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Li Y, Zhu B, Shi K, Lu Y, Zeng X, Li Y, Zhang Q, Feng Y, Wang X. Advances in intrahepatic and extrahepatic vascular dysregulations in cirrhotic portal hypertension. Front Med (Lausanne) 2025; 12:1515400. [PMID: 39958826 PMCID: PMC11825794 DOI: 10.3389/fmed.2025.1515400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 01/20/2025] [Indexed: 02/18/2025] Open
Abstract
Cirrhotic portal hypertension, the most prevalent and clinically significant complication of liver cirrhosis, manifests as elevated portal venous pressure and is associated with severe complications. Although much research on the mechanisms of portal hypertension has focused on liver fibrosis, less attention has been given to the role of intrahepatic and extrahepatic vascular dysfunction, particularly with respect to extrahepatic vasculature. While the role of hepatic fibrosis in cirrhotic portal hypertension is undeniable, the underlying mechanisms involving intrahepatic and extrahepatic vasculature are highly complex. Sinusoidal capillarization and endothelial dysfunction contribute to increased intrahepatic vascular resistance. Hemodynamic changes in the extrahepatic circulation, including splanchnic vasodilation and hyperdynamic circulation, play a significant role in the development of portal hypertension. Additionally, therapeutic strategies targeting these vascular mechanisms are diverse, including improvement of sinusoidal microcirculation, therapies targeting hepatic stellate cells activation, and pharmacological modulation of systemic vascular tone. Therefore, in this review, we will discuss the vascular-related mechanisms and treatment progress of portal hypertension in cirrhosis to provide a new theoretical basis and practical guidance for clinical treatment.
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Affiliation(s)
| | | | | | | | | | | | | | - Ying Feng
- Center for Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xianbo Wang
- Center for Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Wang R, Chen Y, Han J, Ye H, Yang H, Li Q, He Y, Ma B, Zhang J, Ge Y, Wang Z, Sun B, Liu H, Cheng L, Wang Z, Lin G. Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure. Nat Commun 2024; 15:10690. [PMID: 39681560 DOI: 10.1038/s41467-024-55295-7] [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: 04/13/2024] [Accepted: 12/08/2024] [Indexed: 12/18/2024] Open
Abstract
Acute liver failure (ALF) is a hepatology emergency with rapid hepatic destruction, multiple organ failures, and high mortality. Despite decades of research, established ALF has minimal therapeutic options. Here, we report that the small bioactive compound SCM-198 increases the survival of male ALF mice to 100%, even administered 24 hours after ALF establishment. We identify adiponectin receptor 2 (AdipoR2) as a selective target of SCM-198, with the AdipoR2 R335 residue being critical for the binding and signaling of SCM-198-AdipoR2 and AdipoR2 Y274 residue serving as a molecular switch for Ca2+ influx. SCM-198-AdipoR2 binding causes Ca2+ influx and elevates the phosphorylation levels of CaMKII and NOS3 in the AdipoR2-CaM-CaMKII-NOS3 complex identified in this study, rapidly inducing nitric oxide production for liver protection in murine ALF. SCM-198 also protects human ESC-derived liver organoids from APAP/TAA injuries. Thus, selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 is a rapid-acting therapeutic strategy for advanced ALF.
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Affiliation(s)
- Rui Wang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Youwei Chen
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
- School of Medicine, Tongji University, Shanghai, China
| | - Jiazhen Han
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Huikang Ye
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Huiran Yang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Qianyan Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yizhen He
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Boyu Ma
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Junjie Zhang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Yanli Ge
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Zhe Wang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Bo Sun
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Huahua Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Liming Cheng
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China.
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China.
| | - Zhirong Wang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China.
| | - Gufa Lin
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China.
- School of Medicine, Tongji University, Shanghai, China.
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Adarthaiya S, Sehgal A. Moringa oleifera Lam. as a potential plant for alleviation of the metabolic syndrome-A narrative review based on in vivo and clinical studies. Phytother Res 2024; 38:755-775. [PMID: 38015048 DOI: 10.1002/ptr.8079] [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: 04/27/2023] [Revised: 11/06/2023] [Accepted: 11/10/2023] [Indexed: 11/29/2023]
Abstract
The metabolic syndrome (MetS) refers to the co-occurrence of risk factors, including hyperglycaemia, increased body weight, hypertension and dyslipidemia, which eventually lead to diabetes and cardiovascular disease, a common health problem worldwide. Recently, there has been an increasing interest in the use of plant-based products for the management of MetS, because of their less detrimental and more beneficial effects. Moringa oleifera (Moringaceae), commonly known as drumstick, is cultivated worldwide for its nutritional and medicinal properties. This review focuses on the in vivo and human studies concerning the potential of M. oleifera in the alleviation of MetS and its comorbidities. The search for relevant articles was carried out in PubMed and Google Scholar databases. Randomised controlled and clinical trials from the PubMed database were included in this review. The results suggested that the administration of M. oleifera, in vivo, shows clear signs of improvement in MetS indices. Despite fewer human studies, the existing data documented convincing results that uphold the potential of M. oleifera against MetS. Therefore, future research discussing the probable mechanism of action is much needed which could further assure the usage of M. oleifera in the treatment regimen of MetS.
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Affiliation(s)
- Saikrupa Adarthaiya
- Department of Zoology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India
| | - Amit Sehgal
- Department of Zoology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India
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Farag MR, Alagawany M, Mahdy EAA, El-Hady E, Abou-Zeid SM, Mawed SA, Azzam MM, Crescenzo G, Abo-Elmaaty AMA. Benefits of Chlorella vulgaris against Cadmium Chloride-Induced Hepatic and Renal Toxicities via Restoring the Cellular Redox Homeostasis and Modulating Nrf2 and NF-KB Pathways in Male Rats. Biomedicines 2023; 11:2414. [PMID: 37760855 PMCID: PMC10525457 DOI: 10.3390/biomedicines11092414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 09/29/2023] Open
Abstract
In our life scenarios, we are involuntarily exposed to many heavy metals that are well-distributed in water, food, and air and have adverse health effects on animals and humans. Cadmium (Cd) is one of the most toxic 10 chemicals reported by The World Health Organization (WHO), affecting organ structure and function. In our present study, we use one of the green microalga Chlorella vulgaris (ChV, 500 mg/kg body weight) to investigate the beneficial effects against CdCl2-induced hepato-renal toxicity (Cd, 2 mg/kg body weight for 10 days) on adult male Sprague-Dawley rats. In brief, 40 adult male rats were divided into four groups (n = 10); Control, ChV, Cd, and Cd + ChV. Cadmium alters liver and kidney architecture and disturbs the cellular signaling cascade, resulting in loss of body weight, alteration of the hematological picture, and increased ALT, AST, ALP, and urea in the blood serum. Moreover, cadmium puts hepatic and renal cells under oxidative stress due to the up-regulation of lipid peroxidation resulting in a significant increase in the IgG level as an innate immunity protection and induction of the pro-inflammatory cytokines (IL-1β and TNF-α) that causes hepatic hemorrhage, irregular hepatocytes in the liver and focal glomeruli swelling and proximal tubular degeneration in the kidney. ChV additive to CdCl2, could organize the protein translation process via NF-kB/Nrf2 pathways to prevent oxidative damage by maintaining cellular redox homeostasis and improving the survival of and tolerance of cells against oxidative damage caused by cadmium. The present study shed light on the anti-inflammatory and antioxidative properties of Chlorella vulgaris that suppress the toxicity influence of CdCl2.
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Affiliation(s)
- Mayada R. Farag
- Forensic Medicine and Toxicology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig 44519, Egypt
| | - Mahmoud Alagawany
- Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig 44519, Egypt
| | - Eman A. A. Mahdy
- Anatomy and Embryology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig 44519, Egypt; (E.A.A.M.); (E.E.-H.)
| | - Enas El-Hady
- Anatomy and Embryology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig 44519, Egypt; (E.A.A.M.); (E.E.-H.)
| | - Shimaa M. Abou-Zeid
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 6012201, Egypt;
| | - Suzan A. Mawed
- Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt;
| | - Mahmoud M. Azzam
- Department of Animal Production, College of Food & Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Giuseppe Crescenzo
- Department of Veterinary Medicine, University of Bari “Aldo Moro”, Valenzano, 70010 Bari, Italy;
| | - Azza M. A. Abo-Elmaaty
- Pharmacology Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
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Akbari Aghdam M, Romecín P, García-Estañ J, Atucha NM. Role of Nitric Oxide in the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis. Int J Mol Sci 2023; 24:10948. [PMID: 37446122 DOI: 10.3390/ijms241310948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/26/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
INTRODUCTION Previously, we found that intracellular calcium (Ca2+) homeostasis is altered in platelets from an experimental model of liver cirrhosis, namely the bile-duct-ligated (BDL) rat. These alterations are compatible with the existence of a hypercoagulable state. OBJECTIVE In the present study, we analyzed the role of nitric oxide in the abnormal calcium signaling responses of an experimental cirrhosis model, the bile duct-ligated rat. METHODS Chronic treatment with L-NAME was used to inhibit NO production in a group of control and BDL animals, and the responses compared to those obtained in a control and BDL untreated group (n = 6 each). The experiments were conducted on isolated platelets loaded with fura-2, using fluorescence spectrometry. RESULTS Chronic treatment with L-NAME increased thrombin-induced Ca2+ release from internal stores in both control and BDL rats. However, the effect was significantly greater in the BDL rats (p < 0.05). Thrombin-induced calcium entry from the extracellular space was also elevated but at lower doses and, similarly in both control and BDL platelets, treated with the NO synthesis inhibitor. Capacitative calcium entry was also enhanced in the control platelets but not in platelets from BDL rats treated with L-NAME. Total calcium in intracellular stores was elevated in untreated platelets from BDL rats, and L-NAME pretreatment significantly (p < 0.05) elevated these values both in controls and in BDL but significantly more in the BDL rats (p < 0.05). CONCLUSIONS Our results suggest that nitric oxide plays a role in the abnormal calcium signaling responses observed in platelets from BDL rats by interfering with the mechanism that releases calcium from the internal stores.
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Affiliation(s)
- Masoud Akbari Aghdam
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Paola Romecín
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Joaquín García-Estañ
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Noemí M Atucha
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
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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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Qiang X, Li J, Zhu S, He M, Chen W, Al-Abed Y, Brenner M, Tracey KJ, Wang P, Wang H. Human Dermcidin Protects Mice Against Hepatic Ischemia-Reperfusion-Induced Local and Remote Inflammatory Injury. Front Immunol 2022; 12:821154. [PMID: 35095926 PMCID: PMC8795592 DOI: 10.3389/fimmu.2021.821154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/24/2021] [Indexed: 11/13/2022] Open
Abstract
Background Hepatic ischemia and reperfusion (I/R) injury is commonly associated with surgical liver resection or transplantation, and represents a major cause of liver damage and graft failure. Currently, there are no effective therapies to prevent hepatic I/R injury other than ischemic preconditioning and some preventative strategies. Previously, we have revealed the anti-inflammatory activity of a sweat gland-derived peptide, dermcidin (DCD), in macrophage/monocyte cultures. Here, we sought to explore its therapeutic potential and protective mechanisms in a murine model of hepatic I/R. Methods Male C57BL/6 mice were subjected to hepatic ischemia by clamping the hepatic artery and portal vein for 60 min, which was then removed to initiate reperfusion. At the beginning of reperfusion, 0.2 ml saline control or solution of DCD (0.5 mg/kg BW) or DCD-C34S analog (0.25 or 0.5 mg/kg BW) containing a Cys (C)→Ser (S) substitution at residue 34 was injected via the internal jugular vein. For survival experiments, mice were subjected to additional resection to remove non-ischemic liver lobes, and animal survival was monitored for 10 days. For mechanistic studies, blood and tissue samples were collected at 24 h after the onset of reperfusion, and subjected to measurements of various markers of inflammation and tissue injury by real-time RT-PCR, immunoassays, and histological analysis. Results Recombinant DCD or DCD-C34S analog conferred a significant protection against lethal hepatic I/R when given intravenously at the beginning of reperfusion. This protection was associated with a significant reduction in hepatic injury, neutrophilic CXC chemokine (Mip-2) expression, neutrophil infiltration, and associated inflammation. Furthermore, the administration of DCD also resulted in a significant attenuation of remote lung inflammatory injury. Mechanistically, DCD interacted with epidermal growth factor receptor (EGFR), a key regulator of liver inflammation, and significantly inhibited hepatic I/R-induced phosphorylation of EGFR as well as a downstream signaling molecule, protein kinase B (AKT). The suppression of EGFR expression by transducing Egfr-specific shRNA plasmid into macrophages abrogated the DCD-mediated inhibition of nitric oxide (NO) production induced by a damage-associated molecular pattern (DAMP), cold-inducible RNA-binding protein, CIRP. Conclusions The present study suggests that human DCD and its analog may be developed as novel therapeutics to attenuate hepatic I/R-induced inflammatory injury possibly by impairing EGFR signaling.
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Affiliation(s)
- Xiaoling Qiang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Jianhua Li
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Shu Zhu
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Mingzhu He
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Weiqiang Chen
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Yousef Al-Abed
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Max Brenner
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- TheraSource LLC, Manhasset, NY, United States
| | - Kevin J. Tracey
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Ping Wang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- TheraSource LLC, Manhasset, NY, United States
| | - Haichao Wang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
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Hannan MA, Rahman MA, Sohag AAM, Uddin MJ, Dash R, Sikder MH, Rahman MS, Timalsina B, Munni YA, Sarker PP, Alam M, Mohibbullah M, Haque MN, Jahan I, Hossain MT, Afrin T, Rahman MM, Tahjib-Ul-Arif M, Mitra S, Oktaviani DF, Khan MK, Choi HJ, Moon IS, Kim B. Black Cumin ( Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety. Nutrients 2021; 13:1784. [PMID: 34073784 PMCID: PMC8225153 DOI: 10.3390/nu13061784] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 02/07/2023] Open
Abstract
Mounting evidence support the potential benefits of functional foods or nutraceuticals for human health and diseases. Black cumin (Nigella sativa L.), a highly valued nutraceutical herb with a wide array of health benefits, has attracted growing interest from health-conscious individuals, the scientific community, and pharmaceutical industries. The pleiotropic pharmacological effects of black cumin, and its main bioactive component thymoquinone (TQ), have been manifested by their ability to attenuate oxidative stress and inflammation, and to promote immunity, cell survival, and energy metabolism, which underlie diverse health benefits, including protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological disorders, cancer, and so on. Furthermore, black cumin acts as an antidote, mitigating various toxicities and drug-induced side effects. Despite significant advances in pharmacological benefits, this miracle herb and its active components are still far from their clinical application. This review begins with highlighting the research trends in black cumin and revisiting phytochemical profiles. Subsequently, pharmacological attributes and health benefits of black cumin and TQ are critically reviewed. We overview molecular pharmacology to gain insight into the underlying mechanism of health benefits. Issues related to pharmacokinetic herb-drug interactions, drug delivery, and safety are also addressed. Identifying knowledge gaps, our current effort will direct future research to advance potential applications of black cumin and TQ in health and diseases.
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Affiliation(s)
- Md. Abdul Hannan
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh; (A.A.M.S.); (M.T.H.); (M.T.-U.-A.)
| | - Md. Ataur Rahman
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Abdullah Al Mamun Sohag
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh; (A.A.M.S.); (M.T.H.); (M.T.-U.-A.)
| | - Md. Jamal Uddin
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (M.J.U.); (P.P.S.)
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Korea
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
| | - Mahmudul Hasan Sikder
- Department of Pharmacology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh;
| | - Md. Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Gyeonggi-do, Anseong 17546, Korea;
| | - Binod Timalsina
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
| | - Yeasmin Akter Munni
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
| | - Partha Protim Sarker
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (M.J.U.); (P.P.S.)
- Department of Biotechnology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
| | - Mahboob Alam
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
- Division of Chemistry and Biotechnology, Dongguk University, Gyeongju 780-714, Korea
| | - Md. Mohibbullah
- Department of Fishing and Post Harvest Technology, Sher-e-Bangla Agricultural University, Sher-e-Bangla Nagar, Dhaka 1207, Bangladesh;
| | - Md. Nazmul Haque
- Department of Fisheries Biology and Genetics, Patuakhali Science and Technology University, Patuakhali 8602, Bangladesh;
| | - Israt Jahan
- Department of Pharmacy, Faculty of Life and Earth Sciences, Jagannath University, Dhaka 1100, Bangladesh;
| | - Md. Tahmeed Hossain
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh; (A.A.M.S.); (M.T.H.); (M.T.-U.-A.)
| | - Tania Afrin
- Interdisciplinary Institute for Food Security, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh;
| | - Md. Mahbubur Rahman
- Research and Development Center, KNOTUS Co., Ltd., Yeounsu-gu, Incheon 22014, Korea;
| | - Md. Tahjib-Ul-Arif
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh; (A.A.M.S.); (M.T.H.); (M.T.-U.-A.)
| | - Sarmistha Mitra
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
| | - Diyah Fatimah Oktaviani
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
| | - Md Kawsar Khan
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh;
- Department of Biological Sciences, Macquarie University, Sydney, NSW 2109, Australia
| | - Ho Jin Choi
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Korea; (M.A.H.); (R.D.); (B.T.); (Y.A.M.); (M.A.); (S.M.); (D.F.O.); (H.J.C.)
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea;
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
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9
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Neri AA, Dontas IA, Iliopoulos DC, Karatzas T. Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis. In Vivo 2021; 34:953-964. [PMID: 32354880 DOI: 10.21873/invivo.11863] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIM Ischemia and reperfusion injuries may produce deleterious effects on hepatic tissue after liver surgery and transplantation. The impact of ischemia-reperfusion injury (IRI) on the liver depends on its substrate, the percentage of liver ischemic tissue subjected to IRI and the ischemia time. The consequences of IRI are more evident in pathologic liver substrates, such as steatotic livers. This review is the result of an extended bibliographic PubMed search focused on the last 20 years. It highlights basic differences encountered during IRI in lean and steatotic livers based on studies using rodent experimental models. CONCLUSION The main difference in cell death between lean and steatotic livers is the prevalence of apoptosis in the former and necrosis in the latter. There are also major changes in the effect of intracellular mediators, such as TNFα and IL-1β. Further experimental studies are needed in order to increase current knowledge of IRI effects and relevant mechanisms in both lean and steatotic livers, so that new preventive and therapeutic strategies maybe developed.
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Affiliation(s)
- Anna-Aikaterini Neri
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Ismene A Dontas
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Dimitrios C Iliopoulos
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
| | - Theodore Karatzas
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.,2 Department of Propedeutic Surgery, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
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10
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Abdelgawad ME, Darwish H, Nabawy MM, El-mezayen H. Development of novel score based on Angiogenic panel for accurate diagnosis of hepatocellular carcinoma among hepatitis C virus high-risk patients. INFECTION GENETICS AND EVOLUTION 2020; 85:104572. [DOI: 10.1016/j.meegid.2020.104572] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/11/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023]
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11
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Grezzana Filho TDJM, Longo L, Santos JLD, Gabiatti G, Boffil C, Santos EBD, Cerski CTS, Chedid MF, Corso CO. Induction of selective liver hypothermia prevents significant ischemia/reperfusion injury in Wistar rats after 24 hours. Acta Cir Bras 2020; 35:e202000205. [PMID: 32428061 PMCID: PMC7217597 DOI: 10.1590/s0102-865020200020000005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 01/19/2020] [Indexed: 02/08/2023] Open
Abstract
Purpose To investigate the effects of induction of selective liver hypothermia in a rodent model. Methods Seven male Wistar rats were subjected to 90 minutes of partial 70% liver ischemia and topic liver 26°C hypothermia (H group). Other seven male Wistar rats were subjected to 90 minutes of partial 70% normothermic liver ischemia (N group). Five additional rats underwent a midline incision and section of liver ligaments under normothermic conditions and without any liver ischemia (sham group). All animals were sacrificed 24-h after reperfusion, and livers were sampled for analyses. Pathology sections were scored for sinusoidal congestion, ballooning, hepatocelllular necrosis and the presence of neutrophilic infiltrates. Results At the end of the experiment, liver tissue expressions of TNF-ɑ, IL-1β, iNOS and TNF-ɑ/IL-10 ratio were significantly reduced in the H group compared to N group, whereas IL-10 and eNOS were significantly increased in H group. Histopathological injury scores revealed a significant decrease in ischemia/reperfusion (I/R) injuries in H group. Conclusion Selective liver hypothermia prevented I/R injury by inhibiting the release of inflammatory cytokines, preserves microcirculation, prevents hepatocellular necrosis and leukocyte infiltration, allowing maintenance of the liver architecture.
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12
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Abdel-Razik A, Mousa N, Abdelsalam M, Abdelwahab A, Tawfik M, Tawfik AM, Hasan AS, Elhelaly R, El-Wakeel N, Eldars W. Endothelin-1/Nitric Oxide Ratio as a Predictive Factor of Response to Therapy With Terlipressin and Albumin in Patients With Type-1 Hepatorenal Syndrome. Front Pharmacol 2020; 11:9. [PMID: 32076410 PMCID: PMC7006449 DOI: 10.3389/fphar.2020.00009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 01/06/2020] [Indexed: 01/17/2023] Open
Abstract
Background and Purpose Predictors of response to type-1 hepatorenal syndrome (HRS) therapy are urgently needed. This study's purpose is to evaluate the proposed predictors in these patients. Methods Forty-two type-1 HRS patients with cirrhosis were treated with albumin and terlipressin. Clinical, biochemical, and demographic parameters taken at the onset of therapy and changes in endothelin-1/nitric oxide (ET-1/NO) ratio during therapy were analyzed to check their predictive value. Results Response to treatment (serum creatinine level <1.5 mg/dL at the end of therapy) was shown in 20 patients (48%). Independent predictive variables of response to therapy were early reduction of ET-1/NO ratio ≥0.15 at day 3 of therapy and serum bilirubin baseline <8 mg/dL (area under the receiver operating characteristic curve, 0.751; P < 0.001; specificity, 55%; sensitivity, 85%). Response rates in patients with serum bilirubin level <8 and ≥8 mg/dL were 63% and 20%, respectively (P = 0.008). The corresponding values in patients with an early reduction of ET-1/NO ratio ≥0.15 and <0.15 on day 3 were 85% and 13.6%, respectively (P < 0.001). Conclusions Early reduction of ET-1/NO ratio and lower serum bilirubin baseline can predict response to type-1 HRS therapy with albumin and terlipressin. Alternative therapy should be investigated for nonresponder type-1 HRS patients.
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Affiliation(s)
- Ahmed Abdel-Razik
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nasser Mousa
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mostafa Abdelsalam
- Nephrology and Dialysis Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed Abdelwahab
- Nephrology and Dialysis Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mona Tawfik
- Nephrology and Dialysis Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed M Tawfik
- Diagnostic & Interventional Radiology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmad S Hasan
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rania Elhelaly
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Niveen El-Wakeel
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Waleed Eldars
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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13
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Othman AI, Amer MA, Basos AS, El-Missiry MA. Moringa oleifera leaf extract ameliorated high-fat diet-induced obesity, oxidative stress and disrupted metabolic hormones. CLINICAL PHYTOSCIENCE 2019. [DOI: 10.1186/s40816-019-0140-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Abstract
Background
Obesity is a health problem in many countries, and maintaining a perfect weight is challenging. Moringa oleifera leaf extract (ME) is rich in polyphenols with antioxidant and pharmaceutical potential. The present study investigated the potential protective effect of Moringa oleifera leaf extract against obesity induced from a high-fat diet (HFD), oxidative stress and disruption of metabolic hormones compared to simvastatin (SIM) or their combination.
Results
Rats fed a HFD for 6 weeks exhibited a significant increase in body weight and levels of serum glucose and lipid fractions, verifying an obesity state. There were also higher levels of insulin and leptin and lower gherlin in sera of HFD rats compared to the levels in control rats. Homeostasis model assessment for insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and the atherogenic index were elevated, indicating the development of insulin resistance and dyslipidaemia in these rats. These changes were accompanied with a significant increase in oxidative stress, as indicated by elevated lipid peroxidation and protein oxidation with low levels of antioxidants in liver. The activities of liver function enzymes, including aspartate amino transferase, alanine amino transferase, alkaline phosphatase and gamma glutamyltransferase, were also significantly increased in serum. Concurrent treatment with 300 mg/kg ME for 6 weeks ameliorated the increase in body weight and improved the levels of glucose, lipid fractions and metabolic hormones, indicating the anti-obesity effect and amelioration of tissue insulin resistance potential of ME. ME treatment also normalized oxidative stress and antioxidants in liver and improved liver function enzymes, indicating the antioxidant potential of ME. The effects of ME were similar to SIM, and the combination of these agents was better than each agent alone.
Conclusion
We propose that ME extract has anti-obesity and antioxidant potential and may be used as a lipid-lowering drug to control weight, obesity and its pathophysiological consequences.
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14
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Stojanović NM, Randjelović PJ, Mladenović MZ, Ilić IR, Petrović V, Stojiljković N, Ilić S, Radulović NS. Toxic essential oils, part VI: Acute oral toxicity of lemon balm (Melissa officinalis L.) essential oil in BALB/c mice. Food Chem Toxicol 2019; 133:110794. [PMID: 31473339 DOI: 10.1016/j.fct.2019.110794] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 08/23/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023]
Abstract
Despite being renowned for its volatiles, the data on the toxicity of the essential oil of lemon balm (Melissa officinalis L., Lamiaceae) is rather limited compared to its solvent/water-soluble extractibles. In this study, the aerial parts essential oil of M. officinalis, with over 130 constituents identified herein, 26 of which detected for the first time, was investigated for acute oral toxicity in BALB/c mice. The oil, composed of predominantly monoterpene aldehydes, citronellal (21.2-21.8%), neral (17.8-18.4%), and geranial (22.9-23.5%), which were assayed in parallel with the oil in some tests, induced significant changes in animal behavior, as well as altered biochemical parameters reflecting liver and kidney functions. Different pathological changes in the stomach, duodenum, liver, and kidneys were detected when the oil was administered in doses higher than 1 g kg-1. A depletion in the liver/kidney antioxidant capacities and an increased rate of lipid peroxidation was noted for animals treated with lemon balm oil. The calculated value of the oral LD50 in BALB/c mice (2.57 g kg-1) infers that the essential oil is only moderately toxic.
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Affiliation(s)
- Nikola M Stojanović
- Faculty of Medicine, University of Niš, Zorana Đinđića 81, 18000, Niš, Serbia.
| | - Pavle J Randjelović
- Department of Physiology, Faculty of Medicine, University of Niš, Zorana Đinđića 81, 18000, Niš, Serbia
| | - Marko Z Mladenović
- Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia
| | - Ivan R Ilić
- Institute of Pathology, Faculty of Medicine, University of Niš, Zorana Đinđića 81, 18000, Niš, Serbia
| | - Vladimir Petrović
- Department of Histology and Embryology, Faculty of Medicine, University of Niš, Zorana Đinđića 81, 18000, Niš, Serbia
| | - Nenad Stojiljković
- Department of Physiology, Faculty of Medicine, University of Niš, Zorana Đinđića 81, 18000, Niš, Serbia
| | - Sonja Ilić
- Department of Physiology, Faculty of Medicine, University of Niš, Zorana Đinđića 81, 18000, Niš, Serbia
| | - Niko S Radulović
- Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
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15
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Farag MR, Elhady WM, Ahmed SYA, Taha HSA, Alagawany M. Astragalus polysaccharides alleviate tilmicosin-induced toxicity in rats by inhibiting oxidative damage and modulating the expressions of HSP70, NF-kB and Nrf2/HO-1 pathway. Res Vet Sci 2019; 124:137-148. [PMID: 30901666 DOI: 10.1016/j.rvsc.2019.03.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 03/02/2019] [Accepted: 03/12/2019] [Indexed: 12/22/2022]
Abstract
The present study evaluated the toxic effects of Tilmicosin (TIL) on adult rats. The rats received a single subcutaneous injection of TIL at different doses (10, 25, 50, 75 and 100 mg/kg bw). TIL altered the biochemical parameters including liver and kidney function markers, glucose level and lipid profile as well as resulted in histopathological lesions in liver and adrenal glands mostly in rats exposed to 75 and 100 mg/kg bw. Then the role of Astragalus polysaccharide (APS) at 100 and 200 mg/kg bw, in modulating the toxic effects induced by high dose of TIL was evaluated. Single injection of TIL at a dose of 75 mg/kg bw was found to increase the activity of ALT, AST and ALP enzymes, induce the generation of reactive oxygen species (ROS) and decrease the total antioxidant capacity (TAC). TIL upregulated the hepatic mRNA expression of heat shock protein 70 (HSP70) and nuclear factor kappa B (NF-kB) while blocked the Nrf2/HO-1 mediated response. These changes were also associated with increasing tumer necrosis factor-alpha (TNF-α), interlukin1-beta (IL-1β) and nitric oxide levels. On the other hand, the results indicate that APS has a beneficial role particularly at high level in alleviating the stress and the hepatotoxic effects elicited by TIL injection in rats.
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Affiliation(s)
- Mayada Ragab Farag
- Forensic Medicine and Toxicology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig 44519, Egypt.
| | - Wlaa M Elhady
- Forensic Medicine and Toxicology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig 44519, Egypt
| | - Sarah Y A Ahmed
- Microbiology Department, Veterinary Medicine Faculty, Zagazig University, Zagazig 44519, Egypt
| | - Heba S A Taha
- Genetic Department, Faculty of Agriculture, Zagazig University, Zagazig 44519, Egypt
| | - Mahmoud Alagawany
- Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig 44519, Egypt
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16
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Salahshoor MR, Roshankhah S, Hosseni P, Jalili C. Genistein Improves Liver Damage in Male Mice Exposed to Morphine. Chin Med J (Engl) 2018; 131:1598-1604. [PMID: 29941714 PMCID: PMC6032674 DOI: 10.4103/0366-6999.235117] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Background: Morphine is commonly used to treat severe pain. This substance is significantly metabolized in the liver and causes disturbing effects. Genistein is an isoflavone and has antioxidant properties. The aim of this study was to evaluate the effects of genistein against morphine damages on mouse liver. Methods: Between May 2017 and March 2018, 48 male mice were divided into six groups (n = 8 in each group). Various doses of genistein (25 and 50 mg/kg) and morphine plus genistein (25 and 50 mg/kg) were administered intraperitoneally to 48 male mice for 20 consequent days. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), serum nitric oxide (NO) levels, liver weight, and the diameter of hepatocytes and central hepatic vein were studied and compared using one-way analysis of variance. Results: Morphine administration significantly increased the mean diameter of the central hepatic vein (22.76 ± 1.9 μm vs. 15.04 ± 0.60 μm, χ2 = 21.814, P = 0.001) and hepatocytes (3.03 ± 0.10 μm vs. 1.10 ± 0.05 μm, χ2 = 9.873, P = 0.001) respectively, blood serum NO level (38.00% ± 2.09% vs. 18.72% ± 4.40%, χ2 = 20.404, P < 0.001), liver enzyme level (AST: 111.80 ± 5.10 ng/ml vs. 81.93 ± 2.20 ng/ml, χ2 = 32.201, P < 0.0001; ALT: 45.14 ± 4.10 ng/ml vs. 35.49 ± 2.50 ng/ml, χ2 = 18.203, P < 0.0001; and ALP: 3.28 ± 0.20 ng/ml vs. 2.14 ± 0.10, χ2 = 5.04, P < 0.0001, respectively), and decreased liver weight (18.50 ± 0.90 g vs. 27.15 ± 0.50 g, χ2 = 22.415, P = 0.001) compared to saline group (0.535–0.750, P < 0.0001). However, administration of genistein plus morphine significantly enhanced liver weight (25 mg/kg: 21.15 ± 2.13 g vs. 18.50 ± 0.90 g, χ2 = 19.251, P < 0.0001; 50 mg/kg: 21.20 ± 1.00 g vs. 18.5 ± 0.9 g, χ2 = 19.502, P < 0.0001, respectively) and reduced the mean diameter of hepatocyte (25 mg/kg: 2.17 ± 0.30 μm vs. 3.03 ± 0.10 μm, χ2 = 22.780, P = 0.001; 50 mg/kg: 2.01 ± 0.20 μm vs. 3.03 ± 0.10 μm χ2 = 7.120, P = 0.001, respectively), central hepatic vein (25 mg/kg: 19.53 ± 1.00 μm vs. 22.76 ± 1.90 μm, χ2 = 20.681, P = 0.001; 50 mg/kg: 19.44 ± 1.20 μm vs. 22.76 ± 1.90 μm, χ2 = 18.451, P = 0.001, respectively), AST (25 mg/kg: 95.40 ± 5.20 ng/ml vs. 111.80 ± 5.010 ng/ml, P < 0.0001; 50 mg/kg: 90.78 ± 6.00 ng/ml vs. 111.80 ± 5.10 ng/ml, χ2 = 17.112, P < 0.0001, respectively), ALT (25 mg/kg: 35.78 ± 5.01 ng/ml vs. 45.14 ± 4.10 ng/ml, χ2 = 15.320, P < 0.0001; 50 mg/kg: 33.78 ± 2.60 ng/ml vs. 45.14 ± 4.10 ng/ml, χ2 = 14.023, P < 0.0001, respectively), ALP (25 mg/kg: 2.35 ± 0.30 ng/ml vs. 3.28 ± 0.20 ng/ml, χ2 = 4.101, P < 0.0001; 50 mg/kg: 2.34 ± 0.10 ng/ml vs. 3.28 ± 0.20 ng/ml, χ2 = 2.033, P < 0.0001, respectively), and NO levels (25 mg/kg: 25.92% ± 2.30% vs. 38% ± 2.09%, χ2 = 17.103, P < 0.0001; 50 mg/kg: 24.74% ± 4.10% vs. 38% ± 2.09%, χ2 = 25.050, P = 0.001, respectively) compared to morphine group. Conclusion: It seems that genistein administration might improve liver damages induced by morphine in mice.
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Affiliation(s)
- Mohammad Reza Salahshoor
- Department of Anatomical Sciences, University of Kermanshah School of Medicine, Kermanshah, Taghbostan 6714686698, Iran
| | - Shiva Roshankhah
- Department of Anatomical Sciences, University of Kermanshah School of Medicine, Kermanshah, Taghbostan 6714686698, Iran
| | - Payman Hosseni
- Department of Anatomical Sciences, University of Kermanshah School of Medicine, Kermanshah, Taghbostan 6714686698, Iran
| | - Cyrus Jalili
- Department of Anatomical Sciences, University of Kermanshah School of Medicine, Kermanshah, Taghbostan 6714686698, Iran
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Mizobuchi H, Fujii W, Isokawa S, Ishizuka K, Wang Y, Watanabe S, Sanjoba C, Matsumoto Y, Goto Y. Exacerbation of hepatic injury during rodent malaria by myeloid-related protein 14. PLoS One 2018; 13:e0199111. [PMID: 29902248 PMCID: PMC6002122 DOI: 10.1371/journal.pone.0199111] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 05/31/2018] [Indexed: 11/19/2022] Open
Abstract
Hepatic dysfunction is one of the clinical features in severe malaria. However, the mechanism of hepatic injury during malaria is still unknown. Myeloid-related protein (MRP) 14 is abundantly expressed by myeloid cells and involved in various inflammatory diseases. We previously reported that serum MRP14 is elevated in mice infected with Plasmodium berghei ANKA. In order to verify whether extracellular MRP14 is involved in the pathology of hepatic injury during rodent malaria, we intravenously administrated recombinant MRP14 (rMRP14) to mice infected with P. berghei ANKA. The administration of rMRP14 did not affect parasite number or hematocrit. On the other hand, the hepatic injury was exacerbated in rMRP14-treated mice, and their serum concentration of hepatic enzymes increased significantly more than PBS-treated controls. Immunohistochemical analysis of the liver showed that more MRP14+ macrophages accumulated in rMRP14-treated mice than PBS-treated controls after infection. The administration of rMRP14 also promotes the up-regulation of pro-inflammatory molecules in the liver, such as iNOS, IL-1β, IL-12, and TNF-α. Even in the absence of Plasmodium infection, administration of rMRP14 could induce the accumulation of MRP14+ macrophages and up-regulation of the pro-inflammatory molecules in the liver of naïve mice. The results indicate that MRP14 promotes the accumulation of MRP14+ cells and the up-regulation of pro-inflammatory molecules and NO, which amplify inflammatory cascade leading to hepatic injury. In conclusion, MRP14 is a one of key molecules for liver inflammation during rodent malaria.
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Affiliation(s)
- Haruka Mizobuchi
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Wataru Fujii
- Laboratory of Applied Genetics, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Shoko Isokawa
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kanna Ishizuka
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yihan Wang
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Sayoko Watanabe
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Chizu Sanjoba
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yoshitsugu Matsumoto
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yasuyuki Goto
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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18
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Jose SP, Mohanan R, S S, S A, IM K. A novel powder formulation of coconut inflorescence sap inhibits alcoholic liver damage by modulating inflammatory markers, extracellular matrix metalloproteinase, and oxidative stress. J Food Biochem 2018. [DOI: 10.1111/jfbc.12543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Svenia P. Jose
- Department of Biochemistry; St. Thomas College, Pala; Kottayam Kerala India
| | - Ratheesh Mohanan
- Department of Biochemistry; St. Thomas College, Pala; Kottayam Kerala India
| | - Sandya S
- Inorganic and Physical Chemistry; Indian Institute of Science; Bangalore Karnataka India
| | - Asha S
- Department of Biochemistry; St. Thomas College, Pala; Kottayam Kerala India
| | - Krishnakumar IM
- R&D Centre; Akay Flavours & Aromatics Pvt Ltd; Cochin Kerala India
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Salahshoor MR, Vahabi A, Roshankhah S, Darehdori AS, Jalili C. The Effects of Thymoquinone Against Morphine-induced Damages on Male Mice Liver. Int J Prev Med 2018; 9:8. [PMID: 29441185 PMCID: PMC5801588 DOI: 10.4103/ijpvm.ijpvm_144_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 06/19/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Morphine is a pain medication. It is mostly processed in liver and reasons disturbing effects. It can increase the production of free radicals. Thymoquinone is a phytochemical compound found in the plant Nigella sativa. It has diverse pharmacological properties such as antioxidant and anticancer. This study was intended to assess the effects of thymoquinone against morphine damages on the liver of mice. METHODS In this study, various doses of thymoquinone (4.5, 9, and 18 mg/kg) and thymoquinone plus morphine was administered (once a day) intraperitoneally to 48 male mice for 20 consequent days. These mice were randomly assigned to eight groups (n = 6). Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum nitric oxide (NO) levels, liver weight, and histology have been studied. RESULTS The results indicated that morphine administration significantly increased the mean diameter of central hepatic vein and hepatocyte, blood serum NO level, liver enzymes level, and decreased liver weight compared to saline group (P < 0.05). However, thymoquinone and thymoquinone plus morphine administration significantly enhanced liver weight and reduced the mean diameter of hepatocyte, central hepatic vein, liver enzymes, and NO levels in all groups compared to morphine group (P < 0.05). CONCLUSIONS It seems that antioxidant effect of thymoquinone could protect damage of liver parameters against morphine toxicity.
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Affiliation(s)
- Mohammad Reza Salahshoor
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arman Vahabi
- Department of Anatomical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shiva Roshankhah
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Cyrus Jalili
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Zhang P, Tian Y, Liu H, Ren J, Wang H, Zeng R, Long Y, Chen J. In vivo imaging of hepatocellular nitric oxide using a hepatocyte-targeting fluorescent sensor. Chem Commun (Camb) 2018; 54:7231-7234. [DOI: 10.1039/c8cc03240h] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A hepatocyte-targeting fluorescent NO sensor has been fabricated with good water solubility, excellent selectivity, and high sensitivity (∼1.62 nM).
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Affiliation(s)
- Peisheng Zhang
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education
- Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers
- Hunan Province College Key Laboratory of QSAR/QSPR
- School of Chemistry and Chemical Engineering
- Hunan University of Science and Technology
| | - Yong Tian
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education
- Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers
- Hunan Province College Key Laboratory of QSAR/QSPR
- School of Chemistry and Chemical Engineering
- Hunan University of Science and Technology
| | - Hui Liu
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education
- Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers
- Hunan Province College Key Laboratory of QSAR/QSPR
- School of Chemistry and Chemical Engineering
- Hunan University of Science and Technology
| | - Junyu Ren
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education
- Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers
- Hunan Province College Key Laboratory of QSAR/QSPR
- School of Chemistry and Chemical Engineering
- Hunan University of Science and Technology
| | - Hong Wang
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education
- Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers
- Hunan Province College Key Laboratory of QSAR/QSPR
- School of Chemistry and Chemical Engineering
- Hunan University of Science and Technology
| | - Rongjin Zeng
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education
- Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers
- Hunan Province College Key Laboratory of QSAR/QSPR
- School of Chemistry and Chemical Engineering
- Hunan University of Science and Technology
| | - Yunfei Long
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education
- Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers
- Hunan Province College Key Laboratory of QSAR/QSPR
- School of Chemistry and Chemical Engineering
- Hunan University of Science and Technology
| | - Jian Chen
- Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education
- Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers
- Hunan Province College Key Laboratory of QSAR/QSPR
- School of Chemistry and Chemical Engineering
- Hunan University of Science and Technology
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Ajith TA. Role of mitochondria and mitochondria-targeted agents in non-alcoholic fatty liver disease. Clin Exp Pharmacol Physiol 2017; 45:413-421. [PMID: 29112771 DOI: 10.1111/1440-1681.12886] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 10/26/2017] [Accepted: 10/27/2017] [Indexed: 12/18/2022]
Abstract
Mitochondria play a pivotal role in the fatty acid oxidation and have been found to be affected early during the macrovesicular fat accumulation in the hepatocytes. The fatty infiltration is the primary cause of oxidative stress and inflammation in the non-alcoholic fatty liver disease (NAFLD), which can lead to the peroxidation of phospholipids, such as cardiolipin. Oxidative stress-induced damage to mitochondrial DNA can result in the impairment of oxidative phosphorylation and further increases the generation of reactive oxygen species. The mitochondrial damage may eventually lead to apoptotic death of hepatocytes. The apoptosis along with the generated cytokines from the stellate and Kupffer cells further augment the fibrotic changes to advance the disease. Hence, alleviation of the mitochondrial impairment, particularly in the early stages of NAFLD, may prevent the progression of the disease. Among the various experimentally studied mitochondrial-targeted agents, triphenylphosphonium cation ligated ubiquinone Q10 and vitamin E, Szeto-Scheller peptides, and superoxide dismutase mimetic-salen manganese complexes (EUK-8 and EUK-134) have been found to be most promising. In addition to these mitochondrial-targeted agents, a novel area of therapy called mitotherapy have also emerged. However, clinical studies conducted so far are still fragmentary to validate their efficacy. This review article discusses the mitochondria-targeted molecules and their potential role in the treatment of NAFLD.
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Helal MG, Ayoub SE, Elkashefand WF, Ibrahim TM. Caffeine affects HFD-induced hepatic steatosis by multifactorial intervention. Hum Exp Toxicol 2017; 37:983-990. [DOI: 10.1177/0960327117747026] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for hepatic fibrosis. Therefore, there is critical need to develop novel cheap and effective therapeutic approaches to prevent and reverse NAFLD. Caffeine is commonly consumed beverage and has antioxidant and anti-inflammatory activities. This study examined whether caffeine can ameliorate liver injury induced by high-fat diet (HFD) feeding. Four groups of rats were used and treated for 16 weeks as follows: control group, rats were fed a standard diet; HFD group, rats were fed HFD; and caffeine 20 and caffeine 30 groups, rats were fed HFD for 16 weeks in addition to different doses of caffeine (20 or 30 mg/kg, respectively) for last 8 weeks. The HFD-induced liver injury is determined biochemically by evaluating serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, bilirubin, triglycerides, cholesterol, and high-density lipoprotein-cholesterol and by histopathological examination. Tissue malondialdehyde, total nitrate/nitrite, and glutathione concentration were also measured. Real-time reverse transcription polymerase chain reaction technique was used to determine the expression of lipogenic enzyme genes. Caffeine treatment significantly decreased the elevated serum ALT, AST, and bilirubin and increased the reduced albumin level. Interestingly, the hepatic mRNA expression of Fatty acid synthase and acetyl CoA carboxylase was decreased by caffeine, while the protein expression of hepatic carnitine palmitoyltransferase 1 and proliferation-activated receptor α was increased. Furthermore, caffeine reduced tissue lipid peroxidation and oxidative stress. These effects suggest that caffeine could improve HFD-induced hepatic injury by suppressing inflammatory response and oxidative stress and regulating hepatic de novo lipogenesis and β-oxidation.
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Affiliation(s)
- MG Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - SE Ayoub
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafr El-sheikh University, Kafr El-sheikh, Egypt
| | - WF Elkashefand
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - TM Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Quercetin and tin protoporphyrin attenuate hepatic ischemia reperfusion injury: role of HO-1. Naunyn Schmiedebergs Arch Pharmacol 2017; 390:871-881. [DOI: 10.1007/s00210-017-1389-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 05/24/2017] [Indexed: 12/14/2022]
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Attenuation of Ischemia-Reperfusion Injury and Improvement of Survival in Recipients of Steatotic Rat Livers Using CD47 Monoclonal Antibody. Transplantation 2017; 100:1480-9. [PMID: 27331362 DOI: 10.1097/tp.0000000000001186] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Despite the efficacy of orthotopic liver transplantation in the treatment of end-stage liver diseases, its therapeutic utility is severely limited by the availability of donor organs. The ability to rehabilitate marginal organs, such as steatotic allografts, has the potential to address some of the supply limitations of available organs for transplantation. Steatotic livers are more susceptible to ischemia-reperfusion injury (IRI), which is exacerbated by the thrombospondin-1/CD47 pathway through inhibition of nitric oxide signaling. We postulated that CD47 blockade with a monoclonal antibody specific to CD47, clone 400 (CD47mAb400) may reduce the extent of IRI in steatotic liver allografts. METHODS Orthotopic liver transplantation was performed using steatotic liver grafts from Zucker rats transplanted into lean recipients. Control IgG or the CD47mAb400 was administered to the donor livers at procurement. Serum transaminases, histological changes, and animal survival were assessed. Hepatocellular damage, oxidative and nitrosative stress, and inflammation were also quantified. RESULTS Administration of CD47mAb400 to donor livers increased recipient survival and resulted in significant reduction of serum transaminases, bilirubin, triphosphate nick-end labeling staining, caspase-3 activity, oxidative and nitrosative stresses, and proinflammatory cytokine expression of TNF-α, IL-6 and IL-1β. CONCLUSIONS We conclude that administration of CD47mAb400 to donor grafts may reduce IRI through CD47 blockade to result in improved function of steatotic liver allografts and increased survival of recipients and represent a novel strategy to allow the use of livers with higher levels of steatosis.
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Ramaiah S, Rivera C, Arteel G. Early-Phase Alcoholic Liver Disease: An Update on Animal Models, Pathology, and Pathogenesis. Int J Toxicol 2016; 23:217-31. [PMID: 15371166 DOI: 10.1080/10915810490502069] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) remains to be one of the most common etiology of liver disease and is a major cause of morbidity and mortality worldwide. The pathologic stages of ALD comprises of steatosis, steatohepatitis, and fibrosis/cirrhosis. Steatosis and steatohepatitis represents the early phase of ALD and are precursor stages for fibrosis/cirrhosis. Numerous research efforts have been directed at recognizing cofactors interacting with alcohol in the pathogenesis of steatosis and steatohepatitis. This review will elucidate the constellation of complex pathogenesis, available animal models, and microscopic pathologic findings mostly in the early-phase of ALD. The role of endotoxin, reactive oxygen species, alcohol metabolism, and cytokines are discussed. Understanding the mechanisms of early-phase ALD should provide insight into the development of therapeutic strategies and thereby decrease the morbidity and mortality associated with ALD.
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Affiliation(s)
- Shashi Ramaiah
- Department of Pathobiology, Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A and M University, College Station, TX 77843, USA
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Asiedu-Gyekye IJ, Edem Kukuia KK, Seidu AM, Antwi-Boasiako C, N'guessan BB, Frimpong-Manso S, Adjei S, Zobi J, Tettey AT, Nyarko AK. Unsweetened Natural Cocoa Powder Has the Potential to Attenuate High Dose Artemether-Lumefantrine-Induced Hepatotoxicity in Non-Malarious Guinea Pigs. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2016; 2016:7387286. [PMID: 27493672 PMCID: PMC4963575 DOI: 10.1155/2016/7387286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 05/30/2016] [Accepted: 06/08/2016] [Indexed: 02/05/2023]
Abstract
Objective. This study investigated the elemental composition of unsweetened natural cocoa powder (UNCP), its effect on nitric oxide, and its hepatoprotective potential during simultaneous administration with high-dose artemether/lumefantrine (A/L). Method. Macro- and microelements in UNCP were analyzed with EDXRF spectroscopy. Thirty (30) male guinea-pigs were then divided into five groups. For groups 3 (low-dose), 4 (medium-dose), and 5 (high-dose), the animals received oral UNCP prophylactically for 14 days. Group 1 received distilled water (14 days) and group 2 A/L for the last 3 days (days 12 to 14). After euthanisation, biochemical and histopathological examinations were carried out in all groups. Results. Phytochemical analysis of UNCP showed the presence of saponins, flavonoids, tannins, and cardiac glycosides. Thirty-eight (38) macro- and microelements were found. UNCP produced significant decreases in ALT, ALP, GGT, and AST levels. A significant increase in total protein levels was observed during A/L+UNCP administration in comparison to 75 mg/kg A/L group. Histopathological examinations buttressed the protective effects of cocoa administration. UNCP administration increased nitric oxide levels 149.71% (P < 0.05) compared to controls. Conclusion. UNCP increases nitric oxide levels and has hepatoprotective potential during A/L administration. A high level of copper was observed which may be detrimental during high daily consumptions of UNCP.
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Affiliation(s)
- Isaac Julius Asiedu-Gyekye
- Department of Pharmacology and Toxicology, University of Ghana School of Pharmacy, College of Health Sciences, Legon, Ghana
| | - Kennedy Kwami Edem Kukuia
- Department of Pharmacology and Toxicology, University of Ghana School of Pharmacy, College of Health Sciences, Legon, Ghana
| | - Abdulai Mahmood Seidu
- Department of Chemical Pathology, School of Biomedical and Allied Health Sciences, College of Health Sciences, Korle-Bu, Ghana
| | - Charles Antwi-Boasiako
- Department of Physiology, School of Biomedical and Allied Health Sciences, College of Health Sciences, Korle-Bu, Ghana
| | - Benoit Banga N'guessan
- Department of Pharmacology and Toxicology, University of Ghana School of Pharmacy, College of Health Sciences, Legon, Ghana
| | - Samuel Frimpong-Manso
- Department of Pharmaceutical Chemistry, University of Ghana School of Pharmacy, College of Health Sciences, Legon, Ghana
| | - Samuel Adjei
- Department of Animal Experimentation, Noguchi Memorial Institute for Medical Research, College of Health Sciences, Accra, Ghana
| | - Jonathan Zobi
- Department of Pharmacology and Toxicology, University of Ghana School of Pharmacy, College of Health Sciences, Legon, Ghana
| | - Abraham Terkpertey Tettey
- Department of Pharmacology and Toxicology, University of Ghana School of Pharmacy, College of Health Sciences, Legon, Ghana
| | - Alexander Kwadwo Nyarko
- Department of Pharmacology and Toxicology, University of Ghana School of Pharmacy, College of Health Sciences, Legon, Ghana
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Chung MY, Jung SK, Lee HJ, Shon DH, Kim HK. Ethanol Extract of Sarcodon asparatus Mitigates Inflammatory Responses in Lipopolysaccharide-Challenged Mice and Murine Macrophages. J Med Food 2015; 18:1198-206. [DOI: 10.1089/jmf.2014.3422] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Affiliation(s)
| | | | - Hye-Jin Lee
- Korea Food Research Institute, Gyeonggi, Korea
| | | | - Hyun-Ku Kim
- Department of Marine Life Science, Jeju National University, Jeju, Korea
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Jalili C, Tabatabaei H, Kakaberiei S, Roshankhah S, Salahshoor MR. Protective Role of Crocin Against Nicotine-induced Damages on Male Mice Liver. Int J Prev Med 2015; 6:92. [PMID: 26442615 PMCID: PMC4593238 DOI: 10.4103/2008-7802.165203] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 04/07/2015] [Indexed: 12/27/2022] Open
Abstract
Background: Nicotine is a major pharmacologically active substance in cigarette smoke. It is mainly metabolized in liver and causes devastating effects. Crocin is the chemical ingredient primarily responsible for the color of saffron. It has different pharmacological effects such as antioxidant and anticancer. This study was designed to evaluate the protective role of crocin against nicotine on the liver of mice. Methods: Forty-eight mice were equally divided into 8 groups; control (normal saline), nicotine (2.5 mg/kg), crocin (12.5, 25 and 50 mg/kg) and crocin plus nicotine treated groups. Saline, crocin, nicotine and crocin/nicotine (once a day) were intraperitoneally injected for 4 weeks. The liver weight and histology, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and serum nitric oxide levels have been studied. Results: The results indicated that nicotine administration significantly decreased liver weight (48.37%) and increased the mean diameter of hepatocyte (239%), central hepatic vein (28.45%), liver enzymes level (ALP 29.43%, AST 21.81%, ALT 21.55%), and blood serum nitric oxide level (57.18%) compared to saline group (P < 0.05). However, crocin and crocin plus nicotine administration significantly boosted liver weight (49.54%) and decreased the mean diameter of hepatocyte (40.48%), central hepatic vein (15.44%), liver enzymes (ALP 22.02%, AST 19.05%, ALT 23.11%), and nitric oxide levels (35.80%) in all groups compared to nicotine group (percentages represent the maximum dose) (P < 0.05). Conclusions: Crocin showed its partly protective effect against nicotine-induced liver toxicity.
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Affiliation(s)
- Cyrus Jalili
- Department of Anatomy and Cell Biology, Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hadis Tabatabaei
- Department of Anatomy and Cell Biology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyran Kakaberiei
- Department of Anatomy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shiva Roshankhah
- Department of Anatomy and Cell Biology, Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Reza Salahshoor
- Department of Anatomy and Cell Biology, Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Xiao ZY, Banan B, Jia J, Manning PT, Hiebsch RR, Gunasekaran M, Upadhya GA, Frazier WA, Mohanakumar T, Lin Y, Chapman WC. CD47 blockade reduces ischemia/reperfusion injury and improves survival in a rat liver transplantation model. Liver Transpl 2015; 21:468-477. [PMID: 25482981 PMCID: PMC4601606 DOI: 10.1002/lt.24059] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 11/30/2014] [Indexed: 12/17/2022]
Abstract
Orthotopic liver transplantation (OLT) remains the standard treatment option for nonresponsive liver failure. Because ischemia/reperfusion injury (IRI) is an important impediment to the success of OLT, new therapeutic strategies are needed to reduce IRI. We investigated whether blocking the CD47/thrombospondin-1 inhibitory action on nitric oxide signaling with a monoclonal antibody specific to CD47 (CD47mAb400) would reduce IRI in liver grafts. Syngeneic OLT was performed with Lewis rats. Control immunoglobulin G or CD47mAb400 was administered to the donor organ at procurement or to both the organ and the recipient at the time of transplant. Serum transaminases, histological changes of the liver, and animal survival were assessed. Oxidative stress, inflammatory responses, and hepatocellular damage were also quantified. A significant survival benefit was not achieved when CD47mAb400 was administered to the donor alone. However, CD47mAb400 administration to both the donor and the recipient increased animal survival afterward. The CD47mAb400-treated group showed lower serum transaminases, bilirubin, oxidative stress, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, caspase-3 activity, and proinflammatory cytokine expression of tumor necrosis factor α, interleukin-1β, and interleukin-6. Thus, CD47 blockade with CD47mAb400 administered both to the donor and the recipient reduced liver graft IRI in a rat liver transplantation model. This may translate to decreased liver dysfunction and increased survival of liver transplant recipients.
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Affiliation(s)
- Zhen-Yu Xiao
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Babak Banan
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Jianluo Jia
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | | | | | - Muthukumar Gunasekaran
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Gundumi A. Upadhya
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - William A. Frazier
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO
,Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO
| | - Thalachallour Mohanakumar
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
,Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Yiing Lin
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - William C. Chapman
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
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El-Tanbouly DM, Abdelsalam RM, Attia AS, Abdel-Aziz MT. Pretreatment with magnesium ameliorates lipopolysaccharide-induced liver injury in mice. Pharmacol Rep 2015; 67:914-20. [PMID: 26398385 DOI: 10.1016/j.pharep.2015.02.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 02/11/2015] [Accepted: 02/12/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is involved in the pathogenesis of sepsis. LPS administration induces systemic inflammation that mimics many of the initial clinical features of sepsis and has deleterious effects on several organs including the liver and eventually leading to septic shock and death. The present study aimed to investigate the protective effect of magnesium (Mg), a well known cofactor in many enzymatic reactions and a critical component of the antioxidant system, on hepatic damage associated with LPS-induced endotoxima in mice. METHODS Mg (20 and 40mg/kg, po) was administered for 7 consecutive days. Systemic inflammation was induced 1h after the last dose of Mg by a single dose of LPS (2mg/kg, ip) and 3h thereafter plasma was separated, animals were sacrificed and their livers were isolated. RESULTS LPS-treated mice suffered from hepatic dysfunction revealed by histological observation, elevation in plasma transaminases activities, C-reactive protein content and caspase-3, a critical marker of apoptosis. Liver inflammation was evident by elevation in liver cytokines contents (TNF-α and IL-10) and MPO activity. Additionally, oxidative stress was manifested by increased liver lipoperoxidation, glutathione depletion, elevated total nitrate/nitrite (NOx) content and glutathione peroxidase (GPx) activity. Pretreatment with Mg largely mitigated these alternations. CONCLUSION Pretreatment with Mg protects the liver from the acute injury which occurs shortly after septicemia.
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Affiliation(s)
- Dalia M El-Tanbouly
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Rania M Abdelsalam
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Amina S Attia
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mohamed T Abdel-Aziz
- Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Salahshoor M, Mohamadian S, Kakabaraei S, Roshankhah S, Jalili C. Curcumin improves liver damage in male mice exposed to nicotine. J Tradit Complement Med 2015; 6:176-83. [PMID: 27114942 PMCID: PMC4833467 DOI: 10.1016/j.jtcme.2014.11.034] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 11/16/2014] [Accepted: 11/20/2014] [Indexed: 11/26/2022] Open
Abstract
The color of turmeric (薑黃 jiāng huáng) is because of a substance called curcumin. It has different pharmacological effects, such as antioxidant and anti-inflammatory properties. Nicotine is a major pharmacologically active substance in cigarette smoke. It is mainly metabolized in the liver and causes devastating effects. This study was designed to evaluate the protective role of curcumin against nicotine on the liver in mice. Forty-eight mice were equally divided into eight groups; control (normal saline), nicotine (2.5 mg/kg), curcumin (10, 30, and 60 mg/kg) and curcumin plus nicotine-treated groups. Curcumin, nicotine, and curcumin plus nicotine (once a day) were intraperitoneally injected for 4 weeks. The liver weight and histology, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and serum nitric oxide levels have been studied. The results indicated that nicotine administration significantly decreased liver weight and increased the mean diameter of hepatocyte, central hepatic vein, liver enzymes level, and blood serum nitric oxide level compared with the saline group (p < 0.05). However, curcumin and curcumin plus nicotine administration substantially increased liver weight and decreased the mean diameter of hepatocyte, central hepatic vein, liver enzymes, and nitric oxide levels in all groups compared with the nicotine group (p < 0.05). Curcumin demonstrated its protective effect against nicotine-induced liver toxicity.
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Affiliation(s)
- Mohammadreza Salahshoor
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sabah Mohamadian
- Student of medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyran Kakabaraei
- Anatomy Department, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shiva Roshankhah
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Cyrus Jalili
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Corresponding author. Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Ibrahim MA, Abdel-Gaber SA, Amin EF, Ibrahim SA, Mohammed RK, Abdelrahman AM. Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia-reperfusion injury. Eur J Pharmacol 2014; 741:64-73. [DOI: 10.1016/j.ejphar.2014.07.047] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2014] [Revised: 07/12/2014] [Accepted: 07/19/2014] [Indexed: 12/14/2022]
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Red Sea Suberea mollis Sponge Extract Protects against CCl4-Induced Acute Liver Injury in Rats via an Antioxidant Mechanism. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:745606. [PMID: 25214875 PMCID: PMC4157001 DOI: 10.1155/2014/745606] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Revised: 07/22/2014] [Accepted: 07/22/2014] [Indexed: 01/14/2023]
Abstract
Recent studies have demonstrated that marine sponges and their active constituents exhibited several potential medical applications. This study aimed to evaluate the possible hepatoprotective role as well as the antioxidant effect of the Red Sea Suberea mollis sponge extract (SMSE) on carbon tetrachloride- (CCl4-) induced acute liver injury in rats. In vitro antioxidant activity of SMSE was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay. Rats were orally administered three different concentrations (100, 200, and 400 mg/kg) of SMSE and silymarin (100 mg/kg) along with CCl4 (1 mL/kg, i.p., every 72 hr) for 14 days. Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin were measured. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were also measured. Liver specimens were histopathologically examined. SMSE showed strong scavenging activity against free radicals in DPPH assay. SMSE significantly reduced liver enzyme activities. Moreover, SMSE significantly reduced hepatic MDA formation. In addition, SMSE restored GSH, NO, SOD, GPx, and CAT. The histopathological results confirmed these findings. The results of this study suggested a potent protective effect of the SMSE against CCl4-induced hepatic injury. This may be due to its antioxidant and radical scavenging activity.
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Chrzanowska A, Graboń W, Mielczarek-Puta M, Barańczyk-Kuźma A. Significance of arginase determination in body fluids of patients with hepatocellular carcinoma and liver cirrhosis before and after surgical treatment. Clin Biochem 2014; 47:1056-9. [PMID: 24713397 DOI: 10.1016/j.clinbiochem.2014.03.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 03/27/2014] [Accepted: 03/28/2014] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To assess the utility of arginase activity and expression in diagnosis of liver diseases. DESIGN AND METHODS Arginase activity, sensitivity and specificity were determined in serum of 140 patients including 50 with HCC, 60 with LC, 30 with choledocholithiasis (CDL) and 90 healthy controls. In HCC and LC arginase activity in serum was studied before and after tumor resection or liver transplantation. Arginase sensitivity in HCC was compared to that of alpha-fetoprotein (AFP) and aminotransferases (AST, ALT). In LC the activity was determined also in bile before and after transplantation. The expression of arginase isoenzymes in serum was studied by Western blotting. RESULTS In HCC and LC the preoperative arginase activity was significantly higher compared to controls, and it decreased after surgery. The sensitivity of arginase in HCC was much higher than that of AFP, AST and ALT (96, 40, 20 and 18%, respectively). In HCC it was higher than in LC (93%) and CDL (33%). The specificity of arginase was above 80%. In bile of cirrhotic patients the highest activity was immediately after liver transplantation. It decreased with time but increased dramatically at the time of the graft rejection. Arginase AII was present in serum of HCC and LC but not the control cases. CONCLUSIONS The increase of arginase activity in serum accompanied by the presence of isoenzyme AII can be useful in HCC and LC diagnosis. The determination of arginase activity in bile may be helpful in monitoring liver graft recipients.
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Affiliation(s)
- Alicja Chrzanowska
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Banacha 1, Poland
| | - Wojciech Graboń
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Banacha 1, Poland
| | - Magdalena Mielczarek-Puta
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Banacha 1, Poland
| | - Anna Barańczyk-Kuźma
- Chair and Department of Biochemistry, Medical University of Warsaw, 02-097 Warsaw, Banacha 1, Poland.
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Eissa LA, Eisa NH, Ebrahim MA, Ragab M, El-Gayar AM. Nitric Oxide is a Potential Diagnostic Marker for Hepatocellular Carcinoma. Sci Pharm 2013; 81:763-75. [PMID: 24106672 PMCID: PMC3791938 DOI: 10.3797/scipharm.1307-09] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 08/08/2013] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh most common in women. This cancer varies widely in incidence throughout the world, with rising incidence in Egypt. HCC is considered the second most frequent cause of cancer incidence and mortality among men in Egypt. This study aimed to estimate the serum levels of nitric oxide (NO) and glutathione reductase in order to evaluate their role as oxidative status markers in HCC development and progression. For this purpose, serum levels of these parameters were assessed in 50 HCC patients, and 30 cirrhotic patients in addition to 15 healthy subjects as a control group. In the present study, glutathione reductase activity showed a significant increase in HCC as compared to the control group (P= 0.019). On the other hand, no significant difference was observed between the cirrhotic and HCC patients (P= 0.492). Serum NO was significantly higher in patients with HCC than in cirrhotic patients (P= 0.001) or the control group (P= 0.001), with a sensitivity of (74%) and specificity of (88.89%) at a cut-off level of 614.1 μmol/l. While AFP, alpha-fetoprotein, at a cutoff level of 200 ng/ml had a sensitivity of (52%), the specificity was (100%). Indeed, nitric oxide was high in 62.5% of AFP-negative HCC patients. In conclusion, glutathione reductase has no role in HCC diagnosis. However, nitric oxide is a potential diagnostic marker for HCC. The simultaneous determination of serum nitric oxide and AFP gave significant improvement in the detection of HCC patients compared to that of AFP alone.
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Affiliation(s)
- Laila A Eissa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
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Chen CY, Tsai MM, Chi HC, Lin KH. Biological significance of a thyroid hormone-regulated secretome. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2013; 1834:2271-84. [PMID: 23429180 DOI: 10.1016/j.bbapap.2013.02.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 02/07/2013] [Accepted: 02/11/2013] [Indexed: 01/18/2023]
Abstract
The thyroid hormone, 3,3,5-triiodo-L-thyronine (T3), modulates several physiological processes, including cellular growth, differentiation, metabolism and proliferation, via interactions with thyroid hormone response elements (TREs) in the regulatory regions of target genes. Several intracellular and extracellular protein candidates are regulated by T3. Moreover, T3-regulated secreted proteins participate in physiological processes or cellular transformation. T3 has been employed as a marker in several disorders, such as cardiovascular disorder in chronic kidney disease, as well as diseases of the liver, immune system, endocrine hormone metabolism and coronary artery. Our group subsequently showed that T3 regulates several tumor-related secretory proteins, leading to cancer progression via alterations in extracellular matrix proteases and tumor-associated signaling pathways in hepatocellular carcinomas. Therefore, elucidation of T3/thyroid hormone receptor-regulated secretory proteins and their underlying mechanisms in cancers should facilitate the identification of novel therapeutic targets. This review provides a detailed summary on the known secretory proteins regulated by T3 and their physiological significance. This article is part of a Special Issue entitled: An Updated Secretome.
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Affiliation(s)
- Cheng-Yi Chen
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
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Abu-Amara M, Yang SY, Seifalian A, Davidson B, Fuller B. The nitric oxide pathway--evidence and mechanisms for protection against liver ischaemia reperfusion injury. Liver Int 2012; 32:531-43. [PMID: 22316165 DOI: 10.1111/j.1478-3231.2012.02755.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 12/29/2011] [Indexed: 02/13/2023]
Abstract
Ischaemia reperfusion (IR) injury is a clinical entity with a major contribution to the morbidity and mortality of liver surgery and transplantation. A central pathway of protection against IR injury utilizes nitric oxide (NO). Nitric oxide synthase (NOS) enzymes manufacture NO from L-arginine. NO generated by the endothelial NOS (eNOS) isoform protects against liver IR injury, whereas inducible NOS (iNOS)-derived NO may have either a protective or a deleterious effect during the early phase of IR injury, depending on the length of ischaemia, length of reperfusion and experimental model. In late phase hepatic IR injury, iNOS-derived NO plays a protective role. In addition to NOS consumption of L-arginine during NO synthesis, this amino acid may also be metabolized by arginase, an enzyme whose release is increased during prolonged ischaemia, and therefore diverts L-arginine away from NOS metabolism leading to a drop in the rate of NO synthesis. NO most commonly acts through the soluble guanylyl cyclase-cyclic GMP- protein kinase G pathway to ameliorate hepatic IR injury. Both endogenously generated and exogenously administered NO donors protect against liver IR injury. The beneficial effects of NO on liver IR are not, however, universal, and certain conditions, such as steatosis, may influence the protective effects of NO. In this review, the evidence for, and mechanisms of these protective actions of NO are discussed, and areas in need of further research are highlighted.
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Affiliation(s)
- Mahmoud Abu-Amara
- Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, UK
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DU Y, Wang T, Jiang N, Ren RT, Li C, Li CK, Fu FH. Sodium aescinate ameliorates liver injury induced by methyl parathion in rats. Exp Ther Med 2012; 3:818-822. [PMID: 22969975 DOI: 10.3892/etm.2012.479] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2011] [Accepted: 01/06/2012] [Indexed: 11/05/2022] Open
Abstract
Methyl parathion, a highly cytotoxic insecticide, has been used in agricultural pest control for several years. The present study investigated the protective effect of sodium aescinate (SA, the sodium salt of aescin) against liver injury induced by methyl parathion. Forty male Sprague-Dawley rats were randomly divided into 5 groups of 8 animals: the control group; the methyl parathion (15 mg/kg) poisoning (MP) group; and the MP plus SA at doses of 0.45, 0.9 and 1.8 mg/kg groups. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and acetylcholinesterase (AChE) in the plasma were assayed. Nitric oxide (NO) and antioxidative parameters were measured. Histopathological examination of the liver was also performed. The results revealed that SA had no effect on AChE. Treatment with SA decreased the activities of ALT and AST, and the levels of malondialdehyde and NO. Treatment with SA also increased the level of glutathione and the activities of superoxide dismutase and glutathione peroxidase. SA administration also ameliorated liver injury induced by methyl parathion poisoning. The findings indicate that SA protects against liver injury induced by methyl parathion and that the mechanism of action is related to the antioxidative and anti-inflammatory effects of SA.
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Affiliation(s)
- Yuan DU
- Department of Pharmacology, School of Pharmacy, Yantai University, Yantai, Shandong 264005, P.R. China
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Jiang N, Xin W, Wang T, Zhang L, Fan H, Du Y, Li C, Fu F. Protective effect of aescin from the seeds of Aesculus hippocastanum on liver injury induced by endotoxin in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2011; 18:1276-1284. [PMID: 21802269 DOI: 10.1016/j.phymed.2011.06.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Revised: 03/03/2011] [Accepted: 06/16/2011] [Indexed: 05/31/2023]
Abstract
To investigate the effect and underlying mechanism of aescin on acute liver injury induced by endotoxin, liver injury was established by injecting lipopolysaccharide (LPS) in mice. Animals were assigned to seven groups: the control group and groups treated with LPS (40 mg/kg), aescin (3.6 mg/kg), LPS plus dexamethasone (4 mg/kg) and LPS plus aescin (0.9, 1.8 or 3.6 mg/kg). Hepatic histopathological changes were examined under a light microscope. Activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were determined. Levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO) and antioxidative parameters in liver homogenate were measured. Glucocorticoid receptor (GR), 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11 beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expressions in liver were determined by western blotting. Treatment with escin could inhibit immigration of inflammatory cells, alleviate the degree of necrosis, and decrease serum ALT and AST activities. Aescin also down-regulated levels of inflammation mediators (TNF-α, IL-1β and NO) and 11β-HSD2 expression in liver, up-regulated GR expression, enhanced endogenous antioxidative capacity, but have no obvious effect on 11β-HSD1 expression in liver. The findings suggest aescin has protective effects on endotoxin-induced liver injury, and the underlying mechanisms were associated with its anti-inflammatory effects, up-regulating GR expression, down-regulating 11β-HSD2 experssion, and antixoidation.
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Affiliation(s)
- Na Jiang
- Department of Pharmacology, School of Pharmacy, Yantai University, Yantai, PR China
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The role of thioredoxin in the regulation of cellular processes by S-nitrosylation. Biochim Biophys Acta Gen Subj 2011; 1820:689-700. [PMID: 21878369 DOI: 10.1016/j.bbagen.2011.08.012] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 07/27/2011] [Accepted: 08/16/2011] [Indexed: 01/29/2023]
Abstract
BACKGROUND S-nitrosylation (or S-nitrosation) by Nitric Oxide (NO), i.e., the covalent attachment of a NO group to a cysteine thiol and formation of S-nitrosothiols (R-S-N=O or RSNO), has emerged as an important feature of NO biology and pathobiology. Many NO-related biological functions have been directly associated with the S-nitrosothiols and a considerable number of S-nitrosylated proteins have been identified which can positively or negatively regulate various cellular processes including signaling and metabolic pathways. SCOPE OF THE REVIEW Taking account of the recent progress in the field of research, this review focuses on the regulation of cellular processes by S-nitrosylation and Trx-mediated cellular homeostasis of S-nitrosothiols. MAJOR CONCLUSIONS Thioredoxin (Trx) system in mammalian cells utilizes thiol and selenol groups to maintain a reducing intracellular environment to combat oxidative/nitrosative stress. Reduced glutathione (GSH) and Trx system perform the major role in denitrosylation of S-nitrosylated proteins. However, under certain conditions, oxidized form of mammalian Trx can be S-nitrosylated and then it can trans-S-nitrosylate target proteins, such as caspase 3. GENERAL SIGNIFICANCE Investigations on the role of thioredoxin system in relation to biologically relevant RSNOs, their functions, and the mechanisms of S-denitrosylation facilitate the development of drugs and therapies. This article is part of a Special Issue entitled Regulation of Cellular Processes.
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Nitric oxide is an essential mediator of the protective effects of remote ischaemic preconditioning in a mouse model of liver ischaemia/reperfusion injury. Clin Sci (Lond) 2011; 121:257-66. [PMID: 21463257 DOI: 10.1042/cs20100598] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
NO (nitric oxide) may protect the liver from IR (ischaemia/reperfusion) injury. RIPC (remote ischaemic preconditioning) also protects against liver IR injury; however, the molecular mediator(s) of RIPC are currently unknown. The aim of the present study was to assess the role of NO in hindlimb RIPC-induced protection against liver IR injury. Mice were allocated to the following groups: sham group; RIPC group (six cycles of 4×4 min IR of hindlimb); IR group [40 min lobar (70%) hepatic ischaemia and 2-h reperfusion]; RIPC+IR group (RIPC followed by IR group procedures); and C-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt]+RIPC+IR group [C-PTIO (a direct NO scavenger) was administered, followed by the RIPC+IR group procedure]. Hepatic MBF (microcirculatory blood flow) was measured throughout the experiment. Circulating NOx (nitrite and nitrate) levels, plasma liver transaminases, hepatic histopathological and TEM (transmission electron microscopy) studies were performed at the end of the experiment. NOx concentrations were significantly elevated (P<0.05) in the RIPC and RIPC+IR groups. Compared with liver IR alone, RIPC+IR preserved hepatic MBF during liver reperfusion (P<0.05). In contrast, C-PTIO+RIPC+IR reduced MBF compared with RIPC+IR (P<0.05). RIPC+IR reduced plasma transaminases (P<0.05), and histopathological and ultrastructural features of injury compared with IR alone. The protective effects of RIPC+IR in reducing liver IR injury were abrogated in the group that received antecedent C-PTIO (C-PTIO+RIPC+IR). In conclusion, NO is an essential mediator of the protection afforded by hindlimb RIPC against liver IR injury. The mechanisms underlying this protection involve preservation of the sinusoidal structure and maintenance of blood flow through the hepatic microcirculation.
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Zaoualí MA, Reiter RJ, Padrissa-Altés S, Boncompagni E, García JJ, Ben Abnennebi H, Freitas I, García-Gil FA, Rosello-Catafau J. Melatonin protects steatotic and nonsteatotic liver grafts against cold ischemia and reperfusion injury. J Pineal Res 2011; 50:213-21. [PMID: 21108657 DOI: 10.1111/j.1600-079x.2010.00831.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Chronic organ-donor shortage has required the acceptance of steatotic livers for transplantation purposes despite the higher risk of graft dysfunction or nonfunction associated with the cold ischemia-reperfusion injury. This study evaluated the use of melatonin as an additive to Institute Georges Lopez (IGL-1) solution for protecting nonsteatotic and steatotic liver grafts against cold ischemia-reperfusion injury. In the current investigation, we used an ex vivo isolated perfused rat liver model. Steatotic and nonsteatotic livers were preserved for 24 hr (4°C) in University of Wisconsin or IGL-1 solutions with or without melatonin, as well as in University of Wisconsin solution alone. Thereafter, livers were subjected to 2-hr reperfusion (37°C). We assessed hepatic injury (transaminases) and function [bile production and sulfobromophthalein (BSP) clearance, vascular resistance], as well as other factors potentially implicated in the high vulnerability of steatotic livers against ischemia-reperfusion injury (oxidative stress and related inflammatory mediators including nitric oxide and cytokines). We also evaluated well-known cytoprotective factors as hemeoxygenase 1 (HO-1). Fatty livers preserved in IGL-1 solution enriched with melatonin showed lower transaminase levels and higher bile production and BSP clearance when compared to those obtained for livers maintained in IGL-1 solution alone. A significant diminution of vascular resistance was also observed when melatonin was added to the IGL-1 solution. The melatonin benefits correlated with the generation of nitric oxide (through constitutive e-NOS activation) and the prevention of oxidative stress and inflammatory cytokine release including tumor necrosis factor and adiponectin, respectively. The addition of melatonin to IGL-1 solution improved nonsteatotic and steatotic liver graft preservation, limiting their risk against cold ischemia-reperfusion injury.
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Affiliation(s)
- Mohamed Amine Zaoualí
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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Abstract
Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. The poor prognosis of ALD implies that preventing disease progression would be more effective than treating end-stage liver disease. An obvious avenue of prevention would be to remove the damaging agent; however, the infamously high rate of recidivism in alcoholics makes maintaining abstinence a difficult treatment goal to prevent ALD. Indeed, although the progression of ALD is well-characterized, there is no universally accepted therapy available to halt or reverse this process in humans. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of ALD, rational targeted therapy can be developed to treat or prevent ALD. The purpose of this review is to summarize the established and proposed mechanisms by which chronic alcohol abuse damages the liver and to highlight key signaling events known or hypothesized to mediate these effects.
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Affiliation(s)
- Juliane I Beier
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
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Hassan MI, Mabrouk GM, Shehata HH, Aboelhussein MM. Antineoplastic effects of bee honey and Nigella sativa on hepatocellular carcinoma cells. Integr Cancer Ther 2010; 11:354-63. [PMID: 21147814 DOI: 10.1177/1534735410387422] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES To evaluate in vitro antitumor effects of bee honey (BH) and Nigella sativa (NS) on HepG2 through their antioxidant and apoptotic activities. METHODS HepG2 cell line was treated with different concentrations of diluted unfractionated BH and different concentrations of alcohol extract of NS. Exposure lasted for different time durations (6-72 hours), both dose-response and time course-response were conducted. Cell viability was tested by trypan blue exclusion test. Total antioxidant status and caspase-3 activity were estimated in the cell lysate. Nitric oxide levels were measured in culture supernatants of both treated and untreated HepG2 at all indicated times. RESULTS Treatment of HepG2 cells with BH and NS leads to a significant decrease in both the number of viable HepG2 cells and the levels of nitric oxide on one hand, but improvement of the total antioxidant status and caspase-3 activity on the other, especially in HepG2 cells treated with higher doses of BH and NS (20% and 5000 μg/mL, respectively) and for longer duration (72 hours). CONCLUSIONS BH and NS are effective in reducing the viability of HepG2 cells, improving their antioxidant status and inducing their apoptotic death.
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Exogenous Nitric Oxide Donation Causes Desensitization of Arteriolar Relaxing Activity In Vivo: An Intravital Analysis in Mice. J Surg Res 2010; 164:169-74. [DOI: 10.1016/j.jss.2009.07.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2008] [Indexed: 11/23/2022]
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Zaouali MA, Mosbah IB, Boncompagni E, Abdennebi HB, Mitjavila MT, Bartrons R, Freitas I, Rimola A, Roselló-Catafau J. Hypoxia inducible factor-1α accumulation in steatotic liver preservation: Role of nitric oxide. World J Gastroenterol 2010; 16:3499-509. [PMID: 20653058 PMCID: PMC2909549 DOI: 10.3748/wjg.v16.i28.3499] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the relevance of hypoxia inducible factor (HIF-1) and nitric oxide (NO) on the preservation of fatty liver against cold ischemia-reperfusion injury (IRI).
METHODS: We used an isolated perfused rat liver model and we evaluated HIF-1α in steatotic and non-steatotic livers preserved for 24 h at 4°C in University of Wisconsin and IGL-1 solutions, and then subjected to 2 h of normothermic reperfusion. After normoxic reperfusion, liver enzymes, bile production, bromosulfophthalein clearance, as well as HIF-1α and NO [endothelial NO synthase (eNOS) activity and nitrites/nitrates] were also measured. Other factors associated with the higher susceptibility of steatotic livers to IRI, such as mitochondrial damage and vascular resistance were evaluated.
RESULTS: A significant increase in HIF-1α was found in steatotic and non-steatotic livers preserved in IGL-1 after cold storage. Livers preserved in IGL-1 showed a significant attenuation of liver injury and improvement in liver function parameters. These benefits were enhanced by the addition of trimetazidine (an anti-ischemic drug), which induces NO and eNOS activation, to IGL-1 solution. In normoxic reperfusion, the presence of NO favors HIF-1α accumulation, promoting also the activation of other cytoprotective genes, such as heme-oxygenase-1.
CONCLUSION: We found evidence for the role of the HIF-1α/NO system in fatty liver preservation, especially when IGL-1 solution is used.
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Zhong MM, Chen FH, Yuan LP, Wang XH, Wu FR, Yuan FL, Cheng WM. Protective effect of total flavonoids from Bidens bipinnata L. against carbon tetrachloride-induced liver injury in mice. J Pharm Pharmacol 2010; 59:1017-25. [PMID: 17637198 DOI: 10.1211/jpp.59.7.0015] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Abstract
Bidens bipinnata L. is well known in China as a traditional Chinese medicine. This study was designed to evaluate the hepatoprotective activity of the total flavonoids of B. bipinnata L. (TFB) against carbon tetrachloride (CCI4)-induced acute liver injury in mice and to determine its mechanism of action. Oral administration of TFB at doses of 50, 100 and 200 mg kg−1 for 7 days significantly reduced the elevated relative values of liver weight, serum transaminases (alanine aminotransferase and aspartate aminotransferase) and the hepatic morphologic changes induced by CCl4 in mice. In addition, TFB markedly inhibited CCl4-induced lipid peroxidation and enhanced the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase. Moreover, pretreatment with TFB suppressed nitric oxide production and nuclear factor-kB activation in CCl4-treated mice. The results suggest that TFB has significant hepatoprotective activity and its mechanism is related, at least in part, to its antioxidant properties. Further research is required to investigate the detailed mechanism of the protective effect of TFB on acute liver injury.
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Affiliation(s)
- Ming-mei Zhong
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, China
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Bui-Nguyen TM, Pakala SB, Sirigiri DR, Martin E, Murad F, Kumar R. Stimulation of inducible nitric oxide by hepatitis B virus transactivator protein HBx requires MTA1 coregulator. J Biol Chem 2009; 285:6980-6. [PMID: 20022949 DOI: 10.1074/jbc.m109.065987] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Nitric oxide has been implicated in the pathogenesis of inflammatory disorders, including hepatitis B virus-associated hepatocellular carcinoma. Transactivator protein HBx, a major regulator of cellular responses of hepatitis B virus, is known to induce the expression of MTA1 (metastasis-associated protein 1) coregulator via NF-kappaB signaling in hepatic cells. However, the underlying mechanism of HBx regulation of the inducible nitric-oxide synthase (iNOS) pathway remains unknown. Here we provide evidence that MTA1 is a positive regulator of iNOS transcription and plays a mechanistic role in HBx stimulation of iNOS expression and activity. We found that the HBx-MTA1 complex is recruited onto the human iNOS promoter in an NF-kappaB-dependent manner. Pharmacological inhibition of the NF-kappaB signaling prevented the ability of HBx to stimulate the transcription, the expression, and the activity of iNOS; nevertheless, these effects could be substantially rescued by MTA1 dysregulation. We further discovered that HBx-mediated stimulation of MTA1 is paralleled by the suppression of miR-661, a member of the small noncoding RNAs, recently shown to target MTA1. We observed that miR-661 controls of MTA1 expression contributed to the expression and activity of iNOS in HBx-expressing HepG2 cells. Accordingly, depletion of MTA1 by either miR-661 or siRNA in HBx-expressing cells severely impaired the ability of HBx to modulate the endogenous levels of iNOS and nitrite production. Together, these findings reveal an inherent role of MTA1 in HBx regulation of iNOS expression and consequently its function in the liver cancer cells.
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Affiliation(s)
- Tri M Bui-Nguyen
- Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA
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Moustafa AHA, Ali EMM, Mohamed TM, Abdou HI. Oxidative stress and thyroid hormones in patients with liver diseases. Eur J Intern Med 2009; 20:703-8. [PMID: 19818291 DOI: 10.1016/j.ejim.2009.08.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2009] [Revised: 08/11/2009] [Accepted: 08/14/2009] [Indexed: 12/20/2022]
Abstract
BACKGROUND The liver metabolizes the thyroid hormones and regulates their systemic endocrine effects so liver disease could affect thyroid hormone metabolism. Oxidative stress could play a role in the pathogenesis and progression of liver diseases. The objective of this study was to investigate serum levels of oxidative stress and antioxidant in liver diseases as prognostic markers and know the importance of these antioxidants level in relation to thyroid hormones. METHODS Serum nitric oxide (NO), malondialdehyde (MDA) and triiodothyronine (T(3)), thyroxine (T(4)), thyroid stimulating hormone (TSH), apolipoprotein-1 (APOA1) levels and erythrocyte reduced glutathione (GSH) level and glutathione peroxidase (GSHPx) and glutathione reductase (GR) activities were determined in 20 control subjects, 13 patients with non-alcoholic steatohepatitis (NASH), 18 patients with chronic HCV, 17 patients with compensated cirrhotic HCV and 42 patients with decompensated cirrhotic HCV. RESULTS Cirrhotic patients with HCV had higher NO and MDA levels while lower T(3) and erythrocyte GSH levels, and GSHPx activity than the chronic. Serum T(3) showed negative correlation with serum NO and MDA whereas positive correlation with APOA1, GSH, and GSHPx in cirrhotic patients with HCV. CONCLUSION The measurement of the total T(3), NO, MDA, GSH reduced and GSHPx as biomarkers for liver diseases might be a beneficial tool, helping in monitoring the state of liver disease patients.
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Ali EMM, Shehata HH, Ali-Labib R, Esmail Zahra LM. Oxidant and antioxidant of arylesterase and paraoxonase as biomarkers in patients with hepatitis C virus. Clin Biochem 2009; 42:1394-400. [PMID: 19538950 DOI: 10.1016/j.clinbiochem.2009.06.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2009] [Revised: 06/01/2009] [Accepted: 06/04/2009] [Indexed: 10/20/2022]
Abstract
OBJECTIVES Oxidative stress plays a role in the pathogenesis in patients with HCV infection. The objective of this study was to evaluate oxidant and antioxidant biomarkers in patients with HCV. DESIGN AND METHODS Serum malonaldehyde (MDA) and nitric oxide (NO) levels and the activities of myeloperoxidase (MPO), arylesterase (AE) and paraoxonase-1 (PON1) were determined in 23 chronic and 21 cirrhotic patients with HCV and 21 healthy subjects. RESULTS Cirrhotic patients with HCV had higher serum NO level and MPO activity while lower AE and PON1 activities than the chronic. Significant inverse correlation was observed between MDA and PON1 activity in patients with HCV. The most significant HCV biomarker was MDA, AE, NO and PON1. The best combined ones for sensitivity, specificity were MDA+albumin, PON1+AST, and PON1+albumin. CONCLUSIONS The use of the MDA, MPO, AE, NO and PON1 as biomarkers might be useful tools, helping in the monitoring of patients with HCV.
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Affiliation(s)
- Ehab M M Ali
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Egypt.
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