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Deng F, Yang D, Qing L, Chen Y, Zou J, Jia M, Wang Q, Jiang R, Huang L. Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway: a potential therapeutic approach for neurodegenerative diseases. Neural Regen Res 2025; 20:3095-3112. [PMID: 39589173 PMCID: PMC11881707 DOI: 10.4103/nrr.nrr-d-24-00607] [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: 06/01/2024] [Revised: 08/07/2024] [Accepted: 09/10/2024] [Indexed: 11/27/2024] Open
Abstract
The interaction between the gut microbiota and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut-brain axis. The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites, which activates the vagus nerve and modulates the immune and neuroendocrine systems. Conversely, alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota, creating a dynamic network of microbial-host interactions. This reciprocal regulation affects neurodevelopment, neurotransmitter control, and behavioral traits, thus playing a role in the modulation of neurological diseases. The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation, mitochondrial dysfunction, abnormal energy metabolism, microglial activation, oxidative stress, and neurotransmitter release, which collectively influence the onset and progression of neurological diseases. This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway, along with its implications for potential therapeutic interventions in neurological diseases. Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders. This can be achieved through various methods such as dietary modifications, probiotic supplements, Chinese herbal extracts, combinations of Chinese herbs, and innovative dosage forms. These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.
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Affiliation(s)
- Fengcheng Deng
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Dan Yang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Lingxi Qing
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Yifei Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Jilian Zou
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Meiling Jia
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Qian Wang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Runda Jiang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Lihua Huang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
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Lv W, Zhang X, Zhang H, Alitanhua, Xiao Y. Safety of Nutmeg powder by oral exposure: Toxicity prediction and in vivo evaluation. Food Chem Toxicol 2025; 200:115364. [PMID: 40024564 DOI: 10.1016/j.fct.2025.115364] [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: 12/18/2024] [Revised: 02/19/2025] [Accepted: 02/28/2025] [Indexed: 03/04/2025]
Abstract
Nutmeg (Myristica fragrans Houtt.) is widely cultivated in tropical regions and valued for its culinary and medicinal uses. However, its safety profile remains underexplored. This study aimed to evaluate the safety of nutmeg powder through in-silico toxicity predictions, acute oral toxicity, and a 13-week repeated-dose toxicity assessment. In the in-silico study, bioactive compounds identified via High-Performance Liquid Chromatography (HPLC) were analyzed for toxicity parameters using the ProTox II server. For acute toxicity, a single dose of nutmeg powder was administered to mice, with no mortality observed over 14 days, and an LD50 greater than 5000 mg/kg body weight was determined. In the sub-chronic toxicity study, rats received nutmeg powder at 1400 mg/kg and 3500 mg/kg (35 and 87.5 times the human therapeutic dosage, respectively) for 90 days. A 28-day recovery phase was included to assess delayed or reversible effects. The results indicate that a dose of 1400 mg/kg leads to liver damage and hemosiderin deposition in the spleen, while a dose of 3500 mg/kg causes liver and kidney damage, as well as hemosiderin deposition in the spleen. These findings highlight the potential toxicity of long-term nutmeg consumption and underscore the need for further research to ensure its safety in preclinical.
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Affiliation(s)
- Wei Lv
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010110, China
| | - Xin Zhang
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010110, China
| | - Hongli Zhang
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010110, China
| | - Alitanhua
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010110, China
| | - Yunfeng Xiao
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010110, China; Key Laboratory of Drug Safety Evaluation, Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010110, China.
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Gupta AK, Gupta S, Mehan S, Khan Z, Das Gupta G, Narula AS. Exploring the Connection Between BDNF/TrkB and AC/cAMP/PKA/CREB Signaling Pathways: Potential for Neuroprotection and Therapeutic Targets for Neurological Disorders. Mol Neurobiol 2025:10.1007/s12035-025-05001-5. [PMID: 40342191 DOI: 10.1007/s12035-025-05001-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 04/24/2025] [Indexed: 05/11/2025]
Abstract
The BDNF/TrkB and AC/cAMP/PKA/CREB signaling pathways play a vital role in neuroplasticity, neuronal survival, and cognitive functions. This review explores its physiological and pathological implications in neurological disorders, with a focus on neurodegenerative diseases (NDDs) and neuropsychiatric disorders (NPDs). Neurological conditions increasingly burden public health, making understanding the biochemical mechanisms that underpin these diseases critical. BDNF, a neurotrophic factor, binds to the TrkB receptor, activating multiple intracellular signaling cascades that regulate cellular responses essential for neurogenesis, memory, and learning. Dysregulation within this pathway has been linked to various NDDs, as well as NPDs. Key components of the path, including adenylyl cyclase and cyclic AMP, mediate the effects of neurotransmitters and growth factors, influencing downstream targets like PKA and CREB, which are crucial for gene expression and synaptic changes. Furthermore, the review discusses the challenges of targeting this pathway for therapeutic interventions, including receptor isoform diversity, blood-brain barrier penetration, and potential side effects. Future strategies may include the development of selective TrkB modulators, nanoparticle carriers for drug delivery, and innovative gene therapy techniques. Advancing the understanding of this complex signaling network holds promise for effective interventions in treating neurological and psychiatric disorders, ultimately enhancing neuroprotection and cognitive resilience.
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Affiliation(s)
- Abhishek Kumar Gupta
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
| | - Sumedha Gupta
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India.
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India.
| | - Zuber Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
| | - Ghanshyam Das Gupta
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India
| | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC, 27516, USA
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Figueiredo Godoy AC, Frota FF, Araújo LP, Valenti VE, Pereira EDSBM, Detregiachi CRP, Galhardi CM, Caracio FC, Haber RSA, Fornari Laurindo L, Tanaka M, Barbalho SM. Neuroinflammation and Natural Antidepressants: Balancing Fire with Flora. Biomedicines 2025; 13:1129. [PMID: 40426956 DOI: 10.3390/biomedicines13051129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Revised: 05/02/2025] [Accepted: 05/03/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: Major depressive disorder (MDD) is a major global health concern that is intimately linked to neuroinflammation, oxidative stress, mitochondrial dysfunction, and complicated metabolic abnormalities. Traditional antidepressants frequently fall short, highlighting the urgent need for new, safer, and more acceptable therapeutic techniques. Phytochemicals, i.e., natural antidepressants derived from plants, are emerging as powerful plant-based therapies capable of targeting many pathogenic pathways at the same time. Summary: This narrative review synthesizes evidence from preclinical and clinical studies on the efficacy of phytochemicals such as curcumin, polyphenols, flavonoids, and alkaloids in lowering depressed symptoms. Consistent data show that these substances have neuroprotective, anti-inflammatory, and antioxidant properties, altering neuroimmune interactions, reducing oxidative damage, and improving mitochondrial resilience. Particularly, polyphenols and flavonoids have great therapeutic potential because of their capacity to penetrate the blood-brain barrier, inhibit cytokine activity, and encourage neuroplasticity mediated by brain-derived neurotrophic factor (BDNF). Despite promising results, the heterogeneity in study designs, phytochemical formulations, and patient demographics highlights the importance of thorough, standardized clinical studies. Conclusions: This review identifies phytochemicals as compelling adjuvant or independent therapies in depression treatment, providing multimodal mechanisms and enhanced tolerability. Additional research into improved dosage, pharmacokinetics, long-term safety, and integrative therapy approaches is essential. Using phytotherapeutics could considerably improve holistic and customized depression care, encouraging new research routes in integrative neuroscience and clinical psychiatry.
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Affiliation(s)
- Ana Clara Figueiredo Godoy
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Fernanda Fortes Frota
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Larissa Parreira Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Vitor E Valenti
- Autonomic Nervous System Center, School of Philosophy and Sciences, São Paulo State University, Marília 17525-900, SP, Brazil
| | - Eliana de Souza Bastos Mazuqueli Pereira
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Claudia Rucco P Detregiachi
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Cristiano M Galhardi
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Flávia Cristina Caracio
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília 17519-030, SP, Brazil
| | - Rafael S A Haber
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Lucas Fornari Laurindo
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Masaru Tanaka
- Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
| | - Sandra M Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Research Coordinator at UNIMAR Charity Hospital, Marília 17525-902, SP, Brazil
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A RH, Gong Q, Tuo YJ, Zhai ST, He BL, Zou EG, Wang ML, Huang TY, Zha CL, He MZ, Zhong GY, Feng YL, Li J. Syringa oblata Lindl extract alleviated corticosterone-induced depression via the cAMP/PKA-CREB-BDNF pathway. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119274. [PMID: 39756715 DOI: 10.1016/j.jep.2024.119274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/07/2024] [Accepted: 12/19/2024] [Indexed: 01/07/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Syringa oblata Lindl (ZDX) is a plant in the Oleaceae family that is the primary ingredient in the classic Tibetan medicine AKARU sinensis. The plant's stem is used as a medicine, and Tibetan doctors often use it as a sedative, a use with a history of nearly 100 years. Tibetan medicine mainly uses lilac to treat headache, forgetfulness, insomnia, irritability and other symptoms. Depression is a chronic mental disorder characterized by low mood, cognitive impairments, and physical discomfort, and it has become a significant public health issue. Given the limitations of existing treatments, interest in alternative therapies, including herbal medicines, is increasing. AIM To elucidate the mechanism of ZDX extract in the treatment of depression. MATERIALS AND METHODS A depression-like mouse model was established via the subcutaneous injection of corticosterone (CORT) into the groin, and a model of PC12 cell injury was established via CORT treatment. The antidepressant effect of the ZDX extract was subsequently evaluated via weight measurements, the sucrose preference test (SPT), the forced swimming test (FST), the open field test(OFT), the tail suspension test (TST), HE staining, Nissl staining and ELISA. Moreover, immunofluorescence staining, qRT‒PCR and Western blotting were used to determine whether ZDX extract can regulate the cAMP/PKA-CREB-BDNF pathway to prevent depression and neuronal apoptosis. RESULTS ZDX extract significantly improved depression-like behaviours; inhibited decreases in the protein levels of cAMP, PKA, CREB and BDNF; and increased proliferative activity in the hippocampus and cortex. In addition, in vitro, ZDX extract attenuated CORT-induced injury and apoptosis in hippocampal neurons and inhibited CORT-induced decreases in the mRNA expression levels of cAMP, PKA, CREB and BDNF. CONCLUSIONS These findings suggest that ZDX extract has potential as a novel antidepressant therapeutic agent, offering a complementary approach to current treatments by targeting multiple pathways involved in the pathogenesis of depression. Further research is warranted to explore the clinical applications of ZDX extract in the treatment of depression.
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Affiliation(s)
- Ru-Han A
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Qin Gong
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Yan-Jun Tuo
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Shu-Ting Zhai
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Bei-Lan He
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - En-Guo Zou
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Mu-Lan Wang
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Tian-Yu Huang
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Chen-Liang Zha
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China; National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Nanchang, 330006, PR China.
| | - Ming-Zhen He
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Guo-Yue Zhong
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China.
| | - Yu-Lin Feng
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China; National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Nanchang, 330006, PR China.
| | - Jun Li
- Jiangxi University of Chinese Medicine, Nanchang, 330006, PR China; National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Nanchang, 330006, PR China.
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Liu Y, Fu X, Zhao X, Cui R, Yang W. The role of exercise-related FNDC5/irisin in depression. Front Pharmacol 2024; 15:1461995. [PMID: 39484160 PMCID: PMC11524886 DOI: 10.3389/fphar.2024.1461995] [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: 07/09/2024] [Accepted: 10/03/2024] [Indexed: 11/03/2024] Open
Abstract
The complexity of depression presents a significant challenge to traditional treatment methods, such as medication and psychotherapy. Recent studies have shown that exercise can effectively reduce depressive symptoms, offering a new alternative for treating depression. However, some depressed patients are unable to engage in regular physical activity due to age, physical limitations, and other factors. Therefore, pharmacological agents that mimic the effects of exercise become a potential treatment option. A newly discovered myokine, irisin, which is produced during exercise via cleavage of its precursor protein fibronectin type III domain-containing protein 5 (FNDC5), plays a key role in regulating energy metabolism, promoting adipose tissue browning, and improving insulin resistance. Importantly, FNDC5 can promote neural stem cell differentiation, enhance neuroplasticity, and improve mood and cognitive function. This review systematically reviews the mechanisms of action of exercise in the treatment of depression, outlines the physiology of exercise-related irisin, explores possible mechanisms of irisin's antidepressant effects. The aim of this review is to encourage future research and clinical applications of irisin in the prevention and treatment of depression.
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Affiliation(s)
- Yaqi Liu
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xiying Fu
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin, China
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xing Zhao
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Yang
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin, China
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Lin T, Zang X, Chen Y, Zhao L, Zhang Y. Effectiveness and safety of Arecae Semen compounds for patients with depression: a systematic review and meta-analysis. Syst Rev 2024; 13:238. [PMID: 39300549 PMCID: PMC11411766 DOI: 10.1186/s13643-024-02656-4] [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: 06/12/2023] [Accepted: 09/08/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Arecae Semen is a traditional herbal medicine widely used in the medical service and food industry, but in recent years, the carcinogenesis of edible Arecae Semen chewing has aroused comprehensive attention, therefore it is necessary to evaluate its medicinal properties. Increasing evidence has shown that Arecae Semen Compounds (ASC) possess antidepressant ability. This study aimed to evaluate the effectiveness and safety of ASC in the treatment of depression. METHODS We retrieved articles in eight databases from their inception to May 2024. Randomized controlled trials (RCTs) comparing the effects of ASC alone or combined with routine treatment in patients with depression were identified. The Cochrane risk of bias (ROB) tool (ROB 2) was used for assessing the ROB in the included trials. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the certainty of the evidence for the review outcomes. The outcomes included Hamilton depression rating scale (HAMD) scores, depression-related symptoms, serum dopamine levels, and adverse events. Stata 14.0 was used for data analysis calculating standardized mean difference (SMD) for continuous outcomes and relative risk (RR) for binary outcomes, both with 95% confidence intervals (CI). RESULTS Nine RCTs involving 787 patients were included in this review. ASC lowered HAMD scores (SMD - 3.43, 95% CI - 5.24 to - 1.61; I2 = 95.2%, P < 0.001), alleviated depression-related symptoms, increased serum dopamine levels, and reduced the incidence of adverse events slightly (RR 0.18, 95% CI 0.04 to 0.77; I2 = 0, P = 0.775) compared with the control group. Publication bias might account for the asymmetrical presentation of funnel plots. Meta-regression analysis revealed that regarding HAMD scores, there was no significant relationship with duration, sample size, or treatment strategy. The evidence of the outcomes was of very low certainty. CONCLUSIONS ASC may achieve better therapeutic effects, alleviate depression-related symptoms with a lower incidence of adverse events, and provide a potentially effective and safe complementary therapy for patients with depression. However, the evidence is very uncertain so further researches are required to validate our results and explore clinical implications of Arecae Semen in depth. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42022361150.
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Affiliation(s)
- Tong Lin
- Institute of Integrated Traditional Chinese and Western Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xiaoyu Zang
- Graduate School of Changchun University of Chinese Medicine, Changchun, Jilin Province, 130117, China
| | - Yi Chen
- The First School of Clinical Medical Sciences, Guangzhou University of Chinese, Guangzhou, 510405, China
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Ying Zhang
- Center for Evidence-based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Cai MY, Wang RK, Liu ZH, Chen XY, Tan W, Sun YF, Xu XJ, Zhang XM, Yang Z, Tong HY. Bibliometric analysis of Mongolian medicine and medicinal materials in China since 2000. Heliyon 2024; 10:e35499. [PMID: 39170266 PMCID: PMC11336759 DOI: 10.1016/j.heliyon.2024.e35499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 07/19/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024] Open
Abstract
Aim of the study To analyze the progress in Mongolian medicine and medicinal materials and to highlight its development process, emerging trends, and hotspots. Materials and methods Papers on Mongolian medicine and medicinal materials from January 2000 to May 2022 were retrieved from the China National Knowledge Infrastructure (CNKI) database. Using the collaboration network analysis of CiteSpace V and VOSviewer software, the cooperation among individuals and institutions in the field of scientific research was analyzed. The functions of frequency analysis, cluster analysis, and burst analysis were employed to conduct bibliometric analysis on research hotspots and trends in the field of Mongolian medicine research. Furthermore, the data visualization function was utilized to clearly display data trends and changes. Results A total of 8362 papers on Mongolian medicine medicinal materials from CNKI were identified and analyzed.The research on Mongolian medicine has gone through three stages: the initial stage, the exploratory stage, and the developmental stage. The top two institutions in the number of papers are Inner Mongolia Medical University and Inner Mongolia University for Nationalities. Bagenna from Inner Mongolia Medical University is the author with the most papers. "clinical efficacy", "clinical research", and "quality standards" were the most frequently used keywords. Research in the field of Mongolian medicine has focused on several diseases, including skeletal system disorders, cardiovascular diseases, and digestive system disorders. Conclusion Since 2000, there have been growing attention and efforts made in the field of Mongolian medicine and medicinal materials. The research in the field of Mongolian medicine had undergone three stages, namely the initial stage, the exploratory stage, and the developmental stage. The focus shifted from basic research such as the analysis of medicinal ingredients in Mongolian herbs to the application-oriented directions of traditional treatment techniques and advantageous diseases in Mongolian medicine. To make breakthroughs in this field, further research is needed to improve the persuasiveness and authority of Mongolian medicine and medicinal materials in terms of mechanism, standardization, and safety, to promote the development of Mongolian medicine and medicinal materials.
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Affiliation(s)
- Ming-Yang Cai
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, PR China
- Hospital of Pediatrics, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, 450000, PR China
- Pediatric Medical College, Henan University of Traditional Chinese Medicine, 450000, PR China
| | - Rui-Kun Wang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, PR China
- Institute of Ethnic Medicine and Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, PR China
| | - Zhen-Hong Liu
- Institute for Brain Disorders, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, PR China
| | - Xiang-Yun Chen
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, PR China
| | - Wen Tan
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, PR China
| | - Yi-Fan Sun
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, PR China
| | - Xiu-Juan Xu
- School of Pharmacy, Baotou Medical College, Baotou, 014040, PR China
| | - Xiao-Min Zhang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, PR China
- Institute of Ethnic Medicine and Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, PR China
| | - Zhen Yang
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, PR China
| | - Hai-Ying Tong
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, PR China
- Institute of Ethnic Medicine and Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, PR China
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Bai JJ, Ao M, Xing A, Yu LJ, Tong HY, Bao WY, Wang Y. Areca Thirteen Pill Improves Depression in Rat by Modulation of the Chemokine/Chemokine Receptor Axis. Mol Neurobiol 2024; 61:4633-4647. [PMID: 38110645 DOI: 10.1007/s12035-023-03855-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/27/2023] [Indexed: 12/20/2023]
Abstract
Depressive disorder is a severe and complex mental illness. There are a few anti-depressive medications that can reduce depressive symptoms, but with adverse or side effects. GaoYou-13 (GY-13), commonly known as Areca Thirteen Pill, is a traditional medicine for depression treatment with significant clinical impact. However, the molecular mechanism of GY-13 has not been fully elucidated. This study aimed to explore and explain the action and mechanism of GY-13 in treatment for depression. SD male rats were stimulated differently daily for 42 days to construct a depression rat model and divided into six groups: the control, CUMS model, GY-13L, GY-13 M, GY-13H, and FLUO. The body weight of was measured on day 7, 14, 21, 28, 35, and 42 or different days, and the behavioral tests (Open-field test, Sucrose preference test, Morris water maze) were made alongside. After the rats were decapitated, the rat brains were stained with Nissl or H&E dyes. The serums of TNF-α and IL-1β were tested. The protein of p-IKKα, p-IкBα, and p-NFкBp65 was traced. Then nano-LC-MS/MS analysis was made to detect the mechanism of GY-13. The active ingredients, drug targets, and key pathways of GY-13 in treating depression were analyzed through network pharmacology and molecular docking. With immunohistochemistry, quantitative RT-PCR, and western-blot techniques, the therapeutic mechanism of GY-13 was traced and analyzed. This study revealed that GY-13 significantly enhances autonomous and exploratory behavior, sucrose consumption, learning and memory ability, and hippocampal neuronal degeneration, which inhibits inflammation. In addition, omics analysis showed several proteins were altered in the hippocampus of rats following CUMS and GY-13 treatment. Bioinformatics analysis and network pharmacology revealed the antidepressant effects of GY-13 are related to the chemokine/chemokine receptor axis. Immunohistochemistry, western blotting and RT-PCR assay further support the findings of omics analysis. We highlighted the importance of the chemokine/chemokine receptor axis in the treatment of depression, as well as showed GY-13 can be used as a novel targeted therapy for depression treatment.
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Affiliation(s)
- Jing-Jing Bai
- Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563006, People's Republic of China
- Tongliao Institute of agriculture and animal husbandry, Tongliao, Inner Mongolia, People's Republic of China
| | - Min Ao
- Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia, People's Republic of China
| | - An Xing
- Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia, People's Republic of China
| | - Li-Jun Yu
- Inner Mongolia Minzu University, Tongliao, Inner Mongolia, People's Republic of China
| | - Hai-Ying Tong
- Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia, People's Republic of China
| | - Wu-Ye Bao
- Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, Inner Mongolia, People's Republic of China.
| | - Yu Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, 563006, People's Republic of China.
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Ning B, Ge T, Wu Y, Wang Y, Zhao M. Role of Brain-Derived Neurotrophic Factor in Anxiety or Depression After Percutaneous Coronary Intervention. Mol Neurobiol 2024; 61:2921-2937. [PMID: 37946008 DOI: 10.1007/s12035-023-03758-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023]
Abstract
Anxiety or depression after percutaneous coronary intervention (PCI) is one of the key clinical problems in cardiology that need to be solved urgently. Brain-derived neurotrophic factor (BDNF) may be a potential biomarker for the pathogenesis and treatment of anxiety or depression after PCI. This article reviews the correlation between BDNF and cardiovascular system and nervous system from the aspects of synthesis, release and action site of BDNF, and focuses on the latest research progress of the mechanism of BDNF in anxiety or depression after PCI. It includes the specific mechanisms by which BDNF regulates the levels of inflammatory factors, reduces oxidative stress damage, and mediates multiple signaling pathways. In addition, this review summarizes the therapeutic potential of BDNF as a potential biomarker for anxiety or depression after PCI.
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Affiliation(s)
- Bo Ning
- First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Teng Ge
- First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Yongqing Wu
- First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Yuting Wang
- First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
- Affiliated Hospital, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Mingjun Zhao
- First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, 712046, China.
- Affiliated Hospital, Shaanxi University of Chinese Medicine, Xianyang, 712046, China.
- Shaanxi Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Cardiovascular Diseases, Xianyang, 712046, China.
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11
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Sun H, Yu W, Li H, Hu X, Wang X. Bioactive Components of Areca Nut: An Overview of Their Positive Impacts Targeting Different Organs. Nutrients 2024; 16:695. [PMID: 38474823 PMCID: PMC10935369 DOI: 10.3390/nu16050695] [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: 02/01/2024] [Revised: 02/19/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Areca catechu L. is a widely cultivated tropical crop in Southeast Asia, and its fruit, areca nut, has been consumed as a traditional Chinese medicinal material for more than 10,000 years, although it has recently attracted widespread attention due to potential hazards. Areca nut holds a significant position in traditional medicine in many areas and ranks first among the four southern medicines in China. Numerous bioactive compounds have been identified in areca nuts, including alkaloids, polyphenols, polysaccharides, and fatty acids, which exhibit diverse bioactive functions, such as anti-bacterial, deworming, anti-viral, anti-oxidant, anti-inflammatory, and anti-tumor effects. Furthermore, they also display beneficial impacts targeting the nervous, digestive, and endocrine systems. This review summarizes the pharmacological functions and underlying mechanisms of the bioactive ingredients in areca nut. This helps to ascertain the beneficial components of areca nut, discover its medicinal potential, and guide the utilization of the areca nut.
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Affiliation(s)
- Huihui Sun
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (H.S.); (W.Y.); (X.H.)
- Sanya Institute of China Agricultural University, Sanya 572025, China
- Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100083, China;
| | - Wenzhen Yu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (H.S.); (W.Y.); (X.H.)
| | - Hu Li
- Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100083, China;
| | - Xiaosong Hu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (H.S.); (W.Y.); (X.H.)
| | - Xiaofei Wang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China; (H.S.); (W.Y.); (X.H.)
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Tong T, Xu A, Tan S, Jiang H, Liu L, Deng S, Wang H. Biological Effects and Biomedical Applications of Areca Nut and Its Extract. Pharmaceuticals (Basel) 2024; 17:228. [PMID: 38399443 PMCID: PMC10893415 DOI: 10.3390/ph17020228] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/03/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
The dried, mature fruit of the palm tree species Areca catechu L. is known as the areca nut (AN) or betel nut. It is widely cultivated in the tropical regions. In many nations, AN is utilized for traditional herbal treatments or social activities. AN has historically been used to address various health issues, such as diarrhea, arthritis, dyspepsia, malaria, and so on. In this review, we have conducted a comprehensive summary of the biological effects and biomedical applications of AN and its extracts. Initially, we provided an overview of the constituents in AN extract. Subsequently, we summarized the biological effects of AN and its extracts on the digestive system, nervous system, and circulatory system. And we elucidated the contributions of AN and its extracts in antidepressant, anti-inflammatory, antioxidant, and antibacterial applications. Finally, we have discussed the challenges and future perspectives regarding the utilization of AN and its extracts as emerging pharmaceuticals or valuable adjuncts within the pharmaceutical field.
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Affiliation(s)
- Ting Tong
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, Hunan Binglang Science Institute, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Aiqing Xu
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, Hunan Binglang Science Institute, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Shuhua Tan
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, Hunan Binglang Science Institute, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Hengzhi Jiang
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, Hunan Binglang Science Institute, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Lixin Liu
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, Hunan Binglang Science Institute, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Senwen Deng
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, Hunan Binglang Science Institute, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
| | - Haihua Wang
- Hunan Key Laboratory of Economic Crops Genetic Improvement and Integrated Utilization, Hunan Binglang Science Institute, School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, China
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Dai LL, Cho SB, Li HF, A LS, Ji XP, Pan S, Bao ML, Bai L, Ba GN, Fu MH. Lomatogonium rotatum extract alleviates diabetes mellitus induced by a high-fat, high-sugar diet and streptozotocin in rats. World J Diabetes 2023; 14:846-861. [PMID: 37383587 PMCID: PMC10294064 DOI: 10.4239/wjd.v14.i6.846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/21/2023] [Accepted: 04/17/2023] [Indexed: 06/14/2023] Open
Abstract
BACKGROUND Lomatogonium rotatum (LR) is traditionally used in Mongolian folk medicine as a hypoglycemic agent, but its evidence-based pharmacological effects and me-chanisms of action have not been fully elucidated.
AIM To emphasize the hypoglycemic action mechanism of LR in a type 2 diabetic rat model and examine potential biomarkers to obtain mechanistic understanding regarding serum metabolite modifications.
METHODS A high-fat, high-sugar diet and streptozotocin injection-induced type 2 diabetic rat model was established. The chemical composition of the LR was identified by high performance liquid chromatography. LR extract administrated as oral gavage at 0.5 g/kg, 2.5 g/kg, and 5 g/kg for 4 wk. Anti-diabetic effects of LR extract were evaluated based on histopathological examination as well as the measurement of blood glucose, insulin, glucagon-like peptide 1 (GLP-1), and lipid levels. Serum metabolites were analyzed using an untargeted metabolomics approach.
RESULTS According to a chemical analysis, swertiamarin, sweroside, hesperetin, coumarin, 1.7-dihydroxy-3,8-dimethoxyl xanthone, and 1-hydroxy-2,3,5 trimethoxanone are the principal active ingredients in LR. An anti-diabetic experiment revealed that the LR treatment significantly increased plasma insulin and GLP-1 levels while effectively lowering blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and oral glucose tolerance test compared to the model group. Furthermore, untargeted metabolomic analysis of serum samples detected 236 metabolites, among which 86 were differentially expressed between the model and the LR group. It was also found that LR considerably altered the levels of metabolites such as vitamin B6, mevalonate-5P, D-proline, L-lysine, and taurine, which are involved in the regulation of the vitamin B6 metabolic pathway, selenium amino acid metabolic pathway, pyrimidine metabolic pathway, and arginine and proline metabolic pathways.
CONCLUSION These findings indicated that LR may have a hypoglycemic impact and that its role may be related to changes in the serum metabolites and to facilitate the release of insulin and GLP-1, which lower blood glucose and lipid profiles.
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Affiliation(s)
- Li-Li Dai
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Sung-Bo Cho
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Hui-Fang Li
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Li-Sha A
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, Hainan Medical University, Haikou 571199, Hainan Province, China
| | - Xiao-Ping Ji
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Sirigunqiqige Pan
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Ming-Lan Bao
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Laxinamujila Bai
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Gen-Na Ba
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Ming-Hai Fu
- NMPA Key Laboratory of Quality Control of Traditional Chinese Medicine (Mongolian Medicine), Inner Mongolia Minzu University, Tongliao 028000, Inner Mongolia Autonomous Region, China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, Hainan Province, China
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Li JH, Liu JL, Li XW, Liu Y, Yang JZ, Chen LJ, Zhang KK, Xie XL, Wang Q. Gut microbiota from sigma-1 receptor knockout mice induces depression-like behaviors and modulates the cAMP/CREB/BDNF signaling pathway. Front Microbiol 2023; 14:1143648. [PMID: 37089558 PMCID: PMC10116000 DOI: 10.3389/fmicb.2023.1143648] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/20/2023] [Indexed: 04/09/2023] Open
Abstract
IntroductionDepression is a common mental disorder that affects approximately 350 million people worldwide. Much remains unknown about the molecular mechanisms underlying this complex disorder. Sigma-1 receptor (Sig-1R) is expressed at high levels in the central nervous system. Increasing evidence has demonstrated a close association between the Sig-1R and depression. Recently, research has suggested that the gut microbiota may play a crucial role in the development of depression.MethodsMale Sig-1R knockout (Sig-1R KO) and wild-type (WT) mice were used for this study. All transgenic mice were of a pure C57BL/6J background. Mice received a daily gavage of vancomycin (100 mg/kg), neomycin sulfate (200 mg/kg), metronidazole (200 mg/kg), and ampicillin (200 mg/kg) for one week to deplete gut microbiota. Fecal microbiota transplantation (FMT) was conducted to assess the effects of gut microbiota. Depression-like behaviors was evaluated by tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT). Gut microbiota was analyzed by 16s rRNA and hippocampal transcriptome changes were assessed by RNA-seq.ResultsWe found that Sig-1R knockout induced depression-like behaviors in mice, including a significant reduction in immobility time and an increase in latency to immobility in the FST and TST, which was reversed upon clearance of gut microbiota with antibiotic treatment. Sig-1R knockout significantly altered the composition of the gut microbiota. At the genus level, the abundance of Alistipes, Alloprevotella, and Lleibacterium decreased significantly. Gut microbiota dysfunction and depression-like phenotypes in Sig-1R knockout mice could be reproduced through FMT experiments. Additionally, hippocampal RNA sequencing identified multiple KEGG pathways that are associated with depression. We also discovered that the cAMP/CREB/BDNF signaling pathway is inhibited in the Sig-1R KO group along with lower expression of neurotrophic factors including CTNF, TGF-α and NGF. Fecal bacteria transplantation from Sig-1R KO mice also inhibited cAMP/CREB/BDNF signaling pathway.DiscussionIn our study, we found that the gut-brain axis may be a potential mechanism through which Sig-1R regulates depression-like behaviors. Our study provides new insights into the mechanisms by which Sig-1R regulates depression and further supports the concept of the gut-brain axis.
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Affiliation(s)
- Jia-Hao Li
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Jia-Li Liu
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Xiu-Wen Li
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Yi Liu
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Jian-Zheng Yang
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Li-Jian Chen
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Kai-Kai Zhang
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China
| | - Xiao-Li Xie
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), Guangzhou, Guangdong, China
- *Correspondence: Xiao-Li Xie,
| | - Qi Wang
- Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China
- Qi Wang, ;
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Liu Y, Song N, Yao H, Jiang S, Wang Y, Zheng Y, Zhou Y, Ding J, Hu G, Lu M. β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression. J Neuroinflammation 2022; 19:240. [PMID: 36183107 PMCID: PMC9526944 DOI: 10.1186/s12974-022-02597-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 09/13/2022] [Indexed: 12/17/2022] Open
Abstract
Background Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. Methods We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. Results Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK–STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. Conclusions Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02597-6.
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Affiliation(s)
- Yang Liu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Nanshan Song
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Hang Yao
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Siyuan Jiang
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Yueping Wang
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Ying Zheng
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yuanzhang Zhou
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Jianhua Ding
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Gang Hu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China. .,Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.
| | - Ming Lu
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China. .,Neuroprotective Drug Discovery Key Laboratory, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China.
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