of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Nuriye Boduc Bolu
- Department of Pediatric Diseases, Ankara Training and Research Hospital, University of Health Science, Ankara, Turkey
| | - Medine Aysin Tasar
- Department of Pediatric Diseases, Ankara Training and Research Hospital, University of Health Science, Ankara, Turkey
| | - Fatma Sebnem Erdinc
- Department of Infectious Diseases, Ankara Training and Research Hospital, University of Health Science, Ankara, Turkey
| | - Gulay Tuncer Ertem
- Department of Infectious Diseases, Ankara Training and Research Hospital, University of Health Science, Ankara, Turkey
| | - Salim Neselioglu
- Department of Clinical Biochemistry, Yildirim Beyazit University Faculty of Medicine, Ankara, Turkey
| | - Ozcan Erel
- Department of Clinical Biochemistry, Yildirim Beyazit University Faculty of Medicine, Ankara, Turkey
| | - Ali Bülent Cengiz
- Department of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Mehmet Ceyhan
- Department of Pediatric Infectious Diseases, Hacettepe University Faculty of Medicine, Ankara, Turkey
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26
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Bousali M, Papatheodoridis G, Paraskevis D, Karamitros T. Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma. Microorganisms 2021; 9:1787. [PMID: 34442866 PMCID: PMC8398950 DOI: 10.3390/microorganisms9081787] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal-fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO's commitment to eliminate HBV and viral hepatitis by 2030.
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Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - George Papatheodoridis
- Department of Gastroenterology, “Laiko” General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Paraskevis
- Department of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
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Kim M, Lee EJ, Lim KM. Ibuprofen Increases the Hepatotoxicity of Ethanol through Potentiating Oxidative Stress. Biomol Ther (Seoul) 2021; 29:205-210. [PMID: 33024059 PMCID: PMC7921853 DOI: 10.4062/biomolther.2020.108] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/22/2020] [Accepted: 08/25/2020] [Indexed: 12/17/2022] Open
Abstract
Over 30 million prescriptions of NSAIDs (non-steroidal anti-inflammatory drugs) are issued every year. Considering that these drugs are available without a prescription as over the counter (OTC) drugs, their use will be astronomical. With the increasing use of NSAIDs, their adverse effects are drawing attention. Especially, stomach bleeding, kidney toxicity, liver toxicity, and neurological toxicity are reported as common. Ibuprofen, one of the extensively used NSAIDs along with aspirin, can also induce liver toxicity, but few studies are addressing this point. Here we examined the liver toxicity of ibuprofen and investigated whether co-exposure to ethanol can manifest synergistic effects. We employed 2D and 3D cultured human hepatoma cells, HepG2 to examine the synergistic hepatotoxicity of ibuprofen and alcohol concerning cell viability, morphology, and histology of 3D spheroids. As a result, ibuprofen and alcohol provoked synergistic hepatotoxicity against hepatocytes, and their toxicity increased prominently in 3D culture upon extended exposure. Oxidative stress appeared to be the mechanisms underlying the synergistic toxicity of ibuprofen and alcohol as evidenced by increased production of ROS and expression of the endogenous antioxidant system. Collectively, this study has demonstrated that ibuprofen and EtOH can induce synergistic hepatotoxicity, providing a line of evidence for caution against the use of ibuprofen in combination with alcohol.
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Affiliation(s)
- Minjeong Kim
- College of Pharmacy, Ewha Womans University, Seoul 37060, Republic of Korea
| | - Eugenia Jin Lee
- Department of Biological Sciences, Columbia College, Columbia University, NY 10027, USA
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul 37060, Republic of Korea
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28
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Zhang H, Li H, Lan X, Liu F, Li B, Wei Y. Diabetes mellitus affects long-term survival in hepatitis B virus-related hepatocellular carcinoma patients: A propensity score-matched analysis. Medicine (Baltimore) 2021; 100:e24354. [PMID: 33530229 PMCID: PMC7850751 DOI: 10.1097/md.0000000000024354] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 11/12/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) increases the risk of developing hepatocellular carcinoma (HCC), and how DM affects the prognosis of HCC have not been elucidated. The aim of this study was to compare clinicopathological characteristics and survival between hepatitis B virus (HBV)-related HCC patients with and without DM and to determine risk factors for overall survival after hepatectomy.Among 474 patients with HBV-related HCC, 119 patients had DM. Patients were divided into the diabetic group and nondiabetic group. The short-term and long-term outcomes were evaluated by using propensity score matching analysis.After 1:2 propensity score matching, there were 107 patients in diabetic group, 214 patients in nondiabetic group. The proportion of vessels invasion were higher in diabetic group. The overall survival rate in the diabetic group was 44.7% at 3 years, which was lower than that in the nondiabetic group (56.1%, P = .025). The multivariate analysis indicated that fasting blood glucose >7.0, capsular invasion, microvascular invasion and satellite were independent risk factor of poor prognosis in HCC.DM dose affect the recurrence-free survival and overall survival in HBV-related HCC patients after hepatectomy. One of the more significant findings to emerge from this study is that DM induced higher proportion of major vessel invasion in HCC patients implied unfavorable prognosis.
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Affiliation(s)
- Haili Zhang
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu
| | - Hongyu Li
- Liver transplantation center, Beijing friendship hospital, capital medical university. 101 Luyuan east road, Tongzhou district, Beijing, China
| | - Xiang Lan
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu
| | - Fei Liu
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu
| | - Bo Li
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu
| | - Yonggang Wei
- Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu
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The role of hepatitis B infection in anti-tuberculosis drug-induced liver injury: a meta-analysis of cohort studies. Epidemiol Infect 2020; 148:e290. [PMID: 33222713 PMCID: PMC7770377 DOI: 10.1017/s0950268820002861] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Drug-induced liver injury (DILI) is a common adverse drug reaction leading to the interruption of tuberculosis (TB) therapy. We aimed to identify whether the hepatitis B virus (HBV) infection would increase the risk of DILI during first-line TB treatment. A meta-analysis of cohort studies searched in PubMed, Web of Science and China National Knowledge Infrastructure was conducted. Effect sizes were reported as risk ratios (RRs) and 95% confidence intervals (CIs) and calculated by R software. Sixteen studies with 3960 TB patients were eligible for analysis. The risk of DILI appeared to be higher in TB patients co-infected with HBV (RR 2.66; 95% CI 2.13–3.32) than those without HBV infection. Moreover, patients with positive hepatitis B e antigen (HBeAg) were more likely to develop DILI (RR 3.42; 95% CI 1.95–5.98) compared to those with negative HBeAg (RR 2.30; 95% CI 1.66–3.18). Co-infection with HBV was not associated with a higher rate of anti-TB DILI in latent TB patients (RR 4.48; 95% CI 0.80–24.99). The effect of HBV infection on aggravating anti-TB DILI was independent of study participants, whether they were newly diagnosed with TB or not. Besides, TB and HBV co-infection patients had a longer duration of recovery from DILI compared to non-co-infected patients (SMD 2.26; 95% CI 1.87–2.66). To conclude, the results demonstrate that HBV infection would increase the risk of DILI during TB therapy, especially in patients with positive HBeAg, and close liver function monitoring is needed for TB and HBV co-infection patients.
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Liver Cirrhosis in Chronic Hepatitis B Patients Is Associated with Genetic Variations in DNA Repair Pathway Genes. Cancers (Basel) 2020; 12:cancers12113295. [PMID: 33171788 PMCID: PMC7694950 DOI: 10.3390/cancers12113295] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary As DNA repair enzymes affect dynamics of liver damage and are involved in HBV viral replication, this study focused on the role of genetic variations within genes representing key DNA-repair pathways in HBV-induced liver cirrhosis. The obtained results have demonstrated that SNPs within XRCC1, ERCC2 genes may confer susceptibility to liver cirrhosis in chronic hepatitis B patients. Abstract Liver cirrhosis (LC), contributing to more than 1 million of deaths annually, is a major healthcare concern worldwide. Hepatitis B virus (HBV) is a major LC etiological factor, and 15% of patients with chronic HBV infection (CHB) develop LC within 5 years. Recently, novel host genetic determinants were shown to influence HBV lifecycle and CHB course. DNA repair enzymes can affect dynamics of liver damage and are involved in HBV covalently closed circular DNA (cccDNA) formation, an essential step for viral replication. This study aimed to evaluate the possible role of genes representing key DNA-repair pathways in HBV-induced liver damage. MALDI-TOF MS genotyping platform was applied to evaluate variations within XRCC1, XRCC4, ERCC2, ERCC5, RAD52, Mre11, and NBN genes. Apart from older age (p < 0.001), female sex (p = 0.021), portal hypertension (p < 0.001), thrombocytopenia (p < 0.001), high HBV DNA (p = 0.001), and high aspartate aminotransferase (AST) (p < 0.001), we found that G allele at rs238406 (ERCC2, p = 0.025), T allele at rs25487 (XRCC1, p = 0.012), rs13181 GG genotype (ERCC2, p = 0.034), and C allele at rs2735383 (NBN, p = 0.042) were also LC risk factors. The multivariate logistic regression model showed that rs25487 CC (p = 0.005) and rs238406 TT (p = 0.027) were independently associated with lower risk of LC. This study provides evidence for the impact of functional and potentially functional variations in key DNA-repair genes XRCC1 and ERCC2 in HBV-induced liver damage in a Caucasian population.
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31
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Nutrigenetics of antioxidant enzymes and micronutrient needs in the context of viral infections. Nutr Res Rev 2020; 34:174-184. [PMID: 33081856 DOI: 10.1017/s0954422420000244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Sustaining adequate nutritional needs of a population is a challenging task in normal times and a priority in times of crisis. There is no 'one-size-fits-all' solution that addresses nutrition. In relevance to the COVID-19 (coronavirus disease 2019) pandemic crisis, viral infections in general and RNA viruses in particular are known to induce and promote oxidative stress, consequently increasing the body's demand for micronutrients, especially those related to antioxidant enzymic systems, thus draining the body of micronutrients, and so hindering the human body's ability to cope optimally with oxidative stress. Common polymorphisms in major antioxidant enzymes, with world population minor allele frequencies ranging from 0·5 to 50 %, are related to altered enzymic function, with substantial potential effects on the body's ability to cope with viral infection-induced oxidative stress. In this review we highlight common SNP of the major antioxidant enzymes relevant to nutritional components in the context of viral infections, namely: superoxide dismutases, glutathione peroxidases and catalase. We delineate functional polymorphisms in several human antioxidant enzymes that require, especially during a viral crisis, adequate and potentially additional nutritional support to cope with the pathological consequences of disease. Thus, in face of the COVID-19 pandemic, nutrition should be tightly monitored and possibly supplemented, with special attention to those carrying common polymorphisms in antioxidant enzymes.
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32
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Zhang X, Li L. The Significance of 8-oxoGsn in Aging-Related Diseases. Aging Dis 2020; 11:1329-1338. [PMID: 33014540 PMCID: PMC7505272 DOI: 10.14336/ad.2019.1021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 10/21/2019] [Indexed: 01/10/2023] Open
Abstract
Aging is a common risk factor for the occurrence and development of many diseases, such as Parkinson’s disease, Alzheimer’s disease, diabetes, hypertension, atherosclerosis and coronary heart disease, and cancer, among others, and is a key problem threatening the health and life expectancy of the elderly. Oxidative damage is an important mechanism involved in aging. The latest discovery pertaining to oxidative damage is that 8-oxoGsn (8-oxo-7,8-dihydroguanosine), an oxidative damage product of RNA, can represent the level of oxidative stress. The significance of RNA oxidative damage to aging has not been fully explained, but the relationship between the accumulation of 8-oxoGsn, a marker of RNA oxidative damage, and the occurrence of diseases has been confirmed in many aging-related diseases. Studying the aging mechanism, monitoring the aging level of the body and exploring the corresponding countermeasures are of great significance for achieving healthy aging and promoting public health and social development. This article reviews the progress of research on 8-oxoGsn in aging-related diseases.
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Affiliation(s)
- Xinmu Zhang
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Lin Li
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
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Cisplatin and farnesol co-encapsulated PLGA nano-particles demonstrate enhanced anti-cancer potential against hepatocellular carcinoma cells in vitro. Mol Biol Rep 2020; 47:3615-3628. [PMID: 32314187 DOI: 10.1007/s11033-020-05455-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 04/10/2020] [Indexed: 02/08/2023]
Abstract
Cisplatin (CDDP) is a potent chemotherapeutic drug, but its severe side-effects often prohibit its use. Combined treatment with CDDP plus Farnesol (FAR) and their co-encapsulated nano form were investigated in in vitro to examine if synergistic cytotoxicity of this combination could reduce unwanted side-effects of CDDP chemotherapy and potentiate CDDP anticancer activity against hepatocellular carcinoma (HCC) cells. After finding combination therapy of CDDP and FAR successfully combat HCC we formulated co-encapsulation of CDDP and FAR within poly(lactic-co-glycolic acid) copolymer (NCDDPFAR) by following the standardized solvent displacement method. NCDDPFAR treatment caused faster drug mobility, sustained particle release, site-specific action and higher percentage of apoptotic death compared with single drug treatment even at relatively low concentrations. Co-encapsulation of two drugs exhibited additive effects against HCC; FAR reduced CDDP-induced glutathione level by increasing expression of CYP2E1 while CDDP directly interacted with DNA; FAR up-regulated the expression of TopII, thereby promoting DNA breaks and escaping DNA repair machinery. Expression pattern of apoptotic genes like p53, Bax, cytochrome c and caspase-3 suggested that NCDDPFAR induced HCC cell death through mitochondrial intrinsic pathway. Administration of NCDDPFAR had better ability of drug carriage and enhanced anticancer potentials against HCC cells.
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Abstract
Silymarin, an extract from milk thistle seeds, has been used for centuries to treat hepatic conditions. Preclinical data indicate that silymarin can reduce oxidative stress and consequent cytotoxicity, thereby protecting intact liver cells or cells not yet irreversibly damaged. Eurosil 85® is a proprietary formulation developed to maximize the oral bioavailability of silymarin. Most of the clinical research on silymarin has used this formulation. Silymarin acts as a free radical scavenger and modulates enzymes associated with the development of cellular damage, fibrosis and cirrhosis. These hepatoprotective effects were observed in clinical studies in patients with alcoholic or non-alcoholic fatty liver disease, including patients with cirrhosis. In a pooled analysis of trials in patients with cirrhosis, silymarin treatment was associated with a significant reduction in liver-related deaths. Moreover, in patients with diabetes and alcoholic cirrhosis, silymarin was also able to improve glycemic parameters. Patients with drug-induced liver injuries were also successfully treated with silymarin. Silymarin is generally very well tolerated, with a low incidence of adverse events and no treatment-related serious adverse events or deaths reported in clinical trials. For maximum benefit, treatment with silymarin should be initiated as early as possible in patients with fatty liver disease and other distinct liver disease manifestations such as acute liver failure, when the regenerative potential of the liver is still high and when removal of oxidative stress, the cause of cytotoxicity, can achieve the best results.
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Affiliation(s)
- Anton Gillessen
- Department of Internal Medicine, Sacred Heart Hospital, Muenster, Germany.
| | - Hartmut H-J Schmidt
- Department of Medicine B for Gastroenterology and Hepatology, University Hospital Muenster, Muenster, Germany
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Luo L, Zhang G, Mao L, Wang P, Xi C, Shi G, Leavenworth JW. Group II muscarinic acetylcholine receptors attenuate hepatic injury via Nrf2/ARE pathway. Toxicol Appl Pharmacol 2020; 395:114978. [PMID: 32234387 DOI: 10.1016/j.taap.2020.114978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 03/24/2020] [Accepted: 03/26/2020] [Indexed: 12/30/2022]
Abstract
Parasympathetic nervous system dysfunction is common in patients with liver disease. We have previously shown that muscarinic acetylcholine receptors (mAchRs) play an important role in the regulation of hepatic fibrosis and that the receptor agonists and antagonists affect hepatocyte proliferation. However, little is known about the impact of the different mAchR subtypes and associated signaling pathways on liver injury. Here, we treated the human liver cell line HL7702 with 10 mmol/L carbon tetrachloride (CCL4) to induce hepatocyte damage. We found that CCL4 treatment increased the protein levels of group I mAchRs (M1, M3, M5) but reduced the expression of group II mAchRs (M2, M4) and activated the Nrf2/ARE and MAPK signaling pathways. Although overexpression of M1, M3, or M5 led to hepatocyte damage with an intact Nrf2/ARE pathway, overexpression of M2 or M4 increased, and siRNA-mediated knockdown of either M2 or M4 decreased the protein levels of Nrf2 and its downstream target genes. Moreover, CCL4 treatment increased serum ALT levels more significantly, but only induced slight changes in the expression of mAchRs, NQO1 and HO1, while reducing the expression of M2 and M4 in liver tissues of Nrf2-/- mice compared to wild type mice. Our findings suggest that group II mAchRs, M2 and M4, activate the Nrf2/ARE signaling pathway, which regulates the expression of M2 and M4, to protect the liver from CCL4-induced injury.
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Affiliation(s)
- Lin Luo
- School of Pharmacy, Nantong University, PR China..
| | | | - Liuliu Mao
- School of Pharmacy, Nantong University, PR China
| | - Pengbo Wang
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Chenghao Xi
- School of Pharmacy, Nantong University, PR China
| | - Gaoyong Shi
- School of Pharmacy, Nantong University, PR China
| | - Jianmei W Leavenworth
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA..
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Ganesan M, Eikenberry A, Poluektova LY, Kharbanda KK, Osna NA. Role of alcohol in pathogenesis of hepatitis B virus infection. World J Gastroenterol 2020; 26:883-903. [PMID: 32206001 PMCID: PMC7081008 DOI: 10.3748/wjg.v26.i9.883] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and alcohol abuse often contribute to the development of end-stage liver disease. Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically. Importantly, the mechanism by which alcohol promotes the progression of HBV-associated liver disease are not completely understood. Potential mechanisms include a suppressed immune response, oxidative stress, endoplasmic reticulum and Golgi apparatus stresses, and increased HBV replication. Certainly, more research is necessary to gain a better understanding of these mechanisms such that treatment(s) to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed. In this review, we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Allison Eikenberry
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
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GPR43 regulates HBV X protein (HBx)-induced inflammatory response in human LO2 hepatocytes. Biomed Pharmacother 2020; 123:109737. [DOI: 10.1016/j.biopha.2019.109737] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 11/13/2019] [Accepted: 11/27/2019] [Indexed: 12/18/2022] Open
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Yu DY. Relevance of reactive oxygen species in liver disease observed in transgenic mice expressing the hepatitis B virus X protein. Lab Anim Res 2020; 36:6. [PMID: 32206612 PMCID: PMC7081669 DOI: 10.1186/s42826-020-00037-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 02/12/2020] [Indexed: 12/16/2022] Open
Abstract
The hepatitis B virus (HBV) infects approximately 240 million people worldwide, causing chronic liver disease (CLD) and liver cancer. Although numerous studies have been performed to date, unfortunately there is no conclusive drug or treatment for HBV induced liver disease. The hepatitis B virus X (HBx) is considered a key player in inducing CLD and hepatocellular carcinoma (HCC). We generated transgenic (Tg) mice expressing HBx protein, inducing HCC at the age of 11–18 months. The incidence of histological phenotype, including liver tumor, differed depending on the genetic background of HBx Tg mice. Fatty change and tumor generation were observed much earlier in livers of HBx Tg hybrid (C57BL/6 and CBA) (HBx-Tg hybrid) mice than in HBx Tg C57BL/6 (HBx-Tg B6) mice. Inflammation was also enhanced in the HBx-Tg B6 mice as compared to HBx-Tg hybrid mice. HBx may be involved in inducing and promoting hepatic steatosis, glycemia, hepatic fibrosis, and liver cancer. Reactive oxygen species (ROS) generation was remarkably increased in livers of HBx Tg young mice compared to young wild type control mice. Previous studies on HBx Tg mice indicate that the HBx-induced ROS plays a role in inducing and promoting CLD and HCC.
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Affiliation(s)
- Dae-Yeul Yu
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806 South Korea
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Chen W, Li Y, Hsu CT, Niu CS, Pen WH, Cheng KC, Niu HS. Connective tissue growth factor in hepatocytes is elevated by carbon tetrachloride via STAT3 activation. Mol Med Rep 2020; 21:1390-1398. [PMID: 31922209 DOI: 10.3892/mmr.2020.10916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 11/27/2019] [Indexed: 11/06/2022] Open
Abstract
Carbon tetrachloride (CCl4) is widely used to induce hepatic fibrosis. Therapeutic agents alleviate hepatic fibrosis by inhibiting signal transducer and activator of transcription 3 (STAT3) activation. To understand the direct effects of CCl4 on STAT3 expression in the liver, the present study incubated cultured hepatocytes expressing connective tissue growth factor (CTGF) with CCl4. Rats exposed to CCl4 for 8 weeks exhibited hepatic fibrosis, which was confirmed through the assessment of plasma biomarkers. Isolated liver samples were used to determine the protein levels of CTGF and STAT3 using western blotting. In addition, STAT3 expression was silenced in α mouse liver 12 (AML‑12) cells using small interfering RNA transfection. In addition, a pharmacological inhibitor, stattic, was used to inhibit STAT3 expression. The incubation of AML‑12 cells with CCl4 induced a dose‑dependent increase in CTGF expression and STAT3 activation. Notably, silymarin, an extract from milk thistle, inhibited these changes in AML‑12 cells and the antioxidant tiron produced similar effects. Silencing of STAT3 reduced the CTGF expression promoted by CCl4 in the hepatocytes. Additionally, similar to tiron, stattic inhibited CTGF expression induced by CCl4. In conclusion, CCl4 may activate STAT3 through oxidative stress to promote CTGF expression, which is one of the main factors contributing to the risk of hepatic fibrosis.
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Affiliation(s)
- Wenhsu Chen
- Department of Internal Medicine, E‑Da Hospital, I‑Shou University, Kaohsiung 82401, Taiwan, R.O.C
| | - Yingxiao Li
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Chao-Tien Hsu
- Department of Pathology, E‑Da Hospital, I‑Shou University, Kaohsiung 82401, Taiwan, R.O.C
| | - Chiang-Shan Niu
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien 97005, Taiwan, R.O.C
| | - Wen-Huang Pen
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, R.O.C
| | - Kai-Chun Cheng
- Pharmacological Department of Herbal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890‑8520, Japan
| | - Ho-Shan Niu
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien 97005, Taiwan, R.O.C
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Ma N, Liu W, Zhang X, Gao X, Yu F, Guo W, Meng Y, Gao P, Zhou J, Yuan M, Mi Y, Zhang L, Qi S, Li L, Wang L, Su Q, Yang L, Liu D. Oxidative Stress-Related Gene Polymorphisms Are Associated With Hepatitis B Virus-Induced Liver Disease in the Northern Chinese Han Population. Front Genet 2020; 10:1290. [PMID: 31969899 PMCID: PMC6960262 DOI: 10.3389/fgene.2019.01290] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 11/22/2019] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress is closely related to the occurrence and development of various diseases such as cancer, diabetes, and cardiovascular and infectious diseases. We identified six critical genetic variants related to oxidative stress, and evaluated their main effects and their interaction effects on hepatitis B virus (HBV)-induced liver diseases. We enrolled 3,128 Han Chinese subjects into five groups: healthy controls, chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and natural clearance. We then determined the genotypes in each group for CYBA-rs4673, NCF4-rs1883112, NOX4-rs1836882, rs3017887, SOD2-rs4880, and GCLM-rs41303970, and evaluated the association between these variants and HBV-induced liver diseases. Gene-gene interactions were evaluated using generalized multifactor dimensionality reduction, logistic regression, and four-by-two tables. Significant associations were observed between healthy controls and the CIB group (CHB+LC+HCC). The CYBA-rs4673AG genotype was associated with a 1.356 rate of susceptibility of HBV-induced liver disease compared to the wild type GG genotype. The NCF4-rs1883112G allele occurred more frequently in healthy controls than in the CIB group in all three models (dominant, codominant, and recessive). Nox4-rs1836882 TC showed a protective association, being more frequent in healthy controls compared to the wild type TT genotype. GCLM-rs41303970A was associated with HBV-induced liver disease. The overall best model by multifactor dimensionality reduction was a five factor interaction model that had the highest cross validation consistency (10/10) and test accuracy (0.5669), P= 0.001. Oxidative stress-related gene polymorphisms are likely to be associated with HBV-induced liver disease, suggesting that information on these variations is useful for risk assessment of HBV-induced liver disease.
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Affiliation(s)
- Ning Ma
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Wenxuan Liu
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Xiaolin Zhang
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Xia Gao
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Fengxue Yu
- The Hebei Key Laboratory of Gastroenterology, Division of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Weiheng Guo
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yanxin Meng
- Antenatal Diagnosis Center, The Fourth Hospital of Shijiazhuang, Shijiazhuang, China
| | - Ping Gao
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Jin Zhou
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Meina Yuan
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yingjun Mi
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Lei Zhang
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Sufen Qi
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Lu Li
- Hebei Key Laboratory of Environment and Human Health, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Luyao Wang
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Qiao Su
- School of Basic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Lei Yang
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Dianwu Liu
- Hebei Key Laboratory of Environment and Human Health, Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, China
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Rifampicin activates AMPK and alleviates oxidative stress in the liver as mediated with Nrf2 signaling. Chem Biol Interact 2019; 315:108889. [PMID: 31678598 DOI: 10.1016/j.cbi.2019.108889] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 10/15/2019] [Accepted: 10/28/2019] [Indexed: 01/01/2023]
Abstract
Although rifampicin could have a hepatic toxic effect, it has also been shown that this chemical acts as a cellular protectant against oxidative stress. Therefore, we wondered whether rifampicin has a beneficial effect such as an anti-oxidant in the liver, because the efficacy of some drugs sometimes relates with their toxicity as well as protective effects. The present study aimed to investigate the antioxidant effect of rifampicin against arachidonic acid (AA) plus iron (AA + iron) cotreatment and against acetaminophen (APAP, 500 mg/kg)-induced oxidative stress, in vitro and in vivo, respectively. In vivo, oral administration of rifampicin (100 or 200 mg/kg) attenuated elevation of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), serum liver injury markers, against APAP treatment and, histologically, ameliorated tissue damage. Under in vitro examination, MTT assays were used to assess the cell death inhibitory effect of rifampicin against AA + iron-induced oxidative stress. In addition, DCFH-DA and Rh 123 staining showed that rifampicin treatment reduced reactive oxygen species (ROS) production and mitochondrial membrane damage, which had been induced by AA + iron treatment. Further, we explored whether rifampicin treatment enhanced phosphorylation of AMP-activated protein kinase (AMPK) by activation of liver kinase B1 (LKB1), the upstream kinase of AMPKα. Activated AMPKα induced activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), which are proteins functioning in redox balance. Moreover, we confirmed a reversed cell protective effect of rifampicin under compound C (an AMPK inhibitor) treatment. Overall, our data demonstrate that rifampicin effectively protects the liver against cellular oxidative stress through AMPKα and Nrf2 pathway.
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da Silva Caetano CC, Camini FC, Almeida LT, Ferraz AC, da Silva TF, Lima RLS, de Freitas Carvalho MM, de Freitas Castro T, Carneiro CM, de Mello Silva B, de Queiroz Silva S, de Magalhães JC, de Brito Magalhães CL. Mayaro Virus Induction of Oxidative Stress is Associated With Liver Pathology in a Non-Lethal Mouse Model. Sci Rep 2019; 9:15289. [PMID: 31653913 PMCID: PMC6814867 DOI: 10.1038/s41598-019-51713-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 10/01/2019] [Indexed: 02/01/2023] Open
Abstract
Mayaro virus (MAYV) causes Mayaro fever in humans, a self-limiting acute disease, with persistent arthralgia and arthritis. Although MAYV has a remerging potential, its pathogenic mechanisms remain unclear. Here, we characterized a model of MAYV infection in 3-4-week BALB/c mice. We investigated whether the liver acts as a site of viral replication and if the infection could cause histopathological alterations and an imbalance in redox homeostasis, culminating with oxidative stress. MAYV-infected mice revealed lower weight gain; however, the disease was self-resolving. High virus titre, neutralizing antibodies, and increased levels of aspartate and alanine aminotransferases were detected in the serum. Infectious viral particles were recovered in the liver of infected animals and the histological examination of liver tissues revealed significant increase in the inflammatory infiltrate. MAYV induced significant oxidative stress in the liver of infected animals, as well as a deregulation of enzymatic antioxidant components. Collectively, this is the first study to report that oxidative stress occurs in MAYV infection in vivo, and that it may be crucial in virus pathogenesis. Future studies are warranted to address the alternative therapeutic strategies for Mayaro fever, such as those based on antioxidant compounds.
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Affiliation(s)
- Camila Carla da Silva Caetano
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Fernanda Caetano Camini
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Letícia Trindade Almeida
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Ariane Coelho Ferraz
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Tales Fernando da Silva
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | | | - Mayara Medeiros de Freitas Carvalho
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Thalles de Freitas Castro
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Cláudia Martins Carneiro
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Clinical Analysis Departament, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Postgraduate Program of Biotechnology, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Breno de Mello Silva
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Biological Science Departament, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Postgraduate Program of Biotechnology, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - Silvana de Queiroz Silva
- Biological Science Departament, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
- Postgraduate Program of Biotechnology, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil
| | - José Carlos de Magalhães
- Department of Chemistry, Biotechnology and Bioprocess Engineering, Universidade Federal de São João del-Rei, Ouro Branco, Minas Gerais, Brazil
| | - Cintia Lopes de Brito Magalhães
- Postgraduate Program of Biological Science, Biological Sciences Research Center, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
- Biological Science Departament, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
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Yang Y, Shao R, Tang L, Li L, Zhu M, Huang J, Shen Y, Zhang L. Succinate dehydrogenase inhibitor dimethyl malonate alleviates LPS/d-galactosamine-induced acute hepatic damage in mice. Innate Immun 2019; 25:522-529. [PMID: 31474165 PMCID: PMC6900668 DOI: 10.1177/1753425919873042] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In addition to its energy-supplying function, increasing evidence suggests that
mitochondria also play crucial roles in the regulation of inflammation.
Succinate dehydrogenase is also known as mitochondrial complex II, and
inhibition of succinate dehydrogenase by dimethyl malonate has been reported to
suppress the production of pro-inflammatory cytokines. In the present study, the
potential anti-inflammatory benefits of dimethyl malonate were investigated in a
mouse model with LPS/d-galactosamine-induced acute hepatic damage. Male
BALB/c mice were injected i.p. with LPS and d-galactosamine to cause
liver injury. The degree of liver injury, inflammatory response and oxidative
stress and the survival of the experimental animals were determined. The results
indicated dimethyl malonate decreased the level of aminotransferases in plasma,
alleviated histological abnormalities in liver, inhibited the induction of TNF-α
and IL-6 in plasma, suppressed hepatocyte apoptosis and improved the survival of
LPS/d-galactosamine-exposed mice. Therefore, inhibition of
succinate dehydrogenase by dimethyl malonate significantly alleviated
LPS/d-galactosamine-induced hepatic damage, which suggests that
succinate dehydrogenase might become a novel target for the intervention of
inflammation-based hepatic disorders.
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Affiliation(s)
- Yongqiang Yang
- Department of Pathophysiology, Chongqing Medical University, PR China
| | - Ruyue Shao
- Clinical Medical School, Chongqing Medical and Pharmaceutical College, PR China.,Chongqing Engineering Research Center of Pharmaceutical Sciences, PR China
| | - Li Tang
- Department of Pathophysiology, Chongqing Medical University, PR China
| | - Longjiang Li
- Department of Pathophysiology, Chongqing Medical University, PR China
| | - Min Zhu
- Department of Pathology, Karamay Central Hospital, PR China
| | - Jiayi Huang
- Department of Pathophysiology, Chongqing Medical University, PR China
| | - Yi Shen
- Department of Pathophysiology, Chongqing Medical University, PR China
| | - Li Zhang
- Department of Pathophysiology, Chongqing Medical University, PR China
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44
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MONMEESIL P, FUNGFUANG W, TULAYAKUL P, PONGCHAIRERK U. The effects of astaxanthin on liver histopathology and expression of superoxide dismutase in rat aflatoxicosis. J Vet Med Sci 2019; 81:1162-1172. [PMID: 31270307 PMCID: PMC6715921 DOI: 10.1292/jvms.18-0690] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 06/19/2019] [Indexed: 12/27/2022] Open
Abstract
The metabolism of aflatoxin B1 (AFB1) generates reactive oxygen species (ROS) that destroys hepatocytes. Meanwhile, astaxanthin (AX) is known to have stronger antioxidative activity than other carotenoids. This study aimed to investigate hepatoprotective role of AX from AFB1-induced toxicity in rat by histopathological study and immunohistochemistry of Cu/Zn-SOD (SOD1) which acts as the first enzyme in antioxidative reaction against cell injury from ROS. Twenty Wistar rats were randomly divided into 4 groups. The control and AFB1 groups were gavaged by water for 7 days followed by a single DMSO and 1 mg/kg AFB1, respectively. The AXL+ AFB1 and AXH+ AFB1 groups were given of 5 mg/kg and 100 mg/kg AX for 7 days before 1 mg/kg AFB1 administration. The result showed significantly elevated liver weight per 100 g body weight in AFB1 group. The histopathological finding revealed vacuolar degeneration, necrosis, megalocytosis and binucleation of hepatocytes with bile duct hyperplasia in AFB1 group. The severities of pathological changes were sequentially reduced in AXL+AFB1 and AXH+AFB1 groups. Most rats in AXH+AFB1 group owned hypertrophic hepatocytes and atypical proliferation of cholangiocytes which are adaptive responses to severe hepatocyte damage. The SOD1 expression was also significantly higher in AXH+AFB1 group than solely treated AFB1 and AXL+AFB1 groups. In conclusion, AX alleviated AFB1-induced liver damage in rat by stimulating SOD1 expression and transdifferentiation of cholangiocytes in dose dependent manner.
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Affiliation(s)
- Poempool MONMEESIL
- Department of Anatomy, Faculty of Veterinary Medicine,
Kasetsart University, 50 Ngamwongwan Road, Ladyao, Jatuchak, Bangkok 10900, Thailand
| | - Wirasak FUNGFUANG
- Department of Zoology, Faculty of Science, Kasetsart
University, 50 Ngamwongwan Road, Ladyao, Jatuchak, Bangkok 10900, Thailand
| | - Phitsanu TULAYAKUL
- Department of Veterinary Public Health, Faculty of
Veterinary Medicine, Kasetsart University, Malaiman Road, Kamphaeng Saen, Nakhon Pathom
73140, Thailand
| | - Urai PONGCHAIRERK
- Department of Anatomy, Faculty of Veterinary Medicine,
Kasetsart University, 50 Ngamwongwan Road, Ladyao, Jatuchak, Bangkok 10900, Thailand
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Kołota A, Głąbska D, Oczkowski M, Gromadzka-Ostrowska J. Influence of Alcohol Consumption on Body Mass Gain and Liver Antioxidant Defense in Adolescent Growing Male Rats. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16132320. [PMID: 31261999 PMCID: PMC6651161 DOI: 10.3390/ijerph16132320] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 06/28/2019] [Accepted: 06/29/2019] [Indexed: 12/12/2022]
Abstract
The World Health Organization (WHO) reported that alcohol consumption is a serious problem in adolescents. The aim of the study was to assess the influence of the time of exposure of various alcoholic beverages on body mass as well as on select parameters of liver antioxidant defense in adolescent Wistar rats. Thirty-day-old animals were divided into 12 groups (six animals in each): control and groups receiving various beverages containing 10% of alcohol (ethanol, red wine, beer), observed for two, four, and six weeks. The body weight gain and energy supply were analyzed for body mass assessment. The catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase, transferase (GST), reductase activities, total antioxidant status, and glutathione level (GSH) were analyzed, for a liver antioxidant defense assessment. Group receiving red wine was characterized by the highest alcohol intake, lowest dietary intake, and highest total energy supply (p < 0.05). However, this did not influence body weight gain (p > 0.05). Reduced diet intake in groups receiving alcohol was counterbalanced by its energy value. Therefore, the energy supply was not lower than for the control (p > 0.05). Alcohol consumption and the experiment duration influenced CAT, SOD, and GST activities and GSH level. Alcohol consumption may influence hepatic antioxidant defense in adolescent male rats, but without influence on body weight gain.
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Affiliation(s)
- Aleksandra Kołota
- Department of Dietetics, Faculty of Human Nutrition and Consumer Sciences, Warsaw University of Life Sciences (SGGW-WULS), 159c Nowoursynowska Street, 02-776 Warsaw, Poland.
| | - Dominika Głąbska
- Department of Dietetics, Faculty of Human Nutrition and Consumer Sciences, Warsaw University of Life Sciences (SGGW-WULS), 159c Nowoursynowska Street, 02-776 Warsaw, Poland
| | - Michał Oczkowski
- Department of Dietetics, Faculty of Human Nutrition and Consumer Sciences, Warsaw University of Life Sciences (SGGW-WULS), 159c Nowoursynowska Street, 02-776 Warsaw, Poland
| | - Joanna Gromadzka-Ostrowska
- Department of Dietetics, Faculty of Human Nutrition and Consumer Sciences, Warsaw University of Life Sciences (SGGW-WULS), 159c Nowoursynowska Street, 02-776 Warsaw, Poland
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Pascale RM, Peitta G, Simile MM, Feo F. Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma. MEDICINA (KAUNAS, LITHUANIA) 2019; 55:E296. [PMID: 31234428 PMCID: PMC6631235 DOI: 10.3390/medicina55060296] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022]
Abstract
Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of MAT1A gene under-regulation associated with up-regulation of the MAT2A gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of c-myc, H-ras, and K-ras expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor PP2A gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of C/EBPα and UCA1 gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT2A and MAT2B expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC.
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Affiliation(s)
- Rosa M Pascale
- Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
| | - Graziella Peitta
- Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
| | - Maria M Simile
- Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
| | - Francesco Feo
- Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
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Bian X, Liu X, Liu J, Zhao Y, Li H, Zhang L, Li P, Gao Y. Hepatoprotective effect of chiisanoside from Acanthopanax sessiliflorus against LPS/D-GalN-induced acute liver injury by inhibiting NF-κB and activating Nrf2/HO-1 signaling pathways. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2019; 99:3283-3290. [PMID: 30552777 DOI: 10.1002/jsfa.9541] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 11/12/2018] [Accepted: 12/11/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND In China, Acanthopanax sessiliflorus is a delicious wild vegetable. It is also used to treat inflammation and pain. Chiisanoside (CSS) is the main constituent of the leaf of A. sessiliflorus. Combined use of lipopolysaccharide and d-galactosamine (LPS/D-GalN) can induce acute liver failure in human beings, and there are no reports on the protective effect of CSS against LPS/D-GalN-induced acute liver injury in mice. RESULTS Chiisanoside pretreatment evidently reduced the activities of alanine transaminase (ALT) and aspartate transaminase (AST) in the changes induced by LPS/D-GalN, and these histopathological changes induced by LPS/GalN were significantly weakened. Catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) activities increased, and malondialdehyde (MDA) activity decreased after CSS treatment compared with LPS/D-GalN treatment. Pretreatment with CSS also inhibited the expression levels of inflammatory factors. The administration of CSS prevented the phosphorylated expression of inhibitor kappa B (IκB) kinase, and led to a significant increase in heme oxygenase-1 (HO-1) expression and nuclear factor erythroid 2-related factor2 (Nrf2) nuclear translocation. CONCLUSION The protective effects of CSS are attributed to its antioxidative effect and inflammatory suppression in Nuclear factor kappa beta (NF-κB) and Nrf2/HO-1 signaling pathways. Chiisanoside might therefore be a potential ingredient for drug and food development against acute liver injury in the future. © 2018 Society of Chemical Industry.
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Affiliation(s)
- Xingbo Bian
- College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun, China
| | | | | | - Yan Zhao
- College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun, China
| | | | - Lianxue Zhang
- College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun, China
| | | | - Yugang Gao
- College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun, China
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Hago S, Mahrous EA, Moawad M, Abdel-Wahab S, Abdel-Sattar E. Evaluation of antidiabetic activity of Morus nigra L. and Bauhinia variegata L. leaves as Egyptian remedies used for the treatment of diabetes. Nat Prod Res 2019; 35:829-835. [PMID: 30968706 DOI: 10.1080/14786419.2019.1601094] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Morus nigra and Bauhinia variegata are used in the Egyptian folk medicine for their hypoglycemic effects. The standardized ethanolic extracts of both plants caused a significant decrease in fasting blood glucose level at two different doses (250 and 500 mg/kg) in streptozotocin-induced diabetic rats' model. Further, in vitro antioxidant activity and α-glucosidase inhibition assays were conducted as well as the measurement of insulin levels and the biomarkers for both liver and kidney functions in the treated animals. Beneficiary effects of BMLE and BVLE in the treatment of diabetes were found not to be limited to hypoglycemic effect but included preventing liver and kidney tissue damage that are associated with diabetes. A strong inhibition of the α-glucosidase enzyme by both extracts may be a contributing mechanism in the overall anti-diabetic effect that was observed. Further detailed study is needed in the future to explore the mechanism of action of both plants.
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Affiliation(s)
- Salma Hago
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Engy A Mahrous
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mohamed Moawad
- Department of Toxicology and Forensic Medicine, Faculty of Veterinary Medicine, Cairo University, Egypt
| | - Samia Abdel-Wahab
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Essam Abdel-Sattar
- Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Fredericksen F, Villalba M, Maldonado N, Payne G, Torres F, Olavarría VH. Sumoylation of nucleoprotein (NP) mediated by activation of NADPH oxidase complex is a consequence of oxidative cellular stress during infection by Infectious salmon anemia (ISA) virus necessary to viral progeny. Virology 2019; 531:269-279. [PMID: 30974383 DOI: 10.1016/j.virol.2019.03.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 03/19/2019] [Accepted: 03/19/2019] [Indexed: 01/22/2023]
Abstract
The study evaluated the effects of nucleoprotein viral and the infectious virus in SHK-1 cells. The results show a strong respiratory burst activation and the induction of p47phox, SOD, GLURED, and apoptotic genes. Additionally, the cells alter the profile of SUMOylated proteins by the effect of transfection and infection experiments. In silico analyses show a set of structural motifs in NP susceptible of post-translational modification by the SUMO protein. Interestingly, the inhibition of the NADPH oxidase complex blocked the production of reactive oxygen species and the high level of cellular ROS due to the nucleoprotein and the ISAv. At the same time, the blocking of the p38MAPK signaling pathway and the use of Aristotelia chilensis, decreased viral progeny production. These results suggest that the NP triggers a strong production of ROS and modifying the post-translational profile mediated by SUMO-2/3, a phenomenon that favors the production of new virions.
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Affiliation(s)
- Fernanda Fredericksen
- Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Campus Isla Teja S/N, Valdivia, Chile
| | - Melina Villalba
- Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Campus Isla Teja S/N, Valdivia, Chile
| | - Nicolas Maldonado
- Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Campus Isla Teja S/N, Valdivia, Chile
| | - Gardenia Payne
- Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Campus Isla Teja S/N, Valdivia, Chile
| | - Francisco Torres
- Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Campus Isla Teja S/N, Valdivia, Chile
| | - Víctor H Olavarría
- Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Campus Isla Teja S/N, Valdivia, Chile.
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50
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Wei PL, Huang CY, Chang YJ. Propyl gallate inhibits hepatocellular carcinoma cell growth through the induction of ROS and the activation of autophagy. PLoS One 2019; 14:e0210513. [PMID: 30653551 PMCID: PMC6336332 DOI: 10.1371/journal.pone.0210513] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 12/23/2018] [Indexed: 12/19/2022] Open
Abstract
The poor prognosis of hepatocellular carcinoma (HCC) has been attributed to a high frequency of tumor metastasis and recurrence even after successful surgical resection. With less than 30% of patients benefiting from curative treatment, alternative treatment regimens for patients with advanced HCC are needed. Propyl gallate (PG), a synthetic antioxidant used in preserving food and medicinal preparations, has been shown to induce cancer cell death, but the anticancer effects of PG in HCC are unclear. In the present study, we demonstrated that PG inhibited HCC cell proliferation in vitro and in zebrafish models in vivo in a dose- and time-dependent manner. PG also induced cell apoptosis and increased the number of necrotic cells in a time- and dose-dependent manner as determined using a high-content analysis system. We found that PG also increased the intracellular levels of superoxide and reactive oxidative stress as well as the formation of autophagosomes and lysosomes. Regarding the molecular mechanism, PG did not alter the levels of autophagy-related 5 (ATG5), ATG5/12 or Beclin-1 but increased the rate of the LC3-I to LC3-II conversion, suggesting autophagy induction. PG exposure increased the levels of the pro-apoptotic proteins cleaved caspase-3, cleaved PARP, Bax, and Bad and a decreased level of the anti-apoptotic protein Bcl-2. In conclusion, we demonstrate that PG inhibits HCC cell proliferation through enhanced ROS production and autophagy activation. Finally, PG-treated cells induced cell apoptosis and may be a new candidate for HCC therapy.
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Affiliation(s)
- Po-Li Wei
- Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Chien-Yu Huang
- Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
- * E-mail: (YJC); (CYH)
| | - Yu-Jia Chang
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- International PhD Program in Medicine, Taipei Medical University, Taipei, Taiwan
- * E-mail: (YJC); (CYH)
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