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Yamali C, Nenni M, Sakarya MT, Kaplan HA. Pharmaceutical Studies on Piperazine-based Compounds Targeting Serotonin Receptors and Serotonin Reuptake Transporters. Mini Rev Med Chem 2025; 25:58-75. [PMID: 38910275 DOI: 10.2174/0113895575319878240612070850] [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: 04/15/2024] [Revised: 05/15/2024] [Accepted: 05/28/2024] [Indexed: 06/25/2024]
Abstract
Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotoninnoradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs in vitro/in vivo.
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Affiliation(s)
- Cem Yamali
- Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Cukurova University, Adana, 01250, Turkey
| | - Merve Nenni
- Department of Analytical Chemistry, Faculty of Pharmacy, Cukurova University, Adana, 01250, Turkey
| | - Mehtap Tugrak Sakarya
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tokat Gaziosmanpasa University, Tokat, 60250, Turkey
| | - Hasan Alper Kaplan
- Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Cukurova University, Adana, 01250, Turkey
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Jansen R, Milaneschi Y, Schranner D, Kastenmuller G, Arnold M, Han X, Dunlop BW, Rush AJ, Kaddurah-Daouk R, Penninx BWJH. The metabolome-wide signature of major depressive disorder. Mol Psychiatry 2024; 29:3722-3733. [PMID: 38849517 DOI: 10.1038/s41380-024-02613-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 04/25/2024] [Accepted: 05/15/2024] [Indexed: 06/09/2024]
Abstract
Major Depressive Disorder (MDD) is a common, frequently chronic condition characterized by substantial molecular alterations and pathway dysregulations. Single metabolite and targeted metabolomics platforms have revealed several metabolic alterations in depression, including energy metabolism, neurotransmission, and lipid metabolism. More comprehensive coverage of the metabolome is needed to further specify metabolic dysregulations in depression and reveal previously untargeted mechanisms. Here, we measured 820 metabolites using the metabolome-wide Metabolon platform in 2770 subjects from a large Dutch clinical cohort with extensive clinical phenotyping (1101 current MDD, 868 remitted MDD, 801 healthy controls) at baseline, which were repeated in 1805 subjects at 6-year follow up (327 current MDD, 1045 remitted MDD, 433 healthy controls). MDD diagnosis was based on DSM-IV psychiatric interviews. Depression severity was measured with the Inventory of Depressive Symptomatology Self-report. Associations between metabolites and MDD status and depression severity were assessed at baseline and at 6-year follow-up. At baseline, 139 and 126 metabolites were associated with current MDD status and depression severity, respectively, with 79 overlapping metabolites. Adding body mass index and lipid-lowering medication to the models changed results only marginally. Among the overlapping metabolites, 34 were confirmed in internal replication analyses using 6-year follow-up data. Downregulated metabolites were enriched with long-chain monounsaturated (P = 6.7e-07) and saturated (P = 3.2e-05) fatty acids; upregulated metabolites were enriched with lysophospholipids (P = 3.4e-4). Mendelian randomization analyses using genetic instruments for metabolites (N = 14,000) and MDD (N = 800,000) showed that genetically predicted higher levels of the lysophospholipid 1-linoleoyl-GPE (18:2) were associated with greater risk of depression. The identified metabolome-wide profile of depression indicated altered lipid metabolism with downregulation of long-chain fatty acids and upregulation of lysophospholipids, for which causal involvement was suggested using genetic tools. This metabolomics signature offers a window on depression pathophysiology and a potential access point for the development of novel therapeutic approaches.
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Affiliation(s)
- Rick Jansen
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands.
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands.
- Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands.
| | - Yuri Milaneschi
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands
| | - Daniela Schranner
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Gabi Kastenmuller
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Matthias Arnold
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
| | - Xianlin Han
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Boadie W Dunlop
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - A John Rush
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
- Duke National University of Singapore, Singapore, Singapore
| | - Rima Kaddurah-Daouk
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
- Department of Medicine, Duke University, Durham, NC, USA.
- Duke Institute of Brain Sciences, Duke University, Durham, NC, USA.
| | - Brenda W J H Penninx
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands
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Zorkina Y, Ushakova V, Ochneva A, Tsurina A, Abramova O, Savenkova V, Goncharova A, Alekseenko I, Morozova I, Riabinina D, Kostyuk G, Morozova A. Lipids in Psychiatric Disorders: Functional and Potential Diagnostic Role as Blood Biomarkers. Metabolites 2024; 14:80. [PMID: 38392971 PMCID: PMC10890164 DOI: 10.3390/metabo14020080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/07/2023] [Accepted: 12/19/2023] [Indexed: 02/25/2024] Open
Abstract
Lipids are a crucial component of the human brain, serving important structural and functional roles. They are involved in cell function, myelination of neuronal projections, neurotransmission, neural plasticity, energy metabolism, and neuroinflammation. Despite their significance, the role of lipids in the development of mental disorders has not been well understood. This review focused on the potential use of lipids as blood biomarkers for common mental illnesses, such as major depressive disorder, anxiety disorders, bipolar disorder, and schizophrenia. This review also discussed the impact of commonly used psychiatric medications, such as neuroleptics and antidepressants, on lipid metabolism. The obtained data suggested that lipid biomarkers could be useful for diagnosing psychiatric diseases, but further research is needed to better understand the associations between blood lipids and mental disorders and to identify specific biomarker combinations for each disease.
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Affiliation(s)
- Yana Zorkina
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
- Department of Basic and Applied Neurobiology, V. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Kropotkinsky per. 23, 119034 Moscow, Russia
| | - Valeria Ushakova
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
- Department of Basic and Applied Neurobiology, V. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Kropotkinsky per. 23, 119034 Moscow, Russia
| | - Aleksandra Ochneva
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
- Department of Basic and Applied Neurobiology, V. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Kropotkinsky per. 23, 119034 Moscow, Russia
| | - Anna Tsurina
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
| | - Olga Abramova
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
- Department of Basic and Applied Neurobiology, V. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Kropotkinsky per. 23, 119034 Moscow, Russia
| | - Valeria Savenkova
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
| | - Anna Goncharova
- Moscow Center for Healthcare Innovations, 123473 Moscow, Russia;
| | - Irina Alekseenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academi of Science, 142290 Moscow, Russia
- Russia Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 2, Kurchatov Square, 123182 Moscow, Russia
| | - Irina Morozova
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
| | - Daria Riabinina
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
| | - Georgy Kostyuk
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
| | - Anna Morozova
- Mental-Health Clinic No. 1 Named after N.A. Alekseev, Zagorodnoe Highway 2, 115191 Moscow, Russia; (V.U.); (A.O.); (A.T.); (O.A.); (V.S.); (I.M.); (D.R.); (G.K.); (A.M.)
- Department of Basic and Applied Neurobiology, V. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Kropotkinsky per. 23, 119034 Moscow, Russia
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Jansen R, Milaneschi Y, Schranner D, Kastenmuller G, Arnold M, Han X, Dunlop BW, Rush AJ, Kaddurah-Daouk R, Penninx BWJH. The Metabolome-Wide Signature of Major Depressive Disorder. RESEARCH SQUARE 2023:rs.3.rs-3127544. [PMID: 37790319 PMCID: PMC10543022 DOI: 10.21203/rs.3.rs-3127544/v1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Major Depressive Disorder (MDD) is an often-chronic condition with substantial molecular alterations and pathway dysregulations involved. Single metabolite, pathway and targeted metabolomics platforms have indeed revealed several metabolic alterations in depression including energy metabolism, neurotransmission and lipid metabolism. More comprehensive coverage of the metabolome is needed to further specify metabolic dysregulation in depression and reveal previously untargeted mechanisms. Here we measured 820 metabolites using the metabolome-wide Metabolon platform in 2770 subjects from a large Dutch clinical cohort with extensive depression clinical phenotyping (1101 current MDD, 868 remitted MDD, 801 healthy controls) at baseline and 1805 subjects at 6-year follow up (327 current MDD, 1045 remitted MDD, 433 healthy controls). MDD diagnosis was based on DSM-IV psychiatric interviews. Depression severity was measured with the Inventory of Depressive Symptomatology self-report. Associations between metabolites and MDD status and depression severity were assessed at baseline and at the 6-year follow-up. Metabolites consistently associated with MDD status or depression severity on both occasions were examined in Mendelian randomization (MR) analysis using metabolite (N=14,000) and MDD (N=800,000) GWAS results. At baseline, 139 and 126 metabolites were associated with current MDD status and depression severity, respectively, with 79 overlapping metabolites. Six years later, 34 out of the 79 metabolite associations were subsequently replicated. Downregulated metabolites were enriched with long-chain monounsaturated (P=6.7e-07) and saturated (P=3.2e-05) fatty acids and upregulated metabolites with lysophospholipids (P=3.4e-4). Adding BMI to the models changed results only marginally. MR analyses showed that genetically-predicted higher levels of the lysophospholipid 1-linoleoyl-GPE (18:2) were associated with greater risk of depression. The identified metabolome-wide profile of depression (severity) indicated altered lipid metabolism with downregulation of long-chain fatty acids and upregulation of lysophospholipids, for which causal involvement was suggested using genetic tools. This metabolomics signature offers a window on depression pathophysiology and a potential access point for the development of novel therapeutic approaches.
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Affiliation(s)
- Rick Jansen
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands
| | - Yuri Milaneschi
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands
| | - Daniela Schranner
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Gabi Kastenmuller
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Matthias Arnold
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
| | - Xianlin Han
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Boadie W Dunlop
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
| | | | - A John Rush
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
- Duke National University of Singapore, Singapore
| | - Rima Kaddurah-Daouk
- Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA
- Department of Medicine, Duke University, Durham, NC, USA
- Duke Institute of Brain Sciences, Duke University, Durham, NC, USA
| | - Brenda WJH Penninx
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands
- Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands
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Liao XX, Hu K, Xie XH, Wen YL, Wang R, Hu ZW, Zhou YL, Li JJ, Wu MK, Yu JX, Chen JW, Ren P, Wu XY, Zhou JJ. Banxia Xiexin decoction alleviates AS co-depression disease by regulating the gut microbiome-lipid metabolic axis. JOURNAL OF ETHNOPHARMACOLOGY 2023; 313:116468. [PMID: 37044233 DOI: 10.1016/j.jep.2023.116468] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 04/02/2023] [Accepted: 04/04/2023] [Indexed: 05/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Banxia Xiexin decoction (BXD) is a classic Chinese herbal formulation consisting of 7 herbs including Pinelliae Rhizoma, Scutellariae Radix, Zingiberis Rhizoma, Ginseng Radix, Glycyrrhizae Radix, Coptidis Rhizoma, and Jujubae Fructus, which can exert effects on lowering lipids and alleviating depressive mood disorders via affecting gastrointestinal tract. AIM OF THE STUDY The pathogenesis of atherosclerosis (AS) co-depression disease has not been well studied, and the current clinical treatment strategies are not satisfactory. As a result, it is critical to find novel methods of treatment. Based on the hypothesis that the gut microbiome may promote the development of AS co-depression disease by regulating host lipid metabolism, this study sought to evaluate the effectiveness and action mechanism of BXD in regulation of the gut microbiome via an intervention in AS co-depression mice. MATERIALS AND METHODS To determine the primary constituents of BXD, UPLC-Q/TOF-MS analysis was carried out. Sixteen C56BL/6 mice were fed normal chow as a control group; 64 ApoE-/- mice were randomized into four groups (model group and three treatment groups) and fed high-fat chow combined with daily bind stimulation for sixteen weeks to develop the AS co-depression mouse model and were administered saline or low, medium or high concentrations of BXD during the experimental modeling period. The antidepressant efficacy of BXD was examined by weighing, a sucrose preference test, an open field test, and a tail suspension experiment. The effectiveness of BXD as an anti-AS treatment was evaluated by means of biochemical indices, the HE staining method, and the Oil red O staining method. The impacts of BXD on the gut microbiome structure and brain (hippocampus and prefrontal cortex tissue) lipids in mice with the AS co-depression model were examined by 16S rDNA sequencing combined with lipidomics analysis. RESULTS The main components of BXD include baicalin, berberine, ginsenoside Rb1, and 18 other substances. BXD could improve depression-like behavioral characteristics and AS-related indices in AS co-depression mice; BXD could regulate the abundance of some flora (phylum level: reduced abundance of Proteobacteria and Deferribacteres; genus level: reduced abundance of Clostridium_IV, Helicobacter, and Pseudoflavonifractor, Acetatifactor, Oscillibacter, which were significantly different). The lipidomics analysis showed that the differential lipids between the model and gavaged high-dose BXD (BXH) groups were enriched in glycerophospholipid metabolism, and lysophosphatidylcholine (LPC(20:3)(rep)(rep)) in the hippocampus and LPC(20:4)(rep) in the prefrontal cortex both showed downregulation in BXH. The correlation analysis illustrated that the screened differential lipids were mainly linked to Deferribacteres and Actinobacteria. CONCLUSION BXD may exert an anti-AS co-depression therapeutic effect by modulating the abundance of some flora and thus intervening in peripheral lipid and brain lipid metabolism (via downregulation of LPC levels).
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Affiliation(s)
- Xing-Xing Liao
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Ke Hu
- Department of Rehabilitation Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Xin-Hua Xie
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, China
| | - You-Liang Wen
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Rui Wang
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Zi-Wei Hu
- Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Yu-Long Zhou
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Jia-Jun Li
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Ming-Kun Wu
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Jing-Xuan Yu
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Jia-Wei Chen
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Peng Ren
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Xiao-Yun Wu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China.
| | - Jun-Jie Zhou
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, China.
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Favole A, Testori C, Bergagna S, Gennero MS, Ingravalle F, Costa B, Barresi S, Curti P, Barberis F, Ganio S, Orusa R, Vallino Costassa E, Berrone E, Vernè M, Scaglia M, Palmitessa C, Gallo M, Tessarolo C, Pederiva S, Ferrari A, Lorenzi V, Fusi F, Brunelli L, Pastorelli R, Cagnotti G, Casalone C, Caramelli M, Corona C. Brain-Derived Neurotrophic Factor, Kynurenine Pathway, and Lipid-Profiling Alterations as Potential Animal Welfare Indicators in Dairy Cattle. Animals (Basel) 2023; 13:ani13071167. [PMID: 37048423 PMCID: PMC10093196 DOI: 10.3390/ani13071167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/16/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Complete animal welfare evaluation in intensive farming is challenging. With this study, we investigate new biomarkers for animal physical and mental health by comparing plasma expression of biochemical indicators in dairy cows reared in three different systems: (A) semi-intensive free-stall, (B) non-intensive tie-stall, and (C) intensive free-stall. Additionally, protein levels of mature brain-derived neurotrophic factor (mBDNF) and its precursor form (proBDNF) and indoleamine 2,3-dioxygenase (IDO1) specific activity were evaluated in brain samples collected from 12 cattle culled between 73 and 138 months of age. Alterations in plasma lipid composition and in the kynurenine pathway of tryptophan metabolism were observed in the tie-stall-reared animals. The total plasma BDNF concentration was higher in tie-stall group compared to the two free-housing groups. Brain analysis of the tie-stall animals revealed a different mBDNF/proBDNF ratio, with a higher level of proBDNF (p < 0.001). Our data are similar to previous studies on animal models of depression, which reported that inhibition of the conversion of proBDNF in its mature form and/or elevated peripheral kynurenine pathway activation may underlie cerebral biochemical changes and induce depressive-like state behavior in animals.
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Pinto B, Conde T, Domingues I, Domingues MR. Adaptation of Lipid Profiling in Depression Disease and Treatment: A Critical Review. Int J Mol Sci 2022; 23:ijms23042032. [PMID: 35216147 PMCID: PMC8874755 DOI: 10.3390/ijms23042032] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 11/30/2022] Open
Abstract
Major depressive disorder (MDD), also called depression, is a serious disease that impairs the quality of life of patients and has a high incidence, affecting approximately 3.8% of the world population. Its diagnosis is very subjective and is not supported by measurable biomarkers mainly due to the lack of biochemical markers. Recently, disturbance of lipid profiling has been recognized in MDD, in animal models of MDD or in depressed patients, which may contribute to unravel the etiology of the disease and find putative new biomarkers, for a diagnosis or for monitoring the disease and therapeutics outcomes. In this review, we provide an overview of current knowledge of lipidomics analysis, both in animal models of MDD (at the brain and plasma level) and in humans (in plasma and serum). Furthermore, studies of lipidomics analyses after antidepressant treatment in rodents (in brain, plasma, and serum), in primates (in the brain) and in humans (in plasma) were reviewed and give evidence that antidepressants seem to counteract the modification seen in lipids in MDD, giving some evidence that certain altered lipid profiles could be useful MDD biomarkers for future precision medicine.
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Affiliation(s)
- Bruno Pinto
- Centre for Environmental and Marine Studies, CESAM, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal; (B.P.); (T.C.)
- Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Tiago Conde
- Centre for Environmental and Marine Studies, CESAM, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal; (B.P.); (T.C.)
- Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal
- Institute of Biomedicine—iBiMED, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Inês Domingues
- Centre for Environmental and Marine Studies, CESAM, Department of Biology, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - M. Rosário Domingues
- Centre for Environmental and Marine Studies, CESAM, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal; (B.P.); (T.C.)
- Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal
- Correspondence:
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Zhang L, Bao Y, Tao S, Zhao Y, Liu M. The association between cardiovascular drugs and depression/anxiety in patients with cardiovascular disease: A meta-analysis. Pharmacol Res 2021; 175:106024. [PMID: 34890773 DOI: 10.1016/j.phrs.2021.106024] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 11/27/2021] [Accepted: 12/05/2021] [Indexed: 12/26/2022]
Abstract
This study aimed to investigate the association between cardiovascular drugs and depression/anxiety in patients with cardiovascular disease (CVD). This meta-analysis was registered in PROSPERO (International Prospective Register of Systematic Reviews; CRD42020197839) and conducted in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. The PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases were systematically searched to identify all available studies on this topic. Random-effects multivariate meta-regression was performed to investigate the sources of study heterogeneity. Review Manager version 5.3 and Stata 12.0 were used for data analyses. This meta-analysis included 54 studies with a total number of 212,640 patients. Overall, in patients with CVD, aspirin (odds ratio [OR]:0.91, 95% confidence interval [CI]:0.86-0.96, P = 0.02) was associated with a lower risk of depression, while calcium channel blockers (CCB) (OR:1.21, 95%CI:1.05-1.38, P = 0.008), diuretics (OR:1.34, 95%CI:1.14-1.58, P = 0.0005), and nitrate esters (OR:1.32, 95%CI:1.08-1.61, P = 0.006) were associated with a higher risk of depression, additionally, statin (OR:0.79, 95%CI:0.71-0.88, P < 0.0001) was associated with a lower risk of anxiety, but diuretics (OR:1.39, 95%CI:1.26-1.52, P < 0.00001) was associated with a higher risk of anxiety. Subgroup analysis presented that, in patients with hypertension, β-blockers were associated with a higher risk of depression (OR:1.45, 95%CI:1.26-1.67, P < 0.00001); in patients with coronary artery disease (CAD), statin (OR:0.77, 95%CI:0.59-0.99, P = 0.04), and aspirin (OR:0.85, 95%CI:0.75-0.97, P = 0.02) were associated with a lower risk of depression, while CCB (OR:1.32, 95%CI:1.15-1.51, P < 0.0001) and diuretics (OR:1.36, 95%CI:1.12-1.64, P = 0.002) were associated with a higher risk of depression, additionally, diuretics was associated with a higher risk of anxiety (OR:1.41, 95%CI:1.28-1.55, P < 0.00001); in patients with heart failure, nitrate esters (OR:1.93, 95%CI:1.19-3.13, P = 0.007), and diuretics (OR:1.58, 95%CI: 1.02-2.43, P = 0.04) were associated with a higher risk of depression. The use of cardiovascular drugs should be considered when evaluating depression or anxiety in patients with CVD to improve the care and treatment of these patients.
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Affiliation(s)
- Lijun Zhang
- Department of Psycho-cardiology, Capital Medical University Affiliated Beijing Anzhen Hospital, Beijing 100029, China.
| | - Yanping Bao
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China; School of Public Health, Peking University, Beijing 100191, China.
| | - Shuhui Tao
- Department of Psycho-cardiology, Capital Medical University Affiliated Beijing Anzhen Hospital, Beijing 100029, China; School of Basic Medical Sciences, Henan University, Kaifeng, China.
| | - Yimiao Zhao
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China; School of Public Health, Peking University, Beijing 100191, China.
| | - Meiyan Liu
- Department of Psycho-cardiology, Capital Medical University Affiliated Beijing Anzhen Hospital, Beijing 100029, China.
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Anxiety disturbs the blood plasma metabolome in acute coronary syndrome patients. Sci Rep 2021; 11:12897. [PMID: 34145340 PMCID: PMC8213718 DOI: 10.1038/s41598-021-92421-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 05/31/2021] [Indexed: 01/14/2023] Open
Abstract
Coronary heart disease (CHD) is the result of a complex metabolic disorder caused by various environmental and genetic factors, and often has anxiety as a comorbidity. Rupture of atherosclerotic plaque in CHD patients can lead to acute coronary syndrome (ACS). Anxiety is a known independent risk factor for the adverse cardiovascular events and mortality in ACS, but it remains unclear how stress-induced anxiety behavior impacts their blood plasma metabolome and contributes to worsening of CHD. The present study aimed to determine the effect of anxiety on the plasma metabolome in ACS patients. After receiving ethical approval 26 ACS patients comorbid anxiety were recruited and matched 26 ACS patients. Blood plasma samples were collected from the patients and stored at − 80 °C until metabolome profiling. Metabolome analysis was performed by liquid chromatography mass spectrometry (LC–MS), and the data were subjected to multivariate analysis. Disturbance of 39 plasma metabolites was noted in the ACS with comorbid anxiety group compared to the ACS group. These disturbed metabolites were mainly involved in tryptophan metabolism, pyrimidine metabolism, glycerophospholipid metabolism, pentose phosphate pathway, and pentose and glucuronate interconversions. The most significantly affected pathway was tryptophan metabolism including the down-regulation of tryptophan and serotonin. Glycerophospholipids metabolism, pentose and glucuronate interconversions, and pentose phosphate pathway were also greatly affected. These results suggest that anxiety can disturb three translation of material in ACS patients. Besides the above metabolism pathways pyrimidine metabolism was significantly disturbed. Based on the present findings the plasma metabolites monitoring can be recommended and may be conducive to early biomarkers detection for personalized treatment anxiety in CHD patients in future.
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Therapeutic Potential of Porcine Liver Decomposition Product: New Insights and Perspectives for Microglia-Mediated Neuroinflammation in Neurodegenerative Diseases. Biomedicines 2020; 8:biomedicines8110446. [PMID: 33105637 PMCID: PMC7690401 DOI: 10.3390/biomedicines8110446] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 12/23/2022] Open
Abstract
It is widely accepted that microglia-mediated inflammation contributes to the progression of neurodegenerative diseases; however, the precise mechanisms through which these cells contribute remain to be elucidated. Microglia, as the primary immune effector cells of the brain, play key roles in maintaining central nervous system (CNS) homeostasis. Microglia are located throughout the brain and spinal cord and may account for up to 15% of all cells in the brain. Activated microglia express pro-inflammatory cytokines that act on the surrounding brain and spinal cord. Microglia may also play a detrimental effect on nerve cells when they gain a chronic inflammatory function and promote neuropathologies. A key feature of microglia is its rapid morphological change upon activation, characterized by the retraction of numerous fine processes and the gradual acquisition of amoeba-like shapes. These morphological changes are also accompanied by the expression and secretion of inflammatory molecules, including cytokines, chemokines, and lipid mediators that promote systemic inflammation during neurodegeneration. This may be considered a protective response intended to limit further injury and initiate repair processes. We previously reported that porcine liver decomposition product (PLDP) induces a significant increase in the Hasegawa’s Dementia Scale-Revised (HDS-R) score and the Wechsler Memory Scale (WMS) in a randomized, double-blind, placebo-controlled study in healthy humans. In addition, the oral administration of porcine liver decomposition product enhanced visual memory and delayed recall in healthy adults. We believe that PLDP is a functional food that aids cognitive function. In this review, we provide a critical assessment of recent reports of lysophospholipids derived from PLDP, a rich source of phospholipids. We also highlight some recent findings regarding bidirectional interactions between lysophospholipids and microglia and age-related neurodegenerative diseases such as dementia and Alzheimer’s disease.
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Noguchi H, Okubo R, Hamazaki K, Yamashita A, Narisawa T, Matsuoka YJ. Serum polyunsaturated fatty acids and risk of psychiatric disorder at 6 months after acute coronary syndrome: A prospective cohort study. Prostaglandins Leukot Essent Fatty Acids 2019; 149:18-23. [PMID: 31421523 DOI: 10.1016/j.plefa.2019.07.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/05/2019] [Accepted: 07/02/2019] [Indexed: 12/16/2022]
Abstract
Cardiovascular disease is a known risk factor for the development of psychiatric disorder and about 20% of patients with acute coronary syndrome (ACS) develop depression. Our previous prospective study showed that serum linoleic acid (LA) level at baseline (admission) is a risk factor for the development of psychiatric disorder 3 months later. However, it was unclear whether serum LA could predict psychiatric disorders after 3 months. Thus, we examined the effects of polyunsaturated fatty acid (PUFA) levels at ACS onset on comorbid psychiatric disorders at 6 months. The study involved a follow-up investigation of the previous prospective cohort study of ACS patients. The sample with complete participant data at 6 months post-ACS comprised 100 patients. On admission, serum n-3 and n-6 PUFA levels were measured by gas chromatography and patients were interviewed to obtain medical information. Eight patients (8%) showed psychiatric disorder at 6 months. The association between psychiatric disorder and serum PUFA concentrations at ACS onset was examined by multivariable logistic regression analysis. Psychiatric disorders were predicted by baseline serum LA level (odds ratio = 7.27, 95% confidence interval = 1.11-47.76), indicating that it is a significant risk factor for the development of psychiatric disorder at 6 months. Thus, dietary education to reduce the intake of LA-containing foods might be useful for preventing psychiatric disorder in the population at high risk for ACS. However, the prevalence of psychiatric disorder, particularly depressive disorder, may have been too low to identify significant differences in PUFA analysis.
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Affiliation(s)
- Hiroko Noguchi
- School of Distance Learning, Department of Human Sciences, Musashino University, 1-1-20 Shin-machi, Nishitokyo-shi, Tokyo 202-8585, Japan; Division of Health Care Research, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Ryo Okubo
- Division of Health Care Research, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Kei Hamazaki
- Department of Public Health, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan
| | - Akihiro Yamashita
- Department of Psychiatry, National Disaster Medical Center, 3256 Midoricho, Tachikawa, Tokyo 190-0014, Japan
| | - Tomomi Narisawa
- Division of Health Care Research, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Lifestyle Medicine, Cooperative Graduate Program, The Jikei University Graduate School of Medicine, Tokyo 105-8461, Japan
| | - Yutaka J Matsuoka
- Division of Health Care Research, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Lifestyle Medicine, Cooperative Graduate Program, The Jikei University Graduate School of Medicine, Tokyo 105-8461, Japan.
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Abstract
Recently, metabolomics-the study of metabolite profiles within biological samples-has found a wide range of applications. This chapter describes the different techniques available for metabolomic analysis, the various samples that can be utilised for analysis and applications of both global and targeted metabolomic analysis to biomarker discovery in medicine.
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Walther A, Cannistraci CV, Simons K, Durán C, Gerl MJ, Wehrli S, Kirschbaum C. Lipidomics in Major Depressive Disorder. Front Psychiatry 2018; 9:459. [PMID: 30374314 PMCID: PMC6196281 DOI: 10.3389/fpsyt.2018.00459] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 09/04/2018] [Indexed: 01/01/2023] Open
Abstract
Omic sciences coupled with novel computational approaches such as machine intelligence offer completely new approaches to major depressive disorder (MDD) research. The complexity of MDD's pathophysiology is being integrated into studies examining MDD's biology within the omic fields. Lipidomics, as a late-comer among other omic fields, is increasingly being recognized in psychiatric research because it has allowed the investigation of global lipid perturbations in patients suffering from MDD and indicated a crucial role of specific patterns of lipid alterations in the development and progression of MDD. Combinatorial lipid-markers with high classification power are being developed in order to assist MDD diagnosis, while rodent models of depression reveal lipidome changes and thereby unveil novel treatment targets for depression. In this systematic review, we provide an overview of current breakthroughs and future trends in the field of lipidomics in MDD research and thereby paving the way for precision medicine in MDD.
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Affiliation(s)
| | - Carlo Vittorio Cannistraci
- Biomedical Cybernetics Group, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Center for Systems Biology Dresden (CSBD), Department of Physics, TU Dresden, Dresden, Germany
- Brain Bio-Inspired Computing (BBC) Lab, IRCCS Centro Neurolesi “Bonino Pulejo”, Messina, Italy
| | | | - Claudio Durán
- Biomedical Cybernetics Group, Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), Center for Systems Biology Dresden (CSBD), Department of Physics, TU Dresden, Dresden, Germany
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