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1
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Gao K, Cheung-Hoi Yu A. Glutamate, a Key for Astrocytes to Participate in Brain Function and Diseases. Neurochem Res 2025; 50:166. [PMID: 40372498 DOI: 10.1007/s11064-025-04418-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 05/01/2025] [Accepted: 05/02/2025] [Indexed: 05/16/2025]
Abstract
Astrocytes support neurons by maintaining health, regulating the environment, and aiding synaptic transmission, while glutamate is vital for excitatory signaling in learning and memory. The "glutamate-glutamine cycle," verified by Hertz and Schousboe, illustrates the interaction between neurons and astrocytes in glutamate regulation. Recent studies show astrocytes not only manage glutamate levels but also influence synaptic activity through gliotransmission and contribute to brain energy via glutamate metabolism. Dysregulation of this signaling is linked to neurological disorders like epilepsy and Alzheimer's. This mini-review will explore research progress on astrocytes and glutamate, highlighting glutamate's role in brain function and disease.
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Affiliation(s)
- Kai Gao
- Children's Medical Center, Peking University First Hospital, No.5 Le Yuan Road, Daxing District, Beijing, 102627, China.
| | - Albert Cheung-Hoi Yu
- Hai Kang Life Corporation Ltd, Units 15-18, 16/F South Wing Delta House, 3 On Yiu Street, Shatin, N.T., Hong Kong, China.
- Neuroscience Research Institute, Peking University, Beijing, China.
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2
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Choi K, Cho Y, Chae Y, Cheon SY. Cell-cell communications in the brain of hepatic encephalopathy: The neurovascular unit. Life Sci 2025; 363:123413. [PMID: 39863020 DOI: 10.1016/j.lfs.2025.123413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 01/07/2025] [Accepted: 01/21/2025] [Indexed: 01/27/2025]
Abstract
Many patients with liver diseases are exposed to the risk of hepatic encephalopathy (HE). The incidence of HE in liver patients is high, showing various symptoms ranging from mild symptoms to coma. Liver transplantation is one of the ways to overcome HE. However, not all patients can receive liver transplantation. Moreover, patients who have received liver transplantation have limitations in that they are vulnerable to hepatocellular carcinoma, allograft rejection, and infection. To find other therapeutic strategies, it is important to understand pathological factors and mechanisms that lead to HE after liver disease. Oxidative stress, inflammatory response, hyperammonaemia and metabolic disorders seen after liver diseases have been reported as risk factors of HE. These are known to affect the brain and cause HE. These peripheral pathological factors can impair the blood-brain barrier, cause it to collapse and damage the neurovascular unit component of multiple cells, including vascular endothelial cells, astrocytes, microglia, and neurons, leading to HE. Many previous studies on HE have suggested the impairment of neurovascular unit and cell-cell communication in the pathogenesis of HE. This review focuses on pathological factors that appear in HE, cell type-specific pathological mechanisms, miscommunication/incorrect relationships, and therapeutic candidates between brain cells in HE. This review suggests that regulating communications and interactions between cells may be important in overcoming HE.
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Affiliation(s)
- Kyuwan Choi
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Yena Cho
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - Yerin Chae
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea
| | - So Yeong Cheon
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju, Republic of Korea; Research Institute for Biomedical & Health Science (RIBHS), Konkuk University, Chungju, Republic of Korea.
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3
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Abd Elrazik NA, Abd El Salam ASG. Diacerein ameliorates thioacetamide-induced hepatic encephalopathy in rats via modulation of TLR4/AQP4/MMP-9 axis. Metab Brain Dis 2024; 40:10. [PMID: 39556255 PMCID: PMC11573817 DOI: 10.1007/s11011-024-01457-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 09/27/2024] [Indexed: 11/19/2024]
Abstract
Astrocyte swelling, blood brain barrier (BBB) dissipation and the subsequent brain edema are serious consequences of persistent hyperammonemia in hepatic encephalopathy (HE) in which if inadequately controlled it will lead to brain death. The current study highlights the potential neuroprotective effect of diacerein against thioacetamide (TAA)-induced HE in acute liver failure rat model. HE was induced in male Sprague-Dawley rats via I.P. injection of TAA (200 mg/kg) for three alternative times/week at 3rd week of the experiment. Diacerein (50 mg/kg) was gavaged for 14 days prior to induction of HE and for further 7 days together with TAA injection for an overall period of 21 days. Diacerein attenuated TAA-induced HE in acute liver failure rat model; as proofed by significant lowering of serum and brain ammonia concentrations, serum AST and ALT activities and significant attenuation of both brain and hepatic MDA contents and IL-1β with marked increases in GSH contents (P < 0.0001). The neuroprotective effect of diacerein was demonstrated by marked improvement of motor and cognitive deficits, brain histopathological changes; hallmarks of HE. As shown by immunohistochemical results, diacerein markedly downregulated brain TLR4 expression which in turn significantly increased the GFAP expression, and significantly decreased AQP4 expression; the astrocytes swelling biomarkers (P < 0.0001). Moreover, diacerein preserved BBB integrity via downregulation of MMP-9 mediated digestion of tight junction proteins such as occludin (P < 0.0001). Collectively, diacerein ameliorated cerebral edema and maintained BBB integrity via modulation of TLR4/AQP4/MMP-9 axis thus may decrease the progression of HE induced in acute liver failure.
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Affiliation(s)
- Nesma A Abd Elrazik
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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4
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Tong XY, Norenberg MD, Paidas MJ, Shamaladevi N, Salgueiro L, Jaszberenyi M, John B, Hussain H, El Hiba O, Abdeljalil EG, Bilal EM, Natarajan S, Romaguera R, Papayan S, Carden AK, Ramamoorthy R, Elumalai N, Schally AV, Nithura J, Patrizio R, Jayakumar AR. Mechanism of Alzheimer type II astrocyte development in hepatic encephalopathy. Neurochem Int 2024; 180:105866. [PMID: 39369794 DOI: 10.1016/j.neuint.2024.105866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/19/2024] [Accepted: 09/22/2024] [Indexed: 10/08/2024]
Abstract
Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1β, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment in vitro. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.
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Affiliation(s)
- Xiao Y Tong
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
| | - Michael D Norenberg
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
| | - Michael J Paidas
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA; Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, USA
| | | | - Luis Salgueiro
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA
| | - Miklos Jaszberenyi
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA; Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary
| | - Binu John
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA
| | - Hussain Hussain
- Larkin Community Hospital, Department of Internal Medicine and Infectious Disease, Miami, FL, USA
| | - Omar El Hiba
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - El Got Abdeljalil
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - El-Mansoury Bilal
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - Sampath Natarajan
- Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Tamil Nadu, India
| | - Rita Romaguera
- Pathology and Laboratory Medicine, Department of Veterans Affairs, Miami, FL, 33125, USA
| | - Stanislav Papayan
- Pathology and Laboratory Medicine, Department of Veterans Affairs, Miami, FL, 33125, USA
| | - Arianna K Carden
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Rajalakshmi Ramamoorthy
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Nila Elumalai
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Andrew V Schally
- Endocrine, Polypeptide, and Cancer Institute, Department of Veterans Affairs, Miami, FL, 33125, USA
| | | | - Rebecca Patrizio
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Arumugam R Jayakumar
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA; General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA; Neuropathology Section, Veterans Affairs Medical Center, Miami, FL, USA; R&D Services and South Florida VA Foundation for Research and Education Inc, Veterans Affairs Medical Center, Miami, FL, USA.
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5
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Hassan NF, El-Ansary MR, El-Ansary AR, El-Saied MA, Zaki OS. Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP/PPAR-γ/p-ERK1/2/p S536 NF-κB p 65 and p-CREB/BDNF/TrkB in parallel with oxidative and apoptotic trajectories. Biochem Pharmacol 2024; 229:116504. [PMID: 39179118 DOI: 10.1016/j.bcp.2024.116504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 08/12/2024] [Accepted: 08/20/2024] [Indexed: 08/26/2024]
Abstract
Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.
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Affiliation(s)
- Noha F Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Mona R El-Ansary
- Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Amira R El-Ansary
- Department of Internal Medicine, Faculty of Medicine, Misr University for Science and Technology, Giza, Egypt
| | - Mohamed A El-Saied
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Omnia S Zaki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
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6
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Amer K, Flikshteyn B, Lingiah V, Tafesh Z, Pyrsopoulos NT. Mechanisms of Disease and Multisystemic Involvement. Clin Liver Dis 2023; 27:563-579. [PMID: 37380283 DOI: 10.1016/j.cld.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Affiliation(s)
- Kamal Amer
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Ben Flikshteyn
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Vivek Lingiah
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Zaid Tafesh
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 53, Newark, NJ 07101-1709, USA
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 536, Newark, NJ 07101-1709, USA.
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7
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Sakakibara O, Shimoda M, Yamamoto G, Higashi Y, Ikeda-Imafuku M, Ishima Y, Kawahara M, Tanaka KI. Effectiveness of Albumin-Fused Thioredoxin against 6-Hydroxydopamine-Induced Neurotoxicity In Vitro. Int J Mol Sci 2023; 24:ijms24119758. [PMID: 37298708 DOI: 10.3390/ijms24119758] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/29/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder caused by oxidative stress-dependent loss of dopaminergic neurons in the substantia nigra and elevated microglial inflammatory responses. Recent studies show that cell loss also occurs in the hypothalamus in PD. However, effective treatments for the disorder are lacking. Thioredoxin is the major protein disulfide reductase in vivo. We previously synthesized an albumin-thioredoxin fusion protein (Alb-Trx), which has a longer plasma half-life than thioredoxin, and reported its effectiveness in the treatment of respiratory and renal diseases. Moreover, we reported that the fusion protein inhibits trace metal-dependent cell death in cerebrovascular dementia. Here, we investigated the effectiveness of Alb-Trx against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. Alb-Trx significantly inhibited 6-OHDA-induced neuronal cell death and the integrated stress response. Alb-Trx also markedly inhibited 6-OHDA-induced reactive oxygen species (ROS) production, at a concentration similar to that inhibiting cell death. Exposure to 6-OHDA perturbed the mitogen-activated protein kinase pathway, with increased phosphorylated Jun N-terminal kinase and decreased phosphorylated extracellular signal-regulated kinase levels. Alb-Trx pretreatment ameliorated these changes. Furthermore, Alb-Trx suppressed 6-OHDA-induced neuroinflammatory responses by inhibiting NF-κB activation. These findings suggest that Alb-Trx reduces neuronal cell death and neuroinflammatory responses by ameliorating ROS-mediated disruptions in intracellular signaling pathways. Thus, Alb-Trx may have potential as a novel therapeutic agent for PD.
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Affiliation(s)
- Okina Sakakibara
- Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo 202-8585, Japan
| | - Mikako Shimoda
- Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo 202-8585, Japan
| | - Gaku Yamamoto
- Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo 202-8585, Japan
| | - Youichirou Higashi
- Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan
| | - Mayumi Ikeda-Imafuku
- Department of Physical Pharmaceutics, School of Pharmaceutical Sciences, Wakayama Medical University, 25-1 Shichiban-Cho, Wakayama 640-8156, Japan
| | - Yu Ishima
- Department of Biopharmaceutics, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Masahiro Kawahara
- Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo 202-8585, Japan
| | - Ken-Ichiro Tanaka
- Laboratory of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo 202-8585, Japan
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8
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Cellular Pathogenesis of Hepatic Encephalopathy: An Update. Biomolecules 2023; 13:biom13020396. [PMID: 36830765 PMCID: PMC9953810 DOI: 10.3390/biom13020396] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/01/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions.
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Huang Y, Mo S, Jin Y, Zheng Z, Wang H, Wu S, Ren Z, Wu J. Ammonia-induced excess ROS causes impairment and apoptosis in porcine IPEC-J2 intestinal epithelial cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 243:114006. [PMID: 36037632 DOI: 10.1016/j.ecoenv.2022.114006] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/12/2022] [Accepted: 08/19/2022] [Indexed: 06/15/2023]
Abstract
Ammonia is one of the most important toxic metabolites in the intestine of animals. It can cause intestinal damage and associated intestinal diseases through different endogenous or exogenous stimuli. However, the definition of harmful ammonia concentration and the molecular mechanism of ammonia - induced intestinal epithelial injury remain unclear. In this study, we found that the viability of porcine IPEC-J2 intestinal epithelial cells significantly decreased with the increase of NH4Cl dose (20-80 mM). Ammonia (40 mM NH4Cl) increased the expression level of ammonia transporter RHCG and disrupted the intestinal barrier function of IPEC-J2 cells by reducing the expression levels of the tight junction molecules ZO-1 and Claudin-1. Ammonia caused elevated levels of ROS and apoptosis in IPEC-J2 cells. This was manifested by decreased activity of antioxidant enzymes SOD and GPx, decreased mitochondrial membrane potential, and increased cytoplasmic Ca2+ concentration. In addition, the expression levels of apoptosis-related molecules Caspase-9, Caspase-3, Fas, Caspase-8, p53 and Bax were increased, the expression level of anti-apoptotic molecule Bcl-2 was decreased. Moreover, the antioxidant NAC (N-acetyl-L-cysteamine) effectively alleviated ammonia-induced cytotoxicity, reduced ROS level, Ca2+ concentration, and the apoptosis of IPEC-J2 cells. The results suggest that ammonia-induced excess ROS triggered apoptosis through mitochondrial pathway, death receptor pathway and DNA damage. This study can provide reference and theoretical basis for the definition of harmful ammonia concentration in pig intestine and the effect and mechanism of ammonia on pig intestinal health.
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Affiliation(s)
- Yihao Huang
- College of Animal Sciences & Technology/College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
| | - Shangkun Mo
- College of Animal Sciences & Technology/College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
| | - Yi Jin
- College of Animal Sciences & Technology/College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
| | - Zhuoning Zheng
- College of Animal Sciences & Technology/College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
| | - Hanyi Wang
- College of Animal Sciences & Technology/College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
| | - Shaojuan Wu
- College of Animal Sciences & Technology/College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
| | - Zhuqing Ren
- College of Animal Sciences & Technology/College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan 430070, China.
| | - Jian Wu
- College of Animal Sciences & Technology/College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
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10
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Jing G, Yang L, Wang H, Niu J, Li Y, Wang S. Interference of layered double hydroxide nanoparticles with pathways for biomedical applications. Adv Drug Deliv Rev 2022; 188:114451. [PMID: 35843506 DOI: 10.1016/j.addr.2022.114451] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 06/18/2022] [Accepted: 07/09/2022] [Indexed: 11/01/2022]
Abstract
Recent decades have witnessed a surge of explorations into the application of multifarious materials, especially biomedical applications. Among them, layered double hydroxides (LDHs) have been widely developed as typical inorganic layer materials to achieve remarkable advancements. Multiple physicochemical properties endow LDHs with excellent merits in biomedical applications. Moreover, LDH nanoplatforms could serve as "molecular switches", which are capable of the controlled release of payloads under specific physiological pH conditions but are stable during circulation in the bloodstream. In addition, LDHs themselves are composed of several specific cations and possess favorable biological effects or regulatory roles in various cellular functions. These advantages have caused LDHs to become increasingly of interest in the area of nanomedicine. Recent efforts have been devoted to revealing the potential factors that interfere with the biological pathways of LDH-based nanoparticles, such as their applications in shaping the functions of immune cells and in determining the fate of stem cells and tumor treatments, which are comprehensively described herein. In addition, several intracellular signaling pathways interfering with by LDHs in the above applications were also systematically expatiated. Finally, the future development and challenges of LDH-based nanomedicine are discussed in the context of the ultimate goal of practical clinical application.
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Affiliation(s)
- Guoxin Jing
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China
| | - Linnan Yang
- Central Laboratory, First Affiliated Hospital, Anhui Medical University, Hefei, PR China
| | - Hong Wang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China
| | - Jintong Niu
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China
| | - Youyuan Li
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China
| | - Shilong Wang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, PR China.
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11
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Dąbrowska K, Skowrońska K, Popek M, Albrecht J, Zielińska M. The Role of Nrf2 Transcription Factor and Sp1-Nrf2 Protein Complex in Glutamine Transporter SN1 Regulation in Mouse Cortical Astrocytes Exposed to Ammonia. Int J Mol Sci 2021; 22:ijms222011233. [PMID: 34681893 PMCID: PMC8538223 DOI: 10.3390/ijms222011233] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 11/28/2022] Open
Abstract
Ammonia toxicity in the brain primarily affects astrocytes via a mechanism in which oxidative stress (OS), is coupled to the imbalance between glutamatergic and GABAergic transmission. Ammonia also downregulates the astrocytic N system transporter SN1 that controls glutamine supply from astrocytes to neurons for the replenishment of both neurotransmitters. Here, we tested the hypothesis that activation of Nrf2 is the process that links ammonia-induced OS formation in astrocytes to downregulation and inactivation of SN1 and that it may involve the formation of a complex between Nrf2 and Sp1. Treatment of cultured cortical mouse astrocytes with ammonia (5 mM NH4Cl for 24 h) evoked Nrf2 nuclear translocation, increased its activity in a p38 MAPK pathway-dependent manner, and enhanced Nrf2 binding to Slc38a3 promoter. Nrf2 silencing increased SN1 mRNA and protein level without influencing astrocytic [3H]glutamine transport. Ammonia decreased SN1 expression in Nrf2 siRNA treated astrocytes and reduced [3H]glutamine uptake. In addition, while Nrf2 formed a complex with Sp1 in ammonia-treated astrocytes less efficiently than in control cells, treatment of astrocytes with hybrid-mode inactivated Sp1-Nrf2 complex (Nrf2 silencing + pharmacological inhibition of Sp1) did not affect SN1 protein level in ammonia-treated astrocytes. In summary, the results document that SN1 transporter dysregulation by ammonia in astrocytes involves activation of Nrf2 but does not require the formation of the Sp1-Nrf2 complex.
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12
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Singh N, Hsieh CYJ. Exploring Potential Carcinogenic Activity of Per- and Polyfluorinated Alkyl Substances Utilizing High-Throughput Toxicity Screening Data. Int J Toxicol 2021; 40:355-366. [PMID: 33944624 DOI: 10.1177/10915818211010490] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Per- and polyfluorinated alkyl substances (PFAS) are ubiquitous, persistent, and toxic chemicals that pose public health risks. Recent carcinogenicity concerns have arisen based on epidemiological studies, animal tumor findings, and mechanistic data. Thousands of PFAS exist; however, current understanding of their toxicity is informed by studies of a select few, namely, perfluorooctanoic acid and perfluorooctanesulfonic acid. Hence, the computational, high-throughput screening tool, the US EPA CompTox Chemical Dashboard's ToxCast, was utilized to explore the carcinogenicity potential of PFAS. Twenty-three major PFAS that had sufficient in vitro ToxCast data and covered a range of structural subclasses were analyzed with the visual analytics software ToxPi, yielding a qualitative and quantitative assessment of PFAS activity in realms closely linked with carcinogenicity. A comprehensive literature search was also conducted to check the consistency of analyses with other mechanistic data streams. The PFAS were found to induce a vast range of biological perturbations, in line with several of the International Agency for Research on Cancer-defined key carcinogen characteristics. Patterns observed varied by length of fluorine-bonded chains and/or functional group within and between each key characteristic, suggesting some structure-based variability in activity. In general, the major conclusions drawn from the analysis, that is, the most notable activities being modulation of receptor-mediated effects and induction of oxidative stress, were supported by literature findings. The study helps enhance understanding of the mechanistic pathways that underlie the potential carcinogenicity of various PFAS and hence could assist in hazard identification and risk assessment for this emerging and relevant class of environmental toxicants.
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Affiliation(s)
- Nalin Singh
- Office of Environmental Health Hazard Assessment, 7020California Environmental Protection Agency, Sacramento, CA, USA.,University of California, Davis, CA, USA
| | - Ching Yi Jennifer Hsieh
- Office of Environmental Health Hazard Assessment, 7020California Environmental Protection Agency, Sacramento, CA, USA
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13
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McCann MS, Maguire-Zeiss KA. Environmental toxicants in the brain: A review of astrocytic metabolic dysfunction. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 84:103608. [PMID: 33556584 DOI: 10.1016/j.etap.2021.103608] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/24/2021] [Accepted: 01/29/2021] [Indexed: 06/12/2023]
Abstract
Exposure to environmental toxicants is linked to long-term adverse outcomes in the brain and involves the dysfunction of glial and neuronal cells. Astrocytes, the most numerous cell type, are increasingly implicated in the pathogenesis of many diseases of the central nervous system, including neurodegenerative diseases. Astrocytes are critical for proper brain function in part due to their robust antioxidant and unique metabolic capabilities. Additionally, astrocytes are positioned both at the blood-brain barrier, where they are the primary responders to xenobiotic penetrance of the CNS, and at synapses where they are in close contact with neurons and synaptic machinery. While exposure to several classes of environmental toxicants, including chlorinated and fluorinated compounds, and trace metals, have been implicated in neurodegenerative diseases, their impact on astrocytes represents an important and growing field of research. Here, we review existing literature focused on the impact of a range of synthetic compounds on astrocytic function. We focus specifically on perturbed metabolic processes in response to these compounds and consider how perturbation of these pathways impacts disease pathogenesis.
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Affiliation(s)
- Mondona S McCann
- Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, United States.
| | - Kathleen A Maguire-Zeiss
- Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, United States; Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, United States
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14
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Chu YY, Wang X, Dai HL. Update on pharmacotherapy of hepatic encephalopathy. Shijie Huaren Xiaohua Zazhi 2021; 29:58-64. [DOI: 10.11569/wcjd.v29.i2.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a central nervous system disease caused by serious liver diseases or various portal vein systemic circulation abnormalities. The pathogenesis and pathophysiology of HE have not been fully elucidated yet, and among others, the most important is still the theory of ammonia intoxication proposed in the 1930s. Therefore, reducing blood ammonia is currently the main therapeutic strategy for HE, along with improving nervous system function. Thanks to the clarification of the mechanism underlying ammonia-induced brain cell injury in recent years, researchers have proposed some novel therapeutic targets and related drugs. This work will make a brief summary regarding the update of HE drugs with regard to ammonia reduction, nervous system improvement, and intervention of ammonia toxicity targets.
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Affiliation(s)
- Yu-Ying Chu
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Xue Wang
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Hong-Liang Dai
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
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15
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Ahmadi S, Ghaderi H, Saadati N, Samadi S. Mesoporous silica SBA-15 decreases hyperammonemia and affects the gene expression of mitogen-activated protein kinases in the prefrontal cortex of rats with bile duct ligation. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:1293-1300. [PMID: 33149861 PMCID: PMC7585539 DOI: 10.22038/ijbms.2020.44658.10436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVES We aim to examine possible ammonia lowering effects of mesoporous silica SBA-15 in rats after the common bile duct ligation (BDL). We also evaluate the effect of SBA-15 treatments during 28 days of BDL on locomotion and rearing behavior, as well as on the gene expression of Jnk3 and p38alpha (p38α) mitogen-activated protein kinases in the prefrontal cortex (PFC). MATERIALS AND METHODS SBA-15 was prepared with the hydrothermal method from the surfactant P123 and tetraethyl orthosilicate (TEOS), and calcined at 550 ºC. Then, the product was characterized by FT-IR, XRD, SEM, and BJH-BET techniques. Male Wistar rats in sham control and a group with BDL received saline but another group with BDL received SBA-15 during 28 days of BDL. We examined all groups of rats weekly for locomotion and rearing behavior; then on day 28, we sacrificed all rats, collected the blood sample, and finally dissected the PFC from the whole brain. RESULTS The SBA-15 treatments had no effect on locomotion but improved rearing behavior on days 7 and 14 of BDL. Biochemical analysis indicated that the SBA-15 treatments in rats with BDL significantly decreased hyperammonemia. The results also revealed that the SBA-15 treatments in rats with BDL significantly restored the decreased Jnk3 gene expression, and increased the p38α gene expression in the PFC. CONCLUSION We conclude that SBA-15 can be used as an ammonia lowering agent in hepatic encephalopathy; however, its improving effects on locomotion and neuroinflammation, as well as signaling molecules in the brain need more investigations.
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Affiliation(s)
- Shamseddin Ahmadi
- Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Iran,Corresponding author: Shamseddin Ahmadi. Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Iran. Tel: +98-87-33660075; Fax: +98-87-33622702;
| | - Halaleh Ghaderi
- Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Iran
| | - Nazila Saadati
- Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Iran
| | - Saadi Samadi
- Department of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, Iran
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16
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Taherian M, Norenberg MD, Panickar KS, Shamaladevi N, Ahmad A, Rahman P, Jayakumar AR. Additive Effect of Resveratrol on Astrocyte Swelling Post-exposure to Ammonia, Ischemia and Trauma In Vitro. Neurochem Res 2020; 45:1156-1167. [PMID: 32166573 DOI: 10.1007/s11064-020-02997-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 12/12/2019] [Accepted: 02/22/2020] [Indexed: 12/16/2022]
Abstract
Swelling of astrocytes represents a major component of the brain edema associated with many neurological conditions, including acute hepatic encephalopathy (AHE), traumatic brain injury (TBI) and ischemia. It has previously been reported that exposure of cultured astrocytes to ammonia (a factor strongly implicated in the pathogenesis of AHE), oxygen/glucose deprivation, or to direct mechanical trauma results in an increase in cell swelling. Since dietary polyphenols have been shown to exert a protective effect against cell injury, we examined whether resveratrol (RSV, 3,5,4'-trihydroxy-trans-stilbene, a stilbenoid phenol), has a protective effect on astrocyte swelling following its exposure to ammonia, oxygen-glucose deprivation (OGD), or trauma in vitro. Ammonia increased astrocyte swelling, and pre- or post-treatment of astrocytes with 10 and 25 µM RSV displayed an additive effect, while 5 µM did not prevent the effect of ammonia. However, pre-treatment of astrocytes with 25 µM RSV slightly, but significantly, reduced the trauma-induced astrocyte swelling at earlier time points (3 h), while post-treatment had no significant effect on the trauma-induced cell swelling at the 3 h time point. Instead, pre- or post-treatment of astrocytes with 25 µM RSV had an additive effect on trauma-induced astrocyte swelling. Further, pre- or post-treatment of astrocytes with 5 or 10 µM RSV had no significant effect on trauma-induced astrocyte swelling. When 5 or 10 µM RSV were added prior to, or during the process of OGD, as well as post-OGD, it caused a slight, but not statistically significant decline in cell swelling. However, when 25 µM RSV was added during the process of OGD, as well as after the cells were returned to normal condition (90 min period), such treatment showed an additive effect on the OGD-induced astrocyte swelling. Noteworthy, a higher concentration of RSV (25 µM) exhibited an additive effect on levels of phosphorylated forms of ERK1/2, and p38MAPK, as well as an increased activity of the Na+-K+-Cl- co-transporter-1 (NKCC1), factors known to induce astrocytes swelling, when the cells were treated with ammonia or after trauma or ischemia. Further, inhibition of ERK1/2, and p38MAPK diminished the RSV-induced exacerbation of cell swelling post-ammonia, trauma and OGD treatment. These findings strongly suggest that treatment of cultured astrocytes with RSV enhanced the ammonia, ischemia and trauma-induced cell swelling, likely through the exacerbation of intercellular signaling kinases and ion transporters. Accordingly, caution should be exercised when using RSV for the treatment of these neurological conditions, especially when brain edema is also suspected.
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Affiliation(s)
- Mehran Taherian
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL, 33125, USA
| | - Michael D Norenberg
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
- Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, USA
- Department of Neurology and Neurological Surgery, University of Miami School of Medicine, Miami, FL, USA
| | - Kiran S Panickar
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL, 33125, USA
| | | | - Anis Ahmad
- Department of Radiation Oncology, Sylvester Cancer Center, University of Miami School of Medicine, Miami, FL, USA
| | - Purbasha Rahman
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL, 33125, USA
- Department of Microbiology and Immunology, University of Miami, Coral Cables, Miami, FL, USA
| | - Arumugam R Jayakumar
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL, 33125, USA.
- South Florida VA Foundation for Research and Education Inc, Veterans Affairs Medical Center, Miami, FL, 33125, USA.
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, 1201 NW 16th St, Res-151, Room 314, Miami, FL, USA.
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17
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Ahmadi S, Khaledi S. Anxiety in rats with bile duct ligation is associated with activation of JNK3 mitogen-activated protein kinase in the hippocampus. Metab Brain Dis 2020; 35:579-588. [PMID: 32052257 DOI: 10.1007/s11011-020-00542-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 01/30/2020] [Indexed: 12/11/2022]
Abstract
We examine the anxiety-like behaviors in rats with bile duct ligation (BDL), as well as its relationship with the expression of JNK3 and P38 MAPKs in rat hippocampus. Male Wistar rats undergo either sham operation or BDL as a rat model of cirrhotic HE. The anxiety-like behaviors are determined using a light/dark box test two hours befor the surgery on day 1 and on days 7, 14, 21 and 28 of BDL. The gene and protein expression levels of JNK3 and p38 in the hippocampus were examined respectively with qPCR and western blotting methods on day 28 of BDL. The results revealed that anxiety was increased in the cirrhotic HE model rats during 28 days of BDL. The molecular data indicated that the gene expression of Jnk3 and protein levels of JNK3, as well as phospho-JNK3, significantly increased in the hippocampus of the cirrhotic HE model rats compared to the sham control group. However, the results revealed no significant changes in the gene expression and the protein levels of p38 as well as phospho-p38 in the hippocampus of the cirrhotic HE model rats compared to the sham control group. We conclude that the increases in the expression and activation of JNK3 MAPK in the hippocampus may underlie, at least partly, the anxiety-like behaviors in rats with cirrhotic HE.
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Affiliation(s)
- Shamseddin Ahmadi
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran.
| | - Shiler Khaledi
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran
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18
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Sepehrinezhad A, Zarifkar A, Namvar G, Shahbazi A, Williams R. Astrocyte swelling in hepatic encephalopathy: molecular perspective of cytotoxic edema. Metab Brain Dis 2020; 35:559-578. [PMID: 32146658 DOI: 10.1007/s11011-020-00549-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 02/12/2020] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) may occur in patients with liver failure. The most critical pathophysiologic mechanism of HE is cerebral edema following systemic hyperammonemia. The dysfunctional liver cannot eliminate circulatory ammonia, so its plasma and brain levels rise sharply. Astrocytes, the only cells that are responsible for ammonia detoxification in the brain, are dynamic cells with unique phenotypic properties that enable them to respond to small changes in their environment. Any pathological changes in astrocytes may cause neurological disturbances such as HE. Astrocyte swelling is the leading cause of cerebral edema, which may cause brain herniation and death by increasing intracranial pressure. Various factors may have a role in astrocyte swelling. However, the exact molecular mechanism of astrocyte swelling is not fully understood. This article discusses the possible mechanisms of astrocyte swelling which related to hyperammonia, including the possible roles of molecules like glutamine, lactate, aquaporin-4 water channel, 18 KDa translocator protein, glial fibrillary acidic protein, alanine, glutathione, toll-like receptor 4, epidermal growth factor receptor, glutamate, and manganese, as well as inflammation, oxidative stress, mitochondrial permeability transition, ATP depletion, and astrocyte senescence. All these agents and factors may be targeted in therapeutic approaches to HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Asadollah Zarifkar
- Shiraz Neuroscience Research Center and Department of Physiology, Shiraz University of Medical Sciences (SUMS), Shiraz, Iran
| | - Gholamreza Namvar
- Department of Neuroscience and Cognition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Roger Williams
- The Institute of Hepatology London and Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK.
- Faculty of Life Sciences & Medicine, King's College London, London, UK.
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19
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Activation of Protein Kinase Cδ Contributes to the Induction of Src/EGF Receptor/ERK Signaling in Ammonia-treated Astrocytes. J Mol Neurosci 2020; 70:1110-1119. [PMID: 32125625 DOI: 10.1007/s12031-020-01517-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 02/19/2020] [Indexed: 02/06/2023]
Abstract
Previously, we showed that Src-mediated EGF receptor transactivation/ERK activation mediates ammonia-induced astrocyte swelling, which represents a major component of brain edema in hyperammonemic disorders. Here, we tested the role of PKC in the induction of this signaling pathway and its involvement in ammonia-mediated cell swelling. We found that incubating astrocytes with bisindolylmaleimide (BIM, an inhibitor of classical and novel PKC isoforms) or rottlerin, a PKCδ-specific inhibitor, attenuated the ammonia-induced phosphorylation of EGFR, while GF109203X had no effect on this pathway. We further found that BIM or rottlerin pretreatment inhibited the ammonia-induced phosphorylation of Src and that ammonia significantly increased the level of PKCδ pulled down by a Src antibody. AG1478, a specific EGFR kinase activity inhibitor, effectively inhibited phosphorylation at Tyr1068 but had no discernable effect on phosphorylation at Tyr845. Moreover, BIM or rottlerin abrogated ammonia-induced ERK phosphorylation. BIM-, rottlerin-, or GF109203X-treated astrocytes showed a significant reduction in cell swelling compared to that observed after treatment with ammonia alone. Finally, it was found that AG1478 attenuated ammonia-induced PKCα translocation to the particulate fraction. Taken together, our results indicate that PKCδ mediates ammonia-induced astrocyte swelling by activating Src and downstream EGF receptor/ERK signaling, which may contribute to the pathogenesis of neuropsychiatric disorders associated with hyperammonemia.
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20
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Chen Y, Qin C, Huang J, Tang X, Liu C, Huang K, Xu J, Guo G, Tong A, Zhou L. The role of astrocytes in oxidative stress of central nervous system: A mixed blessing. Cell Prolif 2020; 53:e12781. [PMID: 32035016 PMCID: PMC7106951 DOI: 10.1111/cpr.12781] [Citation(s) in RCA: 183] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Revised: 12/17/2019] [Accepted: 01/20/2020] [Indexed: 02/05/2023] Open
Abstract
Central nervous system (CNS) maintains a high level of metabolism, which leads to the generation of large amounts of free radicals, and it is also one of the most vulnerable organs to oxidative stress. Emerging evidences have shown that, as the key homeostatic cells in CNS, astrocytes are deeply involved in multiple aspects of CNS function including oxidative stress regulation. Besides, the redox level in CNS can in turn affect astrocytes in morphology and function. The complex and multiple roles of astrocytes indicate that their correct performance is crucial for the normal functioning of the CNS, and its dysfunction may result in the occurrence and progression of various neurological disorders. To date, the influence of astrocytes in CNS oxidative stress is rarely reviewed. Therefore, in this review we sum up the roles of astrocytes in redox regulation and the corresponding mechanisms under both normal and different pathological conditions.
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Affiliation(s)
- Yaxing Chen
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Chen Qin
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Jianhan Huang
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Tang
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Chang Liu
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Keru Huang
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Jianguo Xu
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Gang Guo
- State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, China
| | - Aiping Tong
- State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, China
| | - Liangxue Zhou
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
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21
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Liotta EM, Kimberly WT. Cerebral edema and liver disease: Classic perspectives and contemporary hypotheses on mechanism. Neurosci Lett 2020; 721:134818. [PMID: 32035166 DOI: 10.1016/j.neulet.2020.134818] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 02/01/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Liver disease is a growing public health concern. Hepatic encephalopathy, the syndrome of brain dysfunction secondary to liver disease, is a frequent complication of both acute and chronic liver disease and cerebral edema (CE) is a key feature. While altered ammonia metabolism is a key contributor to hepatic encephalopathy and CE in liver disease, there is a growing appreciation that additional mechanisms contribute to CE. In this review we will begin by presenting three classic perspectives that form a foundation for a discussion of CE in liver disease: 1) CE is unique to acute liver failure, 2) CE in liver disease is only cytotoxic, and 3) CE in liver disease is primarily an osmotically mediated consequence of ammonia and glutamine metabolism. We will present each classic perspective along with more recent observations that call in to question that classic perspective. After highlighting these areas of debate, we will explore the leading contemporary mechanisms hypothesized to contribute to CE during liver disease.
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Affiliation(s)
- Eric M Liotta
- Northwestern University-Feinberg School of Medicine, Department of Neurology, United States; Northwestern University-Feinberg School of Medicine, Department of Surgery, Division of Organ Transplantation, United States; Northwestern University Transplant Outcomes Research Collaboration, United States.
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22
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Jia X, Liu Y, Li X, Huo C, Li D, Xu R, Hou L, Wang X. Norcepharadione B attenuates H 2O 2-induced neuronal injury by upregulating cellular antioxidants and inhibiting volume-sensitive Cl - channel. Exp Biol Med (Maywood) 2019; 244:1463-1474. [PMID: 31583895 DOI: 10.1177/1535370219881358] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress acts as an essential culprit factor in the development of stroke and Alzheimer’s disease. Norcepharadione B possesses various pharmacologic features as an extract obtained from Houttuynia cordata. Nevertheless, the anti-apoptotic and neuroprotective characteristics of norcepharadione B remain unclear. In this study, the neuronal protection effect provided by norcepharadione B against injury caused by hydrogen peroxide (H2O2) in HT22 cell as well as the fundamental mechanism was systematically explored. The neurotoxicity assays of hippocampal cells, which were co-cultured with H2O2, showed that norcepharadione B had the ability to insulate the toxicity induced by H2O2 with significant reduced cell apoptosis. Besides, norcepharadione B potentiated the activity of superoxide dismutase (SOD), increased the level of glutathione (GSH), and decreased malondialdehyde content. The H2O2-induced apoptotic protein Bax was suppressed, and the anti-apoptotic protein Bcl-2 was boosted by norcepharadione B. Norcepharadione B promoted Akt phosphorylation and further upregulated heme oxygenase (HO-1) in cells exposed to oxidative stress. However, the inductive effect of HO-1 by norcepharadione B was shut off via the PI3K/Akt inhibitor LY294002. Furthermore, 2-h incubation with H2O2 substantially increased cell volume in HT22 cells, while norcepharadione B effectively alleviated such effect by interrupting the activation of VSOR Cl− channel. Collectively, our data revealed protective properties of norcepharadione B in resisting oxidative stress induced by H2O2 through elevation of HO-1 in the dependence of PI3K/Akt and in inhibiting H2O2-induced cell swelling by VSOR Cl− channel obstruction in HT22 cells. Impact statement Norcepharadione B is an aporphine alkaloid compound extracted from Chinese herb Houttuynia cordata. It was well known for its anti-inflammatory, anti-cancer, and anti-platelet aggregation outcomes. Our study demonstrated that Norcepharadione B protected hippocampal neurons against oxidative stress and the resultant cell apoptosis upon H2O2 exposure. Meanwhile, Norcepharadione B also substantially reduced cell swelling induced by H2O2 via inhibiting VSOR Cl− channel in neurons. These findings uncovered the potential mechanisms of Norcepharadione B in protecting neuron apoptosis under oxidative stress and propose that Norcepharadione B may serve as a favorable herb medicine for restoring neuronal injury in the pathogenesis of stroke together with other neurodegenerative diseases.
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Affiliation(s)
- Xin Jia
- Department of Geriatrics, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China
| | - Yan Liu
- Department of Geriatrics, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xing Li
- Department of Geriatrics, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China
| | - Cong Huo
- Department of Geriatrics, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China
| | - Dongtao Li
- Department of Geriatrics, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China
| | - Rong Xu
- Department of Geriatrics, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China
| | - Liming Hou
- Department of Geriatrics, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xiaoming Wang
- Department of Geriatrics, Xijing Hospital, Airforce Military Medical University, Xi'an, Shaanxi 710032, China
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Cheng CH, Ma HL, Su YL, Deng YQ, Feng J, Xie JW, Chen XL, Guo ZX. Ammonia toxicity in the mud crab (Scylla paramamosain): The mechanistic insight from physiology to transcriptome analysis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 179:9-16. [PMID: 31022654 DOI: 10.1016/j.ecoenv.2019.04.033] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 04/04/2019] [Accepted: 04/09/2019] [Indexed: 06/09/2023]
Abstract
Ammonia is a major aquatic environmental pollutants. However, the underlying molecular mechanism of ammonia-induced toxicity is not fully understood. In this study, we investigated the physiological response and molecular mechanism in mud crab (Scylla paramamosain) exposed to the acute total ammonia (30 mg L-1) for 48 h. The results shown that ammonia exposure induced oxidative stress, and subsequently led to cytological damage and DNA damage. Transcriptome analysis was applied to investigate the key genes and pathways involved in the responses to ammonia exposure. A total of 722 differentially expressed genes (DEGs) (526 up-regulated and 196 down-regulated) were identified. DEGs mainly involved in pathways including metabolism, cellular processes, signal transduction and immune functions. Additionally, transcriptome analysis revealed that ATM/p53-Caspase3 pathway involved in apoptosis induced by ammonia stress. These results provided a new insight into the mechanism of the potential toxic effects of ammonia on crustaceans.
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Affiliation(s)
- Chang-Hong Cheng
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, China, PR China
| | - Hong-Ling Ma
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, China, PR China
| | - You-Lu Su
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, China, PR China
| | - Yi-Qin Deng
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, China, PR China
| | - Juan Feng
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, China, PR China
| | - Jia-Wei Xie
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, China, PR China
| | - Xiao-Long Chen
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, China, PR China
| | - Zhi-Xun Guo
- Key Laboratory of South China Sea Fishery Resources Exploitation & Utilization, Ministry of Agriculture, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, Guangdong, 510300, China, PR China.
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Li J, Jia M, Chen G, Nie S, Zheng C, Zeng W, Xu Y, Wang C, Cao X, Liu Q. Involvement of p38 mitogen‐activated protein kinase in altered expressions of AQP1 and AQP4 after carbon monoxide poisoning in rat astrocytes. Basic Clin Pharmacol Toxicol 2019; 125:394-404. [PMID: 31063681 DOI: 10.1111/bcpt.13247] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 04/28/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Jinlan Li
- Department of Neurology Enshi Tujia and Miao Autonomous Prefecture Center Hospital Enshi China
| | - Min Jia
- Department of Neurology Enshi Tujia and Miao Autonomous Prefecture Center Hospital Enshi China
| | - Guiqin Chen
- Department of Neurology Renmin Hospital of Wuhan University Wuhan China
| | - Shuke Nie
- Department of Neurology Renmin Hospital of Wuhan University Wuhan China
| | - Cong Zheng
- Department of Neurology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Weiqi Zeng
- Department of Neurology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Yan Xu
- Department of Neurology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Congping Wang
- Department of Neurology Enshi Tujia and Miao Autonomous Prefecture Center Hospital Enshi China
| | - Xuebing Cao
- Department of Neurology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Qunhui Liu
- Department of Neurology Enshi Tujia and Miao Autonomous Prefecture Center Hospital Enshi China
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Astragaloside IV Alleviates Ammonia-Induced Apoptosis and Oxidative Stress in Bovine Mammary Epithelial Cells. Int J Mol Sci 2019; 20:ijms20030600. [PMID: 30704086 PMCID: PMC6386910 DOI: 10.3390/ijms20030600] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/19/2019] [Accepted: 01/28/2019] [Indexed: 12/14/2022] Open
Abstract
Ammonia is one of the major toxic components of metabolites in blood and tissues of high-producing dairy cows and could affect the health of bovine mammary glands. Bovine mammary epithelial cells are sensitive to oxidative stress induced by intensive cell metabolism. In our previous study, we found that ammonia could induce oxidative stress, apoptosis and inflammatory responses in bovine mammary epithelial cells. In the present study, the cytoprotective effects of astragaloside IV against ammonia in vitro were explored. The results demonstrated that pretreatment of MAC-T cells with astragaloside IV could potently suppress the increase in the level of intracellular reactive oxygen species (ROS) and the rate of cell apoptosis, inhibit the ammonia-induced inflammatory responses, and rescue the decrease of cell viability. Astragaloside IV prevented ammonia-induced endoplasmic reticulum stress. Astragaloside IV also significantly suppressed the levels of BAX, caspase 3 and p53 phosphorylation in ammonia-induced MAC-T cells. Nuclear factor erythroid 2-related factor 2(Nrf2) was essential for cytoprotective effects of astragaloside IV in MAC-T cells, as knockdown of Nrf2 dramatically abolished the prosurvival effects of astragaloside IV on treated cells. Furthermore, the PI3K/AKT and ERK/MAPK pathways were responsible for the induction of Nrf2 by astragaloside IV. In conclusion, astragaloside IV played a beneficial role against ammonia-induced damage of MAC-T cells. This provides a cue for future study to use astragaloside IV as a protective and curative agent against ammonia exposure of mammary glands in dairy cows.
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Silencing of Transcription Factor Sp1 Promotes SN1 Transporter Regulation by Ammonia in Mouse Cortical Astrocytes. Int J Mol Sci 2019; 20:ijms20020234. [PMID: 30634395 PMCID: PMC6359076 DOI: 10.3390/ijms20020234] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 12/27/2018] [Accepted: 12/27/2018] [Indexed: 12/15/2022] Open
Abstract
The involvement of the astrocytic SN1 (SNAT3) transporter in ammonia-induced l-glutamine retention was recently documented in mouse-cultured astrocytes. Here we investigated the involvement of specificity protein 1 (Sp1) transcription factor in SN1 regulation in ammonium chloride (“ammonia”)-treated astrocytes. Sp1 expression and its cellular localization were determined using real-time qPCR, Western blot, and confocal microscopy. Sp1 binding to Snat3 promoter was analyzed by chromatin immunoprecipitation. The role of Sp1 in SN1 expression and SN1-mediated [3H]glutamine uptake in ammonia-treated astrocytes was verified using siRNA and mithramycin A. The involvement of protein kinase C (PKC) isoforms in Sp1 level/phosphorylation status was verified using siRNA technology. Sp1 translocation to the nuclei and its enhanced binding to the Snat3 promoter, along with Sp1 dependence of system N-mediated [3H]glutamine uptake, were observed in astrocytes upon ammonia exposure. Ammonia decreased the level of phosphorylated Sp1, and the effect was reinforced by long-term incubation with PKC modulator, phorbol 12-myristate 13-acetate, which is a treatment likely to dephosphorylate Sp1. Furthermore, silencing of the PKCδ isoform appears to enhance the ammonia effect on the Sp1 level. Collectively, the results demonstrate the regulatory role of Sp1 in regulation of SN1 expression and activity in ammonia-treated astrocytes and implicate altered Sp1 phosphorylation status in this capacity.
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El-Mas MM, Abdel-Rahman AA. Role of Alcohol Oxidative Metabolism in Its Cardiovascular and Autonomic Effects. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1193:1-33. [PMID: 31368095 PMCID: PMC8034813 DOI: 10.1007/978-981-13-6260-6_1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Several review articles have been published on the neurobehavioral actions of acetaldehyde and other ethanol metabolites as well as in major alcohol-related disorders such as cancer and liver and lung disease. However, very few reviews dealt with the role of alcohol metabolism in the adverse cardiac and autonomic effects of alcohol and their potential underlying mechanisms, particularly in vulnerable populations. In this chapter, following a brief overview of the dose-related favorable and adverse cardiovascular effects of alcohol, we discuss the role of ethanol metabolism in its adverse effects in the brainstem and heart. Notably, current knowledge dismisses a major role for acetaldehyde in the adverse autonomic and cardiac effects of alcohol because of its low tissue level in vivo. Contrary to these findings in men and male rodents, women and hypertensive individuals are more sensitive to the adverse cardiac effects of similar amounts of alcohol. To understand this discrepancy, we discuss the autonomic and cardiac effects of alcohol and its metabolite acetaldehyde in a model of hypertension, the spontaneously hypertensive rat (SHR) and female rats. We present evidence that enhanced catalase activity, which contributes to cardioprotection in hypertension (compensatory) and in the presence of estrogen (inherent), becomes detrimental due to catalase catalysis of alcohol metabolism to acetaldehyde. Noteworthy, studies in SHRs and in estrogen deprived or replete normotensive rats implicate acetaldehyde in triggering oxidative stress in autonomic nuclei and the heart via (i) the Akt/extracellular signal-regulated kinases (ERK)/nitric oxide synthase (NOS) cascade and (ii) estrogen receptor-alpha (ERα) mediation of the higher catalase activity, which generates higher ethanol-derived acetaldehyde in female heart. The latter is supported by the ability of ERα blockade or catalase inhibition to attenuate alcohol-evoked myocardial oxidative stress and dysfunction. More mechanistic studies are needed to further understand the mechanisms of this public health problem.
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Affiliation(s)
- Mahmoud M El-Mas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Abdel A Abdel-Rahman
- Department of Pharmacology and Toxicology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
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Cheng ZJ, Dai TM, Shen YY, He JL, Li J, Tu JL. Atorvastatin Pretreatment Attenuates Ischemic Brain Edema by Suppressing Aquaporin 4. J Stroke Cerebrovasc Dis 2018; 27:3247-3255. [PMID: 30093197 DOI: 10.1016/j.jstrokecerebrovasdis.2018.07.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 07/01/2018] [Accepted: 07/05/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Cerebral edema, a serious complication of acute cerebral infarction, has a crucial impact on morbidity and mortality in the early stage of cerebral infarction. And aquaporin 4 (AQP4), a bidirectional water transporting protein, plays a pivotal role in edema formation. At experimental model, it has proven that atorvastatin could exert pleiotropic neuroprotection on acute cerebral infarction independent of its cholesterol-lowering action. It was a common protective manifestation that atorvastatin can reduce the infarct volume and cerebral edema. However, little is known about atorvastatin improving ischemic brain edema by regulating AQP4 expression. This study intended to investigate the neuroprotection effects of atorvastatin pretreatment in rats with cerebral ischemia and further explore the potential relationship between atorvastatin and AQP4 expression. METHODS Fifty-one adult male Sprague Dawley rats were randomly divided into 3 groups: sham, middle cerebral artery occlusion (MCAO), and atorvastatin pretreatment (Ator) group. For Ator group, 20 mg/kg of atorvastatin injectable suspension was administered once for 7days by gavage before operation, whereas the others were administered the same volume of saline matching. Except for sham group, MCAO and Ator groups were subjected to permanent MCAO by modified intraluminal suture method. Infarct volume, neurological deficit, brain water content (BWC), immunohistochemistry, western blot, and polymerase chain reaction (PCR) were measured at 24 hours after MCAO. RESULTS Compared with sham group, the mNSS, infarct volume, and BWC of ischemic hemisphere were significantly increased (P < 0.001) in MCAO group. Positive cells and protein levels of p-p38MAPK and AQP4 in peri-infarction were significantly increased (P < 0.01). The mRNA levels of p38MAPK and AQP4 were also prominently upregulated (P < 0.01). Interestingly, preadministration of atorvastatin dramatically decreased infarct volume and the BWC of ischemic hemisphere compared with MCAO group (P < 0.05). The overexpressions of p-p38MAPK and AQP4 in peri-infarction were significantly decreased (P < 0.05) and their mRNA levels were downregulated by atorvastatin pretreatment (P < 0.05). Neurological deficits were also dramatically improved (P < 0.001). CONCLUSION To the best of our knowledge, this is the first study that demonstrates an effect of atorvastatin on expression of AQP4, and we propose that decreased AQP4 expression through a p38MAPK-suppression pathway may be the mechanism of atorvastatin alleviating ischemic cerebral edema.
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Affiliation(s)
- Zhi-Juan Cheng
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, China.
| | - Ting-Min Dai
- Department of Neurology, Affiliated Hospital of Jiujiang University, China.
| | - Yao-Yao Shen
- Department of Neurology, Affiliated Hospital of Jiujiang University, China.
| | - Jian-Le He
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, China.
| | - Juan Li
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, China.
| | - Jiang-Long Tu
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, China.
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Krawitz S, Lingiah V, Pyrsopoulos NT. Acute Liver Failure: Mechanisms of Disease and Multisystemic Involvement. Clin Liver Dis 2018; 22:243-256. [PMID: 29605064 DOI: 10.1016/j.cld.2018.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Acute liver failure is accompanied by a pathologic syndrome common to numerous different etiologies of liver injury. This acute liver failure syndrome leads to potentially widespread devastating end-organ consequences. Systemic dysregulation and dysfunction is likely propagated via inflammation as well as underlying hepatic failure itself. Decoding the mechanisms of the disease process and multisystemic involvement of acute liver failure offers potential for targeted treatment opportunities and improved clinical outcomes in this sick population.
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Affiliation(s)
- Steven Krawitz
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, H-534, Newark, NJ 07103, USA.
| | - Vivek Lingiah
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, H-530, Newark, NJ 07103, USA
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, 185 South Orange Avenue, H-536, Newark, NJ 07103, USA
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30
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Dhanda S, Sunkaria A, Halder A, Sandhir R. Mitochondrial dysfunctions contribute to energy deficits in rodent model of hepatic encephalopathy. Metab Brain Dis 2018; 33:209-223. [PMID: 29138968 DOI: 10.1007/s11011-017-0136-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 10/12/2017] [Indexed: 12/12/2022]
Abstract
Perturbations in the cerebral energy metabolism are anticipated to be an important factor by which ammonia may exert its toxic effects on the central nervous system. The present study was designed to investigate the role of impaired mitochondrial functions and cerebral energy metabolism in the development hepatic encephalopathy (HE) induced by of bile duct ligation (BDL). After four weeks of BDL, a significant increase in hepatic hydroxyproline and collagen content was observed which confirmed biliary fibrosis. Brain regions viz. cortex, hippocampus, striatum and cerebellum of BDL rats had impaired activity of mitochondrial respiratory chain enzymes. This was accompanied by increase in mitochondrial reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl levels in the brain. Mitochondrial redox ratio was significantly reduced in the brain of BDL rats. In addition, mitochondria from brain of BDL rats were depolarized and swollen compared to the sham controls. Ultrastructure analysis of mitochondria from cortex and hippocampus of BDL animals revealed aberrant cristae, ruptured membranes and non-dense matrix. Further, a significant decrease was observed in creatine kinase activity, glucose uptake and CO2 production in the brain regions of BDL rats. ATP/ADP ratio, a critical parameter of cellular energy status, was also significantly reduced in brain regions of rats with HE. Overall, the findings clearly demonstrate that BDL induced HE involves mitochondrial respiratory chain dysfunctions, mitochondrial depolarization and swelling that accentuates oxidative stress which in turn leads to compromise in cerebral energy metabolism thereby contributing to the pathophysiology of chronic HE.
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Affiliation(s)
- Saurabh Dhanda
- Department of Biochemistry, Panjab University, Basic Medical Science Block-II, Sector-25, Chandigarh, 160014, India
| | - Aditya Sunkaria
- Department of Biochemistry, Panjab University, Basic Medical Science Block-II, Sector-25, Chandigarh, 160014, India
| | - Avishek Halder
- Department of Biochemistry, Panjab University, Basic Medical Science Block-II, Sector-25, Chandigarh, 160014, India
| | - Rajat Sandhir
- Department of Biochemistry, Panjab University, Basic Medical Science Block-II, Sector-25, Chandigarh, 160014, India.
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31
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Jayakumar AR, Taherian M, Panickar KS, Shamaladevi N, Rodriguez ME, Price BG, Norenberg MD. Differential Response of Neural Cells to Trauma-Induced Swelling In Vitro. Neurochem Res 2018; 43:397-406. [PMID: 29150743 DOI: 10.1007/s11064-017-2434-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 11/07/2017] [Accepted: 11/09/2017] [Indexed: 11/26/2022]
Abstract
Brain edema and the associated increase in intracranial pressure are major consequences of traumatic brain injury (TBI) that accounts for most early deaths after TBI. We recently showed that acute severe trauma to cultured astrocytes results in cell swelling. We further examined whether trauma induces cell swelling in neurons and microglia. We found that severe trauma also caused cell swelling in cultured neurons, whereas no swelling was observed in microglia. While severe trauma caused cell swelling in both astrocytes and neurons, mild trauma to astrocytes, neurons, and microglia failed to cell swelling. Since extracellular levels of glutamate are increased in brain post-TBI and microglia are known to release cytokine, and direct exposure of astrocytes to these molecules are known to stimulate cell swelling, we examined whether glutamate or cytokines have any additive effect on trauma-induced cell swelling. Exposure of cultured astrocytes to trauma caused cell swelling, and such swelling was potentiated by the exposure of traumatized astrocytes to glutamate and cytokines. Conditioned medium (CM) from traumatized astrocytes had no effect on neuronal swelling post-trauma, while CM from traumatized neurons and microglia potentiated the effect of trauma on astrocyte swelling. Further, trauma significantly increased the Na-K-Cl co-transporter (NKCC) activity in neurons, and that inhibition of NKCC activity diminished the trauma-induced neuronal swelling. Our results indicate that a differential sensitivity to trauma-induced cell swelling exists in neural cells and that neurons and microglia are likely to be involved in the potentiation of the astrocyte swelling post-trauma.
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Affiliation(s)
- A R Jayakumar
- Laboratory of Neuropathology, Veterans Affairs Medical Center, Miami, FL, USA.
- South Florida Foundation for Research and Education Inc., Miami VA Healthcare System, Miami, FL, 33125, USA.
| | - M Taherian
- Laboratory of Neuropathology, Veterans Affairs Medical Center, Miami, FL, USA
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
| | - K S Panickar
- Laboratory of Neuropathology, Veterans Affairs Medical Center, Miami, FL, USA
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
| | - N Shamaladevi
- Department of Urology, University of Miami School of Medicine, Miami, FL, USA
| | - M E Rodriguez
- Laboratory of Neuropathology, Veterans Affairs Medical Center, Miami, FL, USA
| | - B G Price
- Laboratory of Neuropathology, Veterans Affairs Medical Center, Miami, FL, USA
| | - M D Norenberg
- Laboratory of Neuropathology, Veterans Affairs Medical Center, Miami, FL, USA
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
- Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, USA
- Department of Neurology and Neurological Surgery, University of Miami School of Medicine, Miami, FL, USA
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32
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Wu T, Tang M. The inflammatory response to silver and titanium dioxide nanoparticles in the central nervous system. Nanomedicine (Lond) 2017; 13:233-249. [PMID: 29199887 DOI: 10.2217/nnm-2017-0270] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Despite the increasing number of neurotoxicological studies on metal-containing nanoparticles (NPs), the NP-induced neuroinflammation has not yet been well understood. This review provides a comprehensive understanding of inflammatory responses to two typical metal-containing NPs, namely silver NPs (Ag-NPs) and titanium dioxide NPs (TiO2-NPs). Ag-NPs and TiO2-NPs could translocate into the CNS through damaged blood-brain barrier, nerve afferent signaling and eye-to-brain ways, and even cell uptake. NPs could stimulate the activation of glial cells to release proinflammatory cytokines and generate reactive oxygen species and nitric oxide production, resulting in the neuroinflammation. The potential mechanisms of Ag-NPs and TiO2-NPs causing inflammation are complex, including several immune response relevant signaling pathways. Some parameters governing their ability to cause neuroinflammation are presented as well.
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Affiliation(s)
- Tianshu Wu
- Key Laboratory of Environmental Medicine & Engineering, Ministry of Education, School of Public Health & Collaborative Innovation Center of Suzhou Nano Science & Technology, Southeast University, Nanjing 210009, China.,Jiangsu Key Laboratory for Biomaterials & Devices, Southeast University, Nanjing 210009, China
| | - Meng Tang
- Key Laboratory of Environmental Medicine & Engineering, Ministry of Education, School of Public Health & Collaborative Innovation Center of Suzhou Nano Science & Technology, Southeast University, Nanjing 210009, China.,Jiangsu Key Laboratory for Biomaterials & Devices, Southeast University, Nanjing 210009, China
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Milewski K, Bogacińska-Karaś M, Fręśko I, Hilgier W, Jaźwiec R, Albrecht J, Zielińska M. Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y⁺LAT2 Carrier-Mediated Loss. Int J Mol Sci 2017; 18:ijms18112308. [PMID: 29099056 PMCID: PMC5713277 DOI: 10.3390/ijms18112308] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 10/19/2017] [Accepted: 10/27/2017] [Indexed: 01/24/2023] Open
Abstract
Previously we had shown that ammonia stimulates nitric oxide (NO) synthesis in astrocytes by increasing the uptake of the precursor amino acid, arginine via the heteromeric arginine/glutamine transporter y+LAT2. Ammonia also increases the concentration in the brain of the endogenous inhibitor of nitric oxide synthases (NOS), asymmetric dimethylarginine (ADMA), but distribution of ADMA surplus between the intraastrocytic and extracellular compartments of the brain has not been studied. Here we tested the hypothesis that ammonia modulates the distribution of ADMA and its analog symmetric dimethylarginine (SDMA) between the two compartments of the brain by competition with arginine for the y+LAT2 transporter. In extension of the hypothesis we analyzed the ADMA/Arg interaction in endothelial cells forming the blood-brain barrier. We measured by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) technique the concentration of arginine, ADMA and SDMA in cultured cortical astrocytes and in a rat brain endothelial cell line (RBE-4) treated with ammonia and the effect of silencing the expression of a gene coding y+LAT2. We also tested the expression of ADMA metabolism enzymes: protein arginine methyltransferase (PRMT) and dimethylarginine dimethyl aminohydrolase (DDAH) and arginine uptake to astrocytes. Treatment for 48 h with 5 mM ammonia led to an almost 50% reduction of ADMA and SDMA concentration in both cell types, and the effect in astrocytes was substantially attenuated by silencing of the Slc7a6 gene. Moreover, the y+LAT2-dependent component of ammonia-evoked arginine uptake in astrocytes was reduced in the presence of ADMA in the medium. Our results suggest that increased ADMA efflux mediated by upregulated y+LAT2 may be a mechanism by which ammonia interferes with intra-astrocytic (and possibly intra-endothelial cell) ADMA content and subsequently, NO synthesis in both cell types.
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Affiliation(s)
- Krzysztof Milewski
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Małgorzata Bogacińska-Karaś
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Inez Fręśko
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Wojciech Hilgier
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Radosław Jaźwiec
- Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Jan Albrecht
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
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Dai H, Jia G, Wang W, Liang C, Han S, Chu M, Mei X. Genistein inhibited ammonia induced astrocyte swelling by inhibiting NF-κB activation-mediated nitric oxide formation. Metab Brain Dis 2017; 32:841-848. [PMID: 28255863 DOI: 10.1007/s11011-017-9975-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 02/15/2017] [Indexed: 11/27/2022]
Abstract
Our previous study has indicated the involvement of epidermal growth factor receptor (EGFR) transactivation in ammonia-induced astrocyte swelling, which represents a major pathogenesis of brain edema in hepatic encephalopathy. In this study, we examined the effect of genistein, a naturally occurred broad-spectrum protein tyrosine kinase (PTK) inhibitor, on ammonia-induced cell swelling. We found that genistein pretreatment significantly prevented ammonia-induced astrocyte swelling. Mechanistically, ammonia triggered EGFR/extracellular signal-regulated kinase (ERK) association and subsequent ERK phosphorylation were alleviated by genistein pretreatment. Moreover, ammonia-induced NF-κB nuclear location, iNOS expression, and consequent NO production were all prevented by AG1478 and genistein pretreatment. This study suggested that genistein could alleviate ammonia-induced astrocyte swelling, which may be, at least partly, related to its PTK-inhibiting activity and repression of NF-κB mediated iNOS-derived NO accumulation.
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Affiliation(s)
- Hongliang Dai
- School of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Jinzhou, Liaoning, 121001, China.
| | - Guizhi Jia
- Department of Physiology, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People's Republic of China.
| | - Wei Wang
- Department of Orthopedics, First Affiliated Hospital, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People's Republic of China
| | - Chunguang Liang
- School of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Jinzhou, Liaoning, 121001, China
| | - Siyu Han
- School of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Jinzhou, Liaoning, 121001, China
| | - Minghui Chu
- School of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Jinzhou, Liaoning, 121001, China
| | - Xifan Mei
- Department of Orthopedics, First Affiliated Hospital, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People's Republic of China.
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Dhanda S, Sandhir R. Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins. Mol Neurobiol 2017; 55:3642-3659. [PMID: 28523565 DOI: 10.1007/s12035-017-0521-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 04/06/2017] [Indexed: 12/27/2022]
Abstract
The present study was designed to investigate the mechanisms involved in blood-brain barrier (BBB) permeability in bile duct ligation (BDL) model of chronic hepatic encephalopathy (HE). Four weeks after BDL surgery, a significant increase was observed in serum bilirubin levels. Masson trichrome staining revealed severe hepatic fibrosis in the BDL rats. 99mTc-mebrofenin retention was increased in the liver of BDL rats suggesting impaired hepatobiliary transport. An increase in permeability to sodium fluorescein, Evans blue, and fluorescein isothiocyanate (FITC)-dextran along with increase in water and electrolyte content was observed in brain regions of BDL rats suggesting disrupted BBB. Increased brain water content can be attributed to increase in aquaporin-4 mRNA and protein expression in BDL rats. Matrix metalloproteinase-9 (MMP-9) mRNA and protein expression was increased in brain regions of BDL rats. Additionally, mRNA and protein expression of tissue inhibitor of matrix metalloproteinases (TIMPs) was also increased in different regions of brain. A significant decrease in mRNA expression and protein levels of tight junction proteins, viz., occludin, claudin-5, and zona occluden-1 (ZO-1) was observed in different brain regions of BDL rats. VCAM-1 mRNA and protein expression was also found to be significantly upregulated in different brain regions of BDL animals. The findings from the study suggest that increased BBB permeability in HE involves activation of MMP-9 and loss of tight junction proteins.
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Affiliation(s)
- Saurabh Dhanda
- Department of Biochemistry, Basic Medical Science Block-II, Sector-25, Panjab University, Chandigarh, 160014, India
| | - Rajat Sandhir
- Department of Biochemistry, Basic Medical Science Block-II, Sector-25, Panjab University, Chandigarh, 160014, India.
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Galland F, Negri E, Da Ré C, Fróes F, Strapazzon L, Guerra MC, Tortorelli LS, Gonçalves CA, Leite MC. Hyperammonemia compromises glutamate metabolism and reduces BDNF in the rat hippocampus. Neurotoxicology 2017; 62:46-55. [PMID: 28506823 DOI: 10.1016/j.neuro.2017.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 03/31/2017] [Accepted: 05/11/2017] [Indexed: 12/31/2022]
Abstract
Ammonia is putatively the major toxin associated with hepatic encephalopathy (HE), a neuropsychiatric manifestation that results in cognitive impairment, poor concentration and psychomotor alterations. The hippocampus, a brain region involved in cognitive impairment and depressive behavior, has been studied less than neocortical regions. Herein, we investigated hippocampal astrocyte parameters in a hyperammonemic model without hepatic lesion and in acute hippocampal slices exposed to ammonia. We also measured hippocampal BDNF, a neurotrophin commonly related to synaptic plasticity and cognitive deficit, and peripheral S100B protein, used as a marker for brain damage. Hyperammonemia directly impaired astrocyte function, inducing a decrease in glutamate uptake and in the activity of glutamine synthetase, in turn altering the glutamine-glutamate cycle, glutamatergic neurotransmission and ammonia detoxification itself. Hippocampal BDNF was reduced in hyperammonemic rats via a mechanism that may involve astrocyte production, since the same effect was observed in astrocyte cultures exposed to ammonia. Ammonia induced a significant increase in S100B secretion in cultured astrocytes; however, no significant changes were observed in the serum or in cerebrospinal fluid. Data demonstrating hippocampal vulnerability to ammonia toxicity, particularly due to reduced glutamate uptake activity and BDNF content, contribute to our understanding of the neuropsychiatric alterations in HE.
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Affiliation(s)
- Fabiana Galland
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Elisa Negri
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Carollina Da Ré
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Fernanda Fróes
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Liliane Strapazzon
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Maria Cristina Guerra
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Lucas Silva Tortorelli
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Marina Concli Leite
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
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Yu P, Guan L, Zhou L, Guo J, Guo R, Lin R, Ding W, Li X, Liu W. Upregulation of glutamate metabolism by BYHWD in cultured astrocytes following oxygen-glucose deprivation/reoxygenation in part depends on the activation of p38 MAPK. Exp Ther Med 2017; 13:3089-3096. [PMID: 28587384 DOI: 10.3892/etm.2017.4330] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 01/26/2017] [Indexed: 11/06/2022] Open
Abstract
Recent studies have demonstrated that Buyang Huanwu Decoction (BYHWD) decreased glutamate levels subsequent to cerebral ischemia. Glutamate transporter-1 (GLT-1) and glutamine synthetase (GS), which are located in astrocytes, mainly contribute to glutamate transportation, thus reducing glutamate concentration. BYHWD has previously been demonstrated to upregulate GLT-1 and GS following ischemia in vivo. However, whether BYHWD can directly influence astrocytic GLT-1/GS levels remains unknown. In the present study, the effect of BYHWD containing serum (BYHWD-CS) on GLT-1/GS levels in astrocytes following oxygen-glucose deprivation/reoxygenation (OGD/R) was investigated. The results revealed that BYHWD-CS enhanced the expression levels of GLT-1 and GS in cultured astrocytes, which reduced glutamate concentration in the culture medium. Meanwhile, increased p38 mitogen-activated protein kinase (p38 MAPK) was phosphorylated (activation form) by BYHWD-CS in cultured astrocytes, and the specific p38 inhibitor SB203580 blocked the increase of GLT-1/GS accompanied by decreased cell viability. Furthermore, SB203580 suppressed the effect of BYHWD-CS on the level of glial fibrillary acidic protein (an astrocytic marker), thus confirming that astrocytes are directly involved in the protective role of BYHWD after OGD/R. These findings suggest that BYHWD upregulates GLT-1 and GS via p38 MAPK activation, and protects cultured astrocytes from death caused by OGD/R (typical in vitro model), which complemented the role of astrocytes in the protective effect of BYHWD.
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Affiliation(s)
- Peng Yu
- Department of Physiology, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Li Guan
- Department of Physiology, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Lequan Zhou
- Department of Physiology, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Jianchao Guo
- Department of Physiology, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Ruixian Guo
- Department of Physiology, Zhongshan Medical College, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ruishan Lin
- Department of Physiology, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Wenting Ding
- Department of Physiology, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Xiaoying Li
- Department of Physiology, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Wei Liu
- Department of Physiology, College of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
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Mani R, Natesan V, Arumugam R. Neuroprotective effect of chrysin on hyperammonemia mediated neuroinflammatory responses and altered expression of astrocytic protein in the hippocampus. Biomed Pharmacother 2017; 88:762-769. [DOI: 10.1016/j.biopha.2017.01.081] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 01/12/2017] [Accepted: 01/12/2017] [Indexed: 01/19/2023] Open
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He J, Guo R, Qiu P, Su X, Yan G, Feng J. Exogenous hydrogen sulfide eliminates spatial memory retrieval impairment and hippocampal CA1 LTD enhancement caused by acute stress via promoting glutamate uptake. Neuroscience 2017; 350:110-123. [PMID: 28336411 DOI: 10.1016/j.neuroscience.2017.03.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 02/26/2017] [Accepted: 03/10/2017] [Indexed: 01/27/2023]
Abstract
Acute stress impairs the hippocampus-dependent spatial memory retrieval, and its synaptic mechanisms are associated with hippocampal CA1 long-term depression (LTD) enhancement in the adult rats. Endogenous hydrogen sulfide (H2S) is recognized as a novel gasotransmitter and has the neural protective roles. However, very little attention has been paid to understanding the effects of H2S on spatial memory retrieval impairment. We observed the protective effects of NaHS (a donor of H2S) against spatial memory retrieval impairment caused by acute stress and its synaptic mechanisms. Our results showed that NaHS abolished spatial memory retrieval impairment and hippocampal CA1 LTD enhancement caused by acute stress, but not by glutamate transporter inhibitor l-trans-pyrrolidine-2,4-dicarboxylic (tPDC), indicating that the activation of glutamate transporters is necessary for exogenous H2S to exert its roles. Moreover, NaHS restored the decreased glutamate uptake in the hippocampal CA1 synaptosomal fraction caused by acute stress. Dithiothreitol (DTT, a disulfide reducing agent) abolished a decrease in the glutamate uptake caused by acute stress, and NaHS eradicated the decreased glutamate uptake caused by 5,5'-dithio-bis(2-nitrobenzoic)acid (DTNB, a thiol oxidizing agent), collectively, revealing that exogenous H2S increases glutamate uptake by reducing disulfide bonds of the glutamate transporters. Additionally, NaHS inhibited the increased expression level of phosphorylated c-Jun-N-terminal kinase (JNK) in the hippocampal CA1 region caused by acute stress. The JNK inhibitor SP600125 eliminated spatial memory retrieval impairment, hippocampal CA1 LTD enhancement and the decreased glutamate uptake caused by acute stress, indicating that exogenous H2S exerts these roles by inhibiting the activation of JNK signaling pathway.
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Affiliation(s)
- Jin He
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Ruixian Guo
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Pengxin Qiu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Xingwen Su
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China
| | - Guangmei Yan
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
| | - Jianqiang Feng
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
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Leitão RA, Sereno J, Castelhano JM, Gonçalves SI, Coelho-Santos V, Fontes-Ribeiro C, Castelo-Branco M, Silva AP. Aquaporin-4 as a New Target against Methamphetamine-Induced Brain Alterations: Focus on the Neurogliovascular Unit and Motivational Behavior. Mol Neurobiol 2017; 55:2056-2069. [DOI: 10.1007/s12035-017-0439-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 02/03/2017] [Indexed: 02/01/2023]
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Hancock JT. Harnessing Evolutionary Toxins for Signaling: Reactive Oxygen Species, Nitric Oxide and Hydrogen Sulfide in Plant Cell Regulation. FRONTIERS IN PLANT SCIENCE 2017; 8:189. [PMID: 28239389 PMCID: PMC5301010 DOI: 10.3389/fpls.2017.00189] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 01/30/2017] [Indexed: 05/09/2023]
Abstract
During the early periods of evolution, as well as in niche environments today, organisms have had to learn to tolerate the presence of many reactive compounds, such as reactive oxygen species, nitric oxide, and hydrogen sulfide. It is now known that such compounds are instrumental in the signaling processes in plant cells. There are enzymes which can make them, while downstream of their signaling pathways are coming to light. These include the production of cGMP, the activation of MAP kinases and transcription factors, and the modification of thiol groups on many proteins. However, organisms have also had to tolerate other reactive compounds such as ammonia, methane, and hydrogen gas, and these too are being found to have profound effects on signaling in cells. Before a holistic view of how such signaling works, the full effects and interactions of all such reactive compounds needs to be embraced. A full understanding will be beneficial to both agriculture and future therapeutic strategies.
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Affiliation(s)
- John T. Hancock
- Department of Applied Sciences, Faculty of Health and Applied Sciences, University of the West of EnglandBristol, UK
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42
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Jayakumar AR, Tong XY, Shamaladevi N, Barcelona S, Gaidosh G, Agarwal A, Norenberg MD. Defective synthesis and release of astrocytic thrombospondin-1 mediates the neuronal TDP-43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro
studies. J Neurochem 2017; 140:645-661. [DOI: 10.1111/jnc.13867] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 09/28/2016] [Accepted: 10/05/2016] [Indexed: 12/14/2022]
Affiliation(s)
| | - Xiao Y. Tong
- Departments of Pathology; University of Miami School of Medicine; Miami Florida USA
| | | | - Stephanie Barcelona
- Departments of Pathology; University of Miami School of Medicine; Miami Florida USA
| | - Gabriel Gaidosh
- Ophthalmology; University of Miami School of Medicine; Miami Florida USA
| | - Apeksha Agarwal
- Departments of Pathology; University of Miami School of Medicine; Miami Florida USA
| | - Michael D. Norenberg
- Laboratory of Neuropathology; Veterans Affairs Medical Center; Miami Florida USA
- Departments of Pathology; University of Miami School of Medicine; Miami Florida USA
- Biochemistry & Molecular Biology; University of Miami School of Medicine; Miami Florida USA
- Neurology; University of Miami School of Medicine; Miami Florida USA
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43
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Maus A, Peters GJ. Glutamate and α-ketoglutarate: key players in glioma metabolism. Amino Acids 2017; 49:21-32. [PMID: 27752843 PMCID: PMC5241329 DOI: 10.1007/s00726-016-2342-9] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 09/28/2016] [Indexed: 12/18/2022]
Abstract
Glioblastoma multiforme (GBM), or grade IV astrocytoma, is the most common type of primary brain tumor. It has a devastating prognosis with a 2-year-overall survival rate of only 26 % after standard treatment, which includes surgery, radiation, and adjuvant chemotherapy with temozolomide. Also lower grade gliomas are difficult to treat, because they diffusely spread into the brain, where extensive removal of tissue is critical. Better understanding of the cancer's biology is a key for the development of more effective therapy approaches. The discovery of isocitrate dehydrogenase (IDH) mutations in leukemia and glioma drew attention to specific metabolic aberrations in IDH-mutant gliomas. In the center of the metabolic alterations is α-ketoglutarate (αKG), an intermediate metabolite in the tricarboxylic acid (TCA) cycle, and the associated amino acid glutamate (Glu). This article highlights the role of these metabolites in glioma energy and lipid production and indicates possible weak spots of IDH-mutant and IDH-wt gliomas.
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Affiliation(s)
- Andreas Maus
- Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
- University of Gottingen, Gottingen, Germany
| | - Godefridus J Peters
- Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
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Jayakumar AR, Curtis KM, Panickar KS, Shamaladevi N, Norenberg MD. Decreased STAT3 Phosphorylation Mediates Cell Swelling in Ammonia-Treated Astrocyte Cultures. BIOLOGY 2016; 5:48. [PMID: 27918421 PMCID: PMC5192428 DOI: 10.3390/biology5040048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 11/18/2016] [Accepted: 11/24/2016] [Indexed: 12/25/2022]
Abstract
Brain edema, due largely to astrocyte swelling, and the subsequent increase in intracranial pressure and brain herniation, are major complications of acute liver failure (ALF). Elevated level of brain ammonia has been strongly implicated in the development of astrocyte swelling associated with ALF. The means by which ammonia brings about astrocyte swelling, however, is incompletely understood. Recently, oxidative/nitrosative stress and associated signaling events, including activation of mitogen-activated protein kinases (MAPKs), as well as activation of the transcription factor, nuclear factor-kappaB (NF-κB), have been implicated in the mechanism of ammonia-induced astrocyte swelling. Since these signaling events are known to be regulated by the transcription factor, signal transducer and activator of transcription 3 (STAT3), we examined the state of STAT3 activation in ammonia-treated cultured astrocytes, and determined whether altered STAT3 activation and/or protein expression contribute to the ammonia-induced astrocyte swelling. STAT3 was found to be dephosphorylated (inactivated) at Tyrosine705 in ammonia-treated cultured astrocytes. Total STAT3 protein level was also reduced in ammonia-treated astrocytes. We also found a significant increase in protein tyrosine phosphatase receptor type-1 (PTPRT-1) protein expression in ammonia-treated cultured astrocytes, and that inhibition of PTPRT-1 enhanced the phosphorylation of STAT3 after ammonia treatment. Additionally, exposure of cultured astrocytes to inhibitors of protein tyrosine phosphatases diminished the ammonia-induced cell swelling, while cultured astrocytes over-expressing STAT3 showed a reduction in the astrocyte swelling induced by ammonia. Collectively, these studies strongly suggest that inactivation of STAT3 represents a critical event in the mechanism of the astrocyte swelling associated with acute liver failure.
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Affiliation(s)
- Arumugam R Jayakumar
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
- South Florida Foundation for Research and Education Inc., Miami VA Healthcare System, Miami, FL 33125, USA.
- Veterans Affairs Medical Center, U.S. Department of Veterans Affairs, Miami, FL 33125, USA.
| | - Kevin M Curtis
- Department of Biochemistry & Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
- Geriatric Research Education and Clinical Center, U.S. Department of Veterans Affairs, Miami, FL 33125, USA.
| | - Kiran S Panickar
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
| | - Nagarajarao Shamaladevi
- South Florida Foundation for Research and Education Inc., Miami VA Healthcare System, Miami, FL 33125, USA.
- Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
| | - Michael D Norenberg
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
- South Florida Foundation for Research and Education Inc., Miami VA Healthcare System, Miami, FL 33125, USA.
- Veterans Affairs Medical Center, U.S. Department of Veterans Affairs, Miami, FL 33125, USA.
- Department of Biochemistry & Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.
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Asymmetric Dimethylarginine and Hepatic Encephalopathy: Cause, Effect or Association? Neurochem Res 2016; 42:750-761. [PMID: 27885576 PMCID: PMC5357500 DOI: 10.1007/s11064-016-2111-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 09/07/2016] [Accepted: 11/15/2016] [Indexed: 12/11/2022]
Abstract
The methylated derivative of l-arginine, asymmetric dimethylarginine (ADMA) is synthesized in different mammalian tissues including the brain. ADMA acts as an endogenous, nonselective, competitive inhibitor of all three isoforms of nitric oxide synthase (NOS) and may limit l-arginine supply from the plasma to the enzyme via reducing its transport by cationic amino acid transporters. Hepatic encephalopathy (HE) is a relatively frequently diagnosed complex neuropsychiatric syndrome associated with acute or chronic liver failure, characterized by symptoms linked with impaired brain function leading to neurological disabilities. The l-arginine—nitric oxide (NO) pathway is crucially involved in the pathomechanism of HE via modulating important cerebral processes that are thought to contribute to the major HE symptoms. Specifically, activation of this pathway in acute HE leads to an increase in NO production and free radical formation, thus, contributing to astrocytic swelling and cerebral edema. Moreover, the NO-cGMP pathway seems to be involved in cerebral blood flow (CBF) regulation, altered in HE. For this reason, depressed NO-cGMP signaling accompanying chronic HE and ensuing cGMP deficit contributes to the cognitive and motor failure. However, it should be remembered that ADMA, a relatively little known element limiting NO synthesis in HE, may also influence the NO-cGMP pathway regulation. In this review, we will discuss the contribution of ADMA to the regulation of the NO-cGMP pathway in the brain, correlation of ADMA level with CBF and cognitive alterations observed during HE progression in patients and/or animal models of HE.
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Lisser DFJ, Lister ZM, Pham-Ho PQH, Scott GR, Wilkie MP. Relationship between oxidative stress and brain swelling in goldfish (Carassius auratus) exposed to high environmental ammonia. Am J Physiol Regul Integr Comp Physiol 2016; 312:R114-R124. [PMID: 27784686 DOI: 10.1152/ajpregu.00208.2016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 10/20/2016] [Accepted: 10/21/2016] [Indexed: 12/14/2022]
Abstract
Buildups of ammonia can cause potentially fatal brain swelling in mammals, but such swelling is reversible in the anoxia- and ammonia-tolerant goldfish (Carassius auratus). We investigated brain swelling and its possible relationship to oxidative stress in the brain and liver of goldfish acutely exposed to high external ammonia (HEA; 5 mmol/l NH4Cl) at two different acclimation temperatures (14°C, 4°C). Exposure to HEA at 14°C for 72h resulted in increased internal ammonia and glutamine concentrations in the brain, and it caused cellular oxidative damage in the brain and liver. However, oxidative damage was most pronounced in brain, in which there was a twofold increase in thiobarbituric acid-reactive substances, a threefold increase in protein carbonylation, and a 20% increase in water volume (indicative of brain swelling). Increased activities of catalase, glutathione peroxidase, and glutathione reductase in the brain suggested that goldfish upregulate their antioxidant capacity to partially offset oxidative stress during hyperammonemia at 14°C. Notably, acclimation to colder (4°C) water completely attenuated the oxidative stress response to HEA in both tissues, and there was no change in brain water volume despite similar increases in internal ammonia. We suggest that ammonia-induced oxidative stress may be responsible for the swelling of goldfish brain during HEA, but further studies are needed to establish a mechanistic link between reactive oxygen species production and brain swelling. Nevertheless, a high capacity to withstand oxidative stress in response to variations in internal ammonia likely explains why goldfish are more resilient to this stressor than most other vertebrates.
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Affiliation(s)
- David F J Lisser
- Department of Biology and Laurier Institute for Water Science, Wilfrid Laurier University, Waterloo, Canada; and
| | - Zachary M Lister
- Department of Biology and Laurier Institute for Water Science, Wilfrid Laurier University, Waterloo, Canada; and
| | - Phillip Q H Pham-Ho
- Department of Biology and Laurier Institute for Water Science, Wilfrid Laurier University, Waterloo, Canada; and
| | - Graham R Scott
- Department of Biology, McMaster University, Hamilton, Canada
| | - Michael P Wilkie
- Department of Biology and Laurier Institute for Water Science, Wilfrid Laurier University, Waterloo, Canada; and
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Gonzalez P, Rodríguez FJ. Analysis of the expression of the Wnt family of proteins and its modulatory role on cytokine expression in non activated and activated astroglial cells. Neurosci Res 2016; 114:16-29. [PMID: 27562517 DOI: 10.1016/j.neures.2016.08.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 08/04/2016] [Accepted: 08/15/2016] [Indexed: 12/23/2022]
Abstract
Despite the essential functions of astrocytes and the emerging relevance of the Wnt family of proteins in the CNS under physiological and pathological conditions, the astroglial expression of this family of proteins and its potential modulatory role on astroglial activation is almost unknown. Thus, we have evaluated the expression of all Wnt ligands, receptors and regulators, and the activation state of Wnt-related signaling pathways in non-activated and differentially activated astroglial cultures. We found that numerous Wnt ligands, receptors and regulators were expressed in non-activated astrocytes, while the Wnt-dependent pathways were constitutively active. Moreover, the expression of most detectable Wnt-related molecules and the activity of the Wnt-dependent pathways suffered post-activation variations which frequently depended on the activation system. Finally, the analysis of the effects exerted by Wnt1 and 5a on the astroglial expression of prototypical genes related to astroglial activation showed that both Wnt ligands increased the astroglial expression of interleukin 1β depending on the experimental context, while did not modulate tumor necrosis factor α, interleukin 6, transforming growth factor β1 and glial fibrillary acidic protein expression. These results strongly suggest that the Wnt family of proteins is involved in how astrocytes modulate and respond to the physiological and pathological CNS.
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Affiliation(s)
- Pau Gonzalez
- Laboratory of Molecular Neurology, National Hospital for Paraplegics, Finca la Peraleda s/n, 45071 Toledo, Spain.
| | - Francisco Javier Rodríguez
- Laboratory of Molecular Neurology, National Hospital for Paraplegics, Finca la Peraleda s/n, 45071 Toledo, Spain.
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Renuka M, Vijayakumar N, Ramakrishnan A. Chrysin, a flavonoid attenuates histological changes of hyperammonemic rats: A dose dependent study. Biomed Pharmacother 2016; 82:345-54. [DOI: 10.1016/j.biopha.2016.05.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 05/10/2016] [Accepted: 05/10/2016] [Indexed: 01/12/2023] Open
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Neurotoxicity of Ammonia. Neurochem Res 2016; 42:713-720. [PMID: 27465396 DOI: 10.1007/s11064-016-2014-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 07/15/2016] [Accepted: 07/21/2016] [Indexed: 12/25/2022]
Abstract
Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profoundly with brain metabolism, astrocyte volume regulation, and in particular mitochondrial functions. Gene expression in the brain and excitatory and inhibitory neurotransmission circuits are also affected. Experiments with a number of pertinent animal models have revealed several potential mechanisms which could underlie the pathological phenomena occurring in hepatic encephalopathy.
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Wang Y, Wang N, Cai B, Wang GY, Li J, Piao XX. In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells. Neural Regen Res 2016; 10:2011-7. [PMID: 26889191 PMCID: PMC4730827 DOI: 10.4103/1673-5374.172320] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Drugs for the treatment and prevention of nervous system diseases must permeate the blood-brain barrier to take effect. In vitro models of the blood-brain barrier are therefore important in the investigation of drug permeation mechanisms. However, to date, no unified method has been described for establishing a blood-brain barrier model. Here, we modified an in vitro model of the blood-brain barrier by seeding brain microvascular endothelial cells and astrocytes from newborn rats on a polyester Transwell cell culture membrane with 0.4-µm pores, and conducted transepithelial electrical resistance measurements, leakage tests and assays for specific blood-brain barrier enzymes. We show that the permeability of our model is as low as that of the blood-brain barrier in vivo. Our model will be a valuable tool in the study of the mechanisms of action of neuroprotective drugs.
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Affiliation(s)
- Yan Wang
- Key Laboratory of Xin'an Medicine, Ministry of Education; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Ning Wang
- Key Laboratory of Xin'an Medicine, Ministry of Education; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Biao Cai
- Key Laboratory of Xin'an Medicine, Ministry of Education; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Guang-Yun Wang
- Key Laboratory of Xin'an Medicine, Ministry of Education; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Jing Li
- Key Laboratory of Xin'an Medicine, Ministry of Education; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
| | - Xing-Xing Piao
- Key Laboratory of Xin'an Medicine, Ministry of Education; Institute for Pharmacodynamics and Safety Evaluation of Chinese Medicine, Anhui Academy of Chinese; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province, China
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