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Morimoto N, Nishihama Y, Onishi K, Nakayama SF. Association between blood lipid levels in early pregnancy and urinary organophosphate metabolites in the Japan Environment and Children's Study. ENVIRONMENT INTERNATIONAL 2024; 190:108932. [PMID: 39128375 DOI: 10.1016/j.envint.2024.108932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/22/2024] [Accepted: 08/01/2024] [Indexed: 08/13/2024]
Abstract
BACKGROUND High low-density lipoprotein cholesterol levels (LDL-C) during pregnancy have been associated with adverse pregnancy and offspring outcomes. While previous studies have suggested a potential link between organophosphate pesticide (OPP) exposure and higher LDL-C in the general population and agricultural workers, the relationship in pregnant women and the effect of body mass index on this relationship remain unclear. We examined the association between the urinary concentrations of OPP metabolites (dialkylphosphates) and blood lipid levels in pregnant women. METHODS We used data from the Japan Environment and Children's Study, which included 5,169 pregnant women with urinary dialkylphosphate data. We examined the association between urinary concentrations of six dialkylphosphates (DEP, DETP, DEDTP, DMP, DMTP, DMDTP) and blood lipid levels (LDL-C, total cholesterol, high-density lipoprotein cholesterol, and triglycerides) during the first trimester using multiple linear regression under a Bayesian paradigm. We examined the association between high LDL-C, defined as ≥90th percentile of LDL-C, and urinary dialkylphosphate concentrations, using multiple logistic regression under a Bayesian paradigm. These analyses were repeated in underweight, normal-weight, and overweight participants. RESULTS DEP, DMP, and DMTP were detected in >50 % of the participants. Multiple linear regression analyses did not show associations between LDL-C and these dialkylphosphates. Stratified analyses showed a positive association between DEP and LDL-C in overweight women (beta coefficient = 2.13, 95 % credible interval = 0.86-3.38, probability of direction (PD) = 100 %); however, the association was not significant (percentage in region of practical equivalence (% in ROPE) = 84.0). Higher DEP was significantly associated with high LDL-C (odds ratio = 1.32, 95 % credible interval = 1.13-1.55, PD = 100 %, % in ROPE = 0.2). CONCLUSIONS Among overweight pregnant women in the first trimester, higher urinary DEP concentrations were associated with high LDL-C. The effects of OPP on blood lipid profiles merit further investigation.
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Affiliation(s)
- Nobuhisa Morimoto
- Japan Environment and Children's Study Programme Office, National Institute for Environmental Studies, Ibaraki, Japan; Graduate School of Public Health, St. Luke's International University, Chuo-ku, Tokyo 104-0045, Japan
| | - Yukiko Nishihama
- Japan Environment and Children's Study Programme Office, National Institute for Environmental Studies, Ibaraki, Japan; Paediatric Environmental Medicine, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kazunari Onishi
- Division of Environmental Health, Graduate School of Public Health, St. Luke's International University, Chuo-ku, Tokyo 104-0045, Japan
| | - Shoji F Nakayama
- Japan Environment and Children's Study Programme Office, National Institute for Environmental Studies, Ibaraki, Japan; Graduate School of Public Health, St. Luke's International University, Chuo-ku, Tokyo 104-0045, Japan.
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Jin X, Li Y, Li J, Cheng L, Yao Y, Shen H, Wang B, Ren J, Ying H, Xu J. Acute bone damage through liver-bone axis induced by thioacetamide in rats. BMC Pharmacol Toxicol 2022; 23:29. [PMID: 35526079 PMCID: PMC9080193 DOI: 10.1186/s40360-022-00568-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 04/25/2022] [Indexed: 11/24/2022] Open
Abstract
Background Thioacetamide (TAA) is used in various fields, such as synthetic drugs, organic chemical synthesis, and materials chemistry. TAA is mainly used to establish animal liver injury models and other organ damage models to explore their mechanisms for helping patients with liver disease. Liver damage can lead to abnormal expression of some enzymes in the serum, so we detected the appropriate enzyme levels in the serum of SD rats to verify the damage of TAA to the liver. More importantly, TAA caused bone damage is barely understood. Therefore, our research aims to establish a rat model reflecting the acute bone damage injury caused by TAA. Methods The SD rats were intraperitoneally injected with normal saline (0.9%) or TAA (200 mg/kg, 400 mg/kg) for 1 month (once the other day). After the last intraperitoneal injection, serum samples from rats were used for biochemical tests. Masson staining is used to detect liver damage, and micro-CT is used to detect the changes in bone. Moreover, the three-point bending experiment was used to detect the force range of the hind limbs of SD rats. Results Compared with the control group, after the intraperitoneal injection of TAA, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid (UA), total bile acid (TBA), alkaline phosphatase (ALP), carbamide (UREA) and creatinine (CREA) rose sharply, while the levels of serum content of total protein (TP), lactate dehydrogenase (LDH), calcium (Ca) and phosphorus (P) were severely reduced. After TAA administration, collagen fibers were deposited and liver fibrosis was obvious. Micro-CT results showed that the bone surface, tissue surface, bone volume, and tissue volume of rats with an intraperitoneal injection of TAA were significantly reduced. In addition, the bones of rats with an intraperitoneal injection of TAA can resist less pressure and are prone to fractures. Conclusions TAA can cause liver damage in SD rats, which is explained by the changes in serum biochemical indicators and the deposition of liver collagen. More importantly, TAA can reduce bone mineral density and increase the separation of bone trabeculae in SD rats, and finally lead to bone injury. This suggests that TAA may become an ideal model to investigate abnormal bone metabolism after liver injury.
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Affiliation(s)
- Xiaoli Jin
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yang Li
- FUDAN University, school of basic medical sciences, Shanghai, 200433, PR China
| | - Jianghua Li
- Department of The Third Orthopaedic, The First Affiliated Hospital of Shihezi University School of Medicine Xinjiang Shihezi, Shihezi, 832008, China
| | - Linyan Cheng
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yetao Yao
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hao Shen
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Bili Wang
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jun Ren
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hang Ying
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jian Xu
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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TÜRKMEN NB, YÜCE H, TAŞLIDERE A, ŞAHİN Y, ÇİFTÇİ O. The Ameliorate Effects of Nerolidol on Thioasteamide-induced Oxidative Damage in Heart and Kidney Tissue. Turk J Pharm Sci 2022; 19:1-8. [DOI: 10.4274/tjps.galenos.2021.30806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Sepehrinezhad A, Shahbazi A, Sahab Negah S, Joghataei MT, Larsen FS. Drug-induced-acute liver failure: A critical appraisal of the thioacetamide model for the study of hepatic encephalopathy. Toxicol Rep 2021; 8:962-970. [PMID: 34026559 PMCID: PMC8122178 DOI: 10.1016/j.toxrep.2021.04.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/17/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) following acute and chronic liver failure is defined as a complex of neuropsychiatric abnormalities, such as discrete personal changes, sleep disorder, forgetfulness, confusion, and decreasing the level of consciousness to coma. The use and design of suitable animal models that represent clinical features and pathological changes of HE are valuable to map the molecular mechanisms that result in HE. Among different types of animal models, thioacetamide (TAA) has been used extensively for the induction of acute liver injury and HE. This agent is not directly hepatotoxic but its metabolites induce liver injury through the induction of oxidative stress and produce systemic inflammation similar to that seen in acute HE patients. In this short review article, we shortly review the most important pathological findings in animal models of acute HE following the administration of TAA.
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Key Words
- ALT, alanine aminotransferase
- AQP4, aquaporin 4 water channel
- AST, aspartate aminotransferase
- Acute liver failure
- Animal model
- B7, B7 molecules (CD80+CD86)
- BBB, blood-brain barrier
- CBF, cerebral blood flow
- CCL2, chemokine ligand 2
- CNS, central nervous system
- CTLA4, Cytotoxic T-lymphocyte-associated Protein 4
- CYP2E1, Cytochrome P450 family 2 subfamily E member 1
- GFAP, glial fibrillary acidic protein
- HE, hepatic encephalopathy
- Hepatic encephalopathy
- IL-6, interleukin 6
- IL-β, interleukin 1 β
- Iba1, ionized calcium-binding adaptor molecule 1
- JNK, c-Jun N-terminal kinase
- NAC, N-acetylcysteine
- NF-κB, nuclear factor κB
- OA, L-ornithine-l-aspartate
- ROS, reactive oxygen species
- TAA, thioacetamide
- TASO, thioacetamide sulfoxide
- TASO2, thioacetamide sulfdioxide
- TLR-2, toll-like receptor 2
- TLR-4, toll-like receptor 4
- TNFα, tumor necrosis factor α
- Thioacetamide
- Toxicity pathway
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Taghi Joghataei
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fin Stolze Larsen
- Department of Hepatology CA-3163, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
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Morgan AE, Mc Auley MT. Cholesterol Homeostasis: An In Silico Investigation into How Aging Disrupts Its Key Hepatic Regulatory Mechanisms. BIOLOGY 2020; 9:E314. [PMID: 33007859 PMCID: PMC7599957 DOI: 10.3390/biology9100314] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/21/2020] [Accepted: 09/24/2020] [Indexed: 12/17/2022]
Abstract
The dysregulation of intracellular cholesterol homeostasis is associated with several age-related diseases, most notably cardiovascular disease (CVD). Research in this area has benefitted from using computational modelling to study the inherent complexity associated with the regulation of this system. In addition to facilitating hypothesis exploration, the utility of modelling lies in its ability to represent an array of rate limiting enzymatic reactions, together with multiple feedback loops, which collectively define the dynamics of cholesterol homeostasis. However, to date no model has specifically investigated the effects aging has on this system. This work addresses this shortcoming by explicitly focusing on the impact of aging on hepatic intracellular cholesterol homeostasis. The model was used to investigate the experimental findings that reactive oxygen species induce the total activation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR). Moreover, the model explored the impact of an age-related decrease in hepatic acetyl-CoA acetyltransferase 2 (ACAT2). The model suggested that an increase in the activity of HMGCR does not have as significant an impact on cholesterol homeostasis as a decrease in hepatic ACAT2 activity. According to the model, a decrease in the activity of hepatic ACAT2 raises free cholesterol (FC) and decreases low-density lipoprotein cholesterol (LDL-C) levels. Increased acetyl CoA synthesis resulted in a reduction in the number of hepatic low-density lipoprotein receptors, and increased LDL-C, FC, and cholesterol esters. The rise in LDL-C was restricted by elevated hepatic FC accumulation. Taken together these findings have important implications for healthspan. This is because emerging clinical data suggest hepatic FC accumulation is relevant to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is associated with an increased risk of CVD. These pathophysiological changes could, in part, help to explain the phenomenon of increased mortality associated with low levels of LDL-C which have been observed in certain studies involving the oldest old (≥85 years).
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Affiliation(s)
| | - Mark Tomás Mc Auley
- Faculty of Science and Engineering, University of Chester, Thornton Science Park, Chester CH2 4NU, UK;
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Impact of Sex and Age on the Mevalonate Pathway in the Brain: A Focus on Effects Induced by Maternal Exposure to Exogenous Compounds. Metabolites 2020; 10:metabo10080304. [PMID: 32722471 PMCID: PMC7463490 DOI: 10.3390/metabo10080304] [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: 06/15/2020] [Revised: 07/19/2020] [Accepted: 07/23/2020] [Indexed: 12/21/2022] Open
Abstract
The mevalonate pathway produces cholesterol and other compounds crucial for numerous cellular processes. It is well known that age and sex modulate this pathway in the liver. Recently, similar effects were also noted in different brain areas, suggesting that alterations of the mevalonate pathway are at the root of marked sex-specific disparities in some neurodevelopmental disorders related to disturbed cholesterol homeostasis. Here, we show how the mevalonate pathway is modulated in a sex-, age- and region-specific manner, and how maternal exposure to exogenous compounds can disturb the regulation of this pathway in the brain, possibly inducing functional alterations.
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Sayan M, Karabulut D, Özdamar S. Assessment of the protective and therapeutic effect of melatonin against thioacetamide-induced acute liver damage. J Biochem Mol Toxicol 2020; 34:e22450. [PMID: 31967703 DOI: 10.1002/jbt.22450] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 11/01/2019] [Accepted: 01/08/2020] [Indexed: 12/19/2022]
Abstract
Acute or chronic damage to the liver may occur through alcohol, drugs, viruses, genetic disorders, and toxicity. In this study, we planned to investigate the protective and therapeutic effects of melatonin (Mel) by causing damage to the liver with thioacetamide (TAA). Thirty-five rats were used. Group I: control group (seven pieces), group II: Mel group (seven pieces) the single dose on the first day of the experiment was 10 mg/kg, group III: TAA (seven pieces) 300 mg/kg with 24-hour intervals, two doses, group IV: Mel + TAA group (seven pieces) 10 mg/kg single dose Mel was applied 24 hours before TAA application, group V: TAA + Mel group (seven pieces) single dose (24th hour) of 10 mg/kg Mel was administered after TAA (300 mg/kg) two doses. The liver histology was evaluated. Apoptosis, autophagy, and necrosis markers in tissue were determined by immunohistochemistry. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels in blood serum samples and transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) levels were determined in liver tissue. TAA affected histologically the classical lobule structure both in cell cords and sinusoids. Caspase-3, RIP3, and LC3 levels were increased in group III compared with the control group. TAA did not cause a statistically significant change in TNF-α level but decreased the TGF-β level significantly. AST and ALT levels were statistically significant in group II and V compared with group I, the ALP level was significant in group IV compared with group II. The results of this study showed that TAA caused significant damage to tissues and increased cell death, Mel was found to have more therapeutic than the protective effect on tissues.
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Affiliation(s)
- Meryem Sayan
- Department of Histology and Embryology, Erciyes University, Kayseri, Turkey
| | - Derya Karabulut
- Department of Histology and Embryology, Erciyes University, Kayseri, Turkey
| | - Saim Özdamar
- Department of Histology and Embryology, Pamukkale University, Kayseri, Turkey
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Abstract
The last few decades have witnessed a global rise in the number of older individuals. Despite this demographic shift, morbidity within this population group is high. Many factors influence healthspan; however, an obesity pandemic is emerging as a significant determinant of older people's health. It is well established that obesity adversely affects several metabolic systems. However, due to its close association with overall cardiometabolic health, the impact that obesity has on cholesterol metabolism needs to be recognised. The aim of the present review is to critically discuss the effects that obesity has on cholesterol metabolism and to reveal its significance for healthy ageing.
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9
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Kaur S, Sharma D, Singh AP, Kaur S. Amelioration of hepatic function, oxidative stress, and histopathologic damages by Cassia fistula L. fraction in thioacetamide-induced liver toxicity. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:29930-29945. [PMID: 31407268 DOI: 10.1007/s11356-019-06158-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 07/31/2019] [Indexed: 06/10/2023]
Abstract
Cassia fistula L. (Caesalpinioideae) is a highly admirable medicinal plant and is traditionally recommended for the treatment of rheumatism, liver disorders, jaundice, and other inflammatory diseases. This study was designed to investigate the hepatoprotective properties of ethyl acetate fraction from C. fistula leaves in an animal model. Treatment with thioacetamide significantly elevated the level of serum glutamic-oxaloacetic transaminase (1.75-fold), alkaline phosphatase (4.07-fold), and total bilirubin (2.29-fold) as compared to the control. It was found that pretreatment of fraction followed by consecutive 2 days thioacetamide reduced the conversion of thioacetamide carcinogen to its reactive metabolites by phase I enzymes and increased the level of detoxification phase II along with antioxidative enzymes. The histopathological studies revealed the hepatoprotective nature of the fraction in restoring the normal architecture of thioacetamide-intoxicated damaged liver. The fraction showed downregulation in the expression level of p-PI3K, p-Akt, and p-mTOR pointing towards its chemopreventive potential. The HPLC analysis of the fraction had shown the dominance of three phenolic compounds namely, catechin, epicatechin, and chlorogenic acid. The above studies comprising histopathological, immunohistochemical, and hepatic enzymes are strong indicative of the potential protective ability of ethyl acetate fraction phytoconstituents against thioacetamide-induced toxicity. Graphical abstract.
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Affiliation(s)
- Sandeep Kaur
- Genetic Toxicology Laboratory, Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Dipakshi Sharma
- Genetic Toxicology Laboratory, Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Amrit Pal Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Satwinderjeet Kaur
- Genetic Toxicology Laboratory, Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
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10
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Aires V, Labbé J, Deckert V, Pais de Barros JP, Boidot R, Haumont M, Maquart G, Le Guern N, Masson D, Prost-Camus E, Prost M, Lagrost L. Healthy adiposity and extended lifespan in obese mice fed a diet supplemented with a polyphenol-rich plant extract. Sci Rep 2019; 9:9134. [PMID: 31235831 PMCID: PMC6591401 DOI: 10.1038/s41598-019-45600-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 06/10/2019] [Indexed: 12/13/2022] Open
Abstract
Obesity may not be consistently associated with metabolic disorders and mortality later in life, prompting exploration of the challenging concept of healthy obesity. Here, the consumption of a high-fat/high-sucrose (HF/HS) diet produces hyperglycaemia and hypercholesterolaemia, increases oxidative stress, increases endotoxaemia, expands adipose tissue (with enlarged adipocytes, enhanced macrophage infiltration and the accumulation of cholesterol and oxysterols), and reduces the median lifespan of obese mice. Despite the persistence of obesity, supplementation with a polyphenol-rich plant extract (PRPE) improves plasma lipid levels and endotoxaemia, prevents macrophage recruitment to adipose tissues, reduces adipose accumulation of cholesterol and cholesterol oxides, and extends the median lifespan. PRPE drives the normalization of the HF/HS-mediated functional enrichment of genes associated with immunity and inflammation (in particular the response to lipopolysaccharides). The long-term limitation of immune cell infiltration in adipose tissue by PRPE increases the lifespan through a mechanism independent of body weight and fat storage and constitutes the hallmark of a healthy adiposity trait.
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Affiliation(s)
- Virginie Aires
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France. .,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France. .,LipSTIC LabEx, F-21000, Dijon, France.
| | - Jérôme Labbé
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France.,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France.,LipSTIC LabEx, F-21000, Dijon, France
| | - Valérie Deckert
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France.,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France.,LipSTIC LabEx, F-21000, Dijon, France
| | - Jean-Paul Pais de Barros
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France.,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France.,LipSTIC LabEx, F-21000, Dijon, France.,Lipidomic Platform, F-21000, Dijon, France
| | - Romain Boidot
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France.,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France.,LipSTIC LabEx, F-21000, Dijon, France.,Platform of Transfer in Cancer Biology, Centre Georges-François Leclerc, F-21000, Dijon, France.,Department of Biology and Pathology of Tumours, Centre Georges-François Leclerc, F-21000, Dijon, France
| | - Marc Haumont
- LARA-Spiral Laboratories, F-21560, Couternon, France
| | - Guillaume Maquart
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France.,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France.,LipSTIC LabEx, F-21000, Dijon, France
| | - Naig Le Guern
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France.,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France.,LipSTIC LabEx, F-21000, Dijon, France
| | - David Masson
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France.,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France.,LipSTIC LabEx, F-21000, Dijon, France.,University Hospital of Dijon (CHU), F-21000, Dijon, France
| | | | - Michel Prost
- LARA-Spiral Laboratories, F-21560, Couternon, France.,VITAGORA Competitiveness Cluster, F-21000, Dijon, France
| | - Laurent Lagrost
- University of Bourgogne-Franche-Comté, F-21000, Dijon, France. .,INSERM U1231 "Lipids, Nutrition, Cancer", F-21000, Dijon, France. .,LipSTIC LabEx, F-21000, Dijon, France. .,LARA-Spiral Laboratories, F-21560, Couternon, France. .,VITAGORA Competitiveness Cluster, F-21000, Dijon, France.
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11
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El Awdan SA, Abdel Rahman RF, Ibrahim HM, Hegazy RR, El Marasy SA, Badawi M, Arbid MS. Regression of fibrosis by cilostazol in a rat model of thioacetamide-induced liver fibrosis: Up regulation of hepatic cAMP, and modulation of inflammatory, oxidative stress and apoptotic biomarkers. PLoS One 2019; 14:e0216301. [PMID: 31067255 PMCID: PMC6505801 DOI: 10.1371/journal.pone.0216301] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 04/17/2019] [Indexed: 12/20/2022] Open
Abstract
In liver fibrosis, conversion of fibroblasts to profibrogenic myofibroblasts significantly drives the development of the disease. A crucial role of cyclic adenosine monophosphate (cAMP) in regulation of fibroblast function has been reported. Increase in cAMP levels has been found to decrease fibroblast proliferation, inhibit their conversion to myofibroblast, and stimulate their death. cAMP is generated by adenyl cyclase (AC), and degraded by cyclic nucleotide phosphodiesterase (PDE). In this study, the antifibrotic effect of a PDE inhibitor, cilostazol (Cilo), on a rat model of liver fibrosis induced by thioacetamide (TAA) was investigated. Four groups of rats were used; the first group received the vehicles and served as the normal control group, while liver fibrosis was induced in the other groups using (TAA, 200 mg/kg/biweekly for 8 successive weeks, ip). The last two groups were treated with Cilo (50 and 100 mg/kg/day, po, respectively). Induction of liver fibrosis in TAA-treated rats was observed as evidenced by the biochemical and histopathological findings. On the other hand, a potent antifibrotic effect was observed in the groups treated with Cilo, with preference to the higher dose. In these groups, a significant increase in the liver content of cAMP was demonstrated that was accompanied by reduction in the hepatic expression of key fibrogenic cytokines, growth factors, and inflammatory biomarkers, including interleukin-6, tumor necrosis factor-alpha, nuclear factor kappa B, and transforming growth factor-beta as compared to TAA group. Moreover, amelioration of TAA-induced oxidative stress and apoptosis in the liver has been observed. These findings reveal the antifibrotic effect of Cilo against TAA-induced liver fibrosis in rats, and suggest regulation of cAMP pathway, together with the modulation of oxidative stress, inflammation, and apoptosis as mechanistic cassette underlines this effect.
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Affiliation(s)
- Sally A. El Awdan
- Pharmacology Department, Medical Division, National Research Centre, Giza, Egypt
| | | | - Heba M. Ibrahim
- Pharmacology Department, Medical Division, National Research Centre, Giza, Egypt
| | - Rehab R. Hegazy
- Pharmacology Department, Medical Division, National Research Centre, Giza, Egypt
| | - Salma A. El Marasy
- Pharmacology Department, Medical Division, National Research Centre, Giza, Egypt
| | - Manal Badawi
- Pathology Department, Medical Division, National Research Centre, Giza, Egypt
| | - Mahmoud S. Arbid
- Pharmacology Department, Medical Division, National Research Centre, Giza, Egypt
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12
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Harb AA, Bustanji YK, Abdalla SS. Hypocholesterolemic effect of β-caryophyllene in rats fed cholesterol and fat enriched diet. J Clin Biochem Nutr 2018; 62:230-237. [PMID: 29892161 PMCID: PMC5990408 DOI: 10.3164/jcbn.17-3] [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] [Received: 01/04/2017] [Accepted: 11/06/2017] [Indexed: 12/21/2022] Open
Abstract
Hypercholesterolemia is a major risk factor for cardiovascular diseases. This study investigated the cholesterol-lowering potential of β-caryophyllene in a rat model. Hypercholesterolemia was induced by feeding male Wistar rats a high cholesterol and fat diet for 2 weeks. This was followed by oral administration of β-caryophyllene to hypercholesterolemic rats at 30, 100 and 300 mg/kg b.w. for 4 weeks. A dose of 30 mg/kg of β-caryophyllene significantly lowered serum total cholesterol, low density lipoprotein and the atherogenic index and significantly increased high density lipoprotein level. Moreover, it ameliorated liver injury as evidenced by decreasing hepatomegaly, macrovesicular steatosis and the activity of hepatic marker enzymes alanine aminotransferase and aspartate aminotransferase. Furthermore, it increased the activity of the antioxidant enzyme superoxide dismutase. This dose of β-caryophyllene significantly inhibited the activity of hepatic hydroxy-methylglutaryl coenzyme A reductase. Higher doses (100 and 300 mg/kg) of β-caryophyllene, however, did not induce significant beneficial effects on the studied parameters. These observations demonstrate that β-caryophyllene has a cholesterol-lowering effect on hypercholesterolemic rats, thus offering protection against hypercholesterolemia-induced diseases such as atherosclerosis and fatty liver.
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Affiliation(s)
- Amani A. Harb
- Department of Biological Sciences, Faculty of Science, The University of Jordan, Amman 11942, Jordan
| | | | - Shtaywy S. Abdalla
- Department of Biological Sciences, Faculty of Science, The University of Jordan, Amman 11942, Jordan
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13
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Saad RA, EL-Bab MF, Shalaby AA. Attenuation of acute and chronic liver injury by melatonin in rats. JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 2018. [DOI: 10.1016/j.jtusci.2013.04.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Ramadan A. Saad
- Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Fath EL-Bab
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- Department of Physiology, College of Medicine, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia
| | - Abir A. Shalaby
- Department of Biochemistry, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
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14
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Bashandy SAE, Ebaid H, Abdelmottaleb Moussa SA, Alhazza IM, Hassan I, Alaamer A, Al Tamimi J. Potential effects of the combination of nicotinamide, vitamin B2 and vitamin C on oxidative-mediated hepatotoxicity induced by thioacetamide. Lipids Health Dis 2018; 17:29. [PMID: 29444683 PMCID: PMC5813429 DOI: 10.1186/s12944-018-0674-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 02/05/2018] [Indexed: 02/08/2023] Open
Abstract
Background The liver disease is one of the most important traditional public health problems in Egypt. Oxidative stress is attributed to such pathological condition that further contributes to the initiation and progression of liver injury. In the present study, we have investigated if the strong antioxidant power of Nicotinamide (NA), Vitamin B2 (VB2), and Vitamin C (VC) can ameliorate TAA-induced oxidative stress-mediated liver injury in the rats. Methods Thirty-six albino rats were divided into six groups: Control group; TAA group (IP injection with TAA at a dosage of 200 mg/Kg three times a week for two months); TAA + NA group (rats administered with NA at a dosage of 200 mg/kg daily besides TAA as in the control); TAA + VB2 group (rats administered with vitamin B2 at a dosage of 30 mg/kg daily besides injection with TAA); TAA + VC group (rats administered with vitamin C at a dosage of 200 mg/kg daily along with injection of TAA). TAA + NA + VB + VC group (rats administered the with the three vitamins daily in TAA pre-injected at the respective doses described above). Results Treatment of rats with TAA led to a significant elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, cholesterol, triglycerides, low-density lipoprotein (LDL) and tumor necrosis factor-alpha (TNF-α) in the serum samples. Moreover, malondialdehyde (MDA), hydroxyproline and nitic oxide (NO) were also significantly increased in the TAA-treated rats, while reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were significantly compromised in the hepatic samples. Rats administered with NA, VB2, and VC as individually or in combination ameliorated the deleterious effects of TAA that was confirmed by histopathology. However, the combination of the three vitamins was found more effective as compared to each of the vitamins. Conclusion Our work demonstrates that NA, VB2, and VC cross-talk with each other that act as a more potent biochemical chain of antioxidant defense against TAA-induced toxicities in vivo.
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Affiliation(s)
- Samir A E Bashandy
- Pharmacology Department, Medical Division, National Research Centre, Bohouth St. (former EL Tahrir St.), Dokki, Giza, EL, 33, Egypt
| | - Hossam Ebaid
- Department of Zoology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia. .,Department of Zoology, Faculty of Science, Minia University, Minia, Egypt.
| | - Sherif A Abdelmottaleb Moussa
- Committee of Radiation and Environmental Pollution Protection (CREPP), Department of Physics, College of Science, Al- Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.,Biophysics Group, Biochemistry Department, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Giza, Egypt
| | - Ibrahim M Alhazza
- Department of Zoology, Faculty of Science, Minia University, Minia, Egypt
| | - Iftekhar Hassan
- Department of Zoology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Abdulaziz Alaamer
- Committee of Radiation and Environmental Pollution Protection (CREPP), Department of Physics, College of Science, Al- Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Jameel Al Tamimi
- Pharmacology Department, Medical Division, National Research Centre, Bohouth St. (former EL Tahrir St.), Dokki, Giza, EL, 33, Egypt
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15
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Altered Brain Cholesterol/Isoprenoid Metabolism in a Rat Model of Autism Spectrum Disorders. Neuroscience 2018; 372:27-37. [PMID: 29309878 DOI: 10.1016/j.neuroscience.2017.12.053] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 11/28/2017] [Accepted: 12/28/2017] [Indexed: 12/11/2022]
Abstract
Autism spectrum disorders (ASDs) present a wide range of symptoms characterized by altered sociability, compromised communication and stereotypic/repetitive behaviors. These symptoms are caused by developmental changes, but the mechanisms remain largely unknown. Some lines of evidence suggest an impairment of the cholesterol/isoprenoid metabolism in the brain as a possible cause, but systematic analyses in rodent models of ASDs are lacking. Prenatal exposure to the antiepileptic drug valproate (VPA) is a risk factor for ASDs in humans and generates a well-established model for the disease in rodents. Here, we studied cholesterol/isoprenoid metabolism in different brain areas of infant, adolescent and adult rats prenatally exposed to VPA. VPA-treated rats present autistic-like symptoms, they show changes in cholesterol/isoprenoid homeostasis in some brain areas, a decreased number of oligodendrocytes and impaired myelination in the hippocampus. Together, our data suggest a relation between brain cholesterol/isoprenoid homeostasis and ASDs.
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16
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Abstract
The last few decades have witnessed remarkable progress in our understanding of ageing. From an evolutionary standpoint it is generally accepted that ageing is a non-adaptive process which is underscored by a decrease in the force of natural selection with time. From a mechanistic perspective ageing is characterized by a wide variety of cellular mechanisms, including processes such as cellular senescence, telomere attrition, oxidative damage, molecular chaperone activity, and the regulation of biochemical pathways by sirtuins. These biological findings have been accompanied by an unrelenting rise in both life expectancy and the number of older people globally. However, despite age being recognized demographically as a risk factor for healthspan, the processes associated with ageing are routinely overlooked in disease mechanisms. Thus, a central goal of biogerontology is to understand how diseases such as cardiovascular disease (CVD) are shaped by ageing. This challenge cannot be ignored because CVD is the main cause of morbidity in older people. A worthwhile way to examine how ageing intersects with CVD is to consider the effects ageing has on cholesterol metabolism, because dysregualted cholesterol metabolism is the key factor which underpins the pathology of CVD. The aim of this chapter is to outline a hypothesis which accounts for how ageing intersects with intracellular cholesterol metabolism. Moreover, we discuss the implications of this relationship for the onset of disease in the 'oldest old' (individuals ≥85 years of age). We conclude the chapter by discussing the important role mathematical modelling has to play in improving our understanding of cholesterol metabolism and ageing.
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Mc Auley MT, Mooney KM. LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge. Med Hypotheses 2017; 104:15-19. [PMID: 28673574 DOI: 10.1016/j.mehy.2017.05.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 05/10/2017] [Accepted: 05/15/2017] [Indexed: 01/11/2023]
Abstract
The cardiovascular disease (CVD) risk factor, low density lipoprotein cholesterol (LDL-C) increases with age, up until the midpoint of life in males and females. However, LDL-C can decrease with age in older men and women. Intriguingly, a recent systematic review also revealed an inverse association between LDL-C levels and cardiovascular mortality in older people; low levels of LDL-C were associated with reduced risk of mortality. Such findings are puzzling and require a biological explanation. In this paper a hypothesis is proposed to explain these observations. We hypothesize that the free radical theory of ageing (FRTA) together with disrupted cholesterol homeostasis can account for these observations. Based on this hypothesis, dysregulated hepatic cholesterol homeostasis in older people is characterised by two distinct metabolic states. The first state accounts for an older person who has elevated plasma LDL-C. This state is underpinned by the FRTA which suggests there is a decrease in cellular antioxidant capacity with age. This deficiency enables hepatic reactive oxidative species (ROS) to induce the total activation of HMG-CoA reductase, the key rate limiting enzyme in cholesterol biosynthesis. An increase in cholesterol synthesis elicits a corresponding rise in LDL-C, due to the downregulation of LDL receptor synthesis, and increased production of very low density lipoprotein cholesterol (VLDL-C). In the second state of dysregulation, ROS also trigger the total activation of HMG-CoA reductase. However, due to an age associated decrease in the activity of cholesterol-esterifying enzyme, acyl CoA: cholesterol acyltransferase, there is restricted conversion of excess free cholesterol (FC) to cholesterol esters. Consequently, the secretion of VLDL-C drops, and there is a corresponding decrease in LDL-C. As intracellular levels of FC accumulate, this state progresses to a pathophysiological condition akin to nonalcoholic fatty liver disease. It is our conjecture this deleterious state has the potential to account for the inverse association between LDL-C level and CVD risk observed in older people.
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Affiliation(s)
- Mark T Mc Auley
- Faculty of Science and Engineering, Thornton Science Park, University of Chester, CH2 4NU, UK.
| | - Kathleen M Mooney
- Faculty of Health and Social Care, Edge Hill University, Ormskirk, Lancashire L39 4QP, UK
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18
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Cavallini G, Sgarbossa A, Parentini I, Bizzarri R, Donati A, Lenci F, Bergamini E. Dolichol: A Component of the Cellular Antioxidant Machinery. Lipids 2016; 51:477-86. [PMID: 26968401 DOI: 10.1007/s11745-016-4137-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 02/25/2016] [Indexed: 10/22/2022]
Abstract
Dolichol, an end product of the mevalonate pathway, has been proposed as a biomarker of aging, but its biological role, not to mention its catabolism, has not been fully understood. UV-B radiation was used to induce oxidative stress in isolated rat hepatocytes by the collagenase method. Effects on dolichol, phospholipid-bound polyunsaturated fatty acids (PL-PUFA) and known lipid soluble antioxidants [coenzyme Q (CoQ) and α-tocopherol] were studied. The increase in oxidative stress was detected by a probe sensitive to reactive oxygen species (ROS). Peroxidation of lipids was assessed by measuring the release of thiobarbituric acid reactive substances (TBARS). Dolichol, CoQ, and α-tocopherol were assessed by high-pressure liquid chromatography (HPLC), PL-PUFA by gas-liquid chromatography (GC). UV-B radiation caused an immediate increase in ROS as well as lipid peroxidation and a simultaneous decrease in the levels of dolichol and lipid soluble antioxidants. Decrease in dolichol paralleled changes in CoQ levels and was smaller to that in α-tocopherol. The addition of mevinolin, a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR), magnified the loss of dolichol and was associated with an increase in TBARS production. Changes in PL-PUFA were minor. These findings highlight that oxidative stress has very early and similar effects on dolichol and lipid soluble antioxidants. Lower levels of dolichol are associated with enhanced peroxidation of lipids, which suggest that dolichol may have a protective role in the antioxidant machinery of cell membranes and perhaps be a key to understanding some adverse effects of statin therapy.
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Affiliation(s)
- Gabriella Cavallini
- Interdepartmental Research Centre on Biology and Pathology of Aging, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
| | - Antonella Sgarbossa
- Biophysics Institute of the National Research Council (IBF-CNR), Pisa, Italy.,NEST, Nanoscience Institute of the National Research Council (NANO-CNR) and Scuola Normale Superiore, Pisa, Italy
| | - Ilaria Parentini
- Interdepartmental Research Centre on Biology and Pathology of Aging, University of Pisa, Via Roma 55, 56126, Pisa, Italy
| | - Ranieri Bizzarri
- Biophysics Institute of the National Research Council (IBF-CNR), Pisa, Italy.,NEST, Nanoscience Institute of the National Research Council (NANO-CNR) and Scuola Normale Superiore, Pisa, Italy
| | - Alessio Donati
- Interdepartmental Research Centre on Biology and Pathology of Aging, University of Pisa, Via Roma 55, 56126, Pisa, Italy
| | - Francesco Lenci
- Biophysics Institute of the National Research Council (IBF-CNR), Pisa, Italy
| | - Ettore Bergamini
- Interdepartmental Research Centre on Biology and Pathology of Aging, University of Pisa, Via Roma 55, 56126, Pisa, Italy
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Pecorelli A, Belmonte G, Meloni I, Cervellati F, Gardi C, Sticozzi C, De Felice C, Signorini C, Cortelazzo A, Leoncini S, Ciccoli L, Renieri A, Jay Forman H, Hayek J, Valacchi G. Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder. Free Radic Biol Med 2015; 86:156-65. [PMID: 26006105 PMCID: PMC5572621 DOI: 10.1016/j.freeradbiomed.2015.05.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 05/03/2015] [Accepted: 05/08/2015] [Indexed: 11/24/2022]
Abstract
CDKL5 mutation is associated with an atypical Rett syndrome (RTT) variant. Recently, cholesterol homeostasis perturbation and oxidative-mediated loss of the high-density lipoprotein receptor SRB1 in typical RTT have been suggested. Here, we demonstrate an altered lipid serum profile also in CDKL5 patients with decreased levels of SRB1 and impaired activation of the defensive system Nrf2. In addition, CDKL5 fibroblasts showed an increase in 4-hydroxy-2-nonenal- and nitrotyrosine-SRB1 adducts that lead to its ubiquitination and probable degradation. This study highlights a possible common denominator between two different RTT variants (MECP2 and CDKL5) and a possible common future therapeutic target.
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Affiliation(s)
- Alessandra Pecorelli
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy
| | - Giuseppe Belmonte
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | | | - Franco Cervellati
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Concetta Gardi
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Claudia Sticozzi
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Claudio De Felice
- Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy
| | - Cinzia Signorini
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Alessio Cortelazzo
- Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy
| | - Silvia Leoncini
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy
| | - Lucia Ciccoli
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Alessandra Renieri
- Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Henry Jay Forman
- Life and Environmental Sciences Unit, University of California at Merced, Merced, CA 95344, USA; Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | - Joussef Hayek
- Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, "Santa Maria alle Scotte" General Hospital, Siena, Italy
| | - Giuseppe Valacchi
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
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20
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Saracyn M, Zdanowski R, Brytan M, Kade G, Nowak Z, Patera J, Dyrla P, Gil J, Wańkowicz Z. D-Galactosamine Intoxication in Experimental Animals: Is it Only an Experimental Model of Acute Liver Failure? Med Sci Monit 2015; 21:1469-77. [PMID: 26009004 PMCID: PMC4451715 DOI: 10.12659/msm.893291] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 01/27/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Short-term administration of Galactosamine to experimental animals causes liver damage and acute liver failure (ALF), as well as acute renal failure in some cases. The aim of our study was to describe kidney disorders that developed in the course of galactosamine-induced liver failure. MATERIAL AND METHODS Sprague-Dawley rats were randomly divided into 2 groups: a study group administered galactosamine intraperitoneally and a control group administered saline. RESULTS All the animals in the study group developed liver damage and failure within 48 h, with significant increase of alanine (p<0.001), aspartate aminotransferases (p<0.0001), bilirubin (p<0.004), and ammonia (p<0.005) and decrease of albumin (p<0.001) concentrations. Acute renal failure was observed in all test animals, with a significant increase in creatinine (p<0.001) and urea (p<0.001) concentrations and a decrease in creatinine clearance (p<0.0012). Moreover, osmotic clearance (p<0.001), daily natriuresis (p<0.003), and fractional sodium excretion (p<0.016) decreased significantly in this group of animals. The ratio of urine osmolality to serum osmolality did not change. Histopathology of the liver revealed massive necrosis of hepatocytes, whereas renal histopathology showed no changes. CONCLUSIONS Acute renal failure that developed in the course of galactosamine-induced ALF was of a functional nature, with the kidneys retaining the ability to concentrate urine and retain sodium, and there were no renal changes in the histopathological examination. It seems that the experimental model of ALF induced by galactosamine can be viewed as a model of hepatorenal syndrome that occurs in the course of acute damage and liver failure.
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Affiliation(s)
- Marek Saracyn
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, Poland
| | - Robert Zdanowski
- Department of Regenerative Medicine, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Marek Brytan
- Department of Pharmacology and Toxicology, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Grzegorz Kade
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, Poland
| | - Zbigniew Nowak
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, Poland
| | - Janusz Patera
- Department of Pathology, Military Institute of Medicine, Warsaw, Poland
| | - Przemysław Dyrla
- Department of Gastroenterology, Military Institute of Medicine, Warsaw, Poland
| | - Jerzy Gil
- Department of Gastroenterology, Military Institute of Medicine, Warsaw, Poland
| | - Zofia Wańkowicz
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, Poland
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Hessin A, Hegazy R, Hassan A, Yassin N, Kenawy S. Lactoferrin Enhanced Apoptosis and Protected Against Thioacetamide-Induced Liver Fibrosis in Rats. Open Access Maced J Med Sci 2015; 3:195-201. [PMID: 27275221 PMCID: PMC4877853 DOI: 10.3889/oamjms.2015.038] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 03/12/2015] [Accepted: 03/13/2015] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND: Liver fibrosis is the common pathologic consequence of all chronic liver diseases. AIM: Lactoferrin (Lf) was investigated for its possible hepatoprotective effect against thioacetamide (TAA)-induced liver fibrosis rat model. MATERIAL AND METHODS: Rats received TAA (200 mg/kg/biweekly, ip) for four successive weeks. Lf (200 mg/kg/day, p.o.) or vehicle (VHC) was administered for one month before and another month during TAA injection. Body weight and mortality rate were assessed during the month of TAA-intoxication. Thereafter, serum and liver tissues were analyzed for liver function, oxidative, fibrotic and apoptotic markers. RESULTS: Lf conserved rats against TAA-induced body weight-loss and mortality. Preservation of serum albumin, alkaline phosphatase and total bilirubin levels was also observed. Lf also protected rats against TAA-induced decrease in reduced glutathione and increase in malondialdehyde liver contents. Normal liver contents of hydroxyproline, nuclear factor kappa B and alpha fetoprotein; as markers of fibrosis; were increased with TAA and conserved with Lf-TAA. Lf maintained the normal architecture of the liver and immunohistochemical findings revealed increase in apoptotic bodies compared to TAA that favored necrosis. CONCLUSION: In conclusion, Lf improved liver function, reduced oxidative stress and liver fibrosis, and enhanced apoptosis in rats with liver fibrosis, suggesting it to have useful therapeutic potential in patients with liver fibrosis.
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Affiliation(s)
- Alyaa Hessin
- National Research Center, Medical Division, Pharmacology Department, Giza, Egypt
| | - Rehab Hegazy
- National Research Center, Medical Division, Pharmacology Department, Giza, Egypt
| | - Azza Hassan
- Cairo University, Faculty of Veterinary Medicine, Pathology Department, Giza, Egypt
| | - Nemat Yassin
- National Research Center, Medical Division, Pharmacology Department, Giza, Egypt
| | - Sanaa Kenawy
- Cairo University, Faculty of Pharmacy, Pharmacology and Toxicology Department, Cairo, Egypt
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22
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Wei W, Dirsch O, Mclean AL, Zafarnia S, Schwier M, Dahmen U. Rodent models and imaging techniques to study liver regeneration. Eur Surg Res 2014; 54:97-113. [PMID: 25402256 DOI: 10.1159/000368573] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 09/19/2014] [Indexed: 12/16/2022]
Abstract
The liver has the unique capability of regeneration from various injuries. Different animal models and in vitro methods are used for studying the processes and mechanisms of liver regeneration. Animal models were established either by administration of hepatotoxic chemicals or by surgical approach. The administration of hepatotoxic chemicals results in the death of liver cells and in subsequent hepatic regeneration and tissue repair. Surgery includes partial hepatectomy and portal vein occlusion or diversion: hepatectomy leads to compensatory regeneration of the remnant liver lobe, whereas portal vein occlusion leads to atrophy of the ipsilateral lobe and to compensatory regeneration of the contralateral lobe. Adaptation of modern radiological imaging technologies to the small size of rodents made the visualization of rodent intrahepatic vascular anatomy possible. Advanced knowledge of the detailed intrahepatic 3D anatomy enabled the establishment of refined surgical techniques. The same technology allows the visualization of hepatic vascular regeneration. The development of modern histological image analysis tools improved the quantitative assessment of hepatic regeneration. Novel image analysis tools enable us to quantify reliably and reproducibly the proliferative rate of hepatocytes using whole-slide scans, thus reducing the sampling error. In this review, the refined rodent models and the newly developed imaging technology to study liver regeneration are summarized. This summary helps to integrate the current knowledge of liver regeneration and promises an enormous increase in hepatological knowledge in the near future.
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Affiliation(s)
- Weiwei Wei
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
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23
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Segatto M, Trapani L, Di Tunno I, Sticozzi C, Valacchi G, Hayek J, Pallottini V. Cholesterol metabolism is altered in Rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients. PLoS One 2014; 9:e104834. [PMID: 25118178 PMCID: PMC4130597 DOI: 10.1371/journal.pone.0104834] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 07/17/2014] [Indexed: 12/19/2022] Open
Abstract
Rett (RTT) syndrome is a severe neurological disorder that affects almost exclusively females. Several detectable mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) are responsible for the onset of the disease. MeCP2 is a key transcription regulator involved in gene silencing via methylation-dependent remodeling of chromatin. Recent data highlight that lipid metabolism is perturbed in brains and livers of MECP2-null male mice. In addition, altered plasma lipid profile in RTT patients has been observed. Thus, the aim of the work is to investigate the protein network involved in cholesterol homeostasis maintenance on freshly isolated fibroblasts and plasma from both RTT and healthy donors. To this end, protein expression of 3-hydroxy-3methyl glutaryl Coenzyme A reductase (HMGR), sterol regulatory element binding proteins (SREBPs), low density lipoprotein receptor (LDLr) and scavenger receptor B-1 (SRB-1) was assessed in cultured skin fibroblasts from unaffected individuals and RTT patients. In addition, lipid profile and the abundance of proprotein convertase subtilisin/kexin type 9 (PCSK9) were analyzed on plasma samples. The obtained results demonstrate that the main proteins belonging to cholesterol regulatory network are altered in RTT female patients, providing the proof of principle that cholesterol metabolism may be taken into account as a new target for the treatment of specific features of RTT pathology.
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Affiliation(s)
- Marco Segatto
- Dept. of Science, Section of Biomedical Science and Technologies, University of Roma Tre, Rome, Italy
| | - Laura Trapani
- Dept. of Science, Section of Biomedical Science and Technologies, University of Roma Tre, Rome, Italy
| | - Ilenia Di Tunno
- Dept. of Science, Section of Biomedical Science and Technologies, University of Roma Tre, Rome, Italy
| | - Claudia Sticozzi
- Dept. of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Giuseppe Valacchi
- Dept. of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Joussef Hayek
- Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy
| | - Valentina Pallottini
- Dept. of Science, Section of Biomedical Science and Technologies, University of Roma Tre, Rome, Italy
- * E-mail:
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Parajuli DR, Zhao YZ, Jin H, Chi JH, Li SY, Kim YC, Sohn DH, Lee SH. Anti-fibrotic effect of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, in thioacetamide-induced experimental rats liver fibrosis. Arch Pharm Res 2014; 38:549-55. [PMID: 25005065 DOI: 10.1007/s12272-014-0425-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 06/11/2014] [Indexed: 01/18/2023]
Abstract
We previously reported the in vitro and in vivo hepatoprotective and anti-fibrotic effects of PF2401-SF, a standardized fraction of Salvia miltiorrhiza, against acute and subacute liver injury. The aim of this study was to investigate the effect of PF2401-SF on liver fibrosis induced by thioacetamide (TAA), a chronic liver injury model (12 weeks) that closely resembles fibrosis and cirrhosis in humans. Hepatoprotective activity was indicated by low serum levels of the markers aspartate amino transferase and alanine amino transferase .In addition, compared to the TAA-group livers, the PF2401-SF-treated liver tissues showed no fibrous tissue deposition in the portal areas, hepatocyte morphology more closely resembling normal tissue morphology, and significantly reduced collagen deposition. Furthermore, downregulation of collagen 1(α) and tissue inhibitor of metalloproteinase (TIMP)1 protein and mRNA expression also supports PF2401-SF's anti-fibrotic effect. We also observed reduced expression of α-smooth muscle actin (α-SMA), an important marker of hepatic stellate cells (HSCs) activation. From these results, we conclude that PF2401-SF's anti-fibrotic mechanism in the TAA model involves reduced HSC activation, and may be mediated by downregulation of central markers of fibrosis, including collagen 1(α), TIMP1, and α-SMA.
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Affiliation(s)
- Daya Ram Parajuli
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, 570-749, Republic of Korea
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Ali SO, Darwish HAEM, Ismail NAEF. Modulatory effects of curcumin, silybin-phytosome and alpha-R-lipoic acid against thioacetamide-induced liver cirrhosis in rats. Chem Biol Interact 2014; 216:26-33. [DOI: 10.1016/j.cbi.2014.03.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 03/20/2014] [Accepted: 03/26/2014] [Indexed: 10/25/2022]
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Chan CC, Lee KC, Huang YH, Chou CK, Lin HC, Lee FY. Regulation by resveratrol of the cellular factors mediating liver damage and regeneration after acute toxic liver injury. J Gastroenterol Hepatol 2014; 29:603-13. [PMID: 23981054 DOI: 10.1111/jgh.12366] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/05/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Acute liver injury is manifested by different degree of hepatocyte necrosis and may recover via the process of hepatocyte regeneration once the injury is discontinued. Most of the liver injury is associating with inflammatory cytokines. Resveratrol (RSV) is a natural phytoalexin with powerful anti-inflammatory effects. AIM The effects of RSV on cellular factors mediating liver damage and regeneration in acute carbon tetrachloride (CCl4 ) liver injury were investigated. RESULTS RSV decreased alanine aminotransferase, aspartate aminotransferase, necrosis, and 4-hydroxynonenal in the CCl4 -injured liver. RSV decreased hepatocyte apoptosis by reducing caspase 8 and caspase 3 but not Bax and Bcl-xL. RSV reduced Kupffer cells recruitment, the expressions of tumor necrosis factor-α and interleukin-6, but not interleukin-10. RSV lowered the numbers of anti-5-bromon-2'-deoxyuridine and anti-Ki67-positive hepatocytes. Hepatic hepatocyte growth factor, c-Met and transforming growth factor-α expressions were reduced by RSV, while transforming growth factor-β1 and hepatic stellate cells activation were not changed. RSV reduced the injury-induced CXCL10 elevations in serum and liver in vivo. Besides, RSV inhibited CXCL10 release from CCl4 -injured hepatocytes in vitro. In contrast, recombinant CXCL10 improved the viability of CCl4 -injured hepatocytes. CONCLUSIONS RSV therapy can be beneficial for acute toxic liver injury. RSV reduced hepatocyte apoptosis but limited hepatocyte regeneration possibly through reducing the hepatomitogenic signaling and the release of CXCL10.
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Affiliation(s)
- Che-Chang Chan
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; National Yang-Ming University, School of Medicine, Institute of Clinical Medicine, Taipei, Taiwan
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Kabil NN, Seddiek HA, Yassin NA, Gamal-Eldin MM. Effect of ghrelin on chronic liver injury and fibrogenesis in male rats: possible role of nitric oxide. Peptides 2014; 52:90-7. [PMID: 24333973 DOI: 10.1016/j.peptides.2013.11.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/25/2013] [Accepted: 11/26/2013] [Indexed: 12/11/2022]
Abstract
Recent studies have revealed that ghrelin may be an antioxidant and anti-inflammatory agent in many organs, however its role in chronic liver injury (CLI) remains unclear. The role of nitric oxide (NO) in CLI is controversial as evidence suggests that NO is either a primary mediator of liver cell injury or exhibits a protective effect against injurious stimuli. Recent evidence demonstrated that the therapeutic potential for ghrelin was through eNOS activation and increase in NO production. However, its role on NO production in the liver has not been previously investigated. The aim of this study was to investigate the role of ghrelin in treatment of CLI, and whether this action is mediated through NO. Forty male rats were divided into four groups: Group I: Control; Group II: chronic liver injury (CLI); Group III: CLI+Ghrelin; and Group IV: CLI+Ghrelin+l-NAME. Liver enzymes and tumor necrosis factor alpha (TNF-α), were measured to assess hepatocellular injury. Liver tissue collagen content, malondialdehyde (MDA), gene expression of Bax, Bcl-2, and eNOS were assessed to determine the mechanism of ghrelin action. Results showed that ghrelin decreased serum liver enzymes and TNF-α levels. Ghrelin also reduced liver tissue collagen, MDA, and Bax gene expression, and increased Bcl-2 and eNOS gene expression. The effects on TNF-α, collagen, MDA, Bax, and eNOS were partially reversed in Group IV, suggesting that ghrelin's action could be through modulation of NO levels. Therefore, ghrelin's hepatoprotective effect is partially mediated by NO release.
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Affiliation(s)
- Nashwa N Kabil
- Department of Physiology, Faculty of Pharmacy & Biotechnology, German University in Cairo, Egypt.
| | - Hanan A Seddiek
- Department of Physiology, Kasr Al Aini Faculty of Medicine, Cairo University, Egypt.
| | - Nadia A Yassin
- Department of Physiology, Faculty of Pharmacy & Biotechnology, German University in Cairo, Egypt; Department of Physiology, Kasr Al Aini Faculty of Medicine, Cairo University, Egypt.
| | - Maha M Gamal-Eldin
- Department of Physiology, Faculty of Pharmacy & Biotechnology, German University in Cairo, Egypt; Department of Physiology, Kasr Al Aini Faculty of Medicine, Cairo University, Egypt.
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Segatto M, Di Giovanni A, Marino M, Pallottini V. Analysis of the protein network of cholesterol homeostasis in different brain regions: an age and sex dependent perspective. J Cell Physiol 2013; 228:1561-7. [PMID: 23280554 DOI: 10.1002/jcp.24315] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 12/19/2012] [Indexed: 01/03/2023]
Abstract
Although a great knowledge about the patho-physiological roles of cholesterol metabolism perturbation in several organs has been reached, scarce information is available on the regulation of cholesterol homeostasis in the brain where this lipid is involved in the maintenance of several of neuronal processes. Currently, no study is available in literature dealing how and if sex and age may modulate the major proteins involved in the regulatory network of cholesterol levels in different brain regions. Here, we investigated the behavior of 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMGR) and low-density lipoprotein receptor (LDLr) in adult (3-month-old) and aged (12-month-old) male and female rats. The analyses were performed in four different brain regions: cortex, brain stem, hippocampus, and cerebellum which represent brain areas characterized by different neuronal cell types, metabolism, cytoarchitecture and white matter composition. The results show that in hippocampus HMGR is lower (30%) in adult female rats than in age-matched males. Differences in LDLr expression are also observable in old females with respect to age-matched males: the protein levels increase (40%) in hippocampus and decrease (20%) in cortex, displaying different mechanisms of regulation. The mechanism underlying the observed modifications are ascribable to Insig-1 and SREBP-1 modulation. The obtained data demonstrate that age- and sex-related differences in cholesterol homeostasis maintenance exist among brain regions, such as the hippocampus and the prefrontal cortex, important for learning, memory and affection. Some of these differences could be at the root of marked gender disparities observed in clinical disease incidence, manifestation, and prognosis.
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Affiliation(s)
- Marco Segatto
- Department of Sciences, University of Roma Tre, Rome, Italy
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Role of copper and cholesterol association in the neurodegenerative process. Int J Alzheimers Dis 2013; 2013:414817. [PMID: 24288650 PMCID: PMC3830777 DOI: 10.1155/2013/414817] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2013] [Revised: 09/05/2013] [Accepted: 09/05/2013] [Indexed: 01/22/2023] Open
Abstract
Age is one of the main factors involved in the development of neurological illnesses, in particular, Alzheimer, and it is widely held that the rapid aging of the world population is accompanied by a rise in the prevalence and incidence of Alzheimer disease. However, evidence from recent decades indicates that Cu and Cho overload are emerging causative factors in neurodegeneration, a hypothesis that has been partially investigated in experimental models. The link between these two variables and the onset of Alzheimer disease has opened up interesting new possibilities requiring more in-depth analysis. The aim of the present study was therefore to investigate the effect of the association of Cu + Cho (CuCho) as a possible synergistic factor in the development of an Alzheimer-like pathology in Wistar rats. We measured total- and nonceruloplasmin-bound Cu and Cho (free and sterified) contents in plasma and brain zones (cortex and hippocampus), markers of oxidative stress damage, inflammation, and programmed cell death (caspase-3 and calpain isoforms). The ratio beta-amyloid (1-42)/(1-40) was determined in plasma and brain as neurodegenerative biomarker. An evaluation of visuospatial memory (Barnes maze test) was also performed. The results demonstrate the establishment of a prooxidative and proinflammatory environment after CuCho treatment, hallmarked by increased TBARS, protein carbonyls, and nitrite plus nitrate levels in plasma and brain zones (cortex and hippocampus) with a consequent increase in the activity of calpains and no significant changes in caspase-3. A simultaneous increase in the plasma Aβ1-42/Aβ1-40 ratio was found. Furthermore, a slight but noticeable change in visuospatial memory was observed in rats treated with CuCho. We conclude that our model could reflect an initial stage of neurodegeneration in which Cu and Cho interact with one another to exacerbate neurological damage.
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Shirai M, Arakawa S, Miida H, Matsuyama T, Kinoshita J, Makino T, Kai K, Teranishi M. Thioacetamide-induced Hepatocellular Necrosis Is Attenuated in Diet-induced Obese Mice. J Toxicol Pathol 2013; 26:175-86. [PMID: 23914059 PMCID: PMC3695339 DOI: 10.1293/tox.26.175] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 02/28/2013] [Indexed: 12/31/2022] Open
Abstract
To assess modification of thioacetamide-induced hepatotoxicity in mice fed a high-fat
diet, male C57BL/6J mice were fed a normal rodent diet or a high-fat diet for 8 weeks and
then treated once intraperitoneally with thioacetamide at 50 mg/kg body weight. At 24 and
48 hours after administration, massive centrilobular hepatocellular necrosis was observed
in mice fed the normal rodent diet, while the necrosis was less severe in mice fed the
high-fat diet. In contrast, severe swelling of hepatocytes was observed in mice fed the
high-fat diet. In addition, mice fed the high-fat diet displayed more than a 4-fold higher
number of BrdU-positive hepatocytes compared with mice fed the normal rodent diet at 48
hours after thioacetamide treatment. To clarify the mechanisms by which the hepatic
necrosis was attenuated, we investigated exposure to thioacetamide and one of its
metabolites, the expression of CYP2E1, which converts thioacetamide to reactive
metabolites, and the content of glutathione S-transferases in the liver. However, the
reduced hepatocellular necrosis noted in mice fed the high-fat diet could not be explained
by the differences in exposure to thioacetamide or thioacetamide sulfoxide or by
differences in the expression of drug-metabolizing enzymes. On the other hand, at 8 hours
after thioacetamide administration, hepatic total glutathione in mice fed the high-fat
diet was significantly lower than that in mice fed the normal diet. Hence, decreased
hepatic glutathione amount is a candidate for the mechanism of the attenuated necrosis. In
conclusion, this study revealed that thioacetamide-induced hepatic necrosis was attenuated
in mice fed the high-fat diet.
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Affiliation(s)
- Makoto Shirai
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan
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Westra IM, Pham BT, Groothuis GMM, Olinga P. Evaluation of fibrosis in precision-cut tissue slices. Xenobiotica 2012; 43:98-112. [DOI: 10.3109/00498254.2012.723151] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Wong WL, Abdulla MA, Chua KH, Kuppusamy UR, Tan YS, Sabaratnam V. Hepatoprotective Effects of Panus giganteus (Berk.) Corner against Thioacetamide- (TAA-) Induced Liver Injury in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2012; 2012:170303. [PMID: 22649470 PMCID: PMC3357533 DOI: 10.1155/2012/170303] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2011] [Accepted: 02/23/2012] [Indexed: 12/17/2022]
Abstract
Panus giganteus, a culinary and medicinal mushroom consumed by selected indigenous communities in Malaysia, is currently being considered for large scale cultivation. This study was undertaken to investigate the hepatoprotective effects of P. giganteus against thioacetamide- (TAA-) induced liver injury in Sprague-Dawley rats. The rats were injected intraperitoneally with TAA thrice weekly and were orally administered freeze-dried fruiting bodies of P. giganteus (0.5 or 1 g/kg) daily for two months, while control rats were given vehicle or P. giganteus only. After 60 days, rats administered with P. giganteus showed lower liver body weight ratio, restored levels of serum liver biomarkers and oxidative stress parameters comparable to treatment with the standard drug silymarin. Gross necropsy and histopathological examination further confirmed the hepatoprotective effects of P. giganteus. This is the first report on hepatoprotective effects of P. giganteus. The present study showed that P. giganteus was able to prevent or reduce the severity of TAA-induced liver injury.
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Affiliation(s)
- Wei-Lun Wong
- Mushroom Research Centre, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Mahmood Ameen Abdulla
- Mushroom Research Centre, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Kek-Heng Chua
- Mushroom Research Centre, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Umah Rani Kuppusamy
- Mushroom Research Centre, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Yee-Shin Tan
- Mushroom Research Centre, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Vikineswary Sabaratnam
- Mushroom Research Centre, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
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Chen IS, Chen YC, Chou CH, Chuang RF, Sheen LY, Chiu CH. Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2012; 92:1441-7. [PMID: 22102319 DOI: 10.1002/jsfa.4723] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Revised: 05/27/2011] [Accepted: 07/20/2011] [Indexed: 05/31/2023]
Abstract
BACKGROUND Liver fibrosis is chronic liver damage usually caused by alcohol, viruses or other toxins and is characterised by an excessive accumulation of extracellular matrix proteins such as collagen. The aim of this study was to establish an animal model of chronic liver damage and investigate molecular mechanisms of silymarin hepatoprotective effects. RESULTS Thioacetamide (TAA; 100 mg kg(-1) intraperitoneal (i.p.) injection three times weekly) effectively induced chronic liver fibrosis in male ICR mice. Then 24 ICR mice were randomly divided into four groups: (1) saline (i.p.) + water (gavage); (2) saline (i.p.) + 150 mg kg(-1) silymarin (gavage); (3) 100 mg kg(-1) TAA (i.p.) + water (gavage); (4) 100 mg kg(-1) TAA (i.p.) + 150 mg kg(-1) silymarin (gavage). Eight weeks of TAA treatment resulted in lower body weight, serum cholesterol and triglycerides as well as increased liver size, ALT, AST and LDH values (P < 0.05). These TAA-induced effects were attenuated by silymarin (P < 0.05); therefore silymarin also ameliorated TAA-induced liver lesions. Effects of silymarin on TAA-induced chronic liver damage may be attributed to down-regulation of hepatic MMP-2, MMP-13, TIMP-1, TIMP-2, AP-1, KLF6, TGF-β1, α-SMA and COL-α1. CONCLUSION A mouse model of chronic liver fibrosis was successfully established by injecting 100 mg kg(-1) TAA three times weekly in male ICR mice. Meanwhile, silymarin showed hepatoprotection against TAA-induced damage.
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Affiliation(s)
- I-Shu Chen
- Department of Surgery, Veteran General Hospital, Kaohsiung, Taiwan
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Zhou P, Xia J, Guo G, Huang ZX, Lu Q, Li L, Li HX, Shi YJ, Bu H. A Macaca mulatta model of fulminant hepatic failure. World J Gastroenterol 2012; 18:435-444. [PMID: 22346249 PMCID: PMC3270505 DOI: 10.3748/wjg.v18.i5.435] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Revised: 06/23/2011] [Accepted: 06/30/2011] [Indexed: 02/06/2023] Open
Abstract
AIM To establish an appropriate primate model of fulminant hepatic failure (FHF). METHODS We have, for the first time, established a large animal model of FHF in Macaca mulatta by intraperitoneal infusion of amatoxin and endotoxin. Clinical features, biochemical indexes, histopathology and iconography were examined to dynamically investigate the progress and outcome of the animal model. RESULTS Our results showed that the enzymes and serum bilirubin were markedly increased and the enzyme-bilirubin segregation emerged 36 h after toxin administration. Coagulation activity was significantly decreased. Gradually deteriorated parenchymal abnormality was detected by magnetic resonance imaging (MRI) and ultrasonography at 48 h. The liver biopsy showed marked hepatocyte steatosis and massive parenchymal necrosis at 36 h and 49 h, respectively. The autopsy showed typical yellow atrophy of the liver. Hepatic encephalopathy of the models was also confirmed by hepatic coma, MRI and pathological changes of cerebral edema. The lethal effects of the extrahepatic organ dysfunction were ruled out by their biochemical indices, imaging and histopathology. CONCLUSION We have established an appropriate large primate model of FHF, which is closely similar to clinic cases, and can be used for investigation of the mechanism of FHF and for evaluation of potential medical therapies.
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Kučera O, Lotková H, Staňková P, Podhola M, Roušar T, Mezera V, Cervinková Z. Is rat liver affected by non-alcoholic steatosis more susceptible to the acute toxic effect of thioacetamide? Int J Exp Pathol 2011; 92:281-289. [PMID: 21410800 PMCID: PMC3144517 DOI: 10.1111/j.1365-2613.2011.00765.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 01/13/2011] [Indexed: 01/25/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic condition of the liver in the western world. There is only little evidence about altered sensitivity of steatotic liver to acute toxic injury. The aim of this project was to test whether hepatic steatosis sensitizes rat liver to acute toxic injury induced by thioacetamide (TAA). Male Sprague-Dawley rats were fed ad libitum a standard pelleted diet (ST-1, 10% energy fat) and high-fat gelled diet (HFGD, 71% energy fat) for 6 weeks and then TAA was applied intraperitoneally in one dose of 100 mg/kg. Animals were sacrificed in 24-, 48- and 72-h interval after TAA administration. We assessed the serum biochemistry, the hepatic reduced glutathione, thiobarbituric acid reactive substances, cytokine concentration, the respiration of isolated liver mitochondria and histopathological samples (H+E, Sudan III, bromodeoxyuridine [BrdU] incorporation). Activities of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase and concentration of serum bilirubin were significantly higher in HFGD groups after application of TAA, compared to ST-1. There were no differences in activities of respiratory complexes I and II. Serum tumour necrosis factor alpha at 24 and 48 h, liver tissue interleukin-6 at 72 h and transforming growth factor β1 at 24 and 48 h were elevated in TAA-administrated rats fed with HFGD, but not ST-1. TAA-induced centrilobular necrosis and subsequent regenerative response of the liver were higher in HFGD-fed rats in comparison with ST-1. Liver affected by NAFLD, compared to non-steatotic liver, is more sensitive to toxic effect of TAA.
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Affiliation(s)
- Otto Kučera
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
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Investigation of hepatoprotective activity of induced pluripotent stem cells in the mouse model of liver injury. J Biomed Biotechnol 2011; 2011:219060. [PMID: 21808596 PMCID: PMC3144694 DOI: 10.1155/2011/219060] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Accepted: 05/27/2011] [Indexed: 01/14/2023] Open
Abstract
To date liver transplantation is the only effective treatment for end-stage liver diseases. Considering the potential of pluripotency and differentiation into tridermal lineages, induced pluripotent stem cells (iPSCs) may serve as an alternative of cell-based therapy. Herein, we investigated the effect of iPSC transplantation on thioacetamide- (TAA-) induced acute/fulminant hepatic failure (AHF) in mice. Firstly, we demonstrated that iPSCs had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that expressed various hepatic markers, including albumin, α-fetoprotein, and hepatocyte nuclear factor-3β, and exhibited biological functions. Intravenous transplantation of iPSCs effectively reduced the hepatic necrotic area, improved liver functions and motor activity, and rescued TAA-treated mice from lethal AHF. 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate cell labeling revealed that iPSCs potentially mobilized to the damaged liver area. Taken together, iPSCs can effectively rescue experimental AHF and represent a potentially favorable cell source of cell-based therapy.
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Staňková P, Kučera O, Lotková H, Roušar T, Endlicher R, Cervinková Z. The toxic effect of thioacetamide on rat liver in vitro. Toxicol In Vitro 2010; 24:2097-2103. [PMID: 20600801 DOI: 10.1016/j.tiv.2010.06.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Revised: 05/07/2010] [Accepted: 06/08/2010] [Indexed: 01/23/2023]
Abstract
Thioacetamide (TAA) is a hepatotoxin frequently used for experimental purposes which produces centrilobular necrosis after a single dose administration. In spite of the fact that oxidative stress seems to play a very important role in the mechanism of TAA-induced injury, the effect of TAA on hepatocytes in primary culture with respect to the influence on mitochondria has yet to be verified. Hepatocytes were incubated for 24h in a medium containing TAA (0-70 mmol/l). Glutathione content (GSH/GSSG), reactive oxygen species and malondialdehyde formation were assessed as markers of cell redox state. Toxicity was determined by lactate dehydrogenase leakage and WST-1 assay. The functional capacity of hepatocytes was evaluated from albumin and urea production. Mitochondrial metabolism was assessed by measuring mitochondrial membrane potential and oxygen consumption. Our results show that a profound decrease in the GSH level in hepatocytes precedes a sharp rise in endogenous ROS production. ROS production correlates with an increase in lipoperoxidation. Mitochondria are affected by TAA secondarily as a consequence of oxidative stress. Oxidation of the NADH-dependent substrates of respiratory Complex I is significantly more sensitive to the toxic action of TAA than oxidation of the flavoprotein-dependent substrate of Complex II. Mitochondria can also maintain their membrane potential better when they utilize succinate as a respiratory substrate. It appears that GSH should be depleted below a certain critical level in order to cause a marked increase in lipid peroxidation. Mitochondrial injury can then occur and cell death develops.
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Affiliation(s)
- Pavla Staňková
- Charles University in Prague, Faculty of Medicine in Hradec Králové, Department of Physiology, Šimkova 870, 50038 Hradec Králové, Czech Republic.
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Age-Related Hypercholesterolemia and HMG-CoA Reductase Dysregulation: Sex Does Matter (A Gender Perspective). Curr Gerontol Geriatr Res 2010:420139. [PMID: 20454643 PMCID: PMC2863156 DOI: 10.1155/2010/420139] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 01/26/2010] [Accepted: 02/18/2010] [Indexed: 02/07/2023] Open
Abstract
Although cardiovascular diseases are less prevalent in premenopausal women than in men, their occurrence in women increases at the onset of menopause, and the loss of female sex hormones contributes to the striking increase in cardiovascular morbidity and mortality in postmenopausal women. We present here a description of age-related disruption of lipid homeostasis, which particularly affects 3-hydroxy 3-methylglutaryl Coenzyme A reductase, the key rate-limiting enzyme in the cholesterol biosynthetic pathway. We further discuss the age- and gender-related dysregulation of this enzyme, providing new evidence for the different mechanisms driving dyslipidemia in elderly men and women. In addition, we introduce pharmacological methods of regulating HMGR and maintaining cholesterol homeostasis.
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Tuñón MJ, Alvarez M, Culebras JM, González-Gallego J. An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure. World J Gastroenterol 2009; 15:3086-98. [PMID: 19575487 PMCID: PMC2705730 DOI: 10.3748/wjg.15.3086] [Citation(s) in RCA: 153] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Revised: 05/23/2009] [Accepted: 05/30/2009] [Indexed: 02/06/2023] Open
Abstract
Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.
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Aller M, Vara E, García C, Méndez M, Méndez-López M, Mejía I, López L, Arias J, Arias J. Prehepatic portal hypertension worsens the enterohepatic redox balance in thioacetamide-cirrhotic rats. PATHOPHYSIOLOGY 2008; 15:233-42. [DOI: 10.1016/j.pathophys.2008.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Accepted: 09/19/2008] [Indexed: 02/07/2023] Open
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Martini C, Pallottini V, De Marinis E, Marino M, Cavallini G, Donati A, Straniero S, Trentalance A. Omega-3 as well as caloric restriction prevent the age-related modifications of cholesterol metabolism. Mech Ageing Dev 2008; 129:722-7. [PMID: 18930075 DOI: 10.1016/j.mad.2008.09.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Revised: 09/08/2008] [Accepted: 09/17/2008] [Indexed: 12/23/2022]
Abstract
Intracellular concentration of cholesterol is regulated by the balance between endogenous synthesis and exogenous uptake; endogenous synthesis is subject to feedback control of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase activity, while the exogenous supply is mainly controlled by the modulation of the low-density lipoprotein receptor. During ageing, hepatic lipid modifications occur and caloric restriction are able to prevent these changes. So, the aim of this work was to evaluate the mechanisms underlying the effect exerted both by caloric restrictions and by a diet enriched with Omega-3 fatty acids, on the cholesterol plasma levels during ageing, by studying the regulation of the protein involved in cholesterol homeostasis maintenance. Livers from diet restricted and Omega-3 supplemented diet fed 24-month-old rat were used to analyze, the protein complex of cholesterol homeostasis maintenance and those ones that are able to modulate 3-hydroxy-3-methyl-glutaryl-CoA reductase. The data obtained demonstrate that both caloric restriction and Omega-3 supplemented diets are able to prevent hypercholesterolemia, by regulating HMG-CoAR activation state by controlling ROS production and p38 phosphorylation. Moreover also the age-dependent loss of LDLr membrane exposition is prevented.
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Affiliation(s)
- Chiara Martini
- Department of Biology, University of Roma Tre, Viale Marconi 446, 00146 Rome, Italy
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Role of mammalian cytosolic molybdenum Fe-S flavin hydroxylases in hepatic injury. Life Sci 2008; 82:780-8. [PMID: 18313080 DOI: 10.1016/j.lfs.2008.01.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2007] [Revised: 10/19/2007] [Accepted: 01/18/2008] [Indexed: 11/23/2022]
Abstract
The study was designed to investigate the role of molybdenum iron-sulfur flavin hydroxylases in the pathogenesis of liver injuries induced by structurally and mechanistically diverse hepatotoxicants. While carbon tetrachloride (CCl4), thioacetamide (TAA) and chloroform (CHCl3) inflict liver damage by producing free radicals, acetaminophen (AAP) and bromobenzene (BB) exert their effects by severe glutathione depletion. Appropriate doses of these compounds were administered to induce liver injury in rats. The activities of the Mo-Fe-S flavin hydroxylases were measured and correlated with the biochemical markers of hepatic injury. The activity levels of the anti-oxidative enzymes and glutathione redox cycling enzymes were also determined. The treatment of rats with the hepatotoxins that inflict liver injury by generating free radicals (CCl4, TAA, CHCl3) had elevated activity levels of hepatic Mo-Fe-S flavin hydroxylases (p<0.05). Specific inhibition of these hydroxylases by their common inhibitor, sodium tungstate, suppresses biochemical and oxidative stress markers of hepatic tissue damage. On the contrary, Mo-Fe-S flavin hydroxylases did not show any change in animals receiving AAP and BB. Correspondingly, sodium tungstate could not attenuate damage in AAP and BB treated groups of rats. The study concludes that Mo-Fe-S hydroxylases contribute to the hepatic injury inflicted by free radical generating agents and does not play any role in hepatic injury produced by glutathione depleting agents. The study has implication in understanding human liver diseases caused by a variety of agents, and to investigate the efficacy of the inhibitors of Mo-Fe-S flavin hydroxylases as potential therapeutic agents.
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Guyot C, Combe C, Clouzeau-Girard H, Moronvalle-Halley V, Desmoulière A. Specific activation of the different fibrogenic cells in rat cultured liver slices mimicking in vivo situations. Virchows Arch 2007; 450:503-12. [PMID: 17431675 DOI: 10.1007/s00428-007-0390-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2006] [Revised: 02/06/2007] [Accepted: 02/12/2007] [Indexed: 12/01/2022]
Abstract
Due to the loss of cell-cell and cell-matrix interactions, cell culture models poorly mimic the in vivo situation. Therefore, we tested the applicability of precision-cut liver slices (PCLS) to study the early activation of the two main liver fibrogenic cell subpopulations: hepatic stellate cells (HSC) and portal fibroblasts (PF). PCLS were treated with thioacetamide or acetaminophen to induce HSC activation. In PCLS culture, both were able to trigger centrolobular lesion and HSC activation as observed in vivo. However, thioacetamide also presented a toxic effect on portal tract cells. In this PCLS model of centrolobular lesion, the antioxidant N-acetylcysteine was able to prevent acetaminophen-induced injury. To induce a specific activation of PF, PCLS were treated with epidermal growth factor or beta-oestradiol. As in vivo, epidermal growth factor and beta-oestradiol induced bile duct epithelial cell proliferation accompanied by PF activation; however, beta-oestradiol also triggers sinusoidal cell proliferation. We demonstrated that treatments usually used in vivo to induce liver fibrosis allow, in cultured PCLS, the specific activation of the two main liver fibrogenic cell subpopulations, making this model very useful to study the mechanisms involved in early fibrogenic cell activation.
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Affiliation(s)
- Christelle Guyot
- INSERM, E362, Université Victor Segalen Bordeaux 2, Bordeaux, 33076, France
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