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Yang HM, Hou TZ, Zhang YN, Zhao SD, Wu YL, Zhang H. Blocked metabotropic glutamate receptor 5 enhances chemosensitivity in hepatocellular carcinoma and attenuates chemotoxicity in the normal liver by regulating DNA damage. Cancer Gene Ther 2022; 29:1487-1501. [PMID: 35396501 DOI: 10.1038/s41417-022-00465-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 03/08/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022]
Abstract
DNA damaging agents are used as chemotherapeutics in many cancers, including hepatocellular carcinoma (HCC). However, they are associated with problems such as low sensitivity to chemotherapy and the induction of liver injury, underscoring the need to identify new therapies. Here, we investigated the differential regulatory effect of metabotropic glutamate receptor 5 (mGlu5) on chemosensitivity in HCC and chemotoxicity to the normal liver. The expression of mGlu5 was higher in HCC than in the normal liver, and correlated with poor prognosis according to The Cancer Genome Atlas database and Integrative Molecular Database of Hepatocellular Carcinoma. Cisplatin, oxaliplatin or methyl methanesulfonate (MMS) caused cell death by decreasing mGlu5 expression in HCC cells and increased mGlu5 expression in hepatic cells. In HCC cells, inhibition of mGlu5 aggravated MMS-induced DNA damage by increasing intracellular Ca2+ overload and mitogen-activated protein kinase (MAPK) activation, thereby promoting cell death, and activation of mGlu5 rescued the effect of MMS. However, in hepatic cells, mGlu5 inhibition alleviated MMS-induced DNA damage by downregulating Ca2+-derived MAPK pathways to advance hepatic cell survival. The opposite effects of mGlu5 overexpression or knockdown on MMS-induced DNA damage supported that cell death is a result of the differential regulation of mGlu5 expression. Inhibition of mGlu5 increased chemosensitivity and decreased chemotoxicity in a rat tumor model. This study suggests that mGlu5 inhibition could act synergistically with HCC chemotherapeutics with minimal side effects, which may improve the treatment of patients with HCC in the future.
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Affiliation(s)
- Hui-Min Yang
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China
| | - Tian-Zhong Hou
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China
| | - Ya-Nan Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China
| | - Shu-Dong Zhao
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, 100083, Beijing, China
| | - Yong-Le Wu
- Center of Hepatic and Digestive Disease, Beijing YouAn Hospital, Capital Medical University, 100069, Beijing, China
| | - Hong Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China.
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Protective effects of mild hypothermia against hepatic injury in rats with acute liver failure. Ann Hepatol 2020; 18:770-776. [PMID: 31422029 DOI: 10.1016/j.aohep.2019.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 01/25/2019] [Accepted: 12/17/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Acute liver failure (ALF) is a severe disease which is associated with a high mortality rate. As mild hypothermia has been shown to have protective effects on the brain, this study aimed to determine whether it also provides protection to the liver in rats with ALF and to explore its underlying mechanism. MATERIALS AND METHODS In total, 72 rats were divided into 3 groups: control group (CG, treated with normal saline), normothermia group (NG, treated with d-galactosamine and lipopolysaccharide; d-GalN/LPS), and mild hypothermia group (MHG, treated with d-GalN/LPS and kept in a state of mild hypothermia, defined as an anal temperature of 32-35°C). The rats were examined at 4, 8, and 12h after treatment. RESULTS Mild hypothermia treatment significantly reduced serum alanine transaminase and aspartate transaminase levels and improved the liver condition of rats with d-GalN/LPS-induced ALF at 12h. Serum tumor necrosis factor-alpha levels were significantly lower in the MHG than in the NG at 4h, but no significant differences were observed in the interleukin-10 levels between the NG and MHG at any time. The serum and hepatic levels of high mobility group box 1 were significantly lower in the MHG than in the NG at 8 and 12h. The protein expression levels of cytochrome C and cleaved-caspase 3 in hepatic tissues were significantly lower in the MHG than in the NG at 8h. CONCLUSION Mild hypothermia improved the liver conditions of rats with ALF via its anti-inflammatory and anti-apoptotic effects.
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Choi WM, Kim HH, Kim MH, Cinar R, Yi HS, Eun HS, Kim SH, Choi YJ, Lee YS, Kim SY, Seo W, Lee JH, Shim YR, Kim YE, Yang K, Ryu T, Hwang JH, Lee CH, Choi HS, Gao B, Kim W, Kim SK, Kunos G, Jeong WI. Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis. Cell Metab 2019; 30:877-889.e7. [PMID: 31474565 PMCID: PMC6834910 DOI: 10.1016/j.cmet.2019.08.001] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 06/15/2019] [Accepted: 08/01/2019] [Indexed: 12/12/2022]
Abstract
Activation of hepatocyte cannabinoid receptor-1 (CB1R) by hepatic stellate cell (HSC)-derived 2-arachidonoylglycerol (2-AG) drives de novo lipogenesis in alcoholic liver disease (ALD). How alcohol stimulates 2-AG production in HSCs is unknown. Here, we report that chronic alcohol consumption induced hepatic cysteine deficiency and subsequent glutathione depletion by impaired transsulfuration pathway. A compensatory increase in hepatic cystine-glutamate anti-porter xCT boosted extracellular glutamate levels coupled to cystine uptake both in mice and in patients with ALD. Alcohol also induced the selective expression of metabotropic glutamate receptor-5 (mGluR5) in HSCs where mGluR5 activation stimulated 2-AG production. Consistently, genetic or pharmacologic inhibition of mGluR5 or xCT attenuated alcoholic steatosis in mice via the suppression of 2-AG production and subsequent CB1R-mediated de novo lipogenesis. We conclude that a bidirectional signaling operates at a metabolic synapse between hepatocytes and HSCs through xCT-mediated glutamate-mGluR5 signaling to produce 2-AG, which induces CB1R-mediated alcoholic steatosis.
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Affiliation(s)
- Won-Mook Choi
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Hee-Hoon Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Myung-Ho Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Resat Cinar
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hyon-Seung Yi
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Department of Internal Medicine, Chungnam National University, School of Medicine, Daejeon 35015, Republic of Korea
| | - Hyuk Soo Eun
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Department of Internal Medicine, Chungnam National University, School of Medicine, Daejeon 35015, Republic of Korea
| | - Seok-Hwan Kim
- Department of Surgery, Chungnam National University, College of Medicine, Daejeon 35015, Republic of Korea
| | - Young Jae Choi
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Young-Sun Lee
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Republic of Korea
| | - So Yeon Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Wonhyo Seo
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jun-Hee Lee
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Young-Ri Shim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Ye Eun Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Keungmo Yang
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Tom Ryu
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Jung Hwan Hwang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Hueng-Sik Choi
- School of the Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea
| | - Sang Kyum Kim
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea.
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de Gomes MG, Donato F, Souza LC, Goes AR, Filho CB, Del Fabbro L, Bianchini MC, Hassan W, Boeira SP, Puntel RL, Jesse CR. γ-Oryzanol supplementation modifies the inflammatory and oxidative response in fulminant hepatic failure in mice. PHARMANUTRITION 2018. [DOI: 10.1016/j.phanu.2018.10.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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Bai XX, Gu L, Yang HM, Xi SS, Xia N, Zhang S, Zhang H. Downregulation of metabotropic glutamate receptor 5 inhibits hepatoma development in a neurotoxin rotenone-induced Parkinson's disease model. Toxicol Lett 2018; 288:71-81. [PMID: 29458170 DOI: 10.1016/j.toxlet.2018.02.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 02/13/2018] [Accepted: 02/13/2018] [Indexed: 12/28/2022]
Abstract
Clinical epidemiological studies have shown that there is a link between Parkinson's disease (PD) and cancer, but how PD regulates cancer development remains unknown. In our study, the effect of metabotropic glutamate receptor 5 (mGlu5) on hepatoma was explored in a rotenone-induced PD model both in vitro and in vivo. We found that conditioned media derived from MN9D dopaminergic neuronal cells by rotenone-induced toxicity inhibited the growth, migration, invasion and promoted apoptosis of Hepa1-6 cells, which corresponded with decreased expression of mGlu5. Furthermore, treatment with 2-methyl-6-(phenylethynyl)pyridine (MPEP), a mGlu5 antagonist and knockdown of mGlu5, further reduced ATP levels and migration distance, and increased cleavage of caspase-3 in Hepa1-6 cells. Additionally, we found that conditioned media derived from rotenone-treated MN9D dopaminergic neuronal cells enhanced reactive oxygen species (ROS) generation and JNK phosphorylation, which could be further increased by MPEP treatment, and attenuated by mGlu5 agonist, (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) and ROS scavenger, N-acetyl-l-cysteine (NAC). The results indicated that down-regulation of mGlu5 promoted cell apoptosis through the intracellular ROS/JNK signaling pathway in a rotenone-induced cellular PD model. These findings were confirmed in vivo in a rotenone-induced rat model of PD combined with diethylnitrosamine (DEN)-induced hepatoma. Expression of Ki67 was decreased, and the levels of caspase-3 and p-JNK were increased in this model, which was accompanied by a decrease in protein expression of mGlu5. The study suggest that negative regulation of mGlu5 may inhibit hepatoma development in a rotenone-induced PD model, and as such may help with our further understanding of the correlation between PD and cancer.
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Affiliation(s)
- Xiao Xu Bai
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorder, Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Li Gu
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorder, Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Hui Min Yang
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorder, Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Shao Song Xi
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorder, Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Ning Xia
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorder, Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Song Zhang
- Shanxi Academy of Analytical Science, 030006, China
| | - Hong Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorder, Ministry of Education, Capital Medical University, Beijing 100069, China.
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Ferrigno A, Berardo C, Di Pasqua LG, Siciliano V, Richelmi P, Vairetti M. Localization and role of metabotropic glutamate receptors subtype 5 in the gastrointestinal tract. World J Gastroenterol 2017; 23:4500-4507. [PMID: 28740338 PMCID: PMC5504365 DOI: 10.3748/wjg.v23.i25.4500] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 05/03/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
Metabotropic glutamate receptor subtype 5 (mGluR5) is a Group I mGlu subfamily of receptors coupled to the inositol trisphosphate/diacylglycerol pathway. Like other mGluR subtypes, mGluR5s contain a phylogenetically conserved, extracellular orthosteric binding site and a more variable allosteric binding site, located on the heptahelical transmembrane domain. The mGluR5 receptor has proved to be a key pharmacological target in conditions affecting the central nervous system (CNS) but its presence outside the CNS underscores its potential role in pathologies affecting peripheral organs such as the gastrointestinal (GI) tract and accessory digestive organs such as the tongue, liver and pancreas. Following identification of mGluR5s in the mouth, various studies have subsequently demonstrated its involvement in mechanical allodynia, inflammation, pain and oral cancer. mGluR5 expression has also been identified in gastroesophageal vagal pathways. Indeed, experimental and human studies have demonstrated that mGluR5 blockade reduces transient lower sphincter relaxation and reflux episodes. In the intestine, mGluR5s have been shown to be involved in the control of intestinal inflammation, visceral pain and the epithelial barrier function. In the liver, mGluR5s have a permissive role in the onset of ischemic injury in rat and mice hepatocytes. Conversely, livers from mice treated with selective negative allosteric modulators and mGluR5 knockout mice are protected against ischemic injury. Similar results have been observed in experimental models of free-radical injury and in vivo mouse models of acetaminophen intoxication. Finally, mGluR5s in the pancreas are associated with insulin secretion control. The picture is, however, far from complete as the review attempts to establish in particular as regards identifying specific targets and innovative therapeutic approaches for the treatment of GI disorders.
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Xi SS, Bai XX, Gu L, Bao LH, Yang HM, An W, Wang XM, Zhang H. Metabotropic glutamate receptor 5 mediates the suppressive effect of 6-OHDA-induced model of Parkinson's disease on liver cancer. Pharmacol Res 2017; 121:145-157. [PMID: 28455267 DOI: 10.1016/j.phrs.2017.04.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 03/16/2017] [Accepted: 04/24/2017] [Indexed: 12/29/2022]
Abstract
Numerous epidemiological studies suggested that there is a variable cancer risk in patients with Parkinson's disease (PD). However, the underlying mechanisms remain unclear. In the present study, the role of metabotropic glutamate receptor 5 (mGluR5) has been investigated in 6-hydroxydopamine (6-OHDA)-induced PD combined with liver cancer both in vitro and in vivo. We found that PD cellular model from 6-OHDA-lesioned MN9D cells suppressed the growth, migration, and invasion of Hepa1-6 cells via down-regulation of mGluR5-mediated ERK and Akt pathway. The application of 2-methyl-6-(phenylethyl)-pyridine and knockdown of mGluR5 further decreased the effect on Hepa-1-6 cells when co-cultured with conditioned media. The effect was increased by (S)-3,5-dihydroxyphenylglycine and overexpression of mGluR5. Moreover, more release of glutamate from 6-OHDA-lesioned MN9D cells suppressed mGluR5-mediated effect of Hepa1-6 cells. Application of riluzole eliminated the increased glutamate release induced by 6-OHDA in MN9D cells and aggravated the suppressive effect on Hepa-1-6 cells. In addition, the growth of implanted liver cancer was inhibited in 6-OHDA induced PD-like rats, and was associated with increased glutamate release in the serum and down-regulation of mGluR5 in tumor tissue. Collectively, these results indicate that selective antagonism of glutamate and mGluR5 has a potentially beneficial effect in both liver cancer and PD, and thus may provide more understanding for the clinical investigation and further an additional therapeutic target for these two diseases.
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Affiliation(s)
- Shao-Song Xi
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Xiao-Xu Bai
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Li Gu
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Li-Hui Bao
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Hui-Min Yang
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Wei An
- Department of Cell Biology, School of Basic Medical Sciences, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
| | - Xiao-Min Wang
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China
| | - Hong Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China.
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Aseervatham GSB, Suryakala U, Doulethunisha, Sundaram S, Bose PC, Sivasudha T. Expression pattern of NMDA receptors reveals antiepileptic potential of apigenin 8-C-glucoside and chlorogenic acid in pilocarpine induced epileptic mice. Biomed Pharmacother 2016; 82:54-64. [PMID: 27470339 DOI: 10.1016/j.biopha.2016.04.066] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 04/29/2016] [Accepted: 04/29/2016] [Indexed: 01/09/2023] Open
Abstract
The present study was aimed to evaluate the effect of apigenin 8-C-glucoside (Vitexin) and chlorogenic acid on epileptic mice induced by pilocarpine and explored its possible mechanisms. Intraperitonial administration of pilocarpine (85mg/kg) induced seizure in mice was assessed by behavior observations, which is significantly (p>0.05) reduced by apigenin 8-C-glucoside (AP8CG) (10mg/kg) and chlorogenic acid (CA) (5mg/kg), similar to diazepam. Seizure was accompanied by an imbalance in the levels of Gamma-aminobutyric acid (GABA) and glutamate in the pilocarpine administered group. Moreover, convulsion along with reduced acetylcholinesterase, increased monoamine oxidase and oxidative stress was observed in epileptic mice brain. AP8CG and CA significantly restored back to normal levels even at lower doses. Further, increased lipid peroxidation and nitrite content was also significantly attenuated by AP8CG and CA. However, CA was found to be more effective when compared to AP8CG. In addition, the mRNA expression of N-methyl-d-aspartate receptor (NMDAR), mGluR1 and mGlu5 was significantly (P≤0.05) inhibited by AP8CG and CA in a lower dose. The mRNA expression of GRIK1 did not differ significantly in any of the group and showed a similar pattern of expression. Our result shows that AP8CG and CA selectively inhibit NMDAR, mGluR1 and mGlu5 expression. Modification in the provoked NMDAR calcium response coupled with neuronal death. Hence, these findings underline that the polyphenolics, AP8CG and CA have exerted antiepileptic and neuroprotective activity by suppressing glutamate receptors.
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Affiliation(s)
- G Smilin Bell Aseervatham
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India
| | - U Suryakala
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India
| | - Doulethunisha
- Central Inter-Disciplinary Research Facility, Mahatma Gandhi Medical College and Research Institute Campus, Pillayarkuppam, Puducherry 607 402, India
| | - S Sundaram
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India
| | - P Chandra Bose
- Department of Biotechnology, Anna University, Tiruchirappalli 620 024, Tamilnadu, India
| | - T Sivasudha
- Department of Environmental Biotechnology, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India.
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Pu J, Tian G, Li B, Chen D, He J, Zheng P, Mao X, Yu J, Huang Z, Yu B. Trace Mineral Overload Induced Hepatic Oxidative Damage and Apoptosis in Pigs with Long-Term High-Level Dietary Mineral Exposure. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:1841-1849. [PMID: 26829127 DOI: 10.1021/acs.jafc.5b05613] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
The present study investigated the effects of dietary trace mineral (Cu, Fe, Mn, and Zn) supplemental strategies on liver oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis of pigs. A total of 96 Duroc × Landrace × Yorkshire (DLY) piglets were randomly divided into four groups: considered or not considered the trace mineral concentrations in basal diet, and then added to the requirements proposed by NRC (2012) (+B/NR or -B/NR); and considered or not considered the basal diet's trace mineral concentrations and then added to the level of commercial trace mineral supplement (+B/PL or -B/PL). Pigs were fed from 6.5 to 115 kg. Compared with +B/NR diets, -B/PL diets increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations (P < 0.05), resulted in high levels of Fe, Cu, Mn, and Zn accumulation in liver (P < 0.05), as well as led to hepatic oxidative damage with the high concentrations of thiobarbituric acid reactive substance (TBARS), protein carbonylation (PCO), and 8-hydroxyguanine (8-OHG) in liver (P < 0.05). Furthermore, pigs fed -B/PL diets increased CCAAT/enhancer-binding protein homologous protein (CHOP), eukaryotic initiation factor-2α (eIF-2a), interleukin-6(IL-6), B-cell lymphoma leukemia-2-associated X protein (Bax), and caspase-3, caspase-8, and caspase-9 gene expression (P < 0.05) in liver. -B/PL diets also up-regulated hepatic mRNA expression of phosphoenolpyruvate carboxykinase1 (PEPCK1), glucose-6-phosphatase (G6PC), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS) (P < 0.05) and down-regulated hormone-sensitive lipase (HSL) mRNA expression (P < 0.05) when compared with those of the + B/NR diet group. Taken together, the results indicated that long-term dietary mineral exposure with the commercial supplement level could cause harm to the structure and metabolic function of liver in pigs.
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Affiliation(s)
- Junning Pu
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Gang Tian
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Bin Li
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Daiwen Chen
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Jun He
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Ping Zheng
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Xiangbing Mao
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Jie Yu
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Zhiqing Huang
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
| | - Bing Yu
- Key Laboratory of Animal Disease-Resistance Nutrition, Animal Nutrition Institute, Sichuan Agricultural University , 46 Xinkang Road, Yucheng District, Yaan, Sichuan 625014, China
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Ferrigno A, Vairetti M, Ambrosi G, Rizzo V, Richelmi P, Blandini F, Fuzzati-Armentero MT. Selective blockade of mGlu5 metabotropic glutamate receptors is protective against hepatic mitochondrial dysfunction in 6-OHDA lesioned Parkinsonian rats. Clin Exp Pharmacol Physiol 2016; 42:695-703. [PMID: 25904005 DOI: 10.1111/1440-1681.12410] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 04/10/2015] [Accepted: 04/13/2015] [Indexed: 12/21/2022]
Abstract
Non-motor symptoms including those involving the splanchnic district are present in Parkinson's disease (PD). The authors previously reported that PD-like rats, bearing a lesion of the nigrostriatal pathway induced by the injection of 6-hydroxydopamine (6-OHDA), have impaired hepatic mitochondrial function. Glutamate intervenes at multiple levels in PD and liver pathophysiologies. The metabotropic glutamate receptor 5 (mGluR5) is abundantly expressed in brain and liver and may represent a pharmacological target for PD therapy. This study investigated whether and how chronic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a well-characterized mGluR5 antagonist, may influence hepatic function with regard to neuronal cell loss in PD-like rats. Chronic treatment with MPEP was started immediately (Early) or 4 weeks after (Delayed) intrastriatal injection of 6-OHDA and lasted 4 weeks. Early MPEP treatment significantly prevented the decrease in adenosine triphosphate (ATP) production/content and counteracted increased reactive oxygen species (ROS) formation in isolated hepatic mitochondria of PD-like animals. Early MPEP administration also reduced the toxin-induced neurodegenerative process; improved survival of nigral dopaminergic neurons correlated with enhanced mitochondrial ATP content and production. ATP content/production, in turn, negatively correlated with ROS formation suggesting that the MPEP-dependent improvement in hepatic function positively influenced neuronal cell survival. Delayed MPEP treatment had no effect on hepatic mitochondrial function and neuronal cell loss. Antagonizing mGluR5 may synergistically act against neuronal cell loss and PD-related hepatic mitochondrial alterations and may represent an interesting alternative to non-dopaminergic therapeutic strategies for the treatment of PD.
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Affiliation(s)
- Andrea Ferrigno
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Mariapia Vairetti
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Giulia Ambrosi
- Center for Research in Neurodegenerative Diseases, Laboratory of Functional Neurochemistry, National Neurological Institute C. Mondino, Pavia, Italy
| | - Vittoria Rizzo
- Department of Molecular Medicine, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Plinio Richelmi
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Fabio Blandini
- Center for Research in Neurodegenerative Diseases, Laboratory of Functional Neurochemistry, National Neurological Institute C. Mondino, Pavia, Italy
| | - Marie-Therese Fuzzati-Armentero
- Center for Research in Neurodegenerative Diseases, Laboratory of Functional Neurochemistry, National Neurological Institute C. Mondino, Pavia, Italy
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A protective role of IL-30 via STAT and ERK signaling pathways in macrophage-mediated inflammation. Biochem Biophys Res Commun 2013; 435:306-12. [DOI: 10.1016/j.bbrc.2013.03.136] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 03/27/2013] [Indexed: 01/26/2023]
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12
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Gong X, Zhang L, Jiang R, Wang CD, Yin XR, Wan JY. Hepatoprotective effects of syringin on fulminant hepatic failure induced by D-galactosamine and lipopolysaccharide in mice. J Appl Toxicol 2013; 34:265-71. [PMID: 23620140 DOI: 10.1002/jat.2876] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Revised: 01/30/2013] [Accepted: 02/12/2013] [Indexed: 12/27/2022]
Abstract
The prognosis for fulminant hepatic failure (FHF) still remains extremely poor with a high mortality and, therefore, better treatments are urgently needed. Syringin, a main active substance isolated from Eleutherococcus senticosus, has been reported to exhibit immunomodulatory and anti-inflammatory properties. In this study, we investigated the effects and underlying mechanisms of syringin on lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced FHF in mice. Mice were administered syringin (10, 30 and 100 mg kg(-1), respectively) intraperitoneally (i.p) 30 min before LPS/D-GalN then mortality and liver injury were evaluated subsequently. We found that syringin dose-dependently attenuated LPS/D-GalN-induced FHF, as indicated by reduced mortality, inhibited aminotransferase and malondialdehyde (MDA) content, an increased glutathione (GSH) concentration and alleviated pathological liver injury. In addition, syringin inhibited LPS/D-GalN-induced hepatic caspase-3 activation and hepatocellular apoptosis, myeloperoxidase (MPO) activity and intercellular adhesion molecule-1 (ICAM-1) expression, as well as hepatic tissues tumor necrosis factor-alpha (TNF-α) production and NF-κB activation in a dose-dependent manner. These experimental data indicate that syringin might alleviate the FHF induced by LPS/D-GalN through inhibiting NF-κB activation to reduce TNF-α production.
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Affiliation(s)
- Xia Gong
- Department of Anatamy, Chongqing Medical University, Chongqing, 400016, China
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Wu YL, Wang NN, Gu L, Yang HM, Xia N, Zhang H. The suppressive effect of metabotropic glutamate receptor 5 (mGlu5) inhibition on hepatocarcinogenesis. Biochimie 2012; 94:2366-75. [PMID: 22706282 DOI: 10.1016/j.biochi.2012.06.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 06/04/2012] [Indexed: 01/23/2023]
Abstract
Metabotropic glutamate receptors (mGlus) are G-protein-coupled receptors playing an important role in the central nervous system (CNS). Recently, mGlus have been identified in peripheral tissues, and aberrant expression or inhibition of the receptors functions in the development of certain cancers. However, the correlation of mGlu activity with hepatocellular carcinoma (HCC) remains unknown. In this study, we analyzed the effects of inhibiting mGlu5 activity in hepatocarcinoma cell lines and a xenograft model. Inactivation of mGlu5 with 2-Methyl-6-(phenylethyl)-pyridine (MPEP), a specific antagonist of the receptor, caused inhibition of cell growth, migration, and invasion of HepG2 and Bel-7402 cells, assessed by MTT assay, ATP production, wound healing, and Boyden chamber assay, respectively. Moreover, inhibition of tumor growth and the potential metastasis of hepatocellular carcinoma were also found in nude mice. Furthermore, mGlu5-mediated extracellular signal-regulated kinase (ERK) phosphorylation has been found to be partially involved in cell growth and migration, as detected by stimulation of (S)-3,5-Dihydroxyphenylglycine (DHPG), an agonist of the receptor, and blockage of MPEP and U0126, an inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK). These data indicate that inhibiting the activity of mGlu5 has the molecular potential to suppress oncogenic actions by blocking downstream effector molecules. The study suggests that mGlu5 activity may contribute to understanding the development of HCC.
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Affiliation(s)
- Yong Le Wu
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China
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Abstract
Acute hepatic failure remains an extremely poor prognosis and still results in high mortality. Therefore, better treatment is urgently needed. Melittin, a major component of bee venom, is known to inhibit inflammatory reactions induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α in various cell types. However, there is no evidence of the anti-inflammatory and anti-apoptotic effect of melittin on liver cells. In the present study, we investigated the effects of melittin on D: -galactosamine (GalN)/lipopolysaccharide (LPS)-induced acute hepatic failure. Acute liver injury was induced with GalN/LPS to determine in vivo efficacy of melittin. Mice were randomly divided into four groups: sterile saline treated group (NC), melittin only treated group (NM), GalN/LPS-treated group (GalN/LPS), and GalN/LPS treated with melittin group (M+GalN/LPS). Mice were given intraperitoneal GalN/LPS with or without melittin treatment. Liver injury was assessed biochemically and histologically. Inflammatory cytokines in the serum, apoptosis of hepatocytes, and cleavage of caspase-3 in the liver were determined. The expression of TNF-α and interleukin (IL)-1β were increased in the GalN/LPS group. However, treatment of melittin attenuated the increase of inflammatory cytokines. The M+GalN/LPS group showed significantly fewer apoptotic cells compared to the GalN/LPS group. Melittin significantly inhibited the expression of caspase and bax protein levels as well as cytochrome c release in vivo. In addition, melittin prevented the activation of the transcription factor nuclear factor-kappa B (NF-κB) induced by GalN/LPS. These results clearly indicate that melittin provided protection against GalN/LPS-induced acute hepatic failure through the inhibition of inflammatory cytokines and apoptosis.
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Julio-Pieper M, Flor PJ, Dinan TG, Cryan JF. Exciting times beyond the brain: metabotropic glutamate receptors in peripheral and non-neural tissues. Pharmacol Rev 2011; 63:35-58. [PMID: 21228260 DOI: 10.1124/pr.110.004036] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Metabotropic glutamate (mGlu) receptors are G-protein-coupled receptors expressed primarily on neurons and glial cells, where they are located in the proximity of the synaptic cleft. In the central nervous system (CNS), mGlu receptors modulate the effects of l-glutamate neurotransmission in addition to that of a variety of other neurotransmitters. However, mGlu receptors also have a widespread distribution outside the CNS that has been somewhat neglected to date. Based on this expression, diverse roles of mGlu receptors have been suggested in a variety of processes in health and disease including controlling hormone production in the adrenal gland and pancreas, regulating mineralization in the developing cartilage, modulating lymphocyte cytokine production, directing the state of differentiation in embryonic stem cells, and modulating gastrointestinal secretory function. Understanding the role of mGlu receptors in the periphery will also provide a better insight into potential side effects of drugs currently being developed for neurological and psychiatric conditions. This review summarizes the new potential roles of mGlu receptors and raises the possibility of novel pharmacological targets for various disorders.
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Affiliation(s)
- Marcela Julio-Pieper
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 2010; 60:1017-41. [PMID: 21036182 DOI: 10.1016/j.neuropharm.2010.10.022] [Citation(s) in RCA: 494] [Impact Index Per Article: 32.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2010] [Revised: 10/15/2010] [Accepted: 10/21/2010] [Indexed: 12/24/2022]
Abstract
Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described as glutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been published since then, and subtype-selective mGlu receptor ligands are now under clinical development for the treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson's disease and L-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal reflux disorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a few research groups challenged the general belief that glutamate could only activate ionotropic receptors and all metabolic responses to glutamate were secondary to calcium entry. This review moves from those nostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, and highlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
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Affiliation(s)
- F Nicoletti
- Department of Physiology and Pharmacology, University of Rome, Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy.
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