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Song X, Wang X, Gao Y, Xu G, Yan X, Chen Z, Song G. Exploring the Therapeutic Potential of Glycyrrhiza Compounds in Alzheimer's Disease: A Comprehensive Review. Curr Top Med Chem 2025; 25:286-310. [PMID: 39323338 DOI: 10.2174/0115680266322320240911194626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 08/16/2024] [Accepted: 08/26/2024] [Indexed: 09/27/2024]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Research shows that the development of AD is linked to neuroinflammation, endoplasmic reticulum stress, mitochondrial dysfunction, cell death, and abnormal cholinergic signaling. Glycyrrhiza compounds contain active ingredients and extracts that offer multiple benefits, including targeting various pathways, high efficacy with low toxicity, and long-lasting therapeutic effects. These benefits highlight the significant potential of Glycyrrhiza compounds for preventing and treating AD. This review summarizes recent advancements in Glycyrrhiza compounds for preventing and treating AD. It focuses on their inhibitory effects on key signaling pathways, such as Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and cholinergic signaling. This study aims to establish a scientific framework for using Glycyrrhiza compounds in the clinical prevention and treatment of AD and to support the development of new therapeutic interventions.
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Affiliation(s)
- Xiaona Song
- Department of Basic Medical Sciences, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
- Laboratory Animal Center, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
| | - Xiaotang Wang
- Department of Basic Medical Sciences, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
- Laboratory Animal Center, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
| | - Yao Gao
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, No. 85 Jiefang South Rd, Taiyuan, 030001, China
| | - Guoqiang Xu
- Department of Basic Medical Sciences, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
- Laboratory Animal Center, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
| | - Xiaoru Yan
- Department of Basic Medical Sciences, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
- Laboratory Animal Center, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
| | - Zhaoyang Chen
- Department of Basic Medical Sciences, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
- Laboratory Animal Center, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
| | - Guohua Song
- Department of Basic Medical Sciences, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
- Laboratory Animal Center, Shanxi Medical University, No. 56, Xinjian South Rd, Taiyuan, 030001, China
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Valeria S, Francesco T, Sonia A, Laura VP, Luca C, Marcello S, Roberta L, Patrizia P, Arnau BG, Roberto F, Miriam M. Sex-specific maladaptive responses to acute stress upon in utero THC exposure are mediated by dopamine. Pharmacol Res 2024; 210:107536. [PMID: 39622370 PMCID: PMC7617568 DOI: 10.1016/j.phrs.2024.107536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/04/2024] [Accepted: 11/29/2024] [Indexed: 12/20/2024]
Abstract
Cannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that only male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) impairment. Notably, VTA dopamine neuronal activity is causally linked to the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-β signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent disruption of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.
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Affiliation(s)
- Serra Valeria
- Dept. Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Italy
| | - Traccis Francesco
- Dept. Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Italy
| | - Aroni Sonia
- Dept. Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Italy
| | | | - Concas Luca
- Dept. Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Italy
| | - Serra Marcello
- Dept. Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Italy
| | - Leone Roberta
- Dept. Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Italy
| | - Porcu Patrizia
- Institute of Neurosciences, National Research Council (C.N.R.), Cagliari, Italy
| | | | - Frau Roberto
- Dept. Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Italy
| | - Melis Miriam
- Dept. Biomedical Sciences, Div. Neuroscience and Clinical Pharmacology, University of Cagliari, Italy.
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Del Campo CMZM, Nicolson GL, Sfera A. Neurolipidomics in schizophrenia: A not so well-oiled machine. Neuropharmacology 2024; 260:110117. [PMID: 39153730 DOI: 10.1016/j.neuropharm.2024.110117] [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: 04/17/2024] [Revised: 08/03/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
Most patients with schizophrenia (SCZ) do not exhibit violent behaviors and are more likely to be victims rather than perpetrators of violent acts. However, a subgroup of forensic detainees with SCZ exhibit tendencies to engage in criminal violations. Although numerous models have been proposed, ranging from substance use, serotonin transporter gene, and cognitive dysfunction, the molecular underpinnings of violence in SCZ patients remains elusive. Lithium and clozapine have established anti-aggression properties and recent studies have linked low cholesterol levels and ultraviolet (UV) radiation with human aggression, while vitamin D3 reduces violent behaviors. A recent study found that vitamin D3, omega-3 fatty acids, magnesium, and zinc lower aggression in forensic population. In this review article, we take a closer look at aryl hydrocarbon receptor (AhR) and the dysfunctional lipidome in neuronal membranes, with emphasis on cholesterol and vitamin D3 depletion, as sources of aggressive behavior. We also discuss modalities to increase the fluidity of neuronal double layer via membrane lipid replacement (MLR) and natural or synthetic compounds. This article is part of the Special Issue on "Personality Disorders".
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Affiliation(s)
| | - Garth L Nicolson
- Department of Molecular Pathology, The Institute for Molecular Medicine, Huntington Beach, CA, 92647, USA
| | - Adonis Sfera
- Patton State Hospital, Loma Linda University, Department of Psychiatry, University of California, Riverside, USA.
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4
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Vajdi M, Khorvash F, Askari G. A randomized, double-blind, placebo-controlled parallel trial to test the effect of inulin supplementation on migraine headache characteristics, quality of life and mental health symptoms in women with migraine. Food Funct 2024; 15:10088-10098. [PMID: 39291634 DOI: 10.1039/d4fo02796e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Migraine is a complex neurovascular disorder characterized by recurrent headache attacks that are often accompanied by symptoms such as vomiting, nausea, and sensitivity to sound or light. Preventing migraine attacks is highly important. Recent research has indicated that alterations in gut microbiota may influence the underlying mechanisms of migraines. This study aimed to investigate the effects of inulin supplementation on migraine headache characteristics, quality of life (QOL), and mental health symptoms in women with migraines. In a randomized double-blind placebo-controlled trial, 80 women with migraines aged 20 to 50 years were randomly assigned to receive 10 g day-1 of inulin or a placebo supplement for 12 weeks. Severity, frequency, and duration of migraine attacks, as well as depression, anxiety, stress, QOL, and headache impact test (HIT-6) scores, were examined at the start of the study and after 12 weeks of intervention. In this study, the primary outcome focused on the frequency of headache attacks, while secondary outcomes encompassed the duration and severity of headache attacks, QOL, and mental health. There was a significant reduction in severity (-1.95 vs. -0.84, P = 0.004), duration (-6.95 vs. -2.05, P = 0.023), frequency (-2.09 vs. -0.37, P < 0.001), and HIT-6 score (-10.30 vs. -6.52, P < 0.023) in the inulin group compared with the control. Inulin supplementation improved mental health symptoms, including depression (-4.47 vs. -1.45, P < 0.001), anxiety (-4.37 vs. -0.70, P < 0.001), and stress (-4.40 vs. -1.50, P < 0.001). However, no significant difference was observed between the two groups regarding changes in QOL score. This study provides evidence supporting the beneficial effects of inulin supplement on migraine symptoms and mental health status in women with migraines. Further studies are necessary to confirm these findings. Trial registration: Iranian Registry of Clinical Trials (https://www.irct.ir) (ID: IRCT20121216011763N58).
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Affiliation(s)
- Mahdi Vajdi
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Fariborz Khorvash
- Neurology Research Center, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gholamreza Askari
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
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Qi W, Guan W. GPR56: A potential therapeutic target for neurological and psychiatric disorders. Biochem Pharmacol 2024; 226:116395. [PMID: 38942087 DOI: 10.1016/j.bcp.2024.116395] [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: 03/21/2024] [Revised: 06/17/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
GPR56, also known as GPR56/ADGRG1, is a member of the ADGRG subgroup belonging to adhesion G protein-coupled receptors (aGPCRs). aGPCRs are the second largest subfamily of the GPCR superfamily, which is the largest family of membrane protein receptors in the human genome. Studies in recent years have demonstrated that GPR56 is integral to the normal development of the brain and functions as an important player in cortical development, suggesting that GPR56 is involved in many physiological processes. Indeed, aberrant expression of GPR56 has been implicated in multiple neurological and psychiatric disorders, including bilateral frontoparietal polymicrogyria (BFPP), depression and epilepsy. In a recent study, it was found that upregulated expression of GPR56 reduced depressive-like behaviours in an animal model of depression, indicating that GPR56 plays an important role in the antidepressant response. Given the link of GPR56 with the antidepressant response, the function of GPR56 has become a focus of research. Although GPR56 may be a potential target for the development of antidepressants, the underlying molecular mechanisms remain largely unknown. Therefore, in this review, we will summarize the latest findings of GPR56 function in neurological and psychiatric disorders (depression, epilepsy, autism, and BFPP) and emphasize the mechanisms of GPR56 in activation and signalling in those conditions. After reviewing several studies, attributing to its significant biological functions and exceptionally long extracellular N-terminus that interacts with multiple ligands, we draw a conclusion that GPR56 may serve as an important drug target for neuropsychological diseases.
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Affiliation(s)
- Wang Qi
- Department of Pharmacology, The First People's Hospital of Yancheng, China
| | - Wei Guan
- Department of Pharmacology, Pharmacy College, Nantong University, China.
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6
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Onisiforou A, Zanos P, Georgiou P. Molecular signatures of premature aging in Major Depression and Substance Use Disorders. Sci Data 2024; 11:698. [PMID: 38926475 PMCID: PMC11208564 DOI: 10.1038/s41597-024-03538-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
Major depressive disorder (MDD) and substance-use disorders (SUDs) often lead to premature aging, increasing vulnerability to cognitive decline and other forms of dementia. This study utilized advanced systems bioinformatics to identify aging "signatures" in MDD and SUDs and evaluated the potential for known lifespan-extending drugs to target and reverse these signatures. The results suggest that inhibiting the transcriptional activation of FOS gene family members holds promise in mitigating premature aging in MDD and SUDs. Conversely, antidepressant drugs activating the PI3K/Akt/mTOR pathway, a common mechanism in rapid-acting antidepressants, may accelerate aging in MDD patients, making them unsuitable for those with comorbid aging-related conditions like dementia and Alzheimer's disease. Additionally, this innovative approach identifies potential anti-aging interventions for MDD patients, such as Deferoxamine, Resveratrol, Estradiol valerate, and natural compounds like zinc acetate, genistein, and ascorbic acid, regardless of comorbid anxiety disorders. These findings illuminate the premature aging effects of MDD and SUDs and offer insights into treatment strategies for patients with comorbid aging-related conditions, including dementia and Alzheimer's disease.
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Affiliation(s)
- Anna Onisiforou
- Department of Psychology, University of Cyprus, Nicosia, Cyprus.
| | - Panos Zanos
- Department of Psychology, University of Cyprus, Nicosia, Cyprus
| | - Polymnia Georgiou
- Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
- Department of Psychology, University of Wisconsin Milwaukee, Milwaukee, Wisconsin, USA.
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He J, Tam KY. Dual-target inhibitors of cholinesterase and GSK-3β to modulate Alzheimer's disease. Drug Discov Today 2024; 29:103914. [PMID: 38340951 DOI: 10.1016/j.drudis.2024.103914] [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: 09/21/2023] [Revised: 01/24/2024] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that affects over 55 million patients worldwide. Most of the approved small-molecule drugs for AD have been designed to tackle a single pathological hallmark, such as cholinergic dysfunction or amyloid toxicity, and thus may not fully address the multifactorial nature of the disease. Inhibition of both cholinesterase and glycogen synthase kinase-3β (GSK-3β) has emerged as a promising strategy to modulate AD. However, the dual inhibition of these two targets posts challenges in molecular design: issues related to target engagements and biopharmaceutical properties in particular must be overcome. In this review, we discuss the physiopathological roles and structures of cholinesterase and GSK-3β as well as recently reported dual-target inhibitors. We critically evaluate the current status of the discovery of dual-target inhibitors of cholinesterase and GSK-3β, and highlight further perspectives.
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Affiliation(s)
- Junqiu He
- Faculty of Health Sciences, University of Macau SAR, Avenida de Universidade, Taipa, Macau SAR, China
| | - Kin Yip Tam
- Faculty of Health Sciences, University of Macau SAR, Avenida de Universidade, Taipa, Macau SAR, China.
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Drastichova Z, Trubacova R, Novotny J. Regulation of phosphosignaling pathways involved in transcription of cell cycle target genes by TRH receptor activation in GH1 cells. Biomed Pharmacother 2023; 168:115830. [PMID: 37931515 DOI: 10.1016/j.biopha.2023.115830] [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: 08/29/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/08/2023] Open
Abstract
Thyrotropin-releasing hormone (TRH) is known to activate several cellular signaling pathway, but the activation of the TRH receptor (TRH-R) has not been reported to regulate gene transcription. The aim of this study was to identify phosphosignaling pathways and phosphoprotein complexes associated with gene transcription in GH1 pituitary cells treated with TRH or its analog, taltirelin (TAL), using label-free bottom-up mass spectrometry-based proteomics. Our detailed analysis provided insight into the mechanism through which TRH-R activation may regulate the transcription of genes related to the cell cycle and proliferation. It involves control of the signaling pathways for β-catenin/Tcf, Notch/RBPJ, p53/p21/Rbl2/E2F, Myc, and YY1/Rb1/E2F through phosphorylation and dephosphorylation of their key components. In many instances, the phosphorylation patterns of differentially phosphorylated phosphoproteins in TRH- or TAL-treated cells were identical or displayed a similar trend in phosphorylation. However, some phosphoproteins, especially components of the Wnt/β-catenin/Tcf and YY1/Rb1/E2F pathways, exhibited different phosphorylation patterns in TRH- and TAL-treated cells. This supports the notion that TRH and TAL may act, at least in part, as biased agonists. Additionally, the deficiency of β-arrestin2 resulted in a reduced number of alterations in phosphorylation, highlighting the critical role of β-arrestin2 in the signal transduction from TRH-R in the plasma membrane to transcription factors in the nucleus.
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Affiliation(s)
- Zdenka Drastichova
- Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czechia
| | - Radka Trubacova
- Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czechia; Institute of Physiology, Czech Academy of Sciences, 142 20 Prague, Czechia
| | - Jiri Novotny
- Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czechia.
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Recinella L, Libero ML, Veschi S, Piro A, Marconi GD, Diomede F, Chiavaroli A, Orlando G, Ferrante C, Florio R, Lamolinara A, Cai R, Sha W, Schally AV, Salvatori R, Brunetti L, Leone S. Effects of GHRH Deficiency and GHRH Antagonism on Emotional Disorders in Mice. Cells 2023; 12:2615. [PMID: 37998350 PMCID: PMC10670114 DOI: 10.3390/cells12222615] [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: 09/29/2023] [Revised: 11/06/2023] [Accepted: 11/07/2023] [Indexed: 11/25/2023] Open
Abstract
Growth hormone (GH)-releasing hormone (GHRH) has been suggested to play a crucial role in brain function. We aimed to further investigate the effects of a novel GHRH antagonist of the Miami (MIA) series, MIA-602, on emotional disorders and explore the relationships between the endocrine system and mood disorders. In this context, the effects induced by MIA-602 were also analyzed in comparison to vehicle-treated mice with GH deficiency due to generalized ablation of the GHRH gene (GHRH knock out (GHRHKO)). We show that the chronic subcutaneous administration of MIA-602 to wild type (+/+) mice, as well as generalized ablation of the GHRH gene, is associated with anxiolytic and antidepressant behavior. Moreover, immunohistochemical and Western blot analyses suggested an evident activation of Nrf2, HO1, and NQO1 in the prefrontal cortex of both +/+ mice treated with MIA-602 (+/+ MIA-602) and homozygous GHRHKO (-/- control) animals. Finally, we also found significantly decreased COX-2, iNOS, NFkB, and TNF-α gene expressions, as well as increased P-AKT and AKT levels in +/+ MIA-602 and -/- control animals compared to +/+ mice treated with vehicle (+/+ control). We hypothesize that the generalized ablation of the GHRH gene leads to a dysregulation of neural pathways, which is mimicked by GHRH antagonist treatment.
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Affiliation(s)
- Lucia Recinella
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
| | - Maria Loreta Libero
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14014 Cordoba, Spain
| | - Serena Veschi
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
| | - Anna Piro
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
| | - Guya Diletta Marconi
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (G.D.M.); (F.D.)
| | - Francesca Diomede
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (G.D.M.); (F.D.)
| | - Annalisa Chiavaroli
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
| | - Giustino Orlando
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
| | - Claudio Ferrante
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
| | - Rosalba Florio
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
| | - Alessia Lamolinara
- Department of Neuroscience Imaging and Clinical Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy;
| | - Renzhi Cai
- Veterans Affairs Medical Center, Miami, FL 33125, USA; (R.C.); (W.S.); (A.V.S.)
- Division of Medical/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
| | - Wei Sha
- Veterans Affairs Medical Center, Miami, FL 33125, USA; (R.C.); (W.S.); (A.V.S.)
- Division of Medical/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
| | - Andrew V. Schally
- Veterans Affairs Medical Center, Miami, FL 33125, USA; (R.C.); (W.S.); (A.V.S.)
- Division of Medical/Oncology and Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
| | - Roberto Salvatori
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
| | - Luigi Brunetti
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
| | - Sheila Leone
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy; (L.R.); (S.V.); (A.P.); (A.C.); (G.O.); (C.F.); (R.F.); (S.L.)
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10
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Harkin EF, Nasrallah G, Le François B, Albert PR. Transcriptional Regulation of the Human 5-HT1A Receptor Gene by Lithium: Role of Deaf1 and GSK3β. Int J Mol Sci 2023; 24:15620. [PMID: 37958600 PMCID: PMC10647674 DOI: 10.3390/ijms242115620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/11/2023] [Accepted: 10/21/2023] [Indexed: 11/15/2023] Open
Abstract
Serotonin 1A (5-HT1A) autoreceptors located on serotonin neurons inhibit their activity, and their upregulation has been implicated in depression, suicide and resistance to antidepressant treatment. Conversely, post-synaptic 5-HT1A heteroreceptors are important for antidepressant response. The transcription factor deformed epidermal autoregulatory factor 1 (Deaf1) acts as a presynaptic repressor and postsynaptic enhancer of 5-HT1A transcription, but the mechanism is unclear. Because Deaf1 interacts with and is phosphorylated by glycogen synthase kinase 3β (GSK3β)-a constitutively active protein kinase that is inhibited by the mood stabilizer lithium at therapeutic concentrations-we investigated the role of GSK3β in Deaf1 regulation of human 5-HT1A transcription. In 5-HT1A promoter-reporter assays, human HEK293 kidney and 5-HT1A-expressing SKN-SH neuroblastoma cells, transfection of Deaf1 reduced 5-HT1A promoter activity by ~45%. To identify potential GSK3β site(s) on Deaf1, point mutations of known and predicted phosphorylation sites on Deaf1 were tested. Deaf1 repressor function was not affected by any of the mutants tested except the Y300F mutant, which augmented Deaf1 repression. Both lithium and the selective GSK3 inhibitors CHIR-99021 and AR-014418 attenuated and reversed Deaf1 repression compared to vector. This inhibition was at concentrations that maximally inhibit GSK3β activity as detected by the GSK3β-sensitive TCF/LEF reporter construct. Our results support the hypothesis that GSK3β regulates the activity of Deaf1 to repress 5-HT1A transcription and provide a potential mechanism for actions of GSK3 inhibitors on behavior.
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Affiliation(s)
| | | | | | - Paul R. Albert
- Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, 451 Smyth Road, Ottawa, ON K1H-8M5, Canada (B.L.F.)
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Heitmann T, Barrow JC. The Role of Inositol Hexakisphosphate Kinase in the Central Nervous System. Biomolecules 2023; 13:1317. [PMID: 37759717 PMCID: PMC10526494 DOI: 10.3390/biom13091317] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/23/2023] [Accepted: 08/26/2023] [Indexed: 09/29/2023] Open
Abstract
Inositol is a unique biological small molecule that can be phosphorylated or even further pyrophosphorylated on each of its six hydroxyl groups. These numerous phosphorylation states of inositol along with the kinases and phosphatases that interconvert them comprise the inositol phosphate signaling pathway. Inositol hexakisphosphate kinases, or IP6Ks, convert the fully mono-phosphorylated inositol to the pyrophosphate 5-IP7 (also denoted IP7). There are three isoforms of IP6K: IP6K1, 2, and 3. Decades of work have established a central role for IP6Ks in cell signaling. Genetic and pharmacologic manipulation of IP6Ks in vivo and in vitro has shown their importance in metabolic disease, chronic kidney disease, insulin signaling, phosphate homeostasis, and numerous other cellular and physiologic processes. In addition to these peripheral processes, a growing body of literature has shown the role of IP6Ks in the central nervous system (CNS). IP6Ks have a key role in synaptic vesicle regulation, Akt/GSK3 signaling, neuronal migration, cell death, autophagy, nuclear translocation, and phosphate homeostasis. IP6Ks' regulation of these cellular processes has functional implications in vivo in behavior and CNS anatomy.
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Affiliation(s)
- Tyler Heitmann
- Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, 725 North Wolfe Street Suite 300, Baltimore, MD 21205, USA
- The Lieber Institute for Brain Development, 855 North Wolfe Street Suite 300, Baltimore, MD 21205, USA
| | - James C. Barrow
- Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, 725 North Wolfe Street Suite 300, Baltimore, MD 21205, USA
- The Lieber Institute for Brain Development, 855 North Wolfe Street Suite 300, Baltimore, MD 21205, USA
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12
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Szałach ŁP, Lisowska KA, Cubała WJ, Barbuti M, Perugi G. The immunomodulatory effect of lithium as a mechanism of action in bipolar disorder. Front Neurosci 2023; 17:1213766. [PMID: 37662097 PMCID: PMC10469704 DOI: 10.3389/fnins.2023.1213766] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 08/04/2023] [Indexed: 09/05/2023] Open
Abstract
Bipolar disorder (BD) is a chronic mental disorder characterized by recurrent episodes of mania and depression alternating with periods of euthymia. Although environmental and genetic factors have been described, their pathogenesis is not fully understood. Much evidence suggests a role for inflammatory mediators and immune dysregulation in the development of BD. The first-line treatment in BD are mood-stabilizing agents, one of which is lithium (Li) salts. The Li mechanism of action is not fully understood, but it has been proposed that its robust immunomodulatory properties might be one of the mechanisms responsible for its effectiveness. In this article, the authors present the current knowledge about immune system changes accompanying BD, as well as the immunomodulatory effect of lithium. The results of studies describing connections between immune system changes and lithium effectiveness are often incoherent. Further research is needed to understand the connection between immune system modulation and the therapeutic action of lithium in BD.
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Affiliation(s)
- Łukasz P. Szałach
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Katarzyna A. Lisowska
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Wiesław J. Cubała
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Margherita Barbuti
- Psychiatry Unit 2, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giulio Perugi
- Psychiatry Unit 2, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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13
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Ballester Roig MN, Roy PG, Hannou L, Delignat-Lavaud B, Sully Guerrier TA, Bélanger-Nelson E, Dufort-Gervais J, Mongrain V. Transcriptional regulation of the mouse EphA4, Ephrin-B2 and Ephrin-A3 genes by the circadian clock machinery. Chronobiol Int 2023; 40:983-1003. [PMID: 37551686 DOI: 10.1080/07420528.2023.2237580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 08/09/2023]
Abstract
Circadian rhythms originate from molecular feedback loops. In mammals, the transcription factors CLOCK and BMAL1 act on regulatory elements (i.e. E-boxes) to shape biological functions in a rhythmic manner. The EPHA4 receptor and its ligands Ephrins (EFN) are cell adhesion molecules regulating neurotransmission and neuronal morphology. Previous studies showed the presence of E-boxes in the genes of EphA4 and specific Ephrins, and that EphA4 knockout mice have an altered circadian rhythm of locomotor activity. We thus hypothesized that the core clock machinery regulates the gene expression of EphA4, EfnB2 and EfnA3. CLOCK and BMAL1 (or NPAS2 and BMAL2) were found to have transcriptional activity on distal and proximal regions of EphA4, EfnB2 and EfnA3 putative promoters. A constitutively active form of glycogen synthase kinase 3β (GSK3β; a negative regulator of CLOCK and BMAL1) blocked the transcriptional induction. Mutating the E-boxes of EphA4 distal promoter sequence reduced transcriptional induction. EPHA4 and EFNB2 protein levels did not show circadian variations in the mouse suprachiasmatic nucleus or prefrontal cortex. The findings uncover that core circadian transcription factors can regulate the gene expression of elements of the Eph/Ephrin system, which might contribute to circadian rhythmicity in biological processes in the brain or peripheral tissues.
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Affiliation(s)
- Maria Neus Ballester Roig
- Department of Neuroscience, Université de Montréal, Montreal, Quebec, Canada
- Centre de Recherche du CHUM, Montreal, Quebec, Canada
- Recherche CIUSSS-NIM, Montreal, Quebec, Canada
| | - Pierre-Gabriel Roy
- Department of Neuroscience, Université de Montréal, Montreal, Quebec, Canada
- Recherche CIUSSS-NIM, Montreal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | | | | | | | | | | | - Valérie Mongrain
- Department of Neuroscience, Université de Montréal, Montreal, Quebec, Canada
- Centre de Recherche du CHUM, Montreal, Quebec, Canada
- Recherche CIUSSS-NIM, Montreal, Quebec, Canada
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14
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Li X, Teng T, Yan W, Fan L, Liu X, Clarke G, Zhu D, Jiang Y, Xiang Y, Yu Y, Zhang Y, Yin B, Lu L, Zhou X, Xie P. AKT and MAPK signaling pathways in hippocampus reveals the pathogenesis of depression in four stress-induced models. Transl Psychiatry 2023; 13:200. [PMID: 37308476 DOI: 10.1038/s41398-023-02486-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 05/06/2023] [Accepted: 05/26/2023] [Indexed: 06/14/2023] Open
Abstract
Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder. The pathogenesis of MDD remained unclear, and it may be associated with exposure to different stressors. Most previous studies have focused on molecular changes in a single stress-induced depression model, which limited the identification of the pathogenesis of MDD. The depressive-like behaviors were induced by four well-validated stress models in rats, including chronic unpredictable mild stress, learned helplessness stress, chronic restraint stress and social defeat stress. We applied proteomic and metabolomic to investigate molecular changes in the hippocampus of those four models and revealed 529 proteins and 98 metabolites. Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified differentially regulated canonical pathways, and then we presented a schematic model that simulates AKT and MAPK signaling pathways network and their interactions and revealed the cascade reactions. Further, the western blot confirmed that p-AKT, p-ERK12, GluA1, p-MEK1, p-MEK2, p-P38, Syn1, and TrkB, which were changed in at least one depression model. Importantly, p-AKT, p-ERK12, p-MEK1 and p-P38 were identified as common alterations in four depression models. The molecular level changes caused by different stressors may be dramatically different, and even opposite, between four depression models. However, the different molecular alterations converge on a common AKT and MAPK molecular pathway. Further studies of these pathways could contribute to a better understanding of the pathogenesis of depression, with the ultimate goal of helping to develop or select more effective treatment strategies for MDD.
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Affiliation(s)
- Xuemei Li
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Teng Teng
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Yan
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Li Fan
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xueer Liu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Gerard Clarke
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Dan Zhu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanliang Jiang
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yajie Xiang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ying Yu
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuqing Zhang
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bangmin Yin
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Lu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China.
| | - Xinyu Zhou
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Peng Xie
- NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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15
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Li S, Lu C, Kang L, Li Q, Chen H, Zhang H, Tang Z, Lin Y, Bai M, Xiong P. Study on correlations of BDNF, PI3K, AKT and CREB levels with depressive emotion and impulsive behaviors in drug-naïve patients with first-episode schizophrenia. BMC Psychiatry 2023; 23:225. [PMID: 37013544 PMCID: PMC10071748 DOI: 10.1186/s12888-023-04718-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 03/25/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND The pathogenesis of schizophrenia is still unknown. Nearly a half of schizophrenic patients have depressive symptoms and even some impulsive behaviors. The definite diagnosis of schizophrenia is an immense challenge. Molecular biology plays an essential role in the research on the pathogenesis of schizophrenia. OBJECTIVE This study aims to analyze the correlations of serum protein factor levels with depressive emotion and impulsive behaviors in drug-naïve patients with first-episode schizophrenia. METHODS Seventy drug-naïve patients with first-episode schizophrenia and sixty-nine healthy volunteers from the health check center in the same period participated in this study. In both the patient group and control group, brain-derived neurotrophic factor (BDNF), phosphatidylin-ositol-3-kinase (PI3K), protein kinase B (AKT), and cAMP-response element binding protein (CREB) levels in the peripheral blood were tested by enzyme-linked immunosorbent assay (ELISA). The depressive emotion and impulsive behaviors were evaluated with Chinese versions of the Calgary Depression Scale for Schizophrenia (CDSS) and Short UPPS-P Impulsive Behavior Scale (S-UPPS-P), respectively. RESULTS The serum levels of BDNF, PI3K, and CREB in the patient group were lower than those in the control group, while AKT level, total CDSS score and total S-UPPS-P score were all higher. In the patient group, total CDSS score, and total S-UPPS-P score were both correlated negatively with BDNF, PI3K, and CREB levels but positively with AKT level, and the lack-of-premeditation (PR) sub-scale score was not significantly correlated with BDNF, PI3K, AKT, and CREB levels. CONCLUSION Our study results showed that the peripheral blood levels of BDNF, PI3K, AKT, and CREB in drug-naïve patients with first-episode schizophrenia were significantly different from those in the control group. The levels of these serum protein factors are promising biomarkers to predict schizophrenic depression and impulsive behaviors.
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Affiliation(s)
- Shan Li
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Cailian Lu
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lin Kang
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qianqian Li
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hongxu Chen
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Han Zhang
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ziling Tang
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yanwen Lin
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Meiyan Bai
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Peng Xiong
- Department of Psychiatry, First Affiliated Hospital of Kunming Medical University, Kunming, China.
- Yunnan Clinical Research Center for Mental Disorders, First Affiliated Hospital of Kunming Medical University, Kunming, China.
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16
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Zhang K, Zhang C, Teng X, Wang K, Chen M. Bioinformatics and computational chemistry approaches to explore the mechanism of the anti-depressive effect of ligustilide. Sci Rep 2023; 13:5417. [PMID: 37012370 PMCID: PMC10070278 DOI: 10.1038/s41598-023-32495-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 03/28/2023] [Indexed: 04/05/2023] Open
Abstract
Depression affects people with multiple adverse outcomes, and the side effects of antidepressants are troubling for depression sufferers. Aromatic drugs have been widely used to relieve symptoms of depression with fewer side effects. Ligustilide (LIG) is the main component of volatile oil in angelica sinensis, exhibiting an excellent anti-depressive effect. However, the mechanisms of the anti-depressive effect of LIG remain unclear. Therefore, this study aimed to explore the mechanisms of LIG exerting an anti-depressive effect. We obtained 12,969 depression-related genes and 204 LIG targets by a network pharmacology approach, which were intersected to get 150 LIG anti-depressive targets. Then, we identified core targets by MCODE, including MAPK3, EGF, MAPK14, CCND1, IL6, CASP3, IL2, MYC, TLR4, AKT1, ESR1, TP53, HIF1A, SRC, STAT3, AR, IL1B, and CREBBP. Functional enrichment analysis of core targets showed a significant association with PI3K/AKT and MAPK signaling pathways. Molecular docking showed strong affinities of LIG with AKT1, MAPK14, and ESR1. Finally, we validated the interactions between these proteins and LIG by molecular dynamics (MD) simulations. In conclusion, this study successfully predicted that LIG exerted an anti-depressive effect through multiple targets, including AKT1, MAPK14, and ESR1, and the pathways of PI3K/AKT and MAPK. The study provides a new strategy to explore the molecular mechanisms of LIG in treating depression.
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Affiliation(s)
- Kun Zhang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, 277#, Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Chaoguo Zhang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, 277#, Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Xiuli Teng
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, 277#, Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Ke Wang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, 277#, Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Mingwei Chen
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Xi'an Jiaotong University, 277#, Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
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17
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Xu J, Pittenger C. The histamine H3 receptor modulates dopamine D2 receptor-dependent signaling pathways and mouse behaviors. J Biol Chem 2023; 299:104583. [PMID: 36871761 PMCID: PMC10139999 DOI: 10.1016/j.jbc.2023.104583] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
The histamine H3 receptor (H3R) is highly enriched in the spiny projection neurons (SPNs) of the striatum, in both the D1 receptor (D1R)-expressing and D2 receptor (D2R)-expressing populations. A crossantagonistic interaction between H3R and D1R has been demonstrated in mice, both at the behavioral level and at the biochemical level. Although interactive behavioral effects have been described upon coactivation of H3R and D2R, the molecular mechanisms underlying this interaction are poorly understood. Here, we show that activation of H3R with the selective agonist R-(-)-α-methylhistamine dihydrobromide mitigates D2R agonist-induced locomotor activity and stereotypic behavior. Using biochemical approaches and the proximity ligation assay, we demonstrated the existence of an H3R-D2R complex in the mouse striatum. In addition, we examined consequences of simultaneous H3R-D2R agonism on the phosphorylation levels of several signaling molecules using immunohistochemistry. H3R agonist treatment modulated Akt (serine/threonine PKB)-glycogen synthase kinase 3 beta signaling in response to D2R activation via a β-arrestin 2-dependent mechanism in D2R-SPNs but not in D1R-SPNs. Phosphorylation of mitogen- and stress-activated protein kinase 1 and rpS6 (ribosomal protein S6) was largely unchanged under these conditions. As Akt-glycogen synthase kinase 3 beta signaling has been implicated in several neuropsychiatric disorders, this work may help clarify the role of H3R in modulating D2R function, leading to a better understanding of pathophysiology involving the interaction between histamine and dopamine systems.
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Affiliation(s)
- Jian Xu
- Department of Psychiatry, Yale University. ,
| | - Christopher Pittenger
- Department of Psychiatry, Yale University; Department of Psychology, Yale University; Department of Child Study Center, Yale University; Department of Interdepartmental Neuroscience Program, Yale University; Department of Wu-Tsai Institute, Yale University; Department of Center for Brain and Mind Health, Yale University.
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18
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A focus on Rho/ROCK signaling pathway: An emerging therapeutic target in depression. Eur J Pharmacol 2023; 946:175648. [PMID: 36894049 DOI: 10.1016/j.ejphar.2023.175648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/09/2023]
Abstract
Depression is the most common mental health disorder worldwide; however, the exact cellular and molecular mechanisms of this major depressive disorder are unclear so far. Experimental studies have demonstrated that depression is associated with significant cognitive impairment, dendrite spine loss, and reduction in connectivity among neurons that contribute to symptoms associated with mood disorders. Rho/Rho-associated coiled-coil containing protein kinase (ROCK) receptors are exclusively expressed in the brain and Rho/ROCK signaling has gained considerable attention as it plays a crucial role in the development of neuronal architecture and structural plasticity. Chronic stress-induced activation of the Rho/ROCK signaling pathway promotes neuronal apoptosis and loss of neural processes and synapses. Interestingly, accumulated evidence has identified Rho/ROCK signaling pathways as a putative target for treating neurological disorders. Furthermore, inhibition of the Rho/ROCK signaling pathway has proven to be effective in different models of depression, which signify the potential benefits of clinical Rho/ROCK inhibition. The ROCK inhibitors extensively modulate antidepressant-related pathways which significantly control the synthesis of proteins, and neuron survival and ultimately led to the enhancement of synaptogenesis, connectivity, and improvement in behavior. Therefore, the present review refines the prevailing contribution of this signaling pathway in depression and highlighted preclinical shreds of evidence for employing ROCK inhibitors as disease-modifying targets along with possible underlying mechanisms in stress-associated depression.
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Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles. Biomedicines 2023; 11:biomedicines11030806. [PMID: 36979785 PMCID: PMC10045655 DOI: 10.3390/biomedicines11030806] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/17/2023] [Accepted: 03/04/2023] [Indexed: 03/09/2023] Open
Abstract
Depression is a major public health concern. Unfortunately, the present antidepressants often are insufficiently effective, whilst the discovery of more effective antidepressants has been extremely sluggish. The objective of this review was to combine the literature on depression with the pharmacology of antidepressant compounds, in order to formulate a conceivable pathophysiological process, allowing proposals how to accelerate the discovery process. Risk factors for depression initiate an infection-like inflammation in the brain that involves activation microglial Toll-like receptors and glycogen synthase kinase-3β (GSK3β). GSK3β activity alters the balance between two competing transcription factors, the pro-inflammatory/pro-oxidative transcription factor NFκB and the neuroprotective, anti-inflammatory and anti-oxidative transcription factor NRF2. The antidepressant activity of tricyclic antidepressants is assumed to involve activation of GS-coupled microglial receptors, raising intracellular cAMP levels and activation of protein kinase A (PKA). PKA and similar kinases inhibit the enzyme activity of GSK3β. Experimental antidepressant principles, including cannabinoid receptor-2 activation, opioid μ receptor agonists, 5HT2 agonists, valproate, ketamine and electrical stimulation of the Vagus nerve, all activate microglial pathways that result in GSK3β-inhibition. An in vitro screen for NRF2-activation in microglial cells with TLR-activated GSK3β activity, might therefore lead to the detection of totally novel antidepressant principles with, hopefully, an improved therapeutic efficacy.
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20
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Plausible Role of Stem Cell Types for Treating and Understanding the Pathophysiology of Depression. Pharmaceutics 2023; 15:pharmaceutics15030814. [PMID: 36986674 PMCID: PMC10058940 DOI: 10.3390/pharmaceutics15030814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 03/06/2023] Open
Abstract
Major Depressive Disorder (MDD), colloquially known as depression, is a debilitating condition affecting an estimated 3.8% of the population globally, of which 5.0% are adults and 5.7% are above the age of 60. MDD is differentiated from common mood changes and short-lived emotional responses due to subtle alterations in gray and white matter, including the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and amygdala. It can be detrimental to a person’s overall health if it occurs with moderate or severe intensity. It can render a person suffering terribly to perform inadequately in their personal, professional, and social lives. Depression, at its peak, can lead to suicidal thoughts and ideation. Antidepressants manage clinical depression and function by modulating the serotonin, norepinephrine, and dopamine neurotransmitter levels in the brain. Patients with MDD positively respond to antidepressants, but 10–30% do not recuperate or have a partial response accompanied by poor life quality, suicidal ideation, self-injurious behavior, and an increased relapse rate. Recent research shows that mesenchymal stem cells and iPSCs may be responsible for lowering depression by producing more neurons with increased cortical connections. This narrative review discusses the plausible functions of various stem cell types in treating and understanding depression pathophysiology.
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21
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Xu Z, Wen C, Huang Y, Yuan Q, Zhang X, Lin D, Liu L, Wang W. Effects of Glycogen Synthase Kinase-3 Beta Gene Polymorphisms on the Plasma Concentration of Aripiprazole in Chinese Patients with Schizophrenia: A Preliminary Study. J Mol Neurosci 2023; 73:76-83. [PMID: 36539584 DOI: 10.1007/s12031-022-02079-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/25/2022] [Indexed: 12/24/2022]
Abstract
This study explored the differences in glycogen synthase kinase-3 beta (GSK3β) gene polymorphisms between patients with schizophrenia and healthy controls and investigated the association between gene polymorphisms and plasma concentration of aripiprazole. We enrolled 127 patients with schizophrenia and 125 healthy controls from southern Fujian. The genotypes of the rs6438552, rs12630592, and rs3732361 loci of GSK3β were evaluated by sequencing with amplified polymerase chain reaction, and the plasma concentration of aripiprazole was determined by high-performance liquid chromatography-tandem mass spectrometry. All three loci of GSK3β had three genotypes each. The genotype distribution in each locus was not significantly different, but there was a significant difference in the allele frequency between the schizophrenia and control groups within each locus. Linkage disequilibrium analyses of the three single-nucleotide polymorphisms (SNPs) revealed strong linkage. The haplotype analysis results showed two haplotypes in the three SNPs of GSK3β. The plasma concentrations, dose-corrected concentrations, and normalized concentrations of aripiprazole were significantly different among the different genotypes of the three SNPs. In conclusion, the rs6438552, rs12630592, and rs3732361 loci of GSK3β may be involved in schizophrenia, and GSK3β gene polymorphism may be correlated with the plasma concentration of aripiprazole.
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Affiliation(s)
- Zhizhong Xu
- Department of Mental Health Research, Xiamen Xianyue Hospital, Xiamen, 361012, Fujian, China.
| | - Chunyan Wen
- Department of Mental Health Research, Xiamen Xianyue Hospital, Xiamen, 361012, Fujian, China
| | - Yinghua Huang
- Department of Mental Health Research, Xiamen Xianyue Hospital, Xiamen, 361012, Fujian, China
| | - Qianfa Yuan
- Department of Mental Health Research, Xiamen Xianyue Hospital, Xiamen, 361012, Fujian, China
| | - Xianhua Zhang
- Department of Mental Health Research, Xiamen Xianyue Hospital, Xiamen, 361012, Fujian, China
| | - Duoduo Lin
- Department of Psychiatry, Xiamen Xianyue Hospital, Xiamen, 361012, Fujian, China
| | - Liangsheng Liu
- Department of Psychiatry, Xiamen Xianyue Hospital, Xiamen, 361012, Fujian, China
| | - Wenqiang Wang
- Department of Psychiatry, Xiamen Xianyue Hospital, Xiamen, 361012, Fujian, China.
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22
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Bo M, Zhang H, Xu J, Zhao H, Jia X, Wang G, Lu Z. Systematic review of Kaixinsan in treating depression: Efficacy and pharmacological mechanisms. Front Behav Neurosci 2022; 16:1061877. [PMID: 36560929 PMCID: PMC9763288 DOI: 10.3389/fnbeh.2022.1061877] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/18/2022] [Indexed: 12/12/2022] Open
Abstract
Introduction Kaixinsan (KXS) has been in use as an effective classic formulation of traditional Chinese medicine for depression. However, its active components and action mechanism against depression remain elusive. The purpose of this study was to summarize and evaluate the efficacy and potential pharmacological mechanisms of KXS in antidepressant treatment. Materials and methods Reports on the use of KXS in the treatment of depression were systematically collected from PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Chongqing VIP, and Wanfang Data from the establishment to July 2022, including those on mood disorders in neurological diseases such as Alzheimer's disease. Meta-analysis was conducted with the Review Manager 5.3 software. Online datasets, traditional Chinese medicine system pharmacological analysis platform, GeneCards, online Mendelian inheritance in man, and DisGeNET were used to investigate the depression-related genes. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments were performed to construct the 'component-target-pathways' network using Metascape online analyses. Result Ten studies were included in the analysis. Meta-analysis showed that both low-dose KXS (SMD = 19.66, Z = 7.96, and I 2 = 42%) and high-dose KXS (SMD = 23.84, Z = 8.46, and I 2 = 13%) could increase the sucrose preference in depression models. In addition, 5-hydroxytryptamine (5-HT) (SMD = 10.91, Z = 2.95, and I 2 = 50%) returned to normal level after the treatment at low dose KXS. In network pharmacology, 50 active components and 376 gene targets were screened out. AKT1, GAPDH, ALB, TNF, and TP53 were the core target proteins. GO analysis showed that KXS mainly treats depression in biological processes such as response to drugs, cellular calcium ion homeostasis, and regulation of chemical synaptic signal transmission. KEGG results show that the mechanism of action of KXS in treating depression is through neural activity ligand-receptor interaction, the calcium signaling and CAMP signaling pathways. Discussion The study reveals the active components and potential molecular mechanism of KXS in the treatment of depression and provides evidence for future basic research.
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Affiliation(s)
- Menghan Bo
- VIP Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongjing Zhang
- Teaching Affairs Department, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jia Xu
- VIP Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong Zhao
- Teaching Affairs Department, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinglei Jia
- VIP Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangdong Wang
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China,Guangdong Wang,
| | - Zhengyu Lu
- VIP Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Zhengyu Lu,
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23
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Development of p-Tau Differentiated Cell Model of Alzheimer's Disease to Screen Novel Acetylcholinesterase Inhibitors. Int J Mol Sci 2022; 23:ijms232314794. [PMID: 36499118 PMCID: PMC9741399 DOI: 10.3390/ijms232314794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/30/2022] [Accepted: 11/16/2022] [Indexed: 11/29/2022] Open
Abstract
Alzheimer's disease (AD) is characterized by an initial accumulation of amyloid plaques and neurofibrillary tangles, along with the depletion of cholinergic markers. The currently available therapies for AD do not present any disease-modifying effects, with the available in vitro platforms to study either AD drug candidates or basic biology not fully recapitulating the main features of the disease or being extremely costly, such as iPSC-derived neurons. In the present work, we developed and validated a novel cell-based AD model featuring Tau hyperphosphorylation and degenerative neuronal morphology. Using the model, we evaluated the efficacy of three different groups of newly synthesized acetylcholinesterase (AChE) inhibitors, along with a new dual acetylcholinesterase/glycogen synthase kinase 3 inhibitor, as potential AD treatment on differentiated SH-SY5Y cells treated with glyceraldehyde to induce Tau hyperphosphorylation, and subsequently neurite degeneration and cell death. Testing of such compounds on the newly developed model revealed an overall improvement of the induced defects by inhibition of AChE alone, showing a reduction of S396 aberrant phosphorylation along with a moderate amelioration of the neuron-like morphology. Finally, simultaneous AChE/GSK3 inhibition further enhanced the limited effects observed by AChE inhibition alone, resulting in an improvement of all the key parameters, such as cell viability, morphology, and Tau abnormal phosphorylation.
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24
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Lithium Biological Action Mechanisms after Ischemic Stroke. Life (Basel) 2022; 12:life12111680. [DOI: 10.3390/life12111680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022] Open
Abstract
Lithium is a source of great scientific interest because although it has such a simple structure, relatively easy-to-analyze chemistry, and well-established physical properties, the plethora of effects on biological systems—which influence numerous cellular and molecular processes through not entirely explained mechanisms of action—generate a mystery that modern science is still trying to decipher. Lithium has multiple effects on neurotransmitter-mediated receptor signaling, ion transport, signaling cascades, hormonal regulation, circadian rhythm, and gene expression. The biochemical mechanisms of lithium action appear to be multifactorial and interrelated with the functioning of several enzymes, hormones, vitamins, and growth and transformation factors. The widespread and chaotic marketing of lithium salts in potions and mineral waters, always at inadequate concentrations for various diseases, has contributed to the general disillusionment with empirical medical hypotheses about the therapeutic role of lithium. Lithium salts were first used therapeutically in 1850 to relieve the symptoms of gout, rheumatism, and kidney stones. In 1949, Cade was credited with discovering the sedative effect of lithium salts in the state of manic agitation, but frequent cases of intoxication accompanied the therapy. In the 1960s, lithium was shown to prevent manic and also depressive recurrences. This prophylactic effect was first demonstrated in an open-label study using the “mirror” method and was later (after 1970) confirmed by several placebo-controlled double-blind studies. Lithium prophylaxis was similarly effective in bipolar and also unipolar patients. In 1967, the therapeutic value of lithemia was determined, included in the range of 0.5–1.5 mEq/L. Recently, new therapeutic perspectives on lithium are connected with improved neurological outcomes after ischemic stroke. The effects of lithium on the development and maintenance of neuroprotection can be divided into two categories: short-term effects and long-term effects. Unfortunately, the existing studies do not fully explain the lithium biological action mechanisms after ischemic stroke.
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25
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Gulhane P, Singh S. MicroRNA-520c-3p impacts sphingolipid metabolism mediating PI3K/AKT signaling in NSCLC: Systems perspective. J Cell Biochem 2022; 123:1827-1840. [PMID: 35977046 DOI: 10.1002/jcb.30319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/03/2022] [Accepted: 08/05/2022] [Indexed: 11/09/2022]
Abstract
Increasing research suggests that sphingolipid metabolism is essential for the progression and metastasis of cancer. The underlying mechanistic insight into the dysregulation of sphingolipid metabolism affecting pathways is poorly investigated. As a result, the goal of the current study was to glean knowledge from the systems biology approach to investigate how the sphingolipid metabolism affects the signal transduction network in non-small cell lung cancer (NSCLC), the most common type of cancer in terms of occurrence and death globally. Our paper includes system-level models representing the diseased and healthy states elucidating that sphingolipids and its enzymes mediate PI3K/AKT pathway. Notably, its activation of downstream signaling mediators has led to cancer growth. Considering the critical role of sphingolipids in NSCLC, our study advocates the target CERS6 which can be potentially inhibited using hsa-miR-520c-3p to combat NSCLC for future precision medicine.
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Affiliation(s)
- Pooja Gulhane
- Department of Pathogenesis and Cellular Response, Computational and Systems Biology Lab, National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Shailza Singh
- Department of Pathogenesis and Cellular Response, Computational and Systems Biology Lab, National Centre for Cell Science, SP Pune University Campus, Pune, India
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26
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Fan L, Peng Y, Chen X, Ma P, Li X. Integrated analysis of phytochemical composition, pharmacokinetics, and network pharmacology to probe distinctions between the stems of Cistanche deserticola and C. tubulosa based on antidepressant activity. Food Funct 2022; 13:8542-8557. [PMID: 35880684 DOI: 10.1039/d2fo01357f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Cistanches Herba (CH), as a nutritional and functional supplement used in food and health care products for centuries, consists of the stems of Cistanche deserticola and C. tubulosa. Our previous studies confirmed that the stems of C. tubulosa exerted advantageous antidepressant effect. However, whether the difference in the phytochemical compositions between the stems of C. deserticola and C. tubulosa would lead to diverse bioavailability and accompanying antidepressant effects remain unclear, as well as their specific bioactive compounds and underlying mechanism. In this study, a series of comparative studies showed that the antidepressant activity of C. tubulosa extract (CTE) was stronger than that of the C. deserticola extract (CDE), which was accompanied with the discovery of 10 differential markers from 52 identified compounds between CTE and CDE, and different pharmacokinetic behaviors of 9 prototype and 4 metabolites belonging to the glycosides between the CTE-treated and CDE-treated group in normal and depressive rats were simultaneously found by a validated UPLC-QTRAP-MS/MS method. Subsequently, network pharmacology prediction, in vitro and in vivo experiment verification from these differential markers further revealed that 7 compounds were confirmed to contribute to the antidepressant action of CH by inhibiting neuronal apoptosis mediated by mitochondrial function and activation of the AKT/GSK3β signaling pathway, synchronously indicating most of those, with higher bioavailability in vivo after CTE administration, that were responsible for the stronger antidepressant effect of CTE over CDE. Hence, the integrated analysis of phytochemical composition, pharmacokinetics, and network pharmacology provide new insights into the applications of CH from different botanical origins against depression.
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Affiliation(s)
- Li Fan
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
| | - Ying Peng
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
| | - Xiaonan Chen
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
| | - Ping Ma
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
| | - Xiaobo Li
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
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27
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Lago SG, Tomasik J, van Rees GF, Rustogi N, Vázquez-Bourgon J, Papiol S, Suarez-Pinilla P, Crespo-Facorro B, Bahn S. Peripheral lymphocyte signaling pathway deficiencies predict treatment response in first-onset drug-naïve schizophrenia. Brain Behav Immun 2022; 103:37-49. [PMID: 35381347 DOI: 10.1016/j.bbi.2022.03.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 03/12/2022] [Accepted: 03/31/2022] [Indexed: 12/29/2022] Open
Abstract
Despite being a major cause of disability worldwide, the pathophysiology of schizophrenia and molecular basis of treatment response heterogeneity continue to be unresolved. Recent evidence suggests that multiple aspects of pathophysiology, including genetic risk factors, converge on key cell signaling pathways and that exploration of peripheral blood cells might represent a practical window into cell signaling alterations in the disease state. We employed multiplexed phospho-specific flow cytometry to examine cell signaling epitope expression in peripheral blood mononuclear cell (PBMC) subtypes in drug-naïve schizophrenia patients (n = 49) relative to controls (n = 61) and relate these changes to serum immune response proteins, schizophrenia polygenic risk scores and clinical effects of treatment, including drug response and side effects, over the longitudinal course of antipsychotic treatment. This revealed both previously characterized (Akt1) and novel cell signaling epitopes (IRF-7 (pS477/pS479), CrkL (pY207), Stat3 (pS727), Stat3 (pY705) and Stat5 (pY694)) across PBMC subtypes which were associated with schizophrenia at disease onset, and correlated with type I interferon-related serum molecules CD40 and CXCL11. Alterations in Akt1 and IRF-7 (pS477/pS479) were additionally associated with polygenic risk of schizophrenia. Finally, changes in Akt1, IRF-7 (pS477/pS479) and Stat3 (pS727) predicted development of metabolic and cardiovascular side effects following antipsychotic treatment, while IRF-7 (pS477/pS479) and Stat3 (pS727) predicted early improvements in general psychopathology scores measured using the Brief Psychiatric Rating Scale (BPRS). These findings suggest that peripheral blood cells can provide an accessible surrogate model for intracellular signaling alterations in schizophrenia and have the potential to stratify subgroups of patients with different clinical outcomes or a greater risk of developing metabolic and cardiovascular side effects following antipsychotic therapy.
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Affiliation(s)
- Santiago G Lago
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
| | - Jakub Tomasik
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
| | - Geertje F van Rees
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
| | - Nitin Rustogi
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
| | - Javier Vázquez-Bourgon
- Department of Psychiatry, Marqués de Valdecilla University Hospital, IDIVAL, School of Medicine, University of Cantabria, Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Santander, Spain
| | - Sergi Papiol
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain; Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig Maximilian University, Munich, Germany; Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University, Munich, Germany
| | - Paula Suarez-Pinilla
- Department of Psychiatry, Marqués de Valdecilla University Hospital, IDIVAL, School of Medicine, University of Cantabria, Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Santander, Spain
| | - Benedicto Crespo-Facorro
- Department of Psychiatry, Marqués de Valdecilla University Hospital, IDIVAL, School of Medicine, University of Cantabria, Santander, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Santander, Spain; Department of Psychiatry, School of Medicine, University Hospital Virgen del Rocio, IBiS, Sevilla, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Sevilla, Spain
| | - Sabine Bahn
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom.
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28
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Tsimberidou AM, Skliris A, Valentine A, Shaw J, Hering U, Vo HH, Chan TO, Armen RS, Cottrell JR, Pan JQ, Tsichlis PN. AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology. Cell Biosci 2022; 12:56. [PMID: 35525984 PMCID: PMC9080159 DOI: 10.1186/s13578-022-00793-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/18/2022] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms. METHODS (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors. RESULTS (1) Proteins encoded by AKT3 (AKT3Q60H) and AKT1 (AKT1Q61H) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1, respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10-8). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible. CONCLUSIONS Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring.
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Affiliation(s)
- Apostolia-Maria Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
| | - Antonis Skliris
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA
| | - Alan Valentine
- Department of Psychiatry, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jamie Shaw
- EMD Serono Billerica (a Business of Merck KGaA), 01821, Darmstadt, MA, Germany
| | | | - Henry Hiep Vo
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - Tung On Chan
- Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Roger S Armen
- Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Jeffrey R Cottrell
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Jen Q Pan
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Philip N Tsichlis
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA.
- Department of Cancer Biology and Genetics, College of Medicine, and the Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA.
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29
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Liu J, Fang Y, Cui L, Wang Z, Luo Y, Gao C, Ge W, Huang T, Wen J, Zhou T. Butyrate emerges as a crucial effector of Zhi-Zi-Chi decoctions to ameliorate depression via multiple pathways of brain-gut axis. Biomed Pharmacother 2022; 149:112861. [PMID: 35339110 DOI: 10.1016/j.biopha.2022.112861] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 11/09/2022] Open
Abstract
Gut microbiota has emerged as a crucial target of gut-brain axis to influence depression. Zhi-Zi-Chi decoctions (ZZCD), as a classic oral formula in clinic, is widely applied in depression treatment nowadays. However, the underlying mechanism in the antidepressant activity of ZZCD remains unknown. A classic depression model of chronic mild unpredictable stress (CUMS) was established in rats based on the results of behavioral tests and hippocampal histomorphology. 16S rRNA sequencing analysis indicated that ZZCD could increase short-chain fatty acid-producing and anti-inflammatory bacteria and reduce inflammatory and tryptophan-metabolizing bacteria. Furthermore, ZZCD reversed the alterations of BDNF, TNF-α, pro-inflammatory cytokines and neurotransmitters in the gut, blood and brain along the brain-gut axis and restored the decrease of butyrate in cecal content caused by CUMS. Then, butyrate was utilized to validate its ameliorative effect on pathological characteristics of depressive rats. Taken together, these results show that ZZCD exhibits antidepressant effect through modulating gut microbiota to facilitate the production of butyrate, which further regulate anti-inflammation, neurotransmitters, endocrine and BDNF along the gut-brain axis. Hence, this study fills the gap of the antidepressive mechanism of ZZCD in the light of the brain-gut axis and established a multi-targets and multi-levels platform eventually for further research into the mechanism of other TCM efficacy.
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Affiliation(s)
- Jialin Liu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yichao Fang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Lixun Cui
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Zhongzhao Wang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Changzheng hospital, second affiliated hospital of Second Military Medical University, Shanghai 200003, China
| | - Yusha Luo
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Congcong Gao
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Wen Ge
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | | | - Jun Wen
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Tingting Zhou
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
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30
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Receptor-Mediated AKT/PI3K Signalling and Behavioural Alterations in Zebrafish Larvae Reveal Association between Schizophrenia and Opioid Use Disorder. Int J Mol Sci 2022; 23:ijms23094715. [PMID: 35563106 PMCID: PMC9104710 DOI: 10.3390/ijms23094715] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 02/01/2023] Open
Abstract
The link between substance abuse and the development of schizophrenia remains elusive. In this study, we assessed the molecular and behavioural alterations associated with schizophrenia, opioid addiction, and opioid withdrawal using zebrafish as a biological model. Larvae of 2 days post fertilization (dpf) were exposed to domperidone (DMP), a dopamine-D2 dopamine D2 receptor antagonist, and morphine for 3 days and 10 days, respectively. MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, served as a positive control to mimic schizophrenia-like behaviour. The withdrawal syndrome was assessed 5 days after the termination of morphine treatment. The expressions of schizophrenia susceptibility genes, i.e., pi3k, akt1, slc6a4, creb1 and adamts2, in brains were quantified, and the levels of whole-body cyclic adenosine monophosphate (cAMP), serotonin and cortisol were measured. The aggressiveness of larvae was observed using the mirror biting test. After the short-term treatment with DMP and morphine, all studied genes were not differentially expressed. As for the long-term exposure, akt1 was downregulated by DMP and morphine. Downregulation of pi3k and slc6a4 was observed in the morphine-treated larvae, whereas creb1 and adamts2 were upregulated by DMP. The levels of cAMP and cortisol were elevated after 3 days, whereas significant increases were observed in all of the biochemical tests after 10 days. Compared to controls, increased aggression was observed in the DMP-, but not morphine-, treated group. These two groups showed reduction in aggressiveness when drug exposure was prolonged. Both the short- and long-term morphine withdrawal groups showed downregulation in all genes examined except creb1, suggesting dysregulated reward circuitry function. These results suggest that biochemical and behavioural alterations in schizophrenia-like symptoms and opioid dependence could be controlled by common mechanisms.
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31
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Wu XL, Yan QJ, Zhu F. Abnormal synaptic plasticity and impaired cognition in schizophrenia. World J Psychiatry 2022; 12:541-557. [PMID: 35582335 PMCID: PMC9048451 DOI: 10.5498/wjp.v12.i4.541] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/28/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a severe mental illness that affects several brain domains with relation to cognition and behaviour. SCZ symptoms are typically classified into three categories, namely, positive, negative, and cognitive. The etiology of SCZ is thought to be multifactorial and poorly understood. Accumulating evidence has indicated abnormal synaptic plasticity and cognitive impairments in SCZ. Synaptic plasticity is thought to be induced at appropriate synapses during memory formation and has a critical role in the cognitive symptoms of SCZ. Many factors, including synaptic structure changes, aberrant expression of plasticity-related genes, and abnormal synaptic transmission, may influence synaptic plasticity and play vital roles in SCZ. In this article, we briefly summarize the morphology of the synapse, the neurobiology of synaptic plasticity, and the role of synaptic plasticity, and review potential mechanisms underlying abnormal synaptic plasticity in SCZ. These abnormalities involve dendritic spines, postsynaptic density, and long-term potentiation-like plasticity. We also focus on cognitive dysfunction, which reflects impaired connectivity in SCZ. Additionally, the potential targets for the treatment of SCZ are discussed in this article. Therefore, understanding abnormal synaptic plasticity and impaired cognition in SCZ has an essential role in drug therapy.
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Affiliation(s)
- Xiu-Lin Wu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Qiu-Jin Yan
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
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32
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Zhou Q, Li S, Li M, Ke D, Wang Q, Yang Y, Liu GP, Wang XC, Liu E, Wang JZ. Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration. EBioMedicine 2022; 78:103970. [PMID: 35339896 PMCID: PMC8956943 DOI: 10.1016/j.ebiom.2022.103970] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 03/12/2022] [Accepted: 03/13/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Glycogen synthase kinase-3β (GSK-3β) is one of the most effective kinases in promoting tau hyperphosphorylation and accumulation in Alzheimer's disease (AD). However, it is not clear how GSK-3β activity is regulated during AD progression. METHODS We firstly used mass spectrometry to identify the acetylation site of GSK-3β, and then established the cell and animal models of GSK-3β acetylation. Next, we conducted molecular, cell biological and behavioral tests. Finally, we designed a peptide to test whether blocking tau-mediated GSK-3β acetylation could be beneficial to AD. FINDINGS We found that GSK-3β protein levels increased in the brains of AD patients and the transgenic mice. Overexpressing tau increased GSK-3β protein level with increased acetylation and decreased ubiquitination-related proteolysis. Tau could directly acetylate GSK-3β at K15 both in vitro and in vivo. K15-acetylation inhibited ubiquitination-associated proteolysis of GSK-3β and changed its activity-dependent phosphorylation, leading to over-activation of the kinase. GSK-3β activation by K15-acetylation in turn exacerbated the AD-like pathologies. Importantly, competitively inhibiting GSK-3β K15-acetylation by a novel-designed peptide remarkably improved cognitive impairment and the AD-like pathologies in 3xTg-AD mice. INTERPRETATION Tau can directly acetylate GSK-3β at K15 which reveals a vicious cycle between tau hyperphosphorylation and GSK-3β activation. FUNDING This study was supported in parts by grants from Science and Technology Committee of China (2016YFC1305800), Hubei Province (2018ACA142), Natural Science Foundation of China (91949205, 82001134, 31730035, 81721005), Guangdong Provincial Key S&T Program (018B030336001).
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Affiliation(s)
- Qiuzhi Zhou
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shihong Li
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Mengzhu Li
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dan Ke
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qun Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ying Yang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Gong-Ping Liu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiao-Chuan Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Enjie Liu
- Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Jian-Zhi Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China.
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Monroy-Jaramillo N, Martínez-Magaña JJ, Pérez-Aldana BE, Ortega-Vázquez A, Montalvo-Ortiz J, López-López M. The role of alcohol intake in the pharmacogenetics of treatment with clozapine. Pharmacogenomics 2022; 23:371-392. [PMID: 35311547 DOI: 10.2217/pgs-2022-0006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Clozapine (CLZ) is an atypical antipsychotic reserved for patients with refractory psychosis, but it is associated with a significant risk of severe adverse reactions (ADRs) that are potentiated with the concomitant use of alcohol. Additionally, pharmacogenetic studies have explored the influence of several genetic variants in CYP450, receptors and transporters involved in the interindividual response to CLZ. Herein, we systematically review the current multiomics knowledge behind the interaction between CLZ and alcohol intake, and how its concomitant use might modulate the pharmacogenetics. CYP1A2*1F, *1C and other alleles not yet discovered could support a precision medicine approach for better therapeutic effects and fewer CLZ ADRs. CLZ monitoring systems should be amended and include alcohol intake to protect patients from severe CLZ ADRs.
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Affiliation(s)
- Nancy Monroy-Jaramillo
- Department of Genetics, National Institute of Neurology & Neurosurgery, Manuel Velasco Suárez, La Fama, Tlalpan, Mexico City, 14269, Mexico
| | - José Jaime Martínez-Magaña
- Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, Orange, West Haven, CT 06477, USA
| | - Blanca Estela Pérez-Aldana
- Doctorado en Ciencias Biológicas y de la Salud, Metropolitan Autonomous University, Campus Xochimilco, Villa Quietud, Coyoacán, Mexico City, 04960, Mexico
| | - Alberto Ortega-Vázquez
- Metropolitan Autonomous University, Campus Xochimilco, Villa Quietud, Coyoacán, Mexico City, 04960, Mexico
| | - Janitza Montalvo-Ortiz
- Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, Orange, West Haven, CT 06477, USA
| | - Marisol López-López
- Metropolitan Autonomous University, Campus Xochimilco, Villa Quietud, Coyoacán, Mexico City, 04960, Mexico
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de Oliveira RL, Voss GT, da C. Rodrigues K, Pinz MP, Biondi JV, Becker NP, Blodorn E, Domingues WB, Larroza A, Campos VF, Alves D, Wilhelm EA, Luchese C. Prospecting for a quinoline containing selenium for comorbidities depression and memory impairment induced by restriction stress in mice. Psychopharmacology (Berl) 2022; 239:59-81. [PMID: 35013761 PMCID: PMC8747877 DOI: 10.1007/s00213-021-06039-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 11/29/2021] [Indexed: 12/31/2022]
Abstract
RATIONALE Depression is often associated with memory impairment, a clinical feature of Alzheimer's disease (AD), but no effective treatment is available. 7-Chloro-4-(phenylselanyl) quinoline (4-PSQ) has been studied in experimental models of diseases that affect the central nervous system. OBJECTIVES The pharmacological activity of 4-PSQ in depressive-like behavior associated with memory impairment induced by acute restraint stress (ARS) in male Swiss mice was evaluated. METHODS ARS is an unavoidable stress model that was applied for a period of 240 min. Ten minutes after ARS, animals were intragastrically treated with canola oil (10 ml/kg) or 4-PSQ (10 mg/kg) or positive controls (paroxetine or donepezil) (10 mg/kg). Then, after 30 min, mice were submitted to behavioral tests. Corticosterone levels were evaluated in plasma and oxidative stress parameters; monoamine oxidase (MAO)-A and MAO -B isoform activity; mRNA expression levels of kappa nuclear factor B (NF-κB); interleukin (IL)-1β, IL-18, and IL-33; phosphatidylinositol-se-kinase (PI3K); protein kinase B (AKT2), as well as acetylcholinesterase activity were evaluated in the prefrontal cortex and hippocampus. RESULTS 4-PSQ attenuated the depressive-like behavior, self-care, and memory impairment caused by ARS. Based on the evidence, we believe that effects of 4-PSQ may be associated, at least in part, with the attenuation of HPA axis activation, attenuation of alterations in the monoaminergic system, modulation of oxidative stress, reestablishment of AChE activity, modulation of the PI3K/AKT2 pathway, and reduction of neuroinflammation. CONCLUSIONS These results suggested that 4-PSQ exhibited an antidepressant-like effect and attenuated the memory impairment induced by ARS, and it is a promising molecule to treat these comorbidities.
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Affiliation(s)
- Renata L. de Oliveira
- grid.411221.50000 0001 2134 6519Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica (LaFarBio), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Pelotas, RS CEP 96010-900 Brazil
| | - Guilherme T. Voss
- grid.411221.50000 0001 2134 6519Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica (LaFarBio), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Pelotas, RS CEP 96010-900 Brazil
| | - Karline da C. Rodrigues
- grid.411221.50000 0001 2134 6519Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica (LaFarBio), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Pelotas, RS CEP 96010-900 Brazil
| | - Mikaela P. Pinz
- grid.411221.50000 0001 2134 6519Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica (LaFarBio), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Pelotas, RS CEP 96010-900 Brazil
| | - Julia V. Biondi
- grid.411221.50000 0001 2134 6519Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica (LaFarBio), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Pelotas, RS CEP 96010-900 Brazil
| | - Nicole P. Becker
- grid.411221.50000 0001 2134 6519Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica (LaFarBio), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Pelotas, RS CEP 96010-900 Brazil
| | - Eduardo Blodorn
- grid.411221.50000 0001 2134 6519Laboratório de Genômica Estrutural, Programa de Pós-Graduação Em Biotecnologia, Universidade Federal de Pelotas, Pelotas, RS Brazil
| | - William B. Domingues
- grid.411221.50000 0001 2134 6519Laboratório de Genômica Estrutural, Programa de Pós-Graduação Em Biotecnologia, Universidade Federal de Pelotas, Pelotas, RS Brazil
| | - Allya Larroza
- grid.411221.50000 0001 2134 6519Laboratório de Síntese Orgânica Limpa (LaSOL), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Programa de Pós-Graduação Em Química, Universidade Federal de Pelotas, Pelotas, RS Brazil
| | - Vinícius F. Campos
- grid.411221.50000 0001 2134 6519Laboratório de Genômica Estrutural, Programa de Pós-Graduação Em Biotecnologia, Universidade Federal de Pelotas, Pelotas, RS Brazil
| | - Diego Alves
- grid.411221.50000 0001 2134 6519Laboratório de Síntese Orgânica Limpa (LaSOL), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Programa de Pós-Graduação Em Química, Universidade Federal de Pelotas, Pelotas, RS Brazil
| | - Ethel A. Wilhelm
- grid.411221.50000 0001 2134 6519Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica (LaFarBio), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Pelotas, RS CEP 96010-900 Brazil
| | - Cristiane Luchese
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica (LaFarBio), Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Pelotas, RS, CEP 96010-900, Brazil.
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Shi Y, Chen M, Zhao Z, Pan J, Huang S. Network Pharmacology and Molecular Docking Analyses of Mechanisms Underlying Effects of the Cyperi Rhizoma- Chuanxiong Rhizoma Herb Pair on Depression. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:5704578. [PMID: 34976096 PMCID: PMC8716227 DOI: 10.1155/2021/5704578] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 12/27/2022]
Abstract
OBJECTIVE We aimed to investigate the mechanisms underlying the effects of the Cyperi Rhizoma-Chuanxiong Rhizoma herb pair (CCHP) against depression using a network pharmacology approach. METHODS A network pharmacology approach, including screening of active compounds, target prediction, construction of a protein-protein interaction (PPI) network, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA), were used to explore the mechanisms of CCHP against depression. RESULTS Twenty-six active compounds and 315 and 207 targets of CCHP and depression, respectively, were identified. The PPI network suggested that AKT1, IL-6, TP53, DRD2, MAPK1, NR3C1, TNF, etc., were core targets. GO enrichment analyses showed that positive regulation of transcription from RNA polymerase II promoter, plasma membrane, and protein binding were of great significance. Neuroactive ligand-receptor interaction, PI3K-Akt signaling pathway, dopaminergic synapse, and mTOR signaling pathway were important pathways. Molecular docking results revealed good binding affinities for the core compounds and core targets. MD simulations and MMPBSA validated that quercetin can stably bind to 6hhi. CONCLUSIONS The effects of CCHP against depression involve multiple components, targets, and pathways, and these findings will promote further research on and clinical application of CCHP.
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Affiliation(s)
- Yanan Shi
- Research and Development Center of Traditional Chinese Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Mingqi Chen
- Research and Development Center of Traditional Chinese Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zehua Zhao
- Research and Development Center of Traditional Chinese Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Juhua Pan
- Research and Development Center of Traditional Chinese Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Shijing Huang
- Research and Development Center of Traditional Chinese Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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Ren H, Han R, Liu X, Wang L, Koehler RC, Wang J. Nrf2-BDNF-TrkB pathway contributes to cortical hemorrhage-induced depression, but not sex differences. J Cereb Blood Flow Metab 2021; 41:3288-3301. [PMID: 34238051 PMCID: PMC8669278 DOI: 10.1177/0271678x211029060] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Post-stroke depression, observed in 30-50% of stroke patients, negatively affects quality of life and mortality. The pathogenesis of post-stroke depression is complex, but heightened reactive oxygen species production and inflammation might be two key factors. We have reported that intracerebral hemorrhage (ICH) in cerebral cortex produces depression-like behavior in young male mice. Here, we found that mice lacking nuclear factor erythroid-derived 2-related factor 2 (Nrf2), a transcription factor that upregulates antioxidant proteins and trophic factors such as brain-derived neurotrophic factor (BDNF), had more severe depression-like behavior than wild-type mice at days 21 to 28 after cortical ICH (c-ICH). Moreover, the expression of Nrf2, heme oxygenase-1, BDNF, and TrkB were significantly decreased in wild-type mice after c-ICH. Interestingly, TP-500 (2 mg/kg), a potent Nrf2 inducer, decreased the inflammatory response and reactive oxygen species production on day 28 after c-ICH and improved depression-like behaviors. TrkB receptor antagonist ANA-12 abolished this anti-depression effect. Depression was more severe in female than in male wild-type mice after ICH, but TP-500 improved depression-like behavior in females. These results suggest that downregulation of Nrf2-BDNF-TrkB signaling contributes to development of post-stroke depression, and that Nrf2 inducer TP-500 might improve depression after c-ICH.
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Affiliation(s)
- Honglei Ren
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA
| | - Ranran Han
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA
| | - Xi Liu
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA
| | - Limin Wang
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA
| | - Raymond C Koehler
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA
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Lin R, Liu L, Silva M, Fang J, Zhou Z, Wang H, Xu J, Li T, Zheng W. Hederagenin Protects PC12 Cells Against Corticosterone-Induced Injury by the Activation of the PI3K/AKT Pathway. Front Pharmacol 2021; 12:712876. [PMID: 34721013 PMCID: PMC8551867 DOI: 10.3389/fphar.2021.712876] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 09/28/2021] [Indexed: 12/27/2022] Open
Abstract
Depression is a prevalent psychiatric disorder and a leading cause of disability worldwide. Despite a variety of available treatments currently being used in the clinic, a substantial proportion of patients is unresponsive to these treatments, urging the development of more effective therapeutic approaches. Hederagenin (Hed), a triterpenoid saponin extracted from Fructus Akebiae, has several biological activities including anti-apoptosis, anti-hyperlipidemic and anti-inflammatory properties. Over the years, its potential therapeutic effect in depression has also been proposed, but the information is limited and the mechanisms underlying its antidepressant-like effects are unclear. The present study explored the neuroprotective effects and the potential molecular mechanisms of Hederagenin action in corticosterone (CORT)-injured PC12 cells. Obtained results show that Hederagenin protected PC12 cells against CORT-induced damage in a concentration dependent manner. In adittion, Hederagenin prevented the decline of mitochondrial membrane potential, reduced the production of intracellular reactive oxygen species (ROS) and decreased the apoptosis induced by CORT. The protective effect of Hederagenin was reversed by a specific phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and AKT (also known as protein kinase B) inhibitor MK2206, suggesting that the effect of Hederagenin is mediated by the PI3K/AKT pathway. In line with this, western blot analysis results showed that Hederagenin stimulated the phosphorylation of AKT and its downstream target Forkhead box class O 3a (FoxO3a) and Glycogen synthase kinase-3-beta (GSK3β) in a concentration dependent manner. Taken together, these results indicate that the neuroprotective effect of Hederagenin is likely to occur via stimulation of the PI3K/AKT pathway.
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Affiliation(s)
- Ruohong Lin
- Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao, China
| | - Linlin Liu
- Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao, China
| | - Marta Silva
- Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao, China
| | - Jiankang Fang
- Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao, China
| | - Zhiwei Zhou
- Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao, China
| | - Haitao Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Jiangping Xu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Tiejun Li
- Research and Development Department, Lansson Bio-Pharm Co., Ltd., Guangzhou, China
| | - Wenhua Zheng
- Center of Reproduction, Development and Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macao, China
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Zou XS, Yin HL, Shi L, Li HP, Wang MH, Song WC, Luo Y, Chen WL, Wu HZ, Yang YF, Zan JF, Liu YW, Dan HX, Yin Q, You PT. Treatment with Gaoziban Tablet Ameliorates Depression by Promoting GSK-3β Phosphorylation to Enhance the Wnt/β-catenin Activation in the Hippocampus of Rats. JOURNAL OF EXPLORATORY RESEARCH IN PHARMACOLOGY 2021; 000:000-000. [DOI: 10.14218/jerp.2021.00016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Yuan C, Yao Y, Liu T, Jin Y, Yang C, Loh XJ, Li Z. Research Progress on Natural Compounds Exerting an Antidepressant Effect through Anti-inflammatory. Curr Med Chem 2021; 29:934-956. [PMID: 34420503 DOI: 10.2174/0929867328666210820115259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/18/2021] [Accepted: 06/25/2021] [Indexed: 11/22/2022]
Abstract
Depression is a common mental illness that belongs to the category of emotional disorders that causes serious damage to the health and life of patients, while inflammation is considered to be one of the important factors that causes depression. In this case, it might be important to explore the possible therapeutic approach by using natural compounds exerting an anti-inflammatory and antidepressant effect, which it filed has not been systematically reviewed recently. Hence, this review aims to systematically sort the literature related to the mechanism of exerting an antidepressant effect through anti-inflammatory actions, and to summarize the related natural products in the past 20 years, in terms of a number of inflammatory related pathways (i.e., the protein kinase B (Akt) pathway, monoamine neurotransmitters (5-hydroxytryptamine and norepinephrine) (5-HT and NE), the nod-like receptor protein-3 (NLRP3) inflammasome, proinflammatory cytokines, neurotrophins, or cytokine-signaling pathways), which might provide a useful reference for the potential treatment of depression.
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Affiliation(s)
- Caixia Yuan
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102. China
| | - Yucen Yao
- College Pharmacy, Jiamusi University, 258 Xuefu Street, Jiamusi, Heilongjiang, 154007. China
| | - Tao Liu
- College Pharmacy, Harbin University of commerce, 1Xuehai Street, Harbin, Heilongjiang, 150028. China
| | - Ying Jin
- Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003. China
| | - Chunrong Yang
- College Pharmacy, Jiamusi University, 258 Xuefu Street, Jiamusi, Heilongjiang, 154007, China. China
| | - Xian Jun Loh
- Institute of Materials Research and Engineering, A*STAR (Agency for Science, Technology and Research), 2 Fusionopolis Way, Innovis, #08-03, Singapore 138634. Singapore
| | - Zibiao Li
- Institute of Materials Research and Engineering, A*STAR (Agency for Science, Technology and Research), 2 Fusionopolis Way, Innovis, #08-03, Singapore 138634. Singapore
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Zeng P, Wang XM, Ye CY, Su HF, Fang YY, Zhang T, Tian Q. Mechanistic insights into the anti-depressant effect of emodin: an integrated systems pharmacology study and experimental validation. Aging (Albany NY) 2021; 13:15078-15099. [PMID: 34051074 PMCID: PMC8221295 DOI: 10.18632/aging.203072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 05/11/2021] [Indexed: 11/25/2022]
Abstract
Depression is a complex neuropsychiatric disease involved multiple targets and signaling pathways. Systems pharmacology studies could potentially present a comprehensive molecular mechanism to delineate the anti-depressant effect of emodin (EMO). In this study, we investigated the anti-depressant effects of EMO in the chronic unpredictable mild stress (CUMS) rat model of depression and gained insights into the underlying mechanisms using systems pharmacology and molecular simulation analysis. Forty-three potential targets of EMO for treatment of depression were obtained. GO biological process analysis suggested that the biological functions of these targets mainly involve the regulation of reactive oxygen species metabolic process, response to lipopolysaccharide, regulation of inflammatory response, etc. KEGG pathway enrichment analysis showed that the PI3K-Akt signaling pathway, insulin resistance, IL-17 signaling pathway were the most significantly enriched signaling pathways. The molecular docking analysis revealed that EMO might have a strong combination with ESR1, AKT1 and GSK3B. Immunohistochemical staining and Western blotting showed that 2 weeks' EMO treatment (80 mg/kg/day) reduced depression related microglial activation, neuroinflammation and altered PI3K-Akt signaling pathway. Our findings provide a systemic pharmacology basis for the anti-depressant effects of EMO.
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Affiliation(s)
- Peng Zeng
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiao-Ming Wang
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chao-Yuan Ye
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hong-Fei Su
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ying-Yan Fang
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi 435000, China
| | - Teng Zhang
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan 430030, China
- Department of Neurology, Shanxian Central Hospital, The Affiliated Huxi Hospital of Jining Medical College, Heze 274300, China
| | - Qing Tian
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan 430030, China
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Levenga J, Wong H, Milstead R, LaPlante L, Hoeffer CA. Immunohistological Examination of AKT Isoforms in the Brain: Cell-Type Specificity That May Underlie AKT's Role in Complex Brain Disorders and Neurological Disease. Cereb Cortex Commun 2021; 2:tgab036. [PMID: 34296180 PMCID: PMC8223503 DOI: 10.1093/texcom/tgab036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/18/2021] [Accepted: 05/19/2021] [Indexed: 12/16/2022] Open
Abstract
Protein kinase B (PKB/AKT) is a central kinase involved in many neurobiological processes. AKT is expressed in the brain as three isoforms, AKT1, AKT2, and AKT3. Previous studies suggest isoform-specific roles in neural function, but very few studies have examined AKT isoform expression at the cellular level. In this study, we use a combination of histology, immunostaining, and genetics to characterize cell-type-specific expression of AKT isoforms in human and mouse brains. In mice, we find that AKT1 is the most broadly expressed isoform, with expression in excitatory neurons and the sole detectable AKT isoform in gamma-aminobutyric acid ergic interneurons and microglia. By contrast, we find that AKT2 is the sole isoform expressed in astroglia and is not detected in other neural cell types. We find that AKT3 is expressed in excitatory neurons with AKT1 but shows greater expression levels in dendritic compartments than AKT1. We extend our analysis to human brain tissues and find similar results. Using genetic deletion approaches, we also find that the cellular determinants restricting AKT isoform expression to specific cell types remain intact under Akt deficiency conditions. Because AKT signaling is linked to numerous neurological disorders, a greater understanding of cell-specific isoform expression could improve treatment strategies involving AKT.
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Affiliation(s)
- Josien Levenga
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Helen Wong
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Ryan Milstead
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO 80303, USA.,Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Lauren LaPlante
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO 80303, USA
| | - Charles A Hoeffer
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO 80303, USA.,Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80303, USA.,Linda Crnic Institute, Anschutz Medical Campus, Aurora, CO 80045, USA
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Mizuki Y, Sakamoto S, Okahisa Y, Yada Y, Hashimoto N, Takaki M, Yamada N. Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus. Int J Neuropsychopharmacol 2021; 24:367-382. [PMID: 33315097 PMCID: PMC8130204 DOI: 10.1093/ijnp/pyaa097] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 11/29/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
The mortality rate of patients with schizophrenia is high, and life expectancy is shorter by 10 to 20 years. Metabolic abnormalities including type 2 diabetes mellitus (T2DM) are among the main reasons. The prevalence of T2DM in patients with schizophrenia may be epidemiologically frequent because antipsychotics induce weight gain as a side effect and the cognitive dysfunction of patients with schizophrenia relates to a disordered lifestyle, poor diet, and low socioeconomic status. Apart from these common risk factors and risk factors unique to schizophrenia, accumulating evidence suggests the existence of common susceptibility genes between schizophrenia and T2DM. Functional proteins translated from common genetic susceptibility genes are known to regulate neuronal development in the brain and insulin in the pancreas through several common cascades. In this review, we discuss common susceptibility genes, functional cascades, and the relationship between schizophrenia and T2DM. Many genetic and epidemiological studies have reliably associated the comorbidity of schizophrenia and T2DM, and it is probably safe to think that common cascades and mechanisms suspected from common genes' functions are related to the onset of both schizophrenia and T2DM. On the other hand, even when genetic analyses are performed on a relatively large number of comorbid patients, the results are sometimes inconsistent, and susceptibility genes may carry only a low or moderate risk. We anticipate future directions in this field.
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Affiliation(s)
- Yutaka Mizuki
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
- Shimonoseki Hospital
| | - Shinji Sakamoto
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
| | - Yuko Okahisa
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
| | - Yuji Yada
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
- Okayama Psychiatric Medical Center
| | - Nozomu Hashimoto
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
- Okayama Psychiatric Medical Center
| | - Manabu Takaki
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
| | - Norihito Yamada
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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Mao Y, Xing Y, Li J, Dong D, Zhang S, Zhao Z, Xie J, Wang R, Li H. Guanosine ameliorates positive symptoms of schizophrenia via modulating 5-HT 1A and 5-HT 2A receptors. Am J Transl Res 2021; 13:4040-4054. [PMID: 34149997 PMCID: PMC8205766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/28/2021] [Indexed: 06/12/2023]
Abstract
Schizophrenia is a serious mental disorder characterized by hallucinations, delusions, and extremely disordered thinking and behavior. There are several hypotheses of pathogenesis in schizophrenia: dopaminergic, glutamatergic, or serotonergic hyperfunction. Guanosine reportedly protects the central nervous system by modulating the glutamatergic system. Thus, we assumed that guanosine may exert a positive effect on the pathophysiology of schizophrenia. Herein, we demonstrated that guanosine significantly reduced MK-801-induced hyperlocomotion and stereotyped behaviors, but showed no effect on hyperlocomotion induced by d-amphetamine, indicating that guanosine may directly affect the glutamatergic system. Guanosine dose-dependently reduced 5-HTP-induced wet dog shakes (WDS) and other serotonin syndromes (SS) behaviors, indicating that it might block serotonin 5-HT1A or 5-HT2A receptors. Finally, we confirm that that guanosine modulates serotonin 5-HT1A and 5-HT2A receptors and it might be anti-schizophrenic partly through pertussis toxin-sensitive Gi/o-coupled PI3K/Akt signaling. Collectively, this study provides possible compounds and mechanisms for therapeutic effects on schizophrenia.
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Affiliation(s)
- Yu Mao
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & TechnologyShanghai 200237, China
| | - Yao Xing
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & TechnologyShanghai 200237, China
| | - Jie Li
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & TechnologyShanghai 200237, China
| | - Dong Dong
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & TechnologyShanghai 200237, China
| | - Shoude Zhang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & TechnologyShanghai 200237, China
- State Key Laboratory of Plateau Ecology and Agriculture, Department of Pharmacy, Medical College of Qinghai University, Qinghai UniversityQinghai 810016, China
| | - Zhenjiang Zhao
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & TechnologyShanghai 200237, China
| | - Jingli Xie
- State Key Laboratory of Bioreactor Engineering, College of Bioengineering, East China University of Science & TechnologyShanghai 200237, China
| | - Rui Wang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & TechnologyShanghai 200237, China
| | - Honglin Li
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & TechnologyShanghai 200237, China
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Na + leak-current channel (NALCN) at the junction of motor and neuropsychiatric symptoms in Parkinson's disease. J Neural Transm (Vienna) 2021; 128:749-762. [PMID: 33961117 DOI: 10.1007/s00702-021-02348-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/30/2021] [Indexed: 12/27/2022]
Abstract
Parkinson's disease (PD) is a debilitating movement disorder often accompanied by neuropsychiatric symptoms that stem from the loss of dopaminergic function in the basal ganglia and altered neurotransmission more generally. Akinesia, postural instability, tremors and frozen gait constitute the major motor disturbances, whereas neuropsychiatric symptoms include altered circadian rhythms, disordered sleep, depression, psychosis and cognitive impairment. Evidence is emerging that the motor and neuropsychiatric symptoms may share etiologic factors. Calcium/ion channels (CACNA1C, NALCN), synaptic proteins (SYNJ1) and neuronal RNA-binding proteins (RBFOX1) are among the risk genes that are common to PD and various psychiatric disorders. The Na+ leak-current channel (NALCN) is the focus of this review because it has been implicated in dystonia, regulation of movement, cognitive impairment, sleep and circadian rhythms. It regulates the resting membrane potential in neurons, mediates pace-making activity, participates in synaptic vesicle recycling and is functionally co-localized to the endoplasmic reticulum (ER)-several of the major processes adversely affected in PD. Here, we summarize the literature on mechanisms and pathways that connect the motor and neuropsychiatric symptoms of PD with a focus on recurring relationships to the NALCN. It is hoped that the various connections outlined here will stimulate further discussion, suggest additional areas for exploration and ultimately inspire novel treatment strategies.
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Khayachi A, Schorova L, Alda M, Rouleau GA, Milnerwood AJ. Posttranslational modifications & lithium's therapeutic effect-Potential biomarkers for clinical responses in psychiatric & neurodegenerative disorders. Neurosci Biobehav Rev 2021; 127:424-445. [PMID: 33971223 DOI: 10.1016/j.neubiorev.2021.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/14/2021] [Accepted: 05/03/2021] [Indexed: 01/03/2023]
Abstract
Several neurodegenerative diseases and neuropsychiatric disorders display aberrant posttranslational modifications (PTMs) of one, or many, proteins. Lithium treatment has been used for mood stabilization for many decades, and is highly effective for large subsets of patients with diverse neurological conditions. However, the differential effectiveness and mode of action are not fully understood. In recent years, studies have shown that lithium alters several protein PTMs, altering their function, and consequently neuronal physiology. The impetus for this review is to outline the links between lithium's therapeutic mode of action and PTM homeostasis. We first provide an overview of the principal PTMs affected by lithium. We then describe several neuropsychiatric disorders in which PTMs have been implicated as pathogenic. For each of these conditions, we discuss lithium's clinical use and explore the putative mechanism of how it restores PTM homeostasis, and thereby cellular physiology. Evidence suggests that determining specific PTM patterns could be a promising strategy to develop biomarkers for disease and lithium responsiveness.
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Affiliation(s)
- A Khayachi
- Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.
| | - L Schorova
- McGill University Health Center Research Institute, Montréal, Quebec, Canada
| | - M Alda
- Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
| | - G A Rouleau
- Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
| | - A J Milnerwood
- Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.
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Heinrich IA, Freitas AE, Wolin IAV, Nascimento APM, Walz R, Rodrigues ALS, Leal RB. Neuronal activity regulated pentraxin (narp) and GluA4 subunit of AMPA receptor may be targets for fluoxetine modulation. Metab Brain Dis 2021; 36:711-722. [PMID: 33528752 DOI: 10.1007/s11011-021-00675-x] [Citation(s) in RCA: 4] [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: 11/21/2020] [Accepted: 01/22/2021] [Indexed: 12/28/2022]
Abstract
Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.
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Affiliation(s)
- Isabella A Heinrich
- Graduate Program in Neuroscience, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
| | - Andiara E Freitas
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
- Graduate Program in Biochemistry, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
| | - Ingrid A V Wolin
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
- Graduate Program in Biochemistry, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
| | - Ana Paula M Nascimento
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
- Graduate Program in Biochemistry, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
| | - Roger Walz
- Graduate Program in Neuroscience, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
- Department of Clinical Medicine, Center of Health Sciences, University Hospital, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
- Center of Applied Neuroscience (CeNAp), University Hospital, Federal University of Santa Catarina, Florianópolis, 88040-900, SC, Brazil
| | - Ana Lúcia S Rodrigues
- Graduate Program in Neuroscience, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
- Graduate Program in Biochemistry, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil
| | - Rodrigo B Leal
- Graduate Program in Neuroscience, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil.
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil.
- Graduate Program in Biochemistry, Federal University of Santa Catarina, Campus Universitário, Trindade, Florianópolis, 88040-900, SC, Brazil.
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Zheng Z, Shi X, Xiang Y, Zhang A, Fang Y. Involvement of 5-Hydroxytryptamine Receptor 2A in the Pathophysiology of Medication-Overuse Headache. J Pain Res 2021; 14:453-461. [PMID: 33623427 PMCID: PMC7896776 DOI: 10.2147/jpr.s283734] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 12/19/2020] [Indexed: 11/23/2022] Open
Abstract
Background Recent studies indicated that analgesic overuse upregulated 5-hydroxytryptamine receptor 2A (5-HT2AR) and subsequently activated nitric oxide synthase (NOS) and thus induced latent sensitization, which provided a mechanistic basis for medication-overuse headache (MOH). Moreover, glycogen synthase kinase-3β (GSK-3β) was regulated by serotonin receptors and the phosphorylation of GSK-3β affected NOS activity, indicating that GSK-3β could be involved in the regulation of NOS activity by 5-HT2AR in MOH pathophysiology. Herein, we performed this study to investigate the role of 5-HT2AR in MOH pathophysiology and the role of GSK-3β in the regulation of NOS activity by 5-HT2AR. Materials and Methods Wistar rats were daily administered with paracetamol (200 mg/kg) for 30 days to set animal models for pre-clinical MOH research. After the rat MOH models were successfully established, the expression of 5-HT2AR and NOS, GSK-3β activity in trigeminal nucleus caudalis (TNC) were assayed. Then, 5-HT2AR antagonist ketanserin and agonist DOI were applied to investigate the effect of 5-HT2AR on NOS activity in TNC of MOH rats, and GSK-3β antagonist LiCl and agonist perifosine were applied to explore the role of GSK-3β in the activation of NOS by 5-HT2AR. Results We found that the expression of 5-HT2AR and NOS, GSK-3β activity were enhanced in TNC of MOH rats. 5-HT2AR modulator regulated the activity of NOS and GSK-3β in TNC of MOH rats, and drugs acting on GSK-3β affected NOS activity. Conclusion These data suggest that GSK-3β may mediate the activation of NOS by 5-HT2AR and underline the role of 5-HT2AR in MOH pathophysiology.
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Affiliation(s)
- Zhenyang Zheng
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, People's Republic of China
| | - Xiaolei Shi
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Yue Xiang
- Department of Nursing, Fujian Health College, Fuzhou, 350101, People's Republic of China
| | - Aiwu Zhang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Yannan Fang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
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48
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Park D, Mabunga DFN, Adil KJ, Ryu O, Valencia S, Kim R, Kim HJ, Cheong JH, Kwon KJ, Kim HY, Han SH, Jeon SJ, Shin CY. Synergistic efficacy and diminished adverse effect profile of composite treatment of several ADHD medications. Neuropharmacology 2021; 187:108494. [PMID: 33587920 DOI: 10.1016/j.neuropharm.2021.108494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 01/05/2021] [Accepted: 02/07/2021] [Indexed: 11/26/2022]
Abstract
Although attention-deficit/hyperactivity disorder (ADHD) is widely studied, problems regarding the adverse effect risks and non-responder problems still need to be addressed. Combination pharmacotherapy using standard dose regimens of existing medication is currently being practiced mainly to augment the therapeutic efficacy of each drug. The idea of combining different pharmacotherapies with different molecular targets to alleviate the symptoms of ADHD and its comorbidities requires scientific evidence, necessitating the investigation of their therapeutic efficacy and the mechanisms underlying the professed synergistic effects. Here, we injected male ICR mice with MK-801 to induce ADHD behavioral condition. We then modeled a "combined drug" using sub-optimal doses of methylphenidate, atomoxetine, and fluoxetine and investigated the combined treatment effects in MK-801-treated mice. No sub-optimal dose monotherapy alleviated ADHD behavioral condition in MK-801-treated mice. However, treatment with the combined drug attenuated the impaired behavior of MK-801-treated animals. Growth impediment, sleep disturbances, or risk of substance abuse were not observed in mice treated subchronically with the combined drugs. Finally, we observed that the combined ADHD drug rescued alterations in p-AKT and p-ERK1/2 levels in the prefrontal cortex and hippocampus, respectively, of MK-801-treated mice. Our results provide experimental evidence of a possible new pharmacotherapy option in ameliorating the ADHD behavioral condition without the expected adverse effects. The detailed mechanism of action underlying the synergistic therapeutic efficacy and reduced adverse reaction by combinatorial drug treatment should be investigated further in future studies.
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Affiliation(s)
- Donghyun Park
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea
| | - Darine Froy N Mabunga
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea
| | - Keremkleroo Jym Adil
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea
| | - Onjeon Ryu
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea
| | - Schley Valencia
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea
| | - Ryeongeun Kim
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea
| | - Hee Jin Kim
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarangro, Nowon-gu, Seoul, 01795, Republic of Korea
| | - Jae Hoon Cheong
- Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarangro, Nowon-gu, Seoul, 01795, Republic of Korea
| | - Kyung Ja Kwon
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea
| | - Hahn Young Kim
- Department of Neurology, Konkuk University Medical Center, Center for Geriatric Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Seoul, 05029, Republic of Korea
| | - Seol-Heui Han
- Department of Neurology, Konkuk University Medical Center, Center for Geriatric Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University School of Medicine, Seoul, 05029, Republic of Korea
| | - Se Jin Jeon
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea; TriNeuro Inc., 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
| | - Chan Young Shin
- School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul, 05029, Republic of Korea; TriNeuro Inc., 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
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49
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Palumbo S, Paterson C, Yang F, Hood VL, Law AJ. PKBβ/AKT2 deficiency impacts brain mTOR signaling, prefrontal cortical physiology, hippocampal plasticity and select murine behaviors. Mol Psychiatry 2021; 26:411-428. [PMID: 33328589 PMCID: PMC7854513 DOI: 10.1038/s41380-020-00964-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/31/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022]
Abstract
The serine/threonine protein kinase v-AKT homologs (AKTs), are implicated in typical and atypical neurodevelopment. Akt isoforms Akt1, Akt2, and Akt3 have been extensively studied outside the brain where their actions have been found to be complementary, non-overlapping and often divergent. While the neurological functions of Akt1 and Akt3 isoforms have been investigated, the role for Akt2 remains underinvestigated. Neurobehavioral, electrophysiological, morphological and biochemical assessment of Akt2 heterozygous and knockout genetic deletion in mouse, reveals a novel role for Akt2 in axonal development, dendritic patterning and cell-intrinsic and neural circuit physiology of the hippocampus and prefrontal cortex. Akt2 loss-of-function increased anxiety-like phenotypes, impaired fear conditioned learning, social behaviors and discrimination memory. Reduced sensitivity to amphetamine was observed, supporting a role for Akt2 in regulating dopaminergic tone. Biochemical analyses revealed dysregulated brain mTOR and GSK3β signaling, consistent with observed learning and memory impairments. Rescue of cognitive impairments was achieved through pharmacological enhancement of PI3K/AKT signaling and PIK3CD inhibition. Together these data highlight a novel role for Akt2 in neurodevelopment, learning and memory and show that Akt2 is a critical and non-redundant regulator of mTOR activity in brain.
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Affiliation(s)
- Sara Palumbo
- Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health Intramural Program, Bethesda MD 20892.,Department of Surgical, Medical and Molecular Pathology and Critical Care, University of Pisa, Pisa, Italy (current)
| | - Clare Paterson
- Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health Intramural Program, Bethesda MD 20892.,Department of Psychiatry, University of Colorado, School of Medicine. Aurora, CO 80045
| | - Feng Yang
- Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health Intramural Program, Bethesda MD 20892.,Division of Neurodegenerative Diseases and Translational Sciences Tiantan Hospital & Advanced Innovation Center for Human Brain Protection. Capital Medical University, Beijing, China (current)
| | - Veronica L. Hood
- Department of Psychiatry, University of Colorado, School of Medicine. Aurora, CO 80045
| | - Amanda J. Law
- Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health Intramural Program, Bethesda MD 20892.,Department of Psychiatry, University of Colorado, School of Medicine. Aurora, CO 80045.,To whom correspondence should be addressed:
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50
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Hwang J, Youn K, Lim G, Lee J, Kim DH, Jun M. Discovery of Natural Inhibitors of Cholinesterases from Hydrangea: In Vitro and In Silico Approaches. Nutrients 2021; 13:nu13010254. [PMID: 33477276 PMCID: PMC7830924 DOI: 10.3390/nu13010254] [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: 11/27/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/18/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease conceptualized as a clinical-biological neurodegenerative construct where amyloid-beta pathophysiology is supposed to play a role. The loss of cognitive functions is mostly characterized by the rapid hydrolysis of acetylcholine by cholinesterases including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, both enzymes are responsible for non-catalytic actions such as interacting with amyloid β peptide (Aβ) which further leads to promote senile plaque formation. In searching for a natural cholinesterase inhibitor, the present study focused on two isocoumarines from hydrangea, thunberginol C (TC) and hydrangenol 8-O-glucoside pentaacetate (HGP). Hydrangea-derived compounds were demonstrated to act as dual inhibitors of both AChE and BChE. Furthermore, the compounds exerted selective and non-competitive mode of inhibition via hydrophobic interaction with peripheral anionic site (PAS) of the enzymes. Overall results demonstrated that these natural hydrangea-derived compounds acted as selective dual inhibitors of AChE and BChE, which provides the possibility of potential source of new type of anti-cholinesterases with non-competitive binding property with PAS.
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Affiliation(s)
- Jayeong Hwang
- Department of Food Science and Nutrition, Dong-A University, Busan 49315, Korea; (J.H.); (K.Y.)
| | - Kumju Youn
- Department of Food Science and Nutrition, Dong-A University, Busan 49315, Korea; (J.H.); (K.Y.)
| | - Gyutae Lim
- Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (G.L.); (J.L.)
- Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Sciences and Technology, Daejeon 34113, Korea
| | - Jinhyuk Lee
- Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; (G.L.); (J.L.)
- Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Sciences and Technology, Daejeon 34113, Korea
| | - Dong Hyun Kim
- Department of Medicinal Biotechnology, Dong-A University, Busan 49315, Korea;
- Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Korea
| | - Mira Jun
- Department of Food Science and Nutrition, Dong-A University, Busan 49315, Korea; (J.H.); (K.Y.)
- Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Korea
- Correspondence: ; Tel.: +82-51-200-7323; Fax: +82-51-200-7535
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