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Hall S, Parr BA, Hussey S, Anoopkumar-Dukie S, Arora D, Grant GD. The neurodegenerative hypothesis of depression and the influence of antidepressant medications. Eur J Pharmacol 2024; 983:176967. [PMID: 39222740 DOI: 10.1016/j.ejphar.2024.176967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/27/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
Depression is a complex neurological disease that holds many theories on its aetiology and pathophysiology. The monoamine strategy of treating depression with medications to increase levels of monoamines in the (extra)synapse, primarily through the inhibition of monoamine transporters, does not always work, as seen in patients that lack a response to multiple anti-depressant exposures, as well as a lack of depressive symptoms in healthy volunteers exposed to monoamine reduction. Depression is increasingly being understood not as a single condition, but as a complex interplay of adaptations in various systems, including inflammatory responses and neurotransmission pathways in the brain. This understanding has led to the development of the neurodegenerative hypothesis of depression. This hypothesis, which is gaining widespread acceptance posits that both oxidative stress and inflammation play significant roles in the pathophysiology of depression. This article is a review of the literature focused on neuroinflammation in depression, as well as summarised studies of anti-inflammatory and antioxidant effects of antidepressants.
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Affiliation(s)
- Susan Hall
- School of Pharmacy and Medical Sciences, Griffith University Gold Coast Campus, Southport, 4222, Australia.
| | - Brie-Anne Parr
- School of Pharmacy and Medical Sciences, Griffith University Gold Coast Campus, Southport, 4222, Australia
| | - Sarah Hussey
- School of Pharmacy and Medical Sciences, Griffith University Gold Coast Campus, Southport, 4222, Australia
| | | | - Devinder Arora
- School of Pharmacy and Medical Sciences, Griffith University Gold Coast Campus, Southport, 4222, Australia
| | - Gary D Grant
- School of Pharmacy and Medical Sciences, Griffith University Gold Coast Campus, Southport, 4222, Australia
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2
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Riggott C, Ford AC, Gracie DJ. Review article: The role of the gut-brain axis in inflammatory bowel disease and its therapeutic implications. Aliment Pharmacol Ther 2024; 60:1200-1214. [PMID: 39367676 DOI: 10.1111/apt.18192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/01/2024] [Accepted: 07/10/2024] [Indexed: 10/06/2024]
Abstract
BACKGROUND Treatments targeting the gut-brain axis (GBA) are effective at reducing symptom burden in irritable bowel syndrome (IBS). The prevalence of common mental disorders and IBS-type symptom reporting is significantly higher in inflammatory bowel disease (IBD) than would be expected, suggesting potential GBA effects in this setting. Manipulation of the GBA may offer novel treatment strategies in selected patients with IBD. We present a narrative review of the bi-directional effects of the GBA in IBD and explore the potential for GBA-targeted therapies in this setting. METHODS We searched MEDLINE, EMBASE, EMBASE Classic, PsychINFO, and the Cochrane Central Register of Controlled Trials for relevant articles published by March 2024. RESULTS The bi-directional relationship between psychological well-being and adverse longitudinal disease activity outcomes, and the high prevalence of IBS-type symptom reporting highlight the presence of GBA-mediated effects in IBD. Treatments targeting gut-brain interactions including brain-gut behavioural treatments, neuromodulators, and dietary interventions appear to be useful adjunctive treatments in a subset of patients. CONCLUSIONS Psychological morbidity is prevalent in patients with IBD. The relationship between longitudinal disease activity outcomes, IBS-type symptom reporting, and poor psychological health is mediated via the GBA. Proactive management of psychological health should be integrated into routine care. Further clinical trials of GBA-targeted therapies, conducted in selected groups of patients with co-existent common mental disorders, or those who report IBS-type symptoms, are required to inform effective integrated models of care in the future.
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Affiliation(s)
- Christy Riggott
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - David J Gracie
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
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3
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Chelucci E, Daniele S, Vergassola M, Ceccarelli L, Zucchi S, Boltri L, Martini C. Trazodone counteracts the response of microglial cells to inflammatory stimuli. Eur J Neurosci 2024; 60:5605-5620. [PMID: 39187397 DOI: 10.1111/ejn.16522] [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: 12/20/2023] [Revised: 07/29/2024] [Accepted: 08/13/2024] [Indexed: 08/28/2024]
Abstract
Microglia are resident brain cells that regulate neuronal development and innate immunity. Microglia activation participates in the cellular response to neuroinflammation, thus representing a possible target for pharmacological strategies aimed to counteract the onset and progression of brain disorders, including depression. Antidepressant drugs have been reported to reduce neuroinflammation by acting also on glial cells. Herein, the potential anti-inflammatory and neuroprotective effects of trazodone (TRZ) on the microglial human microglial clone 3 (HMC3) cell line were investigated. HMC3 cells were activated by a double inflammatory stimulus (lipopolysaccharide [LPS] and tumour necrosis factor-alpha [TNF-α], 24 h each), and the induction of inflammation was demonstrated by (i) the increased expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and ionized calcium-binding adapter molecule 1 (IBA-1), and (ii) the increased release of interleukin 6 (IL-6) and transforming growth factor-beta (TGF-β). TRZ effects were evaluated by treating HMC3 cells for 24 h before (pre-treatment) and after (post-treatment) the double inflammatory stimulus. Notably, TRZ treatments significantly decreased the expression of NF-kB and IBA-1 and the release of the cytokines IL-6 and TGF-β. Moreover, TRZ prevented and reduced the release of quinolinic acid (QUIN), a known neurotoxic kynurenine metabolite. Finally, cellular supernatants collected from microglial cells pre-treated LPS-TNF-α with TRZ were able to improve neuronal-like cell viability, demonstrating a potential neuroprotective effect. Overall, this study suggests the anti-inflammatory effects of TRZ on human microglia and strives for its neuroprotective properties.
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Affiliation(s)
| | | | - Matteo Vergassola
- Angelini Pharma S.p.A. Global External Innovation & Drug Discovery, Translational Research Department, Rome, Italy
| | | | - Sara Zucchi
- Angelini Pharma S.p.A. Global R&D PLCM Preclinical Development, Ancona, Italy
| | - Luigi Boltri
- Angelini Pharma S.p.A. Global R&D PLCM Preclinical Development, Ancona, Italy
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Chan YL, Ho CSH, Tay GWN, Tan TWK, Tang TB. MicroRNA classification and discovery for major depressive disorder diagnosis: Towards a robust and interpretable machine learning approach. J Affect Disord 2024; 360:326-335. [PMID: 38788856 DOI: 10.1016/j.jad.2024.05.066] [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: 02/08/2024] [Revised: 04/08/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024]
Abstract
BACKGROUND Major depressive disorder (MDD) is notably underdiagnosed and undertreated due to its complex nature and subjective diagnostic methods. Biomarker identification would help provide a clearer understanding of MDD aetiology. Although machine learning (ML) has been implemented in previous studies to study the alteration of microRNA (miRNA) levels in MDD cases, clinical translation has not been feasible due to the lack of interpretability (i.e. too many miRNAs for consideration) and stability. METHODS This study applied logistic regression (LR) model to the blood miRNA expression profile to differentiate patients with MDD (n = 60) from healthy controls (HCs, n = 60). Embedded (L1-regularised logistic regression) feature selector was utilised to extract clinically relevant miRNAs, and optimized for clinical application. RESULTS Patients with MDD could be differentiated from HCs with the area under the receiver operating characteristic curve (AUC) of 0.81 on testing data when all available miRNAs were considered (which served as a benchmark). Our LR model selected miRNAs up to 5 (known as LR-5 model) emerged as the best model because it achieved a moderate classification ability (AUC = 0.75), relatively high interpretability (feature number = 5) and stability (ϕ̂Z=0.55) compared to the benchmark. The top-ranking miRNAs identified by our model have demonstrated associations with MDD pathways involving cytokine signalling in the immune system, the reelin signalling pathway, programmed cell death and cellular responses to stress. CONCLUSION The LR-5 model, which is optimised based on ML design factors, may lead to a robust and clinically usable MDD diagnostic tool.
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Affiliation(s)
- Yee Ling Chan
- Centre for Intelligent Signal and Imaging Research (CISIR), Universiti Teknologi PETRONAS (UTP), Bandar Seri Iskandar 32610, Perak, Malaysia
| | - Cyrus S H Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117543, Singapore
| | - Gabrielle W N Tay
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117543, Singapore
| | - Trevor W K Tan
- Centre for Sleep and Cognition, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117543, Singapore; Centre for Translational MR Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117543, Singapore; Department of Electrical and Computer Engineering, National University of Singapore, Singapore 117583, Singapore; N.1 Institute for Health & Institute for Digital Medicine (WisDM), National University of Singapore, Singapore 117456, Singapore; Integrative Sciences and Engineering Programme (ISEP), National University of Singapore, Singapore 119077, Singapore
| | - Tong Boon Tang
- Centre for Intelligent Signal and Imaging Research (CISIR), Universiti Teknologi PETRONAS (UTP), Bandar Seri Iskandar 32610, Perak, Malaysia.
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Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, Wang Y, Tang Y, Xia M, Li B. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther 2024; 9:30. [PMID: 38331979 PMCID: PMC10853571 DOI: 10.1038/s41392-024-01738-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/24/2023] [Accepted: 12/28/2023] [Indexed: 02/10/2024] Open
Abstract
Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.
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Affiliation(s)
- Lulu Cui
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Shu Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Siman Wang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Xiafang Wu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Yingyu Liu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Weiyang Yu
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Yijun Wang
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China
- China Medical University Centre of Forensic Investigation, Shenyang, China
| | - Yong Tang
- International Joint Research Centre on Purinergic Signalling/Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China
| | - Maosheng Xia
- Department of Orthopaedics, The First Hospital, China Medical University, Shenyang, China.
| | - Baoman Li
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China.
- Liaoning Province Key Laboratory of Forensic Bio-evidence Sciences, Shenyang, China.
- China Medical University Centre of Forensic Investigation, Shenyang, China.
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Sarmin N, Roknuzzaman ASM, Mouree TZ, Islam MR, Al Mahmud Z. Evaluation of serum interleukin-12 and interleukin-4 as potential biomarkers for the diagnosis of major depressive disorder. Sci Rep 2024; 14:1652. [PMID: 38238514 PMCID: PMC10796357 DOI: 10.1038/s41598-024-51932-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 01/11/2024] [Indexed: 01/22/2024] Open
Abstract
Recently, scientists have focused on pro-inflammatory cytokines and immunological dysregulation in major depressive disorder (MDD). Some research suggests pro-inflammatory cytokines' role in MDD development, whereas anti-inflammatory studies are sparse. There is no systematic investigation of Bangladeshi MDD patients' pro- and anti-inflammatory cytokines. This study examines the blood levels of IL-12 and IL-4 in Bangladeshi patients and healthy controls (HCs) to determine the diagnostic accuracy of these cytokines to identify MDD patients from those without MDD. A total of 110 people with MDD from the department of psychiatry of a teaching hospital in Dhaka and 107 HCs from Dhaka participated in this case-control study. Depression and illness severity were gauged using DSM-5 criteria and Ham-D scores. Commercially marketed ELISA kits were used in accordance with manufacturer guidelines to measure the levels of IL-12 and IL-4 in peripheral blood, allowing a comparison of the patient and control groups. In comparison to HCs, MDD patients (5333.00 ± 307.40 pg/ml) showed noticeably higher levels of IL-12 than in HCs (2331.00 ± 207.40 pg/ml). The increased levels were positively correlated with Ham-D scores (male: r = 0.351, p < 0.050; female: r = 0.389, p < 0.050), suggesting a possible relationship to disease progression. Additionally, compared to HCs (272.81 ± 23.94 pg/ml), MDD patients had significantly higher peripheral blood levels of IL-4 (876.35 ± 66.73 pg/ml) (p < 0.001). Also, there was a positive correlation between IL-4 serum levels and Ham-D scores (male: r = 0.361, p < 0.050; female: r = 0.398, p < 0.050). Therefore, we observed increased levels of these serum cytokines and their association with the severity of depression. The results of this study demonstrate the possibility of IL-12 and IL-4 blood levels as distinct markers capable of differentiating between MDD patients and HCs, possibly acting as markers of MDD susceptibility. To ascertain the diagnostic effectiveness of these two cytokines, more research is necessary.
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Affiliation(s)
- Nisat Sarmin
- Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - A S M Roknuzzaman
- Department of Pharmacy, University of Asia Pacific, Dhaka, 1205, Bangladesh
| | - Tashfiya Zaman Mouree
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Md Rabiul Islam
- School of Pharmacy, BRAC University, KHA 224, Progati Sarani, Merul Badda, Dhaka, 1212, Bangladesh.
| | - Zobaer Al Mahmud
- Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh.
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Xu YQ, Gou Y, Yuan JJ, Zhu YX, Ma XM, Chen C, Huang XX, Yang ZX, Zhou YM. Peripheral Blood Inflammatory Cytokine Factors Expressions are Associated with Response to Acupuncture Therapy in Postpartum Depression Patients. J Inflamm Res 2023; 16:5189-5203. [PMID: 38026248 PMCID: PMC10655746 DOI: 10.2147/jir.s436907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Background Increasing evidences demonstrate that immune dysregulation can result in depression, and it is reported that persistent inflammatory response is related to the unresponsiveness of antidepressant treatment. Purpose This study aimed to explore the reason why some responded but some not responded to acupuncture in treating postpartum depression (PPD), and whether it related to the levels of inflammatory cytokines. Patients and Methods Women diagnosed with PPD were recruited in to accept 8-week acupuncture. All subjects were assessed the 17-item Hamilton Depression Rating Scale (HDRS17) at baseline, week 1, week 2, week 4 and week 8 during the treatment. A panel of 9 cytokines was measured at baseline and 8 weeks. Results Of the 121 participants, 96 completed the 8-week assessment and 46 completed the blood sample collection. HDRS17 scores of 96 subjects showed significant statistical reduction since the first week (P = 0.002) and reached to 5.31 (P < 0.000) at the end of therapy. And we divided the 46 subjects into responders and non-responders according to the response rate of HDRS17 scores. Responders and non-responders did not differ significantly between-group in changes in the 9 cytokines. In responders, IL-6, IL-10 and IFN-γ levels were statistically lower (P = 0.006; P = 0.033; P = 0.024), while TGF-β1 was statistically higher after 8 weeks treatment (P < 0.000). In non-responders, the levels of IL-5, TNF-α and TGF-β1 were statistically higher (P = 0.018; P < 0.000; P < 0.000), while IFN-γ was statistically lower (P = 0.005). Conclusion Acupuncture could alleviate depressive symptoms of patients with PPD and might through adjusting peripheral inflammatory response by up-regulating anti-inflammatory cytokines and down-regulating pro-inflammatory cytokines.
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Affiliation(s)
- Yu-Qin Xu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - YanHua Gou
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Jin-Jun Yuan
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Yan-Xian Zhu
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Xiao-Ming Ma
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Chen Chen
- Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Xing-Xian Huang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Zhuo-Xin Yang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
| | - Yu-Mei Zhou
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, People’s Republic of China
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Önal HT, Yetkin D, Ayaz F. Paroxetine's effect on the proinflammatory cytokine stimulation and intracellular signaling pathways in J774.2 cells. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:3327-3335. [PMID: 37589738 DOI: 10.1007/s00210-023-02669-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/09/2023] [Indexed: 08/18/2023]
Abstract
Paroxetine is extensively utilized in the management of depressive and anxious conditions. Paroxetine works by increasing serotonin levels in nerve cells in the brain. However, limited information is available regarding the direct effects of paroxetine on macrophage cells. Macrophages are a type of leukocytes involved in the body's immune response, playing a crucial role in combating infections. The impact of paroxetine on macrophages has been explored in research, although a comprehensive understanding is still pending. This study aimed to research the potential of administering paroxetine to J774.2 macrophage cells to stimulate the release of GM-CSF, TNF-α, IL-12p40, and IL-6 cytokines. Additionally, we examined the mechanisms of action of paroxetine on the p38 signaling pathway, which is involved in cytokine production, and the PI3K pathway, which is an important mechanism in intracellular signaling. Our findings revealed that paroxetine induced an inflammatory response in macrophages by promoting cytokine synthesis in a non-lipopolysaccharide (LPS) environment. We observed that paroxetine triggered the inflammatory response through the PI3K signaling pathway while suppressing the p38 signaling pathway.
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Affiliation(s)
- Harika Topal Önal
- Medical Laboratory Techniques, Vocational School of Health Services, Toros University, Mersin, Turkey.
| | - Derya Yetkin
- Mersin University Advanced Technology Education Research and Application Center, Mersin, Turkey
| | - Furkan Ayaz
- Science Institute, Faculty of Arts and Science, Department of Biotechnology, Mersin University, Mersin, Turkey.
- Mersin University Biotechnology Research and Application Center, Mersin University, Mersin, Turkey.
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Li Y, Wang H, Zhou J, Wang C. Research progress on the correlation between transforming growth factor- β level and symptoms of depression. Zhejiang Da Xue Xue Bao Yi Xue Ban 2023; 52:646-652. [PMID: 37916311 PMCID: PMC10630060 DOI: 10.3724/zdxbyxb-2023-0269] [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: 06/04/2023] [Accepted: 08/19/2023] [Indexed: 10/08/2023]
Abstract
Transforming growth factor (TGF)-β is a group of cytokines with anti-inflammatory effects in the TGF family, which participates in the development of stress and depression-related mechanisms, and plays roles in the regulation of inflammatory response in depression and the recovery of various cytokine imbalances. The core symptoms of depression is associated with TGF-β level, and the psychological symptoms of depression are related to TGF-β gene polymorphism. Various antidepressants may up-regulate TGF-β level through the complex interaction between neurotransmitters and inflammatory factors, inhibiting inflammatory response and regulating cytokine imbalance to improve depressive symptoms. Studies have shown that recombinant TGF-β1 protein has beneficial effects in mouse depression models, indicating TGF-β1 might be a potential therapeutic target for depression and nasal sprays having the advantage of being fast acting delivery method. This article reviews the research progress on dynamic changes of TGF-β level before and after depression treatment and the application of TGF-β level as an indicator for the improvement of depressive symptoms. We provide ideas for the development of new antidepressants and for the evaluation of the treatment efficacy in depression.
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Affiliation(s)
- Yanran Li
- Department of Psychiatry, the Second Affiliated Hospital of Xinxiang Medical College, Henan Key Laboratory of Biological Psychiatry, Henan Psychological Aid Cloud Platform and Application Engineering Research Center, Xinxiang 453002, Henan Province, China.
| | - Huiying Wang
- Department of Psychiatry, the Second Affiliated Hospital of Xinxiang Medical College, Henan Key Laboratory of Biological Psychiatry, Henan Psychological Aid Cloud Platform and Application Engineering Research Center, Xinxiang 453002, Henan Province, China
| | - Jiansong Zhou
- Department of Psychiatry, the Second Xiangya Hospital of Central South University, National Clinical Medical Research Center for Ment, Changsha 410011, China.
| | - Changhong Wang
- Department of Psychiatry, the Second Affiliated Hospital of Xinxiang Medical College, Henan Key Laboratory of Biological Psychiatry, Henan Psychological Aid Cloud Platform and Application Engineering Research Center, Xinxiang 453002, Henan Province, China.
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Fonseca C, Ettcheto M, Bicker J, Fernandes MJ, Falcão A, Camins A, Fortuna A. Under the umbrella of depression and Alzheimer's disease physiopathology: Can cannabinoids be a dual-pleiotropic therapy? Ageing Res Rev 2023; 90:101998. [PMID: 37414155 DOI: 10.1016/j.arr.2023.101998] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/17/2023] [Accepted: 07/03/2023] [Indexed: 07/08/2023]
Abstract
Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. Depression affects more than 300 million people worldwide while AD affects 60-80% of the 55 million cases of dementia. Both diseases are affected by aging with high prevalence in elderly and share not only the main brain affected areas but also several physiopathological mechanisms. Depression disease is already ascribed as a risk factor to the development of AD. Despite the wide diversity of pharmacological treatments currently available in clinical practice for depression management, they remain associated to a slow recovery process and to treatment-resistant depression. On the other hand, AD treatment is essentially based in symptomatology relieve. Thus, the need for new multi-target treatments arises. Herein, we discuss the current state-of-art regarding the contribution of the endocannabinoid system (ECS) in synaptic transmission processes, synapses plasticity and neurogenesis and consequently the use of exogenous cannabinoids in the treatment of depression and on delaying the progression of AD. Besides the well-known imbalance of neurotransmitter levels, including serotonin, noradrenaline, dopamine and glutamate, recent scientific evidence highlights aberrant spine density, neuroinflammation, dysregulation of neurotrophic factor levels and formation of amyloid beta (Aβ) peptides, as the main physiopathological mechanisms compromised in depression and AD. The contribution of the ECS in these mechanisms is herein specified as well as the pleiotropic effects of phytocannabinoids. At the end, it became evident that Cannabinol, Cannabidiol, Cannabigerol, Cannabidivarin and Cannabichromene may act in novel therapeutic targets, presenting high potential in the pharmacotherapy of both diseases.
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Affiliation(s)
- Carla Fonseca
- Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; CIBIT - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal; Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain; Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain
| | - Miren Ettcheto
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain; Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute, Madrid, Spain
| | - Joana Bicker
- Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; CIBIT - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Maria José Fernandes
- Departamento de Neurologia/Neurocirurgia, Escola Paulista de Medicina, Universidade Federal de São Paulo-UNIFESP, Rua Pedro de Toledo, 669, CEP, São Paulo 04039-032, Brazil
| | - Amílcar Falcão
- Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; CIBIT - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal
| | - Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain; Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute, Madrid, Spain
| | - Ana Fortuna
- Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; CIBIT - Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal.
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11
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Xia X, Yu H, Li Y, Liang Y, Li G, Huang F. Transcriptome Analysis Identifies Biomarkers for the Diagnosis and Management of Psoriasis Complicated with Depression. Clin Cosmet Investig Dermatol 2023; 16:1287-1301. [PMID: 37223217 PMCID: PMC10202145 DOI: 10.2147/ccid.s413887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 05/13/2023] [Indexed: 05/25/2023]
Abstract
Purpose Psoriasis is a systemic inflammatory disease, and the mechanism that links psoriasis to depression is still elusive. Hence, this study aimed to elucidate the potential pathogenesis of psoriasis and depression comorbidity. Methods The gene expression profiles of psoriasis (GSE34248, GSE78097 and GSE161683) and depression (GSE39653) were downloaded from the Gene Expression Omnibus (GEO) DataSets. Functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis were performed, following identification of the common differentially expressed genes (DEGs) of psoriasis and depression. Results A total of 115 common DEGs (55 up-regulated and 60 down-regulated) were identified between psoriasis and depression. Functional analysis indicated that T cell activation and differentiation were predominantly implicated in the potential pathogenesis of these two diseases. In addition, Th17 cell differentiation and cytokines is closely related to both. Finally, 17 hub genes were screened, including CTLA4, LCK, ITK, IL7R, CD3D, SOCS1, IL4R, PRKCQ, SOCS3, IL23A, PDGFB, PAG1, TGFA, FGFR1, RELN, ITGB5 and TNXB, which re-emphasized the importance of the immune system in psoriasis and depression. Conclusion Our study reveals the common pathogenesis of psoriasis and depression. These common pathways and hub genes may apply to a molecular screening tool for depression in psoriasis patients, which could help dermatologists optimize patient management in routine care.
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Affiliation(s)
- Xichun Xia
- Department of Dermatology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519050, People’s Republic of China
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, People’s Republic of China
| | - Hai Yu
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China
| | - Yanxiang Li
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, People’s Republic of China
| | - Yunting Liang
- Department of Dermatology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519050, People’s Republic of China
| | - Guangqiang Li
- The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou, 510632, People’s Republic of China
| | - Fang Huang
- Department of Dermatology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519050, People’s Republic of China
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12
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Önal HT, Yetkin D, Ayaz F. Escitalopram's inflammatory effect on the mammalian macrophages and its intracellular mechanism of action. Prog Neuropsychopharmacol Biol Psychiatry 2023; 125:110762. [PMID: 37031947 DOI: 10.1016/j.pnpbp.2023.110762] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 03/29/2023] [Accepted: 04/06/2023] [Indexed: 04/11/2023]
Abstract
The majority of patients with depression are treated with antidepressant drugs that are in the serotonin reuptake inhibitor (SSRI) group. Different studies have been conducted on the effect of treatment with antidepressants on the level of pro-inflammatory cytokines. There have been studies on the effects of escitalopram, an SSRI group antidepressant, on the pro-inflammatory cytokine levels both in vivo and in vitro. The results of these studies do not overlap and therefore the escitalopram's effect on the immune system should be studied in more depth. In this study, we aimed to examine, in detail, the cytokine production amount by escitalopram treatment of the J774.2 macrophage cells and its intracellular mechanism of action by examining the PI3K and p38 pathways. As a result of our study, we observed that Escitalopram caused a significant increase in TNF-α, IL-6, and GM-CSF levels in mammalian macrophage cells, but did not induce IL-12p40 production. We observed that the p38 and PI3K pathways play a role in inflammation in the presence of Escitalopram.
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Affiliation(s)
- Harika Topal Önal
- Medical Laboratory Techniques, Vocational School of Health Services, Toros University, Mersin, Turkey.
| | - Derya Yetkin
- Mersin University Advanced Technology Education Research and Application Center, Mersin, Turkey
| | - Furkan Ayaz
- Science Institute, Faculty of Arts and Science, Department of Biotechnology, Mersin University, Mersin, Turkey; Mersin University Biotechnology Research and Application Center, Mersin University, Mersin, Turkey.
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13
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Somoza-Moncada MM, Turrubiates-Hernández FJ, Muñoz-Valle JF, Gutiérrez-Brito JA, Díaz-Pérez SA, Aguayo-Arelis A, Hernández-Bello J. Vitamin D in Depression: A Potential Bioactive Agent to Reduce Suicide and Suicide Attempt Risk. Nutrients 2023; 15:1765. [PMID: 37049606 PMCID: PMC10097210 DOI: 10.3390/nu15071765] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Suicide is one of the leading causes of death worldwide. According to the World Health Organization (WHO), every year, more than 700 thousand people die from this cause. Therefore, suicide is a public health issue. The complex interaction between different factors causes suicide; however, depression is one of the most frequent factors in people who have attempted suicide. Several studies have reported that vitamin D deficiency may be a relevant risk factor for depression, and vitamin D supplementation has shown promising effects in the adjunctive treatment of this mood disorder. Among the beneficial mechanisms of vitamin D, it has been proposed that it may enhance serotonin synthesis and modulate proinflammatory cytokines since low serotonin levels and systemic inflammation have been associated with depression and suicide. The present narrative review shows the potential pathogenic role of vitamin D deficiency in depression and suicide and the potential benefits of vitamin D supplementation to reduce their risk.
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Affiliation(s)
- María Montserrat Somoza-Moncada
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico
| | - Francisco Javier Turrubiates-Hernández
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico
- Doctorado en Ciencias de la Nutrición Traslacional, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico
| | - José Francisco Muñoz-Valle
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico
| | - Jesús Alberto Gutiérrez-Brito
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico
| | - Saúl Alberto Díaz-Pérez
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico
| | - Adriana Aguayo-Arelis
- Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico
| | - Jorge Hernández-Bello
- Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara (UdeG), Guadalajara 44340, Jalisco, Mexico
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14
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Holbrook EM, Zambrano CA, Wright CTO, Dubé EM, Stewart JR, Sanders WJ, Frank MG, MacDonald AS, Reber SO, Lowry CA. Mycobacterium vaccae NCTC 11659, a Soil-Derived Bacterium with Stress Resilience Properties, Modulates the Proinflammatory Effects of LPS in Macrophages. Int J Mol Sci 2023; 24:ijms24065176. [PMID: 36982250 PMCID: PMC10049321 DOI: 10.3390/ijms24065176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 03/10/2023] Open
Abstract
Inflammatory conditions, including allergic asthma and conditions in which chronic low-grade inflammation is a risk factor, such as stress-related psychiatric disorders, are prevalent and are a significant cause of disability worldwide. Novel approaches for the prevention and treatment of these disorders are needed. One approach is the use of immunoregulatory microorganisms, such as Mycobacterium vaccae NCTC 11659, which have anti-inflammatory, immunoregulatory, and stress-resilience properties. However, little is known about how M. vaccae NCTC 11659 affects specific immune cell targets, including monocytes, which can traffic to peripheral organs and the central nervous system and differentiate into monocyte-derived macrophages that, in turn, can drive inflammation and neuroinflammation. In this study, we investigated the effects of M. vaccae NCTC 11659 and subsequent lipopolysaccharide (LPS) challenge on gene expression in human monocyte-derived macrophages. THP-1 monocytes were differentiated into macrophages, exposed to M. vaccae NCTC 11659 (0, 10, 30, 100, 300 µg/mL), then, 24 h later, challenged with LPS (0, 0.5, 2.5, 250 ng/mL), and assessed for gene expression 24 h following challenge with LPS. Exposure to M. vaccae NCTC 11659 prior to challenge with higher concentrations of LPS (250 ng/mL) polarized human monocyte-derived macrophages with decreased IL12A, IL12B, and IL23A expression relative to IL10 and TGFB1 mRNA expression. These data identify human monocyte-derived macrophages as a direct target of M. vaccae NCTC 11659 and support the development of M. vaccae NCTC 11659 as a potential intervention to prevent stress-induced inflammation and neuroinflammation implicated in the etiology and pathophysiology of inflammatory conditions and stress-related psychiatric disorders.
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Affiliation(s)
- Evan M. Holbrook
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Cristian A. Zambrano
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Caelan T. O. Wright
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Elizabeth M. Dubé
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Jessica R. Stewart
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA
| | - William J. Sanders
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Matthew G. Frank
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Andrew S. MacDonald
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9NT, UK
| | - Stefan O. Reber
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, 89081 Ulm, Germany
| | - Christopher A. Lowry
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
- Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA
- Center for Neuroscience and Center for Microbial Exploration, University of Colorado, Boulder, CO 80309, USA
- Department of Physical Medicine and Rehabilitation and Center for Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Veterans Health Administration, Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), The Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO 80045, USA
- Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE), Aurora, CO 80045, USA
- Senior Fellow, inVIVO Planetary Health, of the Worldwide Universities Network (WUN), West New York, NJ 07093, USA
- Correspondence: ; Tel.: +1-303-492-6029; Fax: +1-303-492-0811
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15
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Nahar Z, Sal‐Sabil N, Sohan M, Qusar MMAS, Islam MR. Higher serum interleukin-12 levels are associated with the pathophysiology of major depressive disorder: A case-control study results. Health Sci Rep 2023; 6:e1005. [PMID: 36582626 PMCID: PMC9789678 DOI: 10.1002/hsr2.1005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/23/2022] [Accepted: 12/11/2022] [Indexed: 12/25/2022] Open
Abstract
Background and Aims Major depressive disorder (MDD) is the fourth biggest health-related concern that dramatically impacts individuals' mental and physical health. Alteration of serum proinflammatory cytokine levels may take part in the development and progression of MDD. We aimed to explore and compare the role of interleukin-12 (IL-12) in MDD patients and healthy controls (HCs) and its involvement with the disease severity. Methods The present study included 85 patients and 87 age-sex matched HCs. A qualified psychiatrist utilized the diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) criteria to diagnose patients and evaluate HCs. We applied the Ham-D rating scale to measure the severity of depression. Serum IL-12 levels were measured using ELISA kits. Results We observed a notable increase in the serum levels of IL-12 in MDD patients compared to HCs (164.27 ± 10.18 pg/ml and 82.55 ± 4.40 pg/ml; p < 0.001). Moreover, we noticed a positive correlation between serum IL-12 levels and Ham-D scores in MDD patients (r = 0.363; p = 0.001). Receiver operating characteristic analysis showed a good predictive performance (AUC = 0.871; p < 0.001) at the cut-off point of 53.46 pg/ml for serum IL-12. Conclusion The current study findings support that IL-12 levels are involved with the pathogenesis and inflammatory process in MDD. At the same time, this involvement may make this cytokine eligible for the risk evaluation of MDD. However, we recommend further interventional studies to explore more accurate associations between IL-12 and depressive disorder.
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Affiliation(s)
- Zabun Nahar
- Department of PharmacyUniversity of Asia PacificDhakaBangladesh
| | - Nisat Sal‐Sabil
- Department of PharmacyUniversity of Asia PacificDhakaBangladesh
| | - Md. Sohan
- Department of PharmacyUniversity of Asia PacificDhakaBangladesh
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Harsanyi S, Kupcova I, Danisovic L, Klein M. Selected Biomarkers of Depression: What Are the Effects of Cytokines and Inflammation? Int J Mol Sci 2022; 24:578. [PMID: 36614020 PMCID: PMC9820159 DOI: 10.3390/ijms24010578] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/22/2022] [Accepted: 12/25/2022] [Indexed: 12/31/2022] Open
Abstract
Depression is one of the leading mental illnesses worldwide and lowers the quality of life of many. According to WHO, about 5% of the worldwide population suffers from depression. Newer studies report a staggering global prevalence of 27.6%, and it is rising. Professionally, depression belonging to affective disorders is a psychiatric illness, and the category of major depressive disorder (MDD) comprises various diagnoses related to persistent and disruptive mood disorders. Due to this fact, it is imperative to find a way to assess depression quantitatively using a specific biomarker or a panel of biomarkers that would be able to reflect the patients' state and the effects of therapy. Cytokines, hormones, oxidative stress markers, and neuropeptides are studied in association with depression. The latest research into inflammatory cytokines shows that their relationship with the etiology of depression is causative. There are stronger cytokine reactions to pathogens and stressors in depression. If combined with other predisposing factors, responses lead to prolonged inflammatory processes, prolonged dysregulation of various axes, stress, pain, mood changes, anxiety, and depression. This review focuses on the most recent data on cytokines as markers of depression concerning their roles in its pathogenesis, their possible use in diagnosis and management, their different levels in bodily fluids, and their similarities in animal studies. However, cytokines are not isolated from the pathophysiologic mechanisms of depression or other psychiatric disorders. Their effects are only a part of the whole pathway.
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Affiliation(s)
- Stefan Harsanyi
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Ida Kupcova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Martin Klein
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia
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17
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Changes in T-Cell Subpopulations and Cytokine Levels in Patients with Treatment-Resistant Depression-A Preliminary Study. Int J Mol Sci 2022; 24:ijms24010479. [PMID: 36613927 PMCID: PMC9820349 DOI: 10.3390/ijms24010479] [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: 11/27/2022] [Revised: 12/21/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
Although there is some evidence for the involvement of cytokines and T cells in the pathophysiology of treatment-resistant depression (TRD), the nature of this relationship is not entirely clear. Therefore, we compared T-cell subpopulations and serum cytokine levels in TRD patients to find relationships between their immunological profiles, clinical presentation, and episode severity. Blood samples from TRD patients (n = 20) and healthy people (n = 13) were collected and analyzed by flow cytometry. We analyzed the percentages of helper and cytotoxic T cells according to the expression of selected activation markers, including CD28, CD69, CD25, CD95, and HLA-DR. The serum levels of inflammatory cytokines IL12p70, TNF-α, IL-10, IL-6, IL-1β, and IL-8 were also determined. TRD patients had a lower percentage of CD3+CD4+CD25+ and CD3+CD8+CD95+ cells than healthy people. They also had lower serum levels of IL-12p70 and TNF-α, whereas IL-8 levels were significantly higher. Receiver operating characteristic (ROC) analysis demonstrated that serum IL-8 values above 19.55 pg/mL were associated with a 10.26 likelihood ratio of developing TRD. No connections were found between the MADRS score and immunological parameters. These results show that TRD patients have reduced percentages of T cells expressing activation antigens (CD25 and CD95) and higher serum concentrations of proinflammatory and chemotactic IL-8. These changes may indicate reduced activity of the immune system and the important role of IL-8 in maintaining chronic inflammation in the course of depression.
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18
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Önal HT, Yetkin D, Ayaz F. Immunostimulatory activity of fluoxetine in macrophages via regulation of the PI3K and P38 signaling pathways. Immunol Res 2022; 71:413-421. [PMID: 36512200 PMCID: PMC9745289 DOI: 10.1007/s12026-022-09350-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/01/2022] [Indexed: 12/15/2022]
Abstract
Fluoxetine is an antidepressant drug that is heavily preferred in the cure of depression, which is from the selective serotonin reuptake inhibitor (SSRI) group. There are many reports on the effect of fluoxetine on the immune system, and its effect on the macrophage cells has never been looked at before. We aimed to demonstrate the cytokine production potential of fluoxetine antidepressant, which is widely used in the clinic, in the J774.2 cell line and its effect on PI3K and P38 pathways. The use of fluoxetine alone in J774.2 macrophage cells showed immunostimulatory properties by inducing the production of tumor necrosis factor-α (TNF-α), interleukin (IL) IL-6, IL-12p40, and granulocyte–macrophage colony-stimulating factor (GM-CSF) cytokines. It showed anti-inflammatory properties by completely stopping the production of cytokines (IL-6, IL12p40, TNF-α, and GM-CSF) at all concentrations where LPS and fluoxetine were used together. While PI3K and P38 pathways were not effective in the immunostimulatory effect in the presence of the drug agent, we found that the PI3K and P38 pathways were influenced during their anti-inflammatory activity.
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Affiliation(s)
- Harika Topal Önal
- Medical Laboratory Techniques, Vocational School of Health Services, Toros University, 33140 Mersin, Turkey
| | - Derya Yetkin
- Mersin University Advanced Technology Education Research and Application Center, Mersin University, 33110 Mersin, Turkey
| | - Furkan Ayaz
- Department of Biotechnology, Faculty of Arts and Science, Mersin University, Mersin, Turkey 33110
- Mersin University Biotechnology Research and Application Center, Mersin University, 33110, Mersin, Turkey
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Bialek K, Czarny P, Wigner P, Synowiec E, Kolodziej L, Bijak M, Szemraj J, Papp M, Sliwinski T. Agomelatine Changed the Expression and Methylation Status of Inflammatory Genes in Blood and Brain Structures of Male Wistar Rats after Chronic Mild Stress Procedure. Int J Mol Sci 2022; 23:ijms23168983. [PMID: 36012250 PMCID: PMC9409183 DOI: 10.3390/ijms23168983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/09/2022] [Accepted: 08/09/2022] [Indexed: 11/30/2022] Open
Abstract
The preclinical research conducted so far suggest that depression development may be influenced by the inflammatory pathways both at the periphery and within the central nervous system. Furthermore, inflammation is considered to be strongly connected with antidepressant treatment resistance. Thus, this study explores whether the chronic mild stress (CMS) procedure and agomelatine treatment induce changes in TGFA, TGFB, IRF1, PTGS2 and IKBKB expression and methylation status in peripheral blood mononuclear cells (PBMCs) and in the brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or agomelatine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our findings confirm that both CMS and antidepressant agomelatine treatment influenced the expression level and methylation status of the promoter region of investigated genes in PBMCs and the brain. What is more, the present study showed that response to either stress stimuli or agomelatine differed between brain structures. Concluding, our results indicate that TGFA, TGFB, PTGS2, IRF1 and IKBKB could be associated with depression and its treatment.
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Affiliation(s)
- Katarzyna Bialek
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland
| | - Piotr Czarny
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland
| | - Paulina Wigner
- Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
| | - Ewelina Synowiec
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
| | - Lukasz Kolodziej
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland
| | - Michal Bijak
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland
| | - Mariusz Papp
- Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland
| | - Tomasz Sliwinski
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
- Correspondence: ; Tel.: +48-42-635-44-86; Fax: +48-42-635-44-84
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20
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Huang ZH, Fang Y, Wang XL, Wang Q, Wang T. Screening Traditional Chinese Medicine Combination for Co-Treatment of Alzheimer's Disease and Major Depressive Disorder by Network Pharmacology. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221120525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background: Due to their close relationship, the efficacy of major depressive disorder (MDD) drugs in the treatment of Alzheimer's disease (AD) has received widespread attention in recent years. Methods: In this study, we explored the potential therapeutic value of traditional Chinese medicine (TCM) and multitarget components on both MDD and AD by using a comprehensive strategy with network pharmacology and molecular docking technology. Results: In total, 234 MDD-related TCM prescriptions were analyzed and the 10 most commonly used Chinese herbs, correlating to 198 active ingredients, were identified. Through a comparative analysis of 144 prospective ingredient targets, 1095 MDD-related targets, and 1684 AD-related targets, network pharmacology identified 30 common targets, 9 key targets, and 7 representative compounds. The results of GO and KEGG enrichment analysis revealed that common targets were required to regulate multiple pathways related to MDD and AD. In addition, network analysis demonstrated that the combination of Xiangfu (Cyperi Rhizoma)-Gancao (Licorice)-Chaihu (Radix Bupleuri) constituted the major part of the representative ingredients and could be used to treat both diseases. Moreover, ALB, AKT1, ESR1, CASP3, and NOS3 were also chosen as prospective targets for synthetic multitarget ingredient screening. Further docking studies revealed that various natural chemicals exhibited binding affinity with the 5 targets, including quercetin, kaempferol, β-sitosterol, stigmasterol, isorhamnetin, naringenin, and 8-isopentenyl-kaempferol. Conclusion: Taken as a whole, the current study indicates a TCM combination with positive advantages in the combined treatment of AD and MDD.
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Affiliation(s)
- Zhao-han Huang
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Yuan Fang
- Shanghai Center for Women and Children’s Health, Shanghai, People’s Republic of China
| | - Xiao-lu Wang
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Qi Wang
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Tong Wang
- Beijing University of Chinese Medicine, Beijing, People’s Republic of China
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21
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Alhakamy NA, Caruso G, Privitera A, Ahmed OAA, Fahmy UA, Md S, Mohamed GA, Ibrahim SRM, Eid BG, Abdel-Naim AB, Caraci F. Fluoxetine Ecofriendly Nanoemulsion Enhances Wound Healing in Diabetic Rats: In Vivo Efficacy Assessment. Pharmaceutics 2022; 14:1133. [PMID: 35745706 PMCID: PMC9227110 DOI: 10.3390/pharmaceutics14061133] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 02/04/2023] Open
Abstract
Impaired diabetic wound healing is a major concern for health care professionals worldwide, imposing an intense financial burden and reducing the quality of life of patients. A dysregulation of this process can be responsible for the development of intractable ulcers and the formation of excessive scars. Therefore, the identification of novel pharmacological strategies able to promote wound healing and restore the mechanical integrity of injured tissue becomes essential. In the present study, fluoxetine ecofriendly nanoemulsion (FLX-EFNE) was prepared and its potential efficacy in enhancing wound healing was tested in diabetic rats. The Box-Behnken response surface design was used to select the optimized formulation that was prepared by the high-shear homogenization-based technique. A Zetasizer was used for the characterization of the optimized formulation, providing a FLX-EFNE with a globule size of 199 nm. For the in vivo study, a wound was induced by surgical methods, and diabetic rats (streptozotocin-induced) were divided into five groups: untreated control, vehicle-treated, FLX, FLX-EFNE, and positive control receiving a commercially available formula. The treatment continued from the day of wound induction to day 21. Then, the animals were sacrificed and skin tissues were collected at the site of wounding and used for biochemical, histopathological, immunohistochemical, and mRNA expression assessments. In the FLX-EFNE treated group, the rate of wound contraction and signs of healing were significantly higher compared to all other groups. In addition, angiogenesis, proliferation, and collagen deposition were enhanced, while oxidative stress and inflammation decreased. The present data highlight the enhanced wound healing activity of the optimized FLX-EFNE formulation.
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Affiliation(s)
- Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (O.A.A.A.); (U.A.F.); (S.M.)
- Advanced Drug Delivery Research Group, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Giuseppe Caruso
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.P.); (F.C.)
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute—IRCCS, 94018 Troina, Italy
| | - Anna Privitera
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.P.); (F.C.)
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (O.A.A.A.); (U.A.F.); (S.M.)
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (O.A.A.A.); (U.A.F.); (S.M.)
| | - Shadab Md
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (N.A.A.); (O.A.A.A.); (U.A.F.); (S.M.)
| | - Gamal A. Mohamed
- Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Sabrin R. M. Ibrahim
- Preparatory Year Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia;
- Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Basma G. Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (B.G.E.); (A.B.A.-N.)
| | - Ashraf B. Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (B.G.E.); (A.B.A.-N.)
| | - Filippo Caraci
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.P.); (F.C.)
- Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute—IRCCS, 94018 Troina, Italy
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22
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Polysaccharides from Polygonatum cyrtonema Hua Reduce Depression-Like Behavior in Mice by Inhibiting Oxidative Stress-Calpain-1-NLRP3 Signaling Axis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2566917. [PMID: 35498131 PMCID: PMC9045988 DOI: 10.1155/2022/2566917] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/16/2022] [Accepted: 03/29/2022] [Indexed: 12/15/2022]
Abstract
Polysaccharides from Polygonatum cyrtonema Hua (PSP) exert antioxidant, anti-inflammatory, and antidepressant effects. Production of reactive oxygen species (ROS) and activation of the calpain system and the NOD-like receptor protein 3 (NLRP3) inflammasome are closely related to the pathogenesis of depression. However, the relationships among those pathways and the protective effects of PSP have not been characterized. In this study, lipopolysaccharide (LPS) and chronic unpredictable mild stress- (CUMS-) induced depression models were used to evaluate the protective mechanisms of PSP against depression. ROS levels were measured in HT-22 cells using flow cytometry. Brain tissues were collected to determine the levels of oxidation-related indicators and inflammatory cytokines. The protein levels of calpain-1, calpain-2, calpastatin, phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN), suprachiasmatic nucleus circadian oscillatory protein (SCOP), nuclear factor-erythroid factor 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NLRP3, apoptosis-associated speck-like protein (ASC), caspase-1, cleaved-caspase-1, ionized calcium binding adapter molecule 1 (Iba1), phosphorylation of extracellular signal-regulated kinase (p-ERK), nuclear factor-kappa B (NF-κB), interleukin-1β (IL-1β), and glial fibrillary acidic protein (GFAP) were measured using western blotting or immunofluorescence. In cellular experiments, we showed that PSP attenuated LPS-induced production of ROS in HT-22 cells. In animal experiments, we found that LPS increased the expression of calpain-1, NLRP3, ASC, caspase-1, cleaved-caspase-1, Iba1, p-ERK, NF-κB, and GFAP and reduced the expression of calpastatin, PTEN, SCOP, and Nrf2. Administration of PSP reversed these changes. N-Acetyl-L-cysteine (NAC) administration also inhibited oxidative stress and activation of the calpain system and the NLRP3 inflammasome. Furthermore, PSP, calpeptin, MCC950 (a selective NLRP3 inflammasome inhibitor), and NAC reduced LPS-induced proinflammatory cytokine release. We also showed that PSP prevented CUMS-induced changes in the calpain system and the Nrf2 and NLRP3 signaling pathways and reduced depression-like behavior. These results indicate that PSP exerts antidepressant effects through regulation of the oxidative stress-calpain-1-NLRP3 signaling axis.
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23
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Wei Y, Chang L, Hashimoto K. Intranasal administration of transforming growth factor-β1 elicits rapid-acting antidepressant-like effects in a chronic social defeat stress model: A role of TrkB signaling. Eur Neuropsychopharmacol 2021; 50:55-63. [PMID: 33971385 DOI: 10.1016/j.euroneuro.2021.04.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 04/12/2021] [Accepted: 04/14/2021] [Indexed: 12/29/2022]
Abstract
(R,S)-ketamine causes rapid-acting and sustained antidepressant effects in treatment-resistant patients with depression although the precise molecular mechanisms underlying its antidepressant action remain unclear. We recently reported that transforming growth factor (TGF)-β1 might contribute to the antidepressant-like effects of (R)-ketamine that is a more potent enantiomer in rodents. Although TrkB signaling plays a role in the antidepressant-like actions of (R,S)-ketamine and its enantiomers, the role of TrkB signaling in the antidepressant effects of TGF-β1 remains unclear. Using behavioral tests such as tail-suspension test (TST), forced swimming test (FST), and 1% sucrose preference test (SPT), we investigated whether a single intranasal administration of the recombinant TGF-β1 (1.5 and 3.0 μg/kg) causes rapid and sustained antidepressant-like effects in a chronic social defeat stress (CSDS) model. Both doses of TGF-β1 significantly attenuated the increased immobility time of TST and FST in the CSDS susceptible mice. High dose of TGF-β1, but not low dose, significantly ameliorated the decreased sucrose preference of SPT in the CSDS susceptible mice. Pretreatment with a TrkB antagonist ANA-12 (0.5 mg/kg) blocked the antidepressant-like effects of TGF-β1 in CSDS susceptible mice. The data suggest that intranasal administration of TGF-β1 could elicit rapid-acting antidepressant-like effects via TrkB stimulation in a CSDS model. Therefore, it is likely that intranasal administration of TGF-β1 would be a novel therapeutic approach for depression.
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Affiliation(s)
- Yan Wei
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Lijia Chang
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan.
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24
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Nakasujja N, Vecchio AC, Saylor D, Lofgren S, Nakigozi G, Boulware DR, Kisakye A, Batte J, Mayanja R, Anok A, Reynolds SJ, Quinn TC, Pardo CA, Kumar A, Gray RH, Wawer MJ, Sacktor N, Rubin LH. Improvement in depressive symptoms after antiretroviral therapy initiation in people with HIV in Rakai, Uganda. J Neurovirol 2021; 27:519-530. [PMID: 34333739 PMCID: PMC8524346 DOI: 10.1007/s13365-020-00920-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 09/17/2020] [Accepted: 10/08/2020] [Indexed: 10/20/2022]
Abstract
Depression is common following HIV infection and often improves after ART initiation. We aimed to identify distinct dimensions of depression that change following ART initiation in persons with HIV (PWH) with minimal comorbidities (e.g., illicit substance use) and no psychiatric medication use. We expected that dimensional changes in improvements in depression would differ across PWH. In an observational cohort in Rakai, Uganda, 312 PWH (51% male; mean age = 35.6 years) completed the Center for Epidemiologic Studies-Depression (CES-D) scale before and up to 2 years after ART initiation. Twenty-two percent were depressed (CES-D scores ≥ 16) pre-ART that decreased to 8% after ART. All CES-D items were used in a latent class analysis to identify subgroups with similar change phenotypes. Two improvement phenotypes were identified: affective-symptom improvement (n = 58, 19%) and mixed-symptom improvement (effort, appetite, irritability; n = 41, 13%). The affect-improvement subgroup improved on the greatest proportion of symptoms (76%). A third subgroup was classified as no-symptom changes (n = 213, 68%) as they showed no difference is symptom manifestation from baseline (93% did not meet depression criteria) to post-ART. Factors associated with subgroup membership in the adjusted regression analysis included pre-ART self-reported functional capacity, CD4 count, underweight BMI, hypertension, female sex(P's < 0.05). In a subset of PWH with CSF, subgroup differences were seen on Aβ-42, IL-13, and IL-12. Findings support that depression generally improves following ART initiation; however, when improvement is seen the patterns of symptom improvement differ across PWH. Further exploration of this heterogeneity and its biological underpinning is needed to evaluate potential therapeutic implications of these differences.
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Affiliation(s)
| | - Alyssa C Vecchio
- Institute of Global Health, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA
| | - Deanna Saylor
- Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Meyer 6-113, Baltimore, MD, USA
| | - Sarah Lofgren
- Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN, USA
| | | | | | | | - James Batte
- Rakai Health Sciences Program, Kalisizo, Uganda
| | | | - Aggrey Anok
- Rakai Health Sciences Program, Kalisizo, Uganda
| | - Steven J Reynolds
- Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA
- Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas C Quinn
- Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA
- Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Carlos A Pardo
- Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Meyer 6-113, Baltimore, MD, USA
| | | | - Ronald H Gray
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
| | - Maria J Wawer
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
| | - Ned Sacktor
- Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Meyer 6-113, Baltimore, MD, USA
| | - Leah H Rubin
- Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Meyer 6-113, Baltimore, MD, USA.
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.
- Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, USA.
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25
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Shen F, Song Z, Xie P, Li L, Wang B, Peng D, Zhu G. Polygonatum sibiricum polysaccharide prevents depression-like behaviors by reducing oxidative stress, inflammation, and cellular and synaptic damage. JOURNAL OF ETHNOPHARMACOLOGY 2021; 275:114164. [PMID: 33932516 DOI: 10.1016/j.jep.2021.114164] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/21/2021] [Accepted: 04/23/2021] [Indexed: 05/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE According to traditional Chinese medicine (TCM) theory (Yi Xue Zheng Zhuan), the main factors associated with the pathogenesis of depression are deficiencies relating to five zang organs, Qi, and blood. Polygonatum sibiricum F. Delaroche (PS), which may avert these pathological changes, has been used in a variety of formulas to treat depression. However, the effects and mechanism of action of PS, alone, and especially those of its main active component PS polysaccharide (PSP), on depression remain unexplored. AIM OF THE STUDY To determine the effects of PSP on depression-like behaviors and to elucidate its mechanism of action. METHODS PSP was isolated from dried PS rhizomes and qualified using transmission electron microscopy and Fourier transform infrared spectroscopy. Lipopolysaccharide (LPS) and chronic unpredictable mild stress (CUMS)-induced depression models were used to evaluate the antidepressive effects of PSP. Veinal blood and brain tissue were collected to determine the levels of hippocampal 5-HT, serum cortisol (CORT), brain and serum cytokines, and hippocampal oxidation-related indicators. The protein expression levels of phosphorylated extracellular signal-regulated kinase (p-ERK1/2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), glial fibrillary acidic protein (GFAP), phosphorylated protein kinase B (p-Akt), phosphorylation of the mammalian target of rapamycin (mTOR), caspase-3, GluA1 and GluA2, and GluN2A and GluN2B were determined using western blotting and immunofluorescence. Nissl staining was performed to detect histopathological changes in brain tissues. RESULTS Injection of LPS (i.p.) induced depression-like behaviors, reduced the level of hippocampal 5-HT, increased the serum CORT level and hippocampal oxidative stress (ROS), and prompted the activation of ERK1/2, NF-κB, and GFAP and an inflammatory response. Conversely, PSP administration reduced these changes and prevented depression-like behaviors. PSP administration also promoted hippocampal expression of p-Akt, p-mTOR, GluA1, and GluA2; reduced the expression of caspase-3, GluN2A, and GluN2B; and prohibited the loss of granular cells in the DG region. CONCLUSION These results indicate that PSP prevents depression-like behaviors, and synaptic and neuronal damage probably by reducing ROS/HPA axis hyperfunction and the inflammatory response.
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Affiliation(s)
- Fengming Shen
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Chinese Medical Formula, Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China
| | - Zhujin Song
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Chinese Medical Formula, Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China
| | - Pan Xie
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Chinese Medical Formula, Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China
| | - Lei Li
- Anhui Senfeng Agricultural Comprehensive Development Co., Ltd, Hefei, China
| | - Bin Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Chinese Medical Formula, Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.
| | - Daiyin Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Chinese Medical Formula, Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.
| | - Guoqi Zhu
- School of Pharmacy, Anhui University of Chinese Medicine, Anhui Province Key Laboratory of Chinese Medical Formula, Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.
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26
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Al-Hakeim HK, Twayej AJ, Al-Dujaili AH, Maes M. Plasma Indoleamine-2,3-Dioxygenase (IDO) is Increased in Drug-Naï ve Major Depressed Patients and Treatment with Sertraline and Ketoprofen Normalizes IDO in Association with Pro-Inflammatory and Immune- Regulatory Cytokines. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 19:44-54. [PMID: 31894751 DOI: 10.2174/1871527319666200102100307] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/17/2019] [Accepted: 11/20/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of inflammatory and immune-regulatory cytokines and stimulation of indoleamine-2,3-dioxygenase (IDO). There is also evidence that anti-inflammatory drugs may have clinical efficacy in MDD. METHODS This study examined a) IDO in association with interferon (IFN)-γ, Interleukin (IL)-4 and Transforming Growth Factor (TGF)-β1 in 140 drug-naïve MDD patients and 40 normal controls; and b) the effects of an eight-week treatment of sertraline with or without ketoprofen (a nonsteroidal antiinflammatory drug) on the same biomarkers in 44 MDD patients. RESULTS Baseline IDO, IFN-γ, TGF-β1 and IL-4 were significantly higher in MDD patients as compared with controls. Treatment with sertraline with or without ketoprofen significantly reduced the baseline levels of all biomarkers to levels which were in the normal range (IDO, TGF-β1, and IL-4) or still somewhat higher than in controls (IFN-γ). Ketoprofen add-on had a significantly greater effect on IDO as compared with placebo. The reductions in IDO, IL-4, and TGF-β1 during treatment were significantly associated with those in the BDI-II. CONCLUSION MDD is accompanied by activated immune-inflammatory pathways (including IDO) and the Compensatory Immune-Regulatory System (CIRS). The clinical efficacy of antidepressant treatment may be ascribed at least in part to decrements in IDO and the immune-inflammatory response. These treatments also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD while enhancing the CIRS.
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Affiliation(s)
| | - Ahmed Jasim Twayej
- Pathological Analysis Department, College of Health and Medical, Al-Kafeel University, Najaf, Iraq
| | | | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.,Department of Psychiatry, Medical University Plovdiv, Plovdiv, Bulgaria.,IMPACT Research Center, Deakin University, Geelong, Australia
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27
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Grasso M, Caruso G, Godos J, Bonaccorso A, Carbone C, Castellano S, Currenti W, Grosso G, Musumeci T, Caraci F. Improving Cognition with Nutraceuticals Targeting TGF-β1 Signaling. Antioxidants (Basel) 2021; 10:1075. [PMID: 34356309 PMCID: PMC8301008 DOI: 10.3390/antiox10071075] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/11/2022] Open
Abstract
Rescue of cognitive function represents an unmet need in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Nutraceuticals deliver a concentrated form of a presumed bioactive(s) agent(s) that can improve cognitive function alone or in combination with current approved drugs for the treatment of cognitive disorders. Nutraceuticals include different natural compounds such as flavonoids and their subclasses (flavan-3-ols, catechins, anthocyanins, and flavonols), omega-3, and carnosine that can improve synaptic plasticity and rescue cognitive deficits through multiple molecular mechanisms. A deficit of transforming growth factor-β1 (TGF-β1) pathway is an early event in the pathophysiology of cognitive impairment in different neuropsychiatric disorders, from depression to AD. In the present review, we provide evidence that different nutraceuticals, such as Hypericum perforatum (hypericin and hyperforin), flavonoids such as hesperidin, omega-3, and carnosine, can target TGF-β1 signaling and increase TGF-β1 production in the central nervous system as well as cognitive function. The bioavailability of these nutraceuticals, in particular carnosine, can be significantly improved with novel formulations (nanoparticulate systems, nanoliposomes) that increase the efficacy and stability of this peptide. Overall, these studies suggest that the synergism between nutraceuticals targeting the TGF-β1 pathway and current approved drugs might represent a novel pharmacological approach for reverting cognitive deficits in AD patients.
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Affiliation(s)
- Margherita Grasso
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (M.G.); (G.C.); (A.B.); (C.C.); (T.M.); (F.C.)
- Oasi Research Institute—IRCCS, 94018 Troina, Italy
| | - Giuseppe Caruso
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (M.G.); (G.C.); (A.B.); (C.C.); (T.M.); (F.C.)
| | - Justyna Godos
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (J.G.); (W.C.)
| | - Angela Bonaccorso
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (M.G.); (G.C.); (A.B.); (C.C.); (T.M.); (F.C.)
| | - Claudia Carbone
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (M.G.); (G.C.); (A.B.); (C.C.); (T.M.); (F.C.)
| | - Sabrina Castellano
- Department of Educational Sciences, University of Catania, 95124 Catania, Italy;
| | - Walter Currenti
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (J.G.); (W.C.)
| | - Giuseppe Grosso
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (J.G.); (W.C.)
| | - Teresa Musumeci
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (M.G.); (G.C.); (A.B.); (C.C.); (T.M.); (F.C.)
| | - Filippo Caraci
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (M.G.); (G.C.); (A.B.); (C.C.); (T.M.); (F.C.)
- Oasi Research Institute—IRCCS, 94018 Troina, Italy
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28
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Kim YR, Park BK, Seo CS, Kim NS, Lee MY. Antidepressant and Anxiolytic-Like Effects of the Stem Bark Extract of Fraxinus rhynchophylla Hance and Its Components in a Mouse Model of Depressive-Like Disorder Induced by Reserpine Administration. Front Behav Neurosci 2021; 15:650833. [PMID: 34220460 PMCID: PMC8245701 DOI: 10.3389/fnbeh.2021.650833] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 05/11/2021] [Indexed: 11/14/2022] Open
Abstract
There is an urgent need to find antidepressants that can be administered for long periods without inducing severe side effects to replace conventional antidepressants that control monoamine levels, such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRI). We sought to determine the antidepressant effects of Fraxinus rhynchophylla Hance (F. rhynchophylla Hance, FX) and its components on a reserpine-induced mouse model. One hour after oral administration of FX (30, 50, and 100 mg/kg), esculin (50 mg/kg), esculetin (50 mg/kg), fraxin (50 mg/kg), and fluoxetine (20 mg/kg), reserpine was delivered intraperitoneally to mice. Behavioral experiments were conducted to measure anxiety and depressive-like behaviors after 10 days of administration. FX and its components increased the number of entries into the center of an open field as well as distance traveled within it and decreased immobility duration in the forced swim and tail suspension tests. Reserpine-induced increases in plasma corticosterone concentrations were attenuated by the administration of FX and its components, which were also found to decrease the reserpine-induced enhancement of mRNA levels of interleukin (IL)-12 p40, IL-6, and tumor necrosis factor (TNF)-α, pro-inflammatory cytokines. Finally, the diminished expressions of hippocampal phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) by reserpine were increased by FX and its components. Our results suggest that FX and its components regulate anxiety and depressive-like behaviors through stress hormones, immune regulation, and the activation of neuroprotective mechanisms, further supporting the potential of FX and its components as antidepressants.
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Affiliation(s)
- Yu Ri Kim
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Bo-Kyung Park
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Chang-Seob Seo
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - No Soo Kim
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Mi Young Lee
- Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
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29
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Pashaei Y. Drug repurposing of selective serotonin reuptake inhibitors: Could these drugs help fight COVID-19 and save lives? J Clin Neurosci 2021; 88:163-172. [PMID: 33992179 PMCID: PMC7973060 DOI: 10.1016/j.jocn.2021.03.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/05/2021] [Accepted: 03/11/2021] [Indexed: 02/09/2023]
Abstract
The current 2019 novel coronavirus disease (COVID-19), an emerging infectious disease, is undoubtedly the most challenging pandemic in the 21st century. A total of 92,977,768 confirmed cases of COVID-19 and 1,991,289 deaths were reported globally up to January 14, 2021. COVID-19 also affects people's mental health and quality of life. At present, there is no effective therapeutic strategy for the management of this disease. Therefore, in the absence of a specific vaccine or curative treatment, it is an urgent need to identify safe, effective and globally available drugs for reducing COVID-19 morbidity and fatalities. In this review, we focus on selective serotonin reuptake inhibitors (SSRIs: a class of antidepressant drugs with widespread availability and an optimal tolerability profile) that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials. We also summarize the existing literature on what is known about the link between serotonin (5-HT) and the immune system. From the evidence reviewed here, we propose fluoxetine as an adjuvant therapeutic agent for COVID-19 based on its known immunomodulatory, anti-inflammatory and antiviral properties. Fluoxetine may potentially reduce pro-inflammatory chemokine/cytokines levels (such as CCL-2, IL-6, and TNF-α) in COVID-19 patients. Furthermore, fluoxetine may help to attenuate neurological complications of COVID-19.
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Businaro R, Vauzour D, Sarris J, Münch G, Gyengesi E, Brogelli L, Zuzarte P. Therapeutic Opportunities for Food Supplements in Neurodegenerative Disease and Depression. Front Nutr 2021; 8:669846. [PMID: 34055858 PMCID: PMC8160227 DOI: 10.3389/fnut.2021.669846] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022] Open
Abstract
Emerging evidence is showing nutrition as a crucial factor in the high prevalence and incidence of neurodegenerative mental disorders. Preventive interventions on neuroinflammation seem to be able to interfere with neurodegeneration. Supplementation of essential nutrients, such as long-chain-polyunsaturated fatty acids, vitamin E and mineral elements, may minimize inflammation, enhancing antioxidative defense, and lowering the risk and incidence of age-related diseases, such as cardiovascular diseases and neurodegenerative diseases. This manuscript reviews the current evidence on the role of neuroinflammation in the pathophysiology of neurodegenerative and mental disorders, and preventive strategies for food supplementation in these neuropsychiatric diseases. Dietary supplementation-based strategies have been demonstrated to be effective in subjects with mild cognitive impairment, while weaker results have been obtained in patients with advance neurodegenerative disease. Adjunctive supplementation has also been demonstrated to improve depression, this being of marked benefit considering the comorbidity between cognitive impairment/dementia and depression. Further research is needed to improve the prescriptive precision of supplementation in patients, and to better understand potential interactions with clinical and pharmacokinetic factors.
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Affiliation(s)
- Rita Businaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - David Vauzour
- Faculty of Medicine and Health Sciences, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Jerome Sarris
- NICM Health Research Institute, Western Sydney University, Westmead, NSW, Australia.,Professorial Unit, The Melbourne Clinic, Department of Psychiatry, Melbourne University, Melbourne, VIC, Australia
| | - Gerald Münch
- Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Erika Gyengesi
- Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | | | - Pedro Zuzarte
- Psychiatric Clinic, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.,Neuropsychiatry Research Department, GNR Clinical Center, Lisbon, Portugal
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Bialek K, Czarny P, Wigner P, Synowiec E, Barszczewska G, Bijak M, Szemraj J, Niemczyk M, Tota-Glowczyk K, Papp M, Sliwinski T. Chronic Mild Stress and Venlafaxine Treatment Were Associated with Altered Expression Level and Methylation Status of New Candidate Inflammatory Genes in PBMCs and Brain Structures of Wistar Rats. Genes (Basel) 2021; 12:genes12050667. [PMID: 33946816 PMCID: PMC8146372 DOI: 10.3390/genes12050667] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 01/04/2023] Open
Abstract
Preclinical studies conducted to date suggest that depression could be elicited by the elevated expression of proinflammatory molecules: these play a key role in the mediation of neurochemical, neuroendocrine and behavioral changes. Thus, this study investigates the effect of chronic mild stress (CMS) and administration of venlafaxine (SSRI) on the expression and methylation status of new target inflammatory genes: TGFA, TGFB, IRF1, PTGS2 and IKBKB, in peripheral blood mononuclear cells (PMBCs) and in selected brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or venlafaxine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our results indicate that both CMS and chronic treatment with venlafaxine were associated with changes in expression of the studied genes and their promoter methylation status in PMBCs and the brain. Moreover, the effect of antidepressant administration clearly differed between brain structures. Summarizing, our results confirm at least a partial association between TGFA, TGFB, IRF1, PTGS2 and IKBKB and depressive disorders.
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Affiliation(s)
- Katarzyna Bialek
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland; (K.B.); (E.S.); (G.B.)
| | - Piotr Czarny
- Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland; (P.C.); (J.S.)
| | - Paulina Wigner
- Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
| | - Ewelina Synowiec
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland; (K.B.); (E.S.); (G.B.)
| | - Gabriela Barszczewska
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland; (K.B.); (E.S.); (G.B.)
| | - Michal Bijak
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland; (P.C.); (J.S.)
| | - Monika Niemczyk
- Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland; (M.N.); (K.T.-G.); (M.P.)
| | - Katarzyna Tota-Glowczyk
- Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland; (M.N.); (K.T.-G.); (M.P.)
| | - Mariusz Papp
- Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland; (M.N.); (K.T.-G.); (M.P.)
| | - Tomasz Sliwinski
- Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland; (K.B.); (E.S.); (G.B.)
- Correspondence: ; Tel.: +48-42-635-44-86; Fax: +48-42-635-44-84
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Canonical TGF-β signaling regulates the relationship between prenatal maternal depression and amygdala development in early life. Transl Psychiatry 2021; 11:170. [PMID: 33723212 PMCID: PMC7961018 DOI: 10.1038/s41398-021-01292-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 02/18/2021] [Accepted: 02/25/2021] [Indexed: 02/04/2023] Open
Abstract
Canonical transforming growth factor-beta (TGF-β) signaling exerts neuroprotection and influences memory formation and synaptic plasticity. It has been considered as a new target for the prevention and treatment of depression. This study aimed to examine its modulatory role in linking prenatal maternal depressive symptoms and the amygdala volumes from birth to 6 years of age. We included mother-child dyads (birth: n = 161; 4.5 years: n = 131; 6 years: n = 162) and acquired structural brain images of children at these three time points. Perinatal maternal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) questionnaire to mothers at 26 weeks of pregnancy and 3 months postpartum. Our findings showed that the genetic variants of TGF-β type I transmembrane receptor (TGF-βRI) modulated the association between prenatal maternal depressive symptoms and the amygdala volume consistently from birth to 6 years of age despite a trend of significance at 4.5 years of age. Children with a lower gene expression score (GES) of TGF-βRI exhibited larger amygdala volumes in relation to greater prenatal maternal depressive symptoms. Moreover, children with a lower GES of the TGF-β type II transmembrane receptor (TGF-βRII), Smad4, and Smad7 showed larger amygdala volumes at 6 years of age in relation to greater prenatal maternal depressive symptoms. These findings support the involvement of the canonical TGF-β signaling pathway in the brain development of children in the context of in utero maternal environment. Such involvement is age-dependent.
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Could α-Klotho Unlock the Key Between Depression and Dementia in the Elderly: from Animal to Human Studies. Mol Neurobiol 2021; 58:2874-2885. [PMID: 33527303 DOI: 10.1007/s12035-021-02313-0] [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: 06/12/2020] [Accepted: 01/25/2021] [Indexed: 10/22/2022]
Abstract
α-Klotho is known for its aging-related functions and is associated with neurodegenerative diseases, accelerated aging, premature morbidity, and mortality. Recent literature suggests that α-Klotho is also involved in the regulation of mental functions, such as cognition and psychosis. While most of studies of α-Klotho are focusing on its anti-aging functions and protective role in dementia, increasing evidence showed many shared symptoms between depression and dementia, while depression has been proposed as the preclinical stage of dementia such as Alzheimer's disease (AD). To see whether and how α-Klotho can be a key biological link between depression and dementia, in this review, we first gathered the evidence on biological distribution and function of α-Klotho in psychiatric functions from animal studies to human clinical investigations with a focus on the regulation of cognition and mood. Then, we discussed and highlighted the potential common underlying mechanisms of α-Klotho between psychiatric diseases and cognitive impairment. Finally, we hypothesized that α-Klotho might serve as a neurobiological link between depression and dementia through the regulation of oxidative stress and inflammation.
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Song Z, Shen F, Zhang Z, Wu S, Zhu G. Calpain inhibition ameliorates depression-like behaviors by reducing inflammation and promoting synaptic protein expression in the hippocampus. Neuropharmacology 2020; 174:108175. [DOI: 10.1016/j.neuropharm.2020.108175] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/20/2020] [Accepted: 05/26/2020] [Indexed: 02/08/2023]
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Osimo EF, Pillinger T, Rodriguez IM, Khandaker GM, Pariante CM, Howes OD. Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain Behav Immun 2020; 87:901-909. [PMID: 32113908 PMCID: PMC7327519 DOI: 10.1016/j.bbi.2020.02.010] [Citation(s) in RCA: 471] [Impact Index Per Article: 94.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 01/30/2020] [Accepted: 02/20/2020] [Indexed: 12/27/2022] Open
Abstract
IMPORTANCE The magnitude and variability of cytokine alterations in depression are not clear. OBJECTIVE To perform an up to date meta-analysis of mean differences of immune markers in depression, and to quantify and test for evidence of heterogeneity in immune markers in depression by conducting a meta-analysis of variability to ascertain whether only a sub-group of patients with depression show evidence of inflammation. DATA SOURCES Studies that reported immune marker levels in peripheral blood in patients with depression and matched healthy controls in the MEDLINE database from inception to August 29th 2018 were examined. STUDY SELECTION Case-control studies that reported immune marker levels in peripheral blood in patients with depression and healthy controls were selected. DATA EXTRACTION AND SYNTHESIS Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis. MAIN OUTCOMES AND MEASURES Hedges g was used to quantify mean differences. Relative variability of immune marker measurements in patients compared with control groups as indexed by the coefficient of variation ratio (CVR). RESULTS A total of 107 studies that reported measurements from 5,166 patients with depression and 5,083 controls were included in the analyses. Levels of CRP (g = 0.71; 95%CI: 0.50-0.92; p < 0.0001); IL-3 (g = 0.60; 95%CI: 0.31-0.89; p < 0.0001); IL-6 (g = 0.61; 95%CI: 0.39-0.82; p < 0.0001); IL-12 (g = 1.18; 95%CI: 0.74-1.62; p < 0.0001); IL-18 (g = 1.97; 95%CI: 1.00-2.95; p < 0.0001); sIL-2R (g = 0.71; 95%CI: 0.44-0.98; p < 0.0001); and TNFα (g = 0.54; 95%CI: 0.32-0.76; p < 0.0001) were significantly higher in patients with depression. These findings were robust to a range of potential confounds and moderators. Mean-scaled variability, measured as CVR, was significantly lower in patients with depression for CRP (CVR = 0.85; 95%CI: 0.75-0.98; p = 0.02); IL-12 (CVR = 0.61; 95%CI: 0.46-0.80; p < 0.01); and sIL-2R (CVR = 0.85; 95%CI: 0.73-0.99; p = 0.04), while it was unchanged for IL-3, IL-6, IL-18, and TNF α. CONCLUSIONS AND RELEVANCE Depression is confirmed as a pro-inflammatory state. Some of the inflammatory markers elevated in depression, including CRP and IL-12, show reduced variability in patients with depression, therefore supporting greater homogeneity in terms of an inflammatory phenotype in depression. Some inflammatory marker elevations in depression do not appear due to an inflamed sub-group, but rather to a right shift of the immune marker distribution.
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Affiliation(s)
- Emanuele F. Osimo
- MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK,Department of Psychiatry, University of Cambridge, Cambridge, UK,Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Toby Pillinger
- MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK,Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | | | - Golam M. Khandaker
- Department of Psychiatry, University of Cambridge, Cambridge, UK,Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Carmine M. Pariante
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK,National Institute for Health Research, Mental Health Biomedical Research Centre, South London and Maudsley NHS Foundation Trust and King's College London, London, UK,The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London SE5 9RT, UK
| | - Oliver D. Howes
- MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK,Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK,Corresponding author at: MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
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A Specific Inflammatory Profile Underlying Suicide Risk? Systematic Review of the Main Literature Findings. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17072393. [PMID: 32244611 PMCID: PMC7177217 DOI: 10.3390/ijerph17072393] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/09/2020] [Accepted: 03/26/2020] [Indexed: 01/15/2023]
Abstract
Consistent evidence indicates the association between inflammatory markers and suicidal behavior. The burden related to immunological differences have been widely documented in both major affective disorders and suicidal behavior. Importantly, abnormally elevated pro-inflammatory cytokines levels have been reported to correlate with suicidal behavior but whether and to what extent specific inflammatory cytokines abnormalities may contribute to our understanding of the complex pathophysiology of suicide is unknown. The present manuscript aimed to systematically review the current literature about the role of pro-inflammatory cytokines in suicidal behavior. Most studies showed a link between abnormally higher interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), kynurenic acid (KYN), and lower IL-2, IL-4, and interferon (IFN)-γ levels in specific brain regions and suicidal behavior. Unfortunately, most studies are not able to exclude the exact contribution of major depressive disorder (MDD) as a mediator/moderator of the link between inflammatory cytokines abnormalities and suicidal behavior. The association between suicidal patients (both suicide attempters or those with suicidal ideation) and the altered immune system was documented by most studies, but this does not reflect the existence of a specific causal link. Additional studies are needed to clarify the immune pathways underlying suicidal behavior.
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Petralia MC, Mazzon E, Fagone P, Basile MS, Lenzo V, Quattropani MC, Di Nuovo S, Bendtzen K, Nicoletti F. The cytokine network in the pathogenesis of major depressive disorder. Close to translation? Autoimmun Rev 2020; 19:102504. [PMID: 32173514 DOI: 10.1016/j.autrev.2020.102504] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 12/25/2019] [Indexed: 12/18/2022]
Abstract
Major depressive disorder (MDD) is a common condition that afflicts the general population across a broad spectrum of ages and social backgrounds. MDD has been identified by the World Health Organization as a leading cause of disability worldwide. Approximately 30% of patients are poor responsive to standard of care (SOC) treatment and novel therapeutic approaches are warranted. Since chronic inflammation, as it is often observed in certain cancers, type 2 diabetes, psoriasis and chronic arthritis, are accompanied by depression, it has been suggested that immunoinflammatory processes may be involved in the pathogenesis of MDD. Cytokines are a group of glycoproteins secreted from lymphoid and non-lymphoid cells that orchestrate immune responses. It has been suggested that a dysregulated production of cytokines may be implicated in the pathogenesis and maintenance of MDD. On the basis of their functions, cytokines can be subdivided in pro-inflammatory and anti-inflammatory cytokines. Since abnormal blood and cerebrospinal fluid of both pro and anti-inflammatory cytokines are altered in MDD, it has been suggested that abnormal cytokine homeostasis may be implicated in the pathogenesis of MDD and possibly to induction of therapeutic resistance. We review current data that indicate that cytokines may represent a useful tool to identify MDD patients that may benefit from tailored immunotherapeutic approaches and may represent a potential tailored therapeutic target.
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Affiliation(s)
| | | | - Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Maria Sofia Basile
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Vittorio Lenzo
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | | | - Santo Di Nuovo
- Department of Educational Sciences, University of Catania, Catania, Italy
| | | | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
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Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders. Mol Psychiatry 2020; 25:1275-1285. [PMID: 31427751 PMCID: PMC7244402 DOI: 10.1038/s41380-019-0471-8] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 06/14/2019] [Accepted: 06/24/2019] [Indexed: 11/19/2022]
Abstract
Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4-16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12-0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20-1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26-0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06-0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.
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Ferrúa CP, Giorgi R, da Rosa LC, do Amaral CC, Ghisleni GC, Pinheiro RT, Nedel F. MicroRNAs expressed in depression and their associated pathways: A systematic review and a bioinformatics analysis. J Chem Neuroanat 2019; 100:101650. [PMID: 31125682 PMCID: PMC6996133 DOI: 10.1016/j.jchemneu.2019.101650] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/17/2019] [Accepted: 05/19/2019] [Indexed: 01/14/2023]
Abstract
Depression is a debilitating mental illness, one of the most prevalent worldwide. MicroRNAs have been studied to better understand the biological mechanisms that regulate this disease. This study review systematically the literature to identify which microRNAs are currently being associated with depression and their related pathways. The electronic search was conducted in PubMed, Scopus, Scielo, ISI Web of Knowledge, and PsycINFO databases, using the search terms "Depressive Disorder" or "Depression" and "MicroRNAs". After, microRNAs that were up and down-regulated in depression were analyzed by bioinformatics. We observed that among the 77 microRNAs cited by included studies, 54 had their levels altered in depressed individuals compared to controls, 30 being up-regulated and 24 down-regulated. The bioinformatics analysis revealed that among the up-regulated microRNAs there were 81 total and 43 union pathways, with 15 presenting a significant difference. Among the down-regulated microRNAs, 67 total and 45 union pathways were found, with 14 presenting a significant difference. The miR-17-5p and let-7a-5p were the most frequently found microRNAs in the statistically significant pathways. In this study a panel of altered microRNAs in depression was created with their related pathways, which is a step towards understanding the complex network of microRNAs in depression.
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Affiliation(s)
| | | | | | | | | | | | - Fernanda Nedel
- Corresponding author at: Programa de Pós-graduação em Saúde e Comportamento, Universidade Católica de Pelotas, Rua Félix da Cunha, 412, 96010-901, Pelotas, RS, Brazil.
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Arumugasaamy N, Gudelsky A, Hurley-Novatny A, Kim PC, Fisher JP. Model Placental Barrier Phenotypic Response to Fluoxetine and Sertraline: A Comparative Study. Adv Healthc Mater 2019; 8:e1900476. [PMID: 31407872 PMCID: PMC6752965 DOI: 10.1002/adhm.201900476] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 07/10/2019] [Indexed: 12/20/2022]
Abstract
Medications taken during pregnancy may significantly impact fetal development, yet there are few studies that rigorously assess medication safety due to ethical concerns. Selective serotonin reuptake inhibitors (SSRIs) are a class of drug increasingly being prescribed for depression, yet multiple studies have shown that taking SSRIs during pregnancy can lead to preterm birth and potential health concerns for the baby. Therefore, a biomimetic placental barrier model is utilized herein to assess transport profiles and phenotypic effects resulting from SSRI exposure, comparing fluoxetine and sertraline. Results show that the placental barrier quickly uptakes drug from the maternal side, but slowly releases on the fetal side. Phenotypically, there is a dose-dependent change in cell adhesion molecule (CAM) and transforming growth factor beta (TGFβ) secretions, markers of cell adhesion and angiogenesis. Both drugs impact CAM secretions, whereas sertraline alone impacts TGFβ secretions. When evaluating cell type, it becomes clear that endothelial cells, not trophoblast, are the main cell type involved in these phenotypic changes. Overall, these findings further the understanding of SSRI transplacental transport and drug-induced effects on the placental barrier.
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Affiliation(s)
- Navein Arumugasaamy
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742
- Center for Engineering Complex Tissues, University of Maryland, College Park, MD 20742
- Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Health System, Washington, D.C. 20010
| | - Alana Gudelsky
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742
- Center for Engineering Complex Tissues, University of Maryland, College Park, MD 20742
- Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Health System, Washington, D.C. 20010
| | - Amelia Hurley-Novatny
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742
- Center for Engineering Complex Tissues, University of Maryland, College Park, MD 20742
| | - Peter C.W. Kim
- Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Health System, Washington, D.C. 20010
- Department of Surgery, The George Washington University, Washington, D.C. 20037
| | - John P. Fisher
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742
- Center for Engineering Complex Tissues, University of Maryland, College Park, MD 20742
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Torrisi SA, Geraci F, Tropea MR, Grasso M, Caruso G, Fidilio A, Musso N, Sanfilippo G, Tascedda F, Palmeri A, Salomone S, Drago F, Puzzo D, Leggio GM, Caraci F. Fluoxetine and Vortioxetine Reverse Depressive-Like Phenotype and Memory Deficits Induced by Aβ 1-42 Oligomers in Mice: A Key Role of Transforming Growth Factor-β1. Front Pharmacol 2019; 10:693. [PMID: 31293421 PMCID: PMC6598642 DOI: 10.3389/fphar.2019.00693] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/28/2019] [Indexed: 12/15/2022] Open
Abstract
Depression is a risk factor for the development of Alzheimer’s disease (AD), and the presence of depressive symptoms significantly increases the conversion of mild cognitive impairment (MCI) into AD. A long-term treatment with antidepressants reduces the risk to develop AD, and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently being studied for their neuroprotective properties in AD. In the present work, the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype induced by intracerebroventricular injection of amyloid-β (1-42) (Aβ1-42) oligomers in 2-month-old C57BL/6 mice. Starting from 7 days before Aβ injection, fluoxetine (10 mg/kg) and vortioxetine (5 and 10 mg/kg) were intraperitoneally injected daily for 24 days. Chronic treatment with fluoxetine and vortioxetine (both at the dose of 10 mg/kg) was able to rescue the loss of memory assessed 14 days after Aβ injection by the passive avoidance task and the object recognition test. Both antidepressants reversed the increase in immobility time detected 19 days after Aβ injection by forced swim test. Vortioxetine exerted significant antidepressant effects also at the dose of 5 mg/kg. A significant deficit of transforming growth factor-β1 (TGF-β1), paralleling memory deficits and depressive-like phenotype, was found in the hippocampus of Aβ-injected mice in combination with a significant reduction of the synaptic proteins synaptophysin and PSD-95. Fluoxetine and vortioxetine completely rescued hippocampal TGF-β1 levels in Aβ-injected mice as well as synaptophysin and PSD-95 levels. This is the first evidence that a chronic treatment with fluoxetine or vortioxetine can prevent both cognitive deficits and depressive-like phenotype in a non-transgenic animal model of AD with a key contribution of TGF-β1.
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Affiliation(s)
| | - Federica Geraci
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Maria Rosaria Tropea
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Margherita Grasso
- Department of Drug Sciences, University of Catania, Catania, Italy.,Oasi Research Institute-IRCCS, Troina, Italy
| | | | | | - Nicolò Musso
- Bio-nanotech Research and Innovation Tower (BRIT), University of Catania, Catania, Italy
| | - Giulia Sanfilippo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Fabio Tascedda
- Department of Life Sciences and Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy
| | - Agostino Palmeri
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Salvatore Salomone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Daniela Puzzo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.,Oasi Research Institute-IRCCS, Troina, Italy
| | - Gian Marco Leggio
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Filippo Caraci
- Department of Drug Sciences, University of Catania, Catania, Italy.,Oasi Research Institute-IRCCS, Troina, Italy
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Villas Boas GR, Boerngen de Lacerda R, Paes MM, Gubert P, Almeida WLDC, Rescia VC, de Carvalho PMG, de Carvalho AAV, Oesterreich SA. Molecular aspects of depression: A review from neurobiology to treatment. Eur J Pharmacol 2019; 851:99-121. [PMID: 30776369 DOI: 10.1016/j.ejphar.2019.02.024] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 12/14/2022]
Abstract
Major depressive disorder (MDD), also known as unipolar depression, is one of the leading causes of disability and disease worldwide. The signs and symptoms are low self‑esteem, anhedonia, feeling of worthlessness, sense of rejection and guilt, suicidal thoughts, among others. This review focuses on studies with molecular-based approaches involving MDD to obtain an integrated, more detailed and comprehensive view of the brain changes produced by this disorder and its treatment and how the Central Nervous System (CNS) produces neuroplasticity to orchestrate adaptive defensive behaviors. This article integrates affective neuroscience, psychopharmacology, neuroanatomy and molecular biology data. In addition, there are two problems with current MDD treatments, namely: 1) Low rates of responsiveness to antidepressants and too slow onset of therapeutic effect; 2) Increased stress vulnerability and autonomy, which reduces the responses of currently available treatments. In the present review, we encourage the prospection of new bioactive agents for the development of treatments with post-transduction mechanisms, neurogenesis and pharmacogenetics inducers that bring greater benefits, with reduced risks and maximized access to patients, stimulating the field of research on mood disorders in order to use the potential of preclinical studies. For this purpose, improved animal models that incorporate the molecular and anatomical tools currently available can be applied. Besides, we encourage the study of drugs that do not present "classical application" as antidepressants, (e.g., the dissociative anesthetic ketamine and dextromethorphan) and drugs that have dual action mechanisms since they represent potential targets for novel drug development more useful for the treatment of MDD.
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Affiliation(s)
- Gustavo Roberto Villas Boas
- Research Group on Development of Pharmaceutical Products (P&DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil; Faculty of Health Sciences, Federal University of Grande Dourados, Dourados Rodovia Dourados, Itahum Km 12, Cidade Universitaria, Caixa. postal 364, CEP 79804-970, Dourados, Mato Grosso do Sul, Brazil.
| | - Roseli Boerngen de Lacerda
- Department of Pharmacology of the Biological Sciences Center, Federal University of Paraná, Jardim das Américas, Caixa. postal 19031, CEP 81531-990, Curitiba, Paraná, Brazil.
| | - Marina Meirelles Paes
- Research Group on Development of Pharmaceutical Products (P&DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Priscila Gubert
- Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Wagner Luis da Cruz Almeida
- Research Group on Development of Pharmaceutical Products (P&DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Vanessa Cristina Rescia
- Research Group on Development of Pharmaceutical Products (P&DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Pablinny Moreira Galdino de Carvalho
- Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Adryano Augustto Valladao de Carvalho
- Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Silvia Aparecida Oesterreich
- Faculty of Health Sciences, Federal University of Grande Dourados, Dourados Rodovia Dourados, Itahum Km 12, Cidade Universitaria, Caixa. postal 364, CEP 79804-970, Dourados, Mato Grosso do Sul, Brazil.
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Zhang Y, Yu P, Liu H, Yao H, Yao S, Yuan SY, Zhang JC. Hyperforin improves post-stroke social isolation‑induced exaggeration of PSD and PSA via TGF-β. Int J Mol Med 2018; 43:413-425. [PMID: 30387813 PMCID: PMC6257831 DOI: 10.3892/ijmm.2018.3971] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/30/2018] [Indexed: 11/14/2022] Open
Abstract
Stroke survivors often experience social isolation, which can lead to post-stroke depression (PSD) and post-stroke anxiety (PSA) that can compromise neurogenesis and impede functional recovery following the stroke. The present study aimed to investigate the effects and mechanisms of post-stroke social isolation-mediated PSD and PSA on hippocampal neurogenesis and cognitive function. The effects of the natural antidepressant hyperforin on post-stroke social isolation-mediated PSD and PSA were also investigated. In the present study, a model of PSD and PSA using C57BL/6J male mice was successfully established using middle cerebral artery occlusion combined with post-stroke isolated housing conditions. It was observed that PSD and PSA were more prominent in the isolated mice compared with the pair-housed mice at 14 days post-ischemia (dpi). Mice isolated 3 dpi exhibited decreased transforming growth factor-β (TGF-β) levels and impairment of hippocampal neurogenesis and memory function at 14 dpi. Intracerebroventricular administration of recombinant TGF-β for 7 consecutive days, starting at 7 dpi, restored the reduced hippocampal neurogenesis and memory function induced by social isolation. Furthermore, intranasal administration of hyperforin for 7 consecutive days starting at 7 dpi improved PSD and PSA and promoted hippocampal neurogenesis and memory function in the isolated mice at 14 dpi. The inhibition of TGF-β with a neutralizing antibody prevented the effects of hyperforin. In conclusion, the results revealed a previously uncharacterized role of hyperforin in improving post-stroke social isolation-induced exaggeration of PSD and PSA and, in turn, promoting hippocampal neurogenesis and cognitive function via TGF-β.
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Affiliation(s)
- Yujing Zhang
- Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Peiyun Yu
- Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Hong Liu
- Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Hua Yao
- Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Shanglong Yao
- Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Shi-Ying Yuan
- Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jian-Cheng Zhang
- Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Sarapultsev AP, Vassiliev PM, Sarapultsev PA, Chupakhin ON, Ianalieva LR, Sidorova LP. Immunomodulatory Action of Substituted 1,3,4-Thiadiazines on the Course of Myocardial Infarction. Molecules 2018; 23:E1611. [PMID: 30004445 PMCID: PMC6099947 DOI: 10.3390/molecules23071611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 06/29/2018] [Accepted: 06/30/2018] [Indexed: 02/07/2023] Open
Abstract
This review focuses on the biological action of the compounds from the group of substituted 1,3,4-thiadiazines on stress response and myocardial infarction. The aim of this review is to propose the possible mechanisms of action of 1,3,4-thiadiazines and offer prospectives in the development of new derivatives as therapeutic agents. It is known, that compounds that have biological effects similar to those used as antidepressants can down-regulate the secretion of proinflammatory cytokines, up-regulate the release of anti-inflammatory ones and affect cell recruitment, which allows them to be considered immunomodulators as well. The results of pharmacological evaluation, in silico studies, and in vivo experiments of several compounds from the group of substituted 1,3,4-thiadiazines with antidepressant properties are presented. It is proposed that the cardioprotective effects of substituted 1,3,4-thiadiazines might be explained by the peculiarities of their multi-target action: the ability of the compounds to interact with various types of receptors and transporters of dopaminergic, serotonergic and acetylcholinergic systems and to block the kinase signal pathway PI3K-AKT. The described effects of substituted 1,3,4-thiadiazines suggest that it is necessary to search for a new agents for limiting the peripheral inflammatory/ischemic damage through the entral mechanisms of stress reaction and modifying pro-inflammatory cytokine signaling pathways in the brain.
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Affiliation(s)
- Alexey P Sarapultsev
- Institute of Immunology and Physiology of the Ural Branch of RAS, Pervomayskaya 106, Ekaterinburg 620049, Russia.
| | - Pavel M Vassiliev
- Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov Square 1, Volgograd 400131, Russia.
| | - Petr A Sarapultsev
- Institute of Immunology and Physiology of the Ural Branch of RAS, Pervomayskaya 106, Ekaterinburg 620049, Russia.
| | - Oleg N Chupakhin
- The IJ Postovsky Institute of Organic Synthesis of the Ural Branch of RAS, Akademicheskaya/S. Kovalevskoi, 22/20, Ekaterinburg 620990, Russia.
- Ural Federal University named after the First President of Russia B. N. Yeltsin, 19 Mira Street, Ekaterinburg 620002, Russia.
| | - Laura R Ianalieva
- Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov Square 1, Volgograd 400131, Russia.
| | - Larisa P Sidorova
- Ural Federal University named after the First President of Russia B. N. Yeltsin, 19 Mira Street, Ekaterinburg 620002, Russia.
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45
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Zou W, Feng R, Yang Y. Changes in the serum levels of inflammatory cytokines in antidepressant drug-naïve patients with major depression. PLoS One 2018; 13:e0197267. [PMID: 29856741 PMCID: PMC5983476 DOI: 10.1371/journal.pone.0197267] [Citation(s) in RCA: 165] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Accepted: 04/30/2018] [Indexed: 01/09/2023] Open
Abstract
Major depressive disorder (MDD) is a common condition that afflicts the general population across a broad spectrum of ages and social backgrounds. The inflammatory hypothesis of depression posits that immune hyperactivation and dysregulated cytokine production are involved in depression. To investigate cytokine profiles in patients with MDD, we examined the levels of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, and those of the anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-β1 in antidepressant drug-naïve patients with MDD. Compared to healthy controls, patients with MDD had significantly higher levels of IL-1β, IL-10, and TNF-α, but significantly lower levels of IL-8. There were no significant differences in the levels of IL-6 or TGF-β1. We found linear correlations between IL-1β, TNF-α, and IL-8, and the severity of depression, as well as between IL-8 and anxiety level in patients with comorbid anxiety disorder. In addition, higher IL-1β and TNF-α levels were associated with higher Hamilton Depression Rating Scale (HAMD) scores, while higher IL-8 levels were associated with lower HAMD and Hamilton Anxiety Rating Scale scores. Here we present evidence of changes in cytokine levels in antidepressant drug-naïve patients with MDD. Abnormal expression of inflammatory cytokines in patients with depression suggests that depression activates an inflammatory process. Immunological abnormalities may be involved in the pathophysiology of depression.
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Affiliation(s)
- Wei Zou
- Department of Neurology and Psychiatry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Renjie Feng
- Department of Neurology and Psychiatry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Yang
- Department of Neurology and Psychiatry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- * E-mail:
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Bernstein LJ, Pond GR, Gan HK, Tirona K, Chan KK, Hope A, Kim J, Chen EX, Siu LL, Razak ARA. Pretreatment neurocognitive function and self-reported symptoms in patients with newly diagnosed head and neck cancer compared with noncancer cohort. Head Neck 2018; 40:2029-2042. [DOI: 10.1002/hed.25198] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 01/24/2017] [Accepted: 03/13/2018] [Indexed: 12/29/2022] Open
Affiliation(s)
- Lori J. Bernstein
- Department of Supportive Care, Princess Margaret Cancer Centre; University of Toronto; Canada
| | - Gregory R. Pond
- Department of Biostatistics; McMaster University; Hamilton Canada
| | - Hui K. Gan
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto; Canada
| | - Kattleya Tirona
- Department of Supportive Care, Princess Margaret Cancer Centre; University of Toronto; Canada
| | - Kelvin K. Chan
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto; Canada
| | - Andrew Hope
- Department of Radiation Oncology, Princess Margaret Cancer Centre; University of Toronto; Canada
| | - John Kim
- Department of Radiation Oncology, Princess Margaret Cancer Centre; University of Toronto; Canada
| | - Eric X. Chen
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto; Canada
| | - Lillian L. Siu
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto; Canada
| | - Albiruni R. Abdul Razak
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto; Canada
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Neurobiological links between depression and AD: The role of TGF-β1 signaling as a new pharmacological target. Pharmacol Res 2018; 130:374-384. [DOI: 10.1016/j.phrs.2018.02.007] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/03/2018] [Accepted: 02/07/2018] [Indexed: 12/19/2022]
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Adzic M, Brkic Z, Mitic M, Francija E, Jovicic MJ, Radulovic J, Maric NP. Therapeutic Strategies for Treatment of Inflammation-related Depression. Curr Neuropharmacol 2018; 16:176-209. [PMID: 28847294 PMCID: PMC5883379 DOI: 10.2174/1570159x15666170828163048] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 08/17/2017] [Accepted: 08/24/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation- withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation. METHODS In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies. RESULTS Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression. CONCLUSION The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of antiinflammatory co-treatments, is required.
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Affiliation(s)
- Miroslav Adzic
- Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia
| | - Zeljka Brkic
- Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia
| | - Milos Mitic
- Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia
| | - Ester Francija
- Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia
| | - Milica J. Jovicic
- Clinic for Psychiatry, Clinical Centre of Serbia, Pasterova 2, 11000, Belgrade, Serbia
| | - Jelena Radulovic
- Department of Psychiatry and Behavioral Sciences, The Asher Center of Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Nadja P. Maric
- Clinic for Psychiatry, Clinical Centre of Serbia, Pasterova 2, 11000, Belgrade, Serbia
- School of Medicine, University of Belgrade, Dr Subotica 8, 11000, Belgrade, Serbia
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Kashima R, Hata A. The role of TGF-β superfamily signaling in neurological disorders. Acta Biochim Biophys Sin (Shanghai) 2018; 50:106-120. [PMID: 29190314 PMCID: PMC5846707 DOI: 10.1093/abbs/gmx124] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 11/02/2017] [Indexed: 12/12/2022] Open
Abstract
The TGF-β superfamily signaling is involved in a variety of biological processes during embryogenesis and in adult tissue homeostasis. Faulty regulation of the signaling pathway that transduces the TGF-β superfamily signals accordingly leads to a number of ailments, such as cancer and cardiovascular, metabolic, urinary, intestinal, skeletal, and immune diseases. In recent years, a number of studies have elucidated the essential roles of TGF-βs and BMPs during neuronal development in the maintenance of appropriate innervation and neuronal activity. The new advancement implicates significant roles of the aberrant TGF-β superfamily signaling in the pathogenesis of neurological disorders. In this review, we compile a number of reports implicating the deregulation of TGF-β/BMP signaling pathways in the pathogenesis of cognitive and neurodegenerative disorders in animal models and patients. We apologize in advance that the review falls short of providing details of the role of TGF-β/BMP signaling or mechanisms underlying the pathogenesis of neurological disorders. The goal of this article is to reveal a gap in our knowledge regarding the association between TGF-β/BMP signaling pathways and neuronal tissue homeostasis and development and facilitate the research with a potential to develop new therapies for neurological ailments by modulating the pathways.
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Affiliation(s)
- Risa Kashima
- Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA
| | - Akiko Hata
- Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA
- Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA
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Trojan E, Ślusarczyk J, Chamera K, Kotarska K, Głombik K, Kubera M, Basta-Kaim A. The Modulatory Properties of Chronic Antidepressant Drugs Treatment on the Brain Chemokine - Chemokine Receptor Network: A Molecular Study in an Animal Model of Depression. Front Pharmacol 2017; 8:779. [PMID: 29163165 PMCID: PMC5671972 DOI: 10.3389/fphar.2017.00779] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 10/16/2017] [Indexed: 12/26/2022] Open
Abstract
An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine - chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-β, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-β signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1-CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences.
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Affiliation(s)
- Ewa Trojan
- Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Joanna Ślusarczyk
- Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Katarzyna Chamera
- Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Katarzyna Kotarska
- Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Katarzyna Głombik
- Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Marta Kubera
- Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Agnieszka Basta-Kaim
- Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
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