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Tuna A, Boyacioglu O, Dondu A, Orenay-Boyacioglu S. miR-26b, miR-30e, and miR-206 Polymorphisms May Play a Role in BDNF-mediated Development of Alzheimer's-type Dementia. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE : THE OFFICIAL SCIENTIFIC JOURNAL OF THE KOREAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY 2025; 23:193-201. [PMID: 40223253 PMCID: PMC12000675 DOI: 10.9758/cpn.24.1223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/26/2024] [Accepted: 10/08/2024] [Indexed: 04/15/2025]
Abstract
Objective The brain-derived neurotrophic factor (BDNF) playing a crucial role in neuron survival and function, particularly in neurodegenerative diseases like Alzheimer's disease (AD). Our study seeks to explore polymorphisms in miRNAs that regulate the BDNF gene in individuals with AD, and to reveal the relationship between these polymorphisms and APOE genotypes. Methods Seventy AD patients who applied to the Psychiatry outpatient clinic were recruited for the study as well as 70 healthy individuals in the same age. The cases were examined for 5 miRNAs regulating BDNF and 2 APOE SNPs using the SNPType method on the Fluidigm platform. Results In comparisons of the genotype distributions for three polymorphisms (miR-206 rs16882131, miR-30e rs112439044, miR-26b rs188612260) (p < 0.01 all) and the allele frequencies for two polymorphisms (miR-30e rs112439044, miR-26b rs188612260) (p < 0.01) detected significant differences between groups. While the APOE e4/e4 genotype was detected in 4.50% of the AD group, no individual with this genotype was observed in the control group. When the correlation between miRNA polymorphisms and APOE genotypic distributions were investigated, the miR-30e rs10489167 polymorphism showed a statistically significant positive correlation with the ε2/ε2 genotype and a statistically significant negative correlation with the e2/e3 genotype (p < 0.08 and p < 0.001, respectively). On the other hand, the miR-30e rs112439044 polymorphism exhibited a statistically significant positive correlation with the e2/e2 and ε2/ε2 genotypes (p < 0.03 and p < 0.07, respectively). Conclusion These findings could potentially offer insights into the mechanisms underlying AD.
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Affiliation(s)
- Ayten Tuna
- Molecular Biotechnology Program, Institute of Health Sciences, Aydın Adnan Menderes University, Efeler, Aydın, Türkiye
| | - Olcay Boyacioglu
- Faculty of Engineering, Aydın Adnan Menderes University, Efeler, Aydın, Türkiye
| | - Ayse Dondu
- Department of Psychiatry, Faculty of Medicine, Aydın Adnan Menderes University, Efeler, Aydın, Türkiye
| | - Seda Orenay-Boyacioglu
- Department of Medical Genetics, Faculty of Medicine, Aydın Adnan Menderes University, Efeler, Aydın, Türkiye
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Chahardehi AM, Arefnezhad R, Pourbafrani A, Tajik L, Asadi SA, Salehi H, Yazdanian S, Nakhaee A, Esfahani MS, Behzad P, Haghani H, Niknam Z, Sefati N, Rezaei-Tazangi F, Tavakoli MR. MicroRNAs modulation by curcumin, catalpol, and other natural products in Alzheimer's disease: a review. Mol Biol Rep 2025; 52:445. [PMID: 40327129 DOI: 10.1007/s11033-025-10543-x] [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: 01/23/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited pharmacological treatment options, necessitating the exploration of alternative therapeutic strategies. Emerging evidence suggests that microRNAs (miRNAs), such as miR-132, miR-34a, and miR-124, play crucial roles in AD pathogenesis, influencing amyloid-beta (Aβ) aggregation, tau phosphorylation, neuroinflammation, and oxidative stress. Natural products have been identified as potential modulators of miRNA expression, offering neuroprotective benefits through multi-target mechanisms. This review systematically examines the impact of curcumin, catalpol, Allium jesdianum, Tanshinone IIA (Tan IIA), and Tiaoxin Recipe (TXR) on miRNA regulation in AD, summarizing their molecular targets and therapeutic potential. Furthermore, we discuss challenges related to bioavailability and clinical translation, highlighting the need for advanced delivery systems and personalized medicine approaches. By integrating recent findings, this review provides a comprehensive perspective on the role of miRNA modulation in AD therapy and underscores the potential of natural products as novel therapeutic agents.
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Affiliation(s)
| | - Reza Arefnezhad
- Coenzyme R Research Institute, Tehran, Iran
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran
| | - Alireza Pourbafrani
- Department of Motor Behavior, Faculty of Physical Education, Allameh Tabatbai University, Tehran, Iran
| | - Leila Tajik
- Faculty of Medicine, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
| | | | - Hossein Salehi
- Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Asma Nakhaee
- Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Parnian Behzad
- Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Helia Haghani
- Coenzyme R Research Institute, Tehran, Iran
- Department of Biotechnology, Islamic Azad University, Yadegar-e-Imam Khomeini (RAH) City of Rey Branch, Tehran, Iran
| | - Zahra Niknam
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Niloofar Sefati
- Department of Anatomy, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran.
| | - Marziye Ranjbar Tavakoli
- Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran
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Wang JF, Wang MC, Jiang LL, Lin NM. The neuroscience in breast cancer: Current insights and clinical opportunities. Heliyon 2025; 11:e42293. [PMID: 39975839 PMCID: PMC11835589 DOI: 10.1016/j.heliyon.2025.e42293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 01/25/2025] [Accepted: 01/25/2025] [Indexed: 02/21/2025] Open
Abstract
The involvement of nerves in the development of breast cancer has emerged as a significant factor. Interaction between the nervous system and breast cancer can influence tumor initiation, growth, invasion, metastasis, reverse resistance to drugs, promote inflammation in tumors, and impair the immune system's ability to combat cancer. This review examined the intricate relationship linking the nervous system with breast cancer, emphasizing both central and peripheral aspects of the nervous system. Moreover, we reviewed neural cell factors and their impact on breast cancer progression, alongside the interactions between nerves and immunology, microbiota in breast cancer. Furthermore, the study discussed the potential of nerves as biomarkers for diagnosing and prognosticating breast cancer, and evaluated prospects for improving chemotherapy and immunotherapy therapeutic outcomes in breast cancer treatment. We hope to provide a deeper understanding of the neurobiological underpinnings of breast cancer and pave the way for the discovery of innovative therapeutic targets and prognostic markers.
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Affiliation(s)
- Jia-feng Wang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Meng-chuan Wang
- Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, 315300, China
| | - Lei-lei Jiang
- The First Affiliated Hospital of Anhui University of Chinese Medicine,Hefei, 230031, China
| | - Neng-ming Lin
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, 310024, China
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Zheng YB, Jin X. Evidence for the Contribution of the miR-206/BDNF Pathway in the Pathophysiology of Depression. Int J Neuropsychopharmacol 2024; 27:pyae039. [PMID: 39219169 PMCID: PMC11461769 DOI: 10.1093/ijnp/pyae039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 08/30/2024] [Indexed: 09/04/2024] Open
Abstract
Depression is a complex disorder with substantial impacts on individual health and has major public health implications. Depression results from complex interactions between genetic and environmental factors. Epigenetic mechanisms, including DNA methylation, microRNAs (miRNAs), and histone modifications, can produce heritable phenotypic changes without a change in DNA sequence and recently were proven to mediate lasting increases in the risk of depression following exposure to adverse life events. Of these, miRNAs are gaining attention for their role in the pathogenesis of many stress-associated mental disorders, including depression. One such miRNA is microRNA-206 (miR-206), which is a critical candidate for increasing the susceptibility to stress. Although miR-206 is thought to be a typical muscle-specific miRNA, it is expressed throughout the brain, particularly in the hippocampus and prefrontal cortex. Until now, only a few studies have been conducted on rodents to understand the role of miR-206 in stress-related abnormalities in neurogenesis. However, the precise underlying molecular mechanism of miR-206-mediated depression-like behaviors remains largely unknown. Here, we reviewed recent advances in the field of biomedical and clinical research on the role of miR-206 in the pathogenesis of depression from studies using different tissues and various experimental designs and described how abnormalities in miR-206 expression in these tissues can affect neuronal functions. Moreover, we focused on studies investigating the brain-derived neurotrophic factor (BDNF) as a functional target of miR-206, where miR-206 has been implicated in the pathogenesis of depression by suppressing the expression of the BDNF. In summary, these studies confirm the existence of a tight correlation between the pathogenesis of depression and the miR-206/BDNF pathway.
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Affiliation(s)
- Ya-Bin Zheng
- Department of Neurology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiang Jin
- Department of Pharmacy, The Second People’s Hospital of Nantong, Nantong, China
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Dubey H, Dubey A, Gulati K, Ray A. S-nitrosoglutathione modulates HDAC2 and BDNF levels in the brain and improves cognitive deficits in experimental model of Alzheimer's disease in rats. Int J Neurosci 2024; 134:777-785. [PMID: 36408590 DOI: 10.1080/00207454.2022.2150190] [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: 02/24/2022] [Revised: 11/02/2022] [Accepted: 11/10/2022] [Indexed: 11/22/2022]
Abstract
AIM Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by cognitive deficits and abnormal memory formation. Histone acetylation is essential for hippocampal memory formation and improving the cognitive deficits, and histone deacetylase 2 (HDAC2) is increased in the hippocampus of AD patients. The present study evaluated the effects of the nitric oxide (NO) mimetics, L-arginine and the nitrosothiol NO donor, s-nitrosoglutathione (GSNO), on memory and brain HDAC2 levels in experimental animal model of sporadic Alzheimer's disease (sAD). METHODS AD was induced experimentally in rats by intracerebroventricular injection of streptozotocin (STZ, 3mg/kg). The effects of NO mimetics, GSNO and L-arginine, were assessed on STZ induced cognitive deficits in the Morris water maze (MWM) test, and, following this, the hippocampal homogenates were assayed for amyloid-β, brain derived neurotropic factor (BDNF) and HDAC2 levels. The neurobehavioral and biochemical data of the drug treated groups were compared with those of experimental control group. RESULTS The results showed that icv-STZ induced cognitive deficits were differentially attenuated by GSNO (50µg/kg) and, to a lesser extent, L-arginine (100mg/kg) with improvement in the spatial learning tasks in MWM test. These behavioral changes were associated with decreased levels of biochemical markers viz. amyloid β, BDNF and HDAC2 levels in hippocampus. CONCLUSIONS It is inferred that NO donors like GSNO could influence AD pathophysiology via epigenetic modification of HDAC2 inhibition.
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Affiliation(s)
- Harikesh Dubey
- Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
- Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI, USA
| | - Anamika Dubey
- Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
| | - Kavita Gulati
- Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
| | - Arunabha Ray
- Department of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
- Department of Pharmacology, Hamdard Institute of Medical Sciences and Research, Hamdard University, New Delhi, India
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De Assis GG, Murawska-Ciałowicz E. BDNF Modulation by microRNAs: An Update on the Experimental Evidence. Cells 2024; 13:880. [PMID: 38786102 PMCID: PMC11119608 DOI: 10.3390/cells13100880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/06/2024] [Accepted: 05/18/2024] [Indexed: 05/25/2024] Open
Abstract
MicroRNAs can interfere with protein function by suppressing their messenger RNA translation or the synthesis of its related factors. The function of brain-derived neurotrophic factor (BDNF) is essential to the proper formation and function of the nervous system and is seen to be regulated by many microRNAs. However, understanding how microRNAs influence BDNF actions within cells requires a wider comprehension of their integrative regulatory mechanisms. Aim: In this literature review, we have synthesized the evidence of microRNA regulation on BDNF in cells and tissues, and provided an analytical discussion about direct and indirect mechanisms that appeared to be involved in BDNF regulation by microRNAs. Methods: Searches were conducted on PubMed.gov using the terms "BDNF" AND "MicroRNA" and "brain-derived neurotrophic factor" AND "MicroRNA", updated on 1 September 2023. Papers without open access were requested from the authors. One hundred and seventy-one papers were included for review and discussion. Results and Discussion: The local regulation of BDNF by microRNAs involves a complex interaction between a series of microRNAs with target proteins that can either inhibit or enhance BDNF expression, at the core of cell metabolism. Therefore, understanding this homeostatic balance provides resources for the future development of vector-delivery-based therapies for the neuroprotective effects of BDNF.
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Affiliation(s)
- Gilmara Gomes De Assis
- Department of Restorative Dentistry, Araraquara School of Dentistry, São Paulo State University (UNESP), Araraquara 14801-385, SP, Brazil
| | - Eugenia Murawska-Ciałowicz
- Department of Physiology and Biochemistry, Wroclaw University of Health and Sport Sciences, 51-612 Wrocław, Poland;
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Prasanth MI, Sivamaruthi BS, Cheong CSY, Verma K, Tencomnao T, Brimson JM, Prasansuklab A. Role of Epigenetic Modulation in Neurodegenerative Diseases: Implications of Phytochemical Interventions. Antioxidants (Basel) 2024; 13:606. [PMID: 38790711 PMCID: PMC11118909 DOI: 10.3390/antiox13050606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
Epigenetics defines changes in cell function without involving alterations in DNA sequence. Neuroepigenetics bridges neuroscience and epigenetics by regulating gene expression in the nervous system and its impact on brain function. With the increase in research in recent years, it was observed that alterations in the gene expression did not always originate from changes in the genetic sequence, which has led to understanding the role of epigenetics in neurodegenerative diseases (NDDs) including Alzheimer's disease (AD) and Parkinson's disease (PD). Epigenetic alterations contribute to the aberrant expression of genes involved in neuroinflammation, protein aggregation, and neuronal death. Natural phytochemicals have shown promise as potential therapeutic agents against NDDs because of their antioxidant, anti-inflammatory, and neuroprotective effects in cellular and animal models. For instance, resveratrol (grapes), curcumin (turmeric), and epigallocatechin gallate (EGCG; green tea) exhibit neuroprotective effects through their influence on DNA methylation patterns, histone acetylation, and non-coding RNA expression profiles. Phytochemicals also aid in slowing disease progression, preserving neuronal function, and enhancing cognitive and motor abilities. The present review focuses on various epigenetic modifications involved in the pathology of NDDs, including AD and PD, gene expression regulation related to epigenetic alterations, and the role of specific polyphenols in influencing epigenetic modifications in AD and PD.
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Affiliation(s)
- Mani Iyer Prasanth
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Bhagavathi Sundaram Sivamaruthi
- Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand;
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Clerance Su Yee Cheong
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kanika Verma
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Tewin Tencomnao
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - James Michael Brimson
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- Research, Innovation and International Affairs, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Anchalee Prasansuklab
- Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand; (M.I.P.); (C.S.Y.C.); (K.V.); (T.T.); (J.M.B.)
- College of Public Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
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Dubey H, Ray A, Dubey A, Gulati K. S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway. Neuropsychobiology 2024; 83:101-113. [PMID: 38744261 DOI: 10.1159/000538348] [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: 05/09/2023] [Accepted: 03/05/2024] [Indexed: 05/16/2024]
Abstract
INTRODUCTION The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. METHOD AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aβ)-40, Aβ42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. RESULTS Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aβ levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. CONCLUSION The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.
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Affiliation(s)
- Harikesh Dubey
- Departments of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India
- The Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan, USA
| | - Arunabha Ray
- Departments of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India
- Departments of Pharmacology, Hamdard Institute of Medical Sciences and Research (HIMSR), Hamdard University, New Delhi, India
| | - Anamika Dubey
- Departments of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India
| | - Kavita Gulati
- Departments of Pharmacology, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India
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Khalifa M, Fayed RH, Ahmed YH, Sedik AA, El-Dydamony NM, Khalil HMA. Mitigating effect of ferulic acid on di-(2-ethylhexyl) phthalate-induced neurocognitive dysfunction in male rats with a comprehensive in silico survey. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3493-3512. [PMID: 37966574 PMCID: PMC11074231 DOI: 10.1007/s00210-023-02831-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/30/2023] [Indexed: 11/16/2023]
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate threatening public health-induced neurotoxicity. This neurotoxicity is associated with behavioral and biochemical deficits in male rats. Our study investigated the neuroprotective effect of ferulic acid (FA) on male rats exposed to DEHP. Thirty-two male Wistar rats were assigned to four groups. Group I control rats received corn oil, group II intoxicated rats received 300 mg/kg of DEHP, group III received 300 mg/kg of DEHP + 50 mg/kg of FA, and group IV received 50 mg/kg of FA, all agents administrated daily per os for 30 days. Anxiety-like behavior, spatial working memory, and recognition memory were assessed. Also, brain oxidative stress biomarkers, including brain malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), brain-derived neurotrophic factor (BDNF) as well as heme oxygenase-1 (HO-1) were measured. Moreover, brain histopathology examinations associated with immunohistochemistry determination of brain caspase-3 were also evaluated. Furthermore, docking simulation was adapted to understand the inhibitory role of FA on caspase-3 and NO synthase. Compared to DEHP-intoxicated rats, FA-treated rats displayed improved cognitive memory associated with a reduced anxious state. Also, the redox state was maintained with increased BNDF levels. These changes were confirmed by restoring the normal architecture of brain tissue and a decrement in the immunohistochemistry caspase-3. In conclusion, FA has potent antioxidant and antiapoptotic properties that confirm the neuroprotective activity of FA, with a possible prospect for its therapeutic capabilities and nutritional supplement value.
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Affiliation(s)
- Mhasen Khalifa
- Veterinary Hygiene and Management Department, Faculty of Vet. Medicine, Cairo University, Giza, 12211, Egypt
| | - Rabie H Fayed
- Veterinary Hygiene and Management Department, Faculty of Vet. Medicine, Cairo University, Giza, 12211, Egypt.
| | - Yasmine H Ahmed
- Cytology and Histology Department, Faculty of Vet. Medicine, Cairo University, Giza, 12211, Egypt
| | - Ahmed A Sedik
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, 12622, Egypt
| | - Nehad M El-Dydamony
- Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6Th of October City, 12585, Egypt
| | - Heba M A Khalil
- Veterinary Hygiene and Management Department, Faculty of Vet. Medicine, Cairo University, Giza, 12211, Egypt.
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Qi W, Guan W. A Comprehensive Review on the Importance of MiRNA-206 in the Animal Model and Human Diseases. Curr Neuropharmacol 2024; 22:1064-1079. [PMID: 37032500 PMCID: PMC10964108 DOI: 10.2174/1570159x21666230407124146] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/08/2023] [Accepted: 02/15/2023] [Indexed: 04/11/2023] Open
Abstract
MicroRNA-206 (miR-206) is a microRNA that is involved in many human diseases, such as myasthenia gravis, osteoarthritis, depression, cancers, etc. Both inhibition effects and progression roles of miR-206 have been reported for the past few years. High expression of miR-206 was observed in patients with osteoarthritis, gastric cancer and epithelial ovarian cancer compared to normal people. The study also showed that miR-206 promotes cancer progression in breast cancer patients and avascular necrosis of the femoral head. Meanwhile, several studies have shown that expression levels of miR-206 were down-regulated in laryngeal carcinoma cell multiplication, as well as in hepatocellular carcinoma, non-small lung cancer and infantile hemangioma. Moreover, miR-206 was up-regulated in the mild stage of amyotrophic lateral sclerosis patients and then down-regulated in the moderate and severe stages, indicating that miR-206 has the double effects of starting and aggravating the disease. In neuropsychiatric disorders, such as depression, miR-206 also plays an important role in the progression of the disease; the level of miR-206 is most highly expressed in the brains of patients with depression. In the current review, we summarize the role of miR-206 in various diseases, and miR-206 may be developed as a new biomarker for diagnosing diseases in the near future.
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Affiliation(s)
- Wang Qi
- Department of Pharmacology, The First People's Hospital of Yancheng, Yancheng, 224000, Jiangsu, China
| | - Wei Guan
- Department of Pharmacology, Pharmacy College, Nantong University, Nantong, 226001, Jiangsu, China
- School of Medicine, Nantong University, Nantong, China
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11
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Olufunmilayo EO, Holsinger RMD. Roles of Non-Coding RNA in Alzheimer's Disease Pathophysiology. Int J Mol Sci 2023; 24:12498. [PMID: 37569871 PMCID: PMC10420049 DOI: 10.3390/ijms241512498] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 07/25/2023] [Accepted: 08/03/2023] [Indexed: 08/13/2023] Open
Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is accompanied by deficits in memory and cognitive functions. The disease is pathologically characterised by the accumulation and aggregation of an extracellular peptide referred to as amyloid-β (Aβ) in the form of amyloid plaques and the intracellular aggregation of a hyperphosphorelated protein tau in the form of neurofibrillary tangles (NFTs) that cause neuroinflammation, synaptic dysfunction, and oxidative stress. The search for pathomechanisms leading to disease onset and progression has identified many key players that include genetic, epigenetic, behavioural, and environmental factors, which lend support to the fact that this is a multi-faceted disease where failure in various systems contributes to disease onset and progression. Although the vast majority of individuals present with the sporadic (non-genetic) form of the disease, dysfunctions in numerous protein-coding and non-coding genes have been implicated in mechanisms contributing to the disease. Recent studies have provided strong evidence for the association of non-coding RNAs (ncRNAs) with AD. In this review, we highlight the current findings on changes observed in circular RNA (circRNA), microRNA (miRNA), short interfering RNA (siRNA), piwi-interacting RNA (piRNA), and long non-coding RNA (lncRNA) in AD. Variations in these ncRNAs could potentially serve as biomarkers or therapeutic targets for the diagnosis and treatment of Alzheimer's disease. We also discuss the results of studies that have targeted these ncRNAs in cellular and animal models of AD with a view for translating these findings into therapies for Alzheimer's disease.
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Affiliation(s)
- Edward O. Olufunmilayo
- Laboratory of Molecular Neuroscience and Dementia, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Department of Medicine, University College Hospital, Queen Elizabeth Road, Oritamefa, Ibadan 200212, Nigeria
| | - R. M. Damian Holsinger
- Laboratory of Molecular Neuroscience and Dementia, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
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12
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Khalilian S, Hosseini Imani SZ, Ghafouri-Fard S. Emerging roles and mechanisms of miR-206 in human disorders: a comprehensive review. Cancer Cell Int 2022; 22:412. [PMID: 36528620 PMCID: PMC9758816 DOI: 10.1186/s12935-022-02833-2] [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: 08/18/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
As a member of the miR-1 family, miR-206 is located between IL-17 and PKHD1 genes in human. This miRNA has been shown to be involved in the pathogenic processes in a variety of human disorders including cancers, amyotrophic lateral sclerosis, Alzheimer's disease, atherosclerosis, bronchopulmonary dysplasia, coronary artery disease, chronic obstructive pulmonary disease, epilepsy, nonalcoholic fatty liver disease, Hirschsprung disease, muscular dystrophies, pulmonary arterial hypertension, sepsis and ulcerative colitis. In the current review, we summarize the role of miR-206 in both malignant and non-malignant situations and explain its possible therapeutic implications.
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Affiliation(s)
- Sheyda Khalilian
- grid.411600.2Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran ,grid.411600.2Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran ,grid.411600.2USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyedeh Zahra Hosseini Imani
- grid.411750.60000 0001 0454 365XDivision of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Esfahān, Iran
| | - Soudeh Ghafouri-Fard
- grid.411600.2Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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13
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Noureddine S, Saccon T, Rudeski-Rohr T, Gesing A, Mason JB, Schneider A, Dhabhi J, Puig KL, Rakoczy S, Brown-Borg HM, Masternak MM. GH deficiency confers protective advantages against Alzheimer's disease through rescued miRNA expression profile in APP/PS1 mice. GeroScience 2022; 44:2885-2893. [PMID: 35900661 PMCID: PMC9768053 DOI: 10.1007/s11357-022-00633-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 07/21/2022] [Indexed: 01/07/2023] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia, affecting approximately 6.5 million Americans age 65 or older. AD is characterized by increased cognitive impairment and treatment options available provide minimal disease attenuation. Additionally, diagnostic methods for AD are not conclusive with definitive diagnoses requiring postmortem brain evaluations. Therefore, miRNAs, a class of small, non-coding RNAs, have garnered attention for their ability to regulate a variety of mRNAs and their potential to serve as both therapeutic targets and biomarkers of AD. Several miRNAs have already been implicated with AD and have been found to directly target genes associated with AD pathology. The APP/PS1 mice is an AD model that expresses the human mutated form of the amyloid precursor protein (APP) and presenilin-1 (PS1) genes. In a previous study, it was identified that crossing long-living growth hormone (GH)-deficient Ames dwarf (df/df) mice with APP/PS1 mice provided protection from AD through a reduction in IGF-1, amyloid-β (Aβ) deposition, and gliosis. Hence, we hypothesized that changes in the expression of miRNAs associated with AD mediated such benefits. To test this hypothesis, we sequenced miRNAs in hippocampi of df/df, wild type (+ / +), df/ + /APP/PS1 (phenotypically normal APP/PS1), and df/df/APP/PS1 mice. Results of this study demonstrated significantly upregulated and downregulated miRNAs between df/df/APP/PS1 and df/ + /APP/PS1 mice that suggest the df/df mutation provides protection from AD progression. Additionally, changes in miRNA expression with age were identified in both df/df and wild-type mice as well as df/df/APP/PS1 and APP/PS1 mice, with predictive functional roles in the Pi3k-AKT/mTOR/FOXO pathways potentially contributing to disease pathogenesis.
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Affiliation(s)
- Sarah Noureddine
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL, 32827, USA
| | - Tatiana Saccon
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL, 32827, USA
| | - Trina Rudeski-Rohr
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL, 32827, USA
| | - Adam Gesing
- Department of Endocrinology of Ageing, Medical University of Lodz, Lodz, Poland
| | - Jeffrey B Mason
- School of Veterinary Medicine, Department of Animal, Dairy and Veterinary Sciences, Center for Integrated BioSystems, Utah State University, Logan, UT, 84322, USA
| | - Augusto Schneider
- Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Joseph Dhabhi
- Department of Medical Education, School of Medicine, California University of Science & Medicine, San Bernardino, USA
| | - Kendra L Puig
- Department of Biomedical Sciences, Dakota School of Medicine and Health Sciences, University of North, Grand Forks, ND, 58203, USA
| | - Sharlene Rakoczy
- Department of Biomedical Sciences, Dakota School of Medicine and Health Sciences, University of North, Grand Forks, ND, 58203, USA
| | - Holly M Brown-Borg
- Department of Biomedical Sciences, Dakota School of Medicine and Health Sciences, University of North, Grand Forks, ND, 58203, USA
| | - Michal M Masternak
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL, 32827, USA.
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, Poznan, Poland.
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14
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Hajjo R, Sabbah DA, Abusara OH, Al Bawab AQ. A Review of the Recent Advances in Alzheimer's Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics. Diagnostics (Basel) 2022; 12:diagnostics12122975. [PMID: 36552984 PMCID: PMC9777434 DOI: 10.3390/diagnostics12122975] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022] Open
Abstract
Alzheimer's disease (AD) is a polygenic multifactorial neurodegenerative disease that, after decades of research and development, is still without a cure. There are some symptomatic treatments to manage the psychological symptoms but none of these drugs can halt disease progression. Additionally, over the last few years, many anti-AD drugs failed in late stages of clinical trials and many hypotheses surfaced to explain these failures, including the lack of clear understanding of disease pathways and processes. Recently, different epigenetic factors have been implicated in AD pathogenesis; thus, they could serve as promising AD diagnostic biomarkers. Additionally, network biology approaches have been suggested as effective tools to study AD on the systems level and discover multi-target-directed ligands as novel treatments for AD. Herein, we provide a comprehensive review on Alzheimer's disease pathophysiology to provide a better understanding of disease pathogenesis hypotheses and decipher the role of genetic and epigenetic factors in disease development and progression. We also provide an overview of disease biomarkers and drug targets and suggest network biology approaches as new tools for identifying novel biomarkers and drugs. We also posit that the application of machine learning and artificial intelligence to mining Alzheimer's disease multi-omics data will facilitate drug and biomarker discovery efforts and lead to effective individualized anti-Alzheimer treatments.
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Affiliation(s)
- Rima Hajjo
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
- Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carlina at Chapel Hill, Chapel Hill, NC 27599, USA
- National Center for Epidemics and Communicable Disease Control, Amman 11118, Jordan
- Correspondence:
| | - Dima A. Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
| | - Osama H. Abusara
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
| | - Abdel Qader Al Bawab
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
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15
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Hu J, Chen W, Shen L, Chen Z, Huang J. Crosstalk between the peripheral nervous system and breast cancer influences tumor progression. Biochim Biophys Acta Rev Cancer 2022; 1877:188828. [PMID: 36283598 DOI: 10.1016/j.bbcan.2022.188828] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 11/18/2022]
Abstract
Recent studies have shown that peripheral nerves play an important role in the progression of breast cancer. Breast cancer cells (BCCs) promote local peripheral nerve growth and branching by secreting neuroactive molecules, including neurotrophins and axon guidance molecules (AGMs). Sympathetic nerves promote breast cancer progression, while parasympathetic and sensory nerves mainly have anti-tumor effects in the progression of breast cancer. Specifically, peripheral nerves can influence the progression of breast cancer by secreting neurotransmitters not only directly binding to the corresponding receptors of BCCs, but also indirectly acting on immune cells to modulate anti-tumor immunity. In this review, we summarize the crosstalk between breast cancer and peripheral nerves and the roles of important neuroactive molecules in the progression of breast cancer. In addition, we summarize indicators, including nerve fiber density and perineural invasion (PNI), that may help determine the prognosis of breast cancer based on current research results, as well as potential therapeutic approaches, such as β-blockers and retroviral-mediated genetic neuroengineering techniques, that may enhance the prognosis of breast cancer. In addition, we propose suggestions for future research priorities based on a current lack of knowledge in this area.
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Affiliation(s)
- Jianming Hu
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Wuzhen Chen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lesang Shen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Zhigang Chen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China..
| | - Jian Huang
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China..
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16
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Chen Z, Wu M, Lai Q, Zhou W, Wen X, Yin X. Epigenetic regulation of synaptic disorder in Alzheimer’s disease. Front Neurosci 2022; 16:888014. [PMID: 35992921 PMCID: PMC9382295 DOI: 10.3389/fnins.2022.888014] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 07/15/2022] [Indexed: 01/15/2023] Open
Abstract
Synapses are critical structures involved in neurotransmission and neuroplasticity. Their activity depends on their complete structure and function, which are the basis of learning, memory, and cognitive function. Alzheimer’s disease (AD) is neuropathologically characterized by synaptic loss, synaptic disorder, and plasticity impairment. AD pathogenesis is characterized by complex interactions between genetic and environmental factors. Changes in various receptors on the postsynaptic membrane, synaptic components, and dendritic spines lead to synaptic disorder. Changes in epigenetic regulation, including DNA methylation, RNA interference, and histone modification, are closely related to AD. These can affect neuronal and synaptic functions by regulating the structure and expression of neuronal genes. Some drugs have ameliorated synaptic and neural dysfunction in AD models via epigenetic regulation. We reviewed the recent progress on pathological changes and epigenetic mechanisms of synaptic dysregulation in AD to provide a new perspective on this disease.
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Affiliation(s)
- Zhiying Chen
- Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, China
| | - Moxin Wu
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, China
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Qin Lai
- Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Weixin Zhou
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, China
| | - Xiaoqing Wen
- Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Xiaoping Yin
- Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, China
- *Correspondence: Xiaoping Yin,
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17
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MicroRNAs in Learning and Memory and Their Impact on Alzheimer’s Disease. Biomedicines 2022; 10:biomedicines10081856. [PMID: 36009403 PMCID: PMC9405363 DOI: 10.3390/biomedicines10081856] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 12/15/2022] Open
Abstract
Learning and memory formation rely on the precise spatiotemporal regulation of gene expression, such as microRNA (miRNA)-associated silencing, to fine-tune gene expression for the induction and maintenance of synaptic plasticity. Much progress has been made in presenting direct evidence of miRNA regulation in learning and memory. Here, we summarize studies that have manipulated miRNA expression using various approaches in rodents, with changes in cognitive performance. Some of these are involved in well-known mechanisms, such as the CREB-dependent signaling pathway, and some of their roles are in fear- and stress-related disorders, particularly cognitive impairment. We also summarize extensive studies on miRNAs correlated with pathogenic tau and amyloid-β that drive the processes of Alzheimer’s disease (AD). Although altered miRNA profiles in human patients with AD and in mouse models have been well studied, little is known about their clinical applications and therapeutics. Studies on miRNAs as biomarkers still show inconsistencies, and more challenges need to be confronted in standardizing blood-based biomarkers for use in AD.
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18
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The Potential Role of miRNA-Regulated Autophagy in Alzheimer’s Disease. Int J Mol Sci 2022; 23:ijms23147789. [PMID: 35887134 PMCID: PMC9317523 DOI: 10.3390/ijms23147789] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/03/2022] [Accepted: 07/07/2022] [Indexed: 01/18/2023] Open
Abstract
As a neurodegenerative disease, Alzheimer’s disease (AD) shows a higher incidence during the aging process, mainly revealing the characteristics of a significant decrease in cognition, uncontrolled emotion, and reduced learning and memory capacity, even leading to death. In the prevention and treatment of AD, some pharmacological therapy has been applied in clinical practice. Unfortunately, there are still limited effective treatments for AD due to the absence of clear and defined targets. Currently, it is recognized that the leading causes of AD include amyloid-β peptide (Aβ) deposition, hyperphosphorylation of tau protein, neurofibrillary tangles, mitochondrial dysfunction, and inflammation. With in-depth mechanistic exploration, it has been found that these causes are highly correlated with the dysfunctional status of autophagy. Numerous experimental results have also confirmed that the development and progression of AD is accompanied by an abnormal functional status of autophagy; therefore, regulating the functional status of autophagy has become one of the important strategies for alleviating or arresting the progression of AD. With the increasing attention given to microRNAs (miRNAs), more and more studies have found that a series of miRNAs are involved in the development and progression of AD through the indirect regulation of autophagy. Therefore, regulating autophagy through targeting these miRNAs may be an essential breakthrough for the prevention and treatment of AD. This article summarizes the regulation of miRNAs in autophagy, with the aim of providing a new theoretical reference point for the prevention and treatment of AD through the indirect regulation of miRNA-mediated autophagy.
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19
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Ju H, Yang Z. H19 silencing decreases kainic acid-induced hippocampus neuron injury via activating the PI3K/AKT pathway via the H19/miR-206 axis. Exp Brain Res 2022; 240:2109-2120. [PMID: 35781830 DOI: 10.1007/s00221-022-06392-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 05/23/2022] [Indexed: 11/29/2022]
Abstract
Temporal lobe epilepsy (TLE) is the most common type of intractable epilepsy and is refractory to medications. However, the role and mechanism of H19 in regulating TLE remains largely undefined. Expression of H19 and miR-206 was detected using real-time quantitative PCR (RT-qPCR). Cell apoptosis, autophagy and inflammatory response were determined by flow cytometry, western blotting and enzyme-linked immunosorbent assay (ELISA). The interaction between H19 and miR-206 was predicted on the miRcode database and confirmed by luciferase reporter assay, RNA immunoprecipitation (RIP) and RNA pull-down. H19 was upregulated and miR-206 was downregulated in the rat hippocampus neurons after kainic acid (KA) treatment. Functionally, both H19 knockdown and miR-206 overexpression weakened KA-induced apoptosis, autophagy, inflammatory response, and oxidative stress in hippocampus neurons. Mechanically, the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway was activated by H19 knockdown and miR-206 was confirmed to be targeted and negatively regulated by H19. Moreover, downregulation of miR-206 could counteract the effects of H19 knockdown in KA-induced hippocampus neurons. Knockdown of H19 suppressed hippocampus neuronal apoptosis, autophagy and inflammatory response presumably through directly upregulating miR-206 and activating the PI3K/AKT signaling pathway.
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Affiliation(s)
- Haichao Ju
- Department of Pediatrics, Weihai Central Hospital, No. 3, West Mishandong Road, Wendeng District, Weihai, 264400, Shandong, China
| | - Zhimin Yang
- Department of Pediatrics, Weihai Central Hospital, No. 3, West Mishandong Road, Wendeng District, Weihai, 264400, Shandong, China.
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20
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Martinez B, Peplow PV. MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis. Neural Regen Res 2022; 17:1412-1422. [PMID: 34916411 PMCID: PMC8771095 DOI: 10.4103/1673-5374.330591] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/16/2021] [Accepted: 06/28/2021] [Indexed: 11/04/2022] Open
Abstract
Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.
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Affiliation(s)
- Bridget Martinez
- Department of Medicine, St. Georges University School of Medicine, Grenada
| | - Philip V. Peplow
- Department of Anatomy, University of Otago, Dunedin, New Zealand
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21
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Guan W, Xu DW, Ji CH, Wang CN, Liu Y, Tang WQ, Gu JH, Chen YM, Huang J, Liu JF, Jiang B. Hippocampal miR-206-3p participates in the pathogenesis of depression via regulating the expression of BDNF. Pharmacol Res 2021; 174:105932. [PMID: 34628001 DOI: 10.1016/j.phrs.2021.105932] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 12/14/2022]
Abstract
As a widely-known neuropsychiatric disorder, the exact pathogenesis of depression remains elusive. MiRNA-206 (miR-206) is conventionally known as one of the myomiRs and has two forms: miR-206-3p and miR-206-5p. Recently, miR-206 has been demonstrated to regulate the biosynthesis of brain-derived neurotrophic factor (BDNF), a very popular target involved in depression and antidepressant responses. Here we assumed that miR-206 may play a role in depression, and various methods including the chronic social defeat stress (CSDS) model of depression, quantitative real-time reverse transcription PCR, western blotting, immuofluorescence and virus-mediated gene transfer were used together. It was found that CSDS robustly increased the level of miR-206-3p but not miR-206-5p in the hippocampus. Both genetic overexpression of hippocampal miR-206-3p and intranasal administration of AgomiR-206-3p induced not only notable depressive-like behaviors but also significantly decreased hippocampal BDNF signaling cascade and neurogenesis in naïve C57BL/6J mice. In contrast, both genetic knockdown of hippocampal miR-206-3p and intranasal administration of AntagomiR-206-3p produced significant antidepressant-like effects in the CSDS model of depression. Furthermore, it was found that the antidepressant-like effects induced by miR-206-3p inhibition require the hippocampal BDNF-TrkB system. Taken together, hippocampal miR-206-3p participates in the pathogenesis of depression by regulating BDNF biosynthesis and is a feasible antidepressant target.
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Affiliation(s)
- Wei Guan
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Da-Wei Xu
- Department of Orthopaedics, Affiliated Hospital 2 of Nantong University, Nantong 226001, Jiangsu, China
| | - Chun-Hui Ji
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Cheng-Niu Wang
- Basic Medical Research Centre, Medical College, Nantong University; Nantong 226001, Jiangsu, China
| | - Yue Liu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Wen-Qian Tang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Jiang-Hong Gu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Yan-Mei Chen
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Jie Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Jian-Feng Liu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Bo Jiang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China.
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22
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The neurobiology of non-coding RNAs and Alzheimer's disease pathogenesis: Pathways, mechanisms and translational opportunities. Ageing Res Rev 2021; 71:101425. [PMID: 34384901 DOI: 10.1016/j.arr.2021.101425] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/13/2022]
Abstract
In the past two decades, advances in sequencing technology and analysis of the human and mouse genome have led to the discovery of many non-protein-coding RNAs (ncRNAs) including: microRNA, small-interfering RNAs, piwi-associated small RNAs, transfer RNA-derived small RNAs, long-non-coding RNAs and circular RNAs. Compared with healthy controls, levels of some ncRNAs are significantly altered in the central nervous system and blood of patients affected by neurodegenerative disorders like Alzheimer's disease (AD). Although the mechanisms are still not fully elucidated, studies have revealed that these highly conserved ncRNAs are important modulators of gene expression, amyloid-β production, tau phosphorylation, inflammation, synaptic plasticity and neuronal survival, all features considered central to AD pathogenesis. Despite considerable difficulties due to their large heterogeneity, and the complexity of their regulatory pathways, research in this rapidly growing field suggests that ncRNAs hold great potential as biomarkers and therapeutic targets against AD. Herein, we summarize the current knowledge regarding the neurobiology of ncRNA in the context of AD pathophysiology.
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Zhang Y, Zhao Y, Ao X, Yu W, Zhang L, Wang Y, Chang W. The Role of Non-coding RNAs in Alzheimer's Disease: From Regulated Mechanism to Therapeutic Targets and Diagnostic Biomarkers. Front Aging Neurosci 2021; 13:654978. [PMID: 34276336 PMCID: PMC8283767 DOI: 10.3389/fnagi.2021.654978] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/11/2021] [Indexed: 01/05/2023] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. AD is characterized by the production and aggregation of beta-amyloid (Aβ) peptides, hyperphosphorylated tau proteins that form neurofibrillary tangles (NFTs), and subsequent neuroinflammation, synaptic dysfunction, autophagy and oxidative stress. Non-coding RNAs (ncRNAs) can be used as potential therapeutic targets and biomarkers due to their vital regulatory roles in multiple biological processes involved in disease development. The involvement of ncRNAs in the pathogenesis of AD has been increasingly recognized. Here, we review the ncRNAs implicated in AD and elaborate on their main regulatory pathways, which might have contributions for discovering novel therapeutic targets and drugs for AD.
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Affiliation(s)
- Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yanfang Zhao
- Institute of Biomedical Research, School for Life Science, Shandong University of Technology, Zibo, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao University, Qingdao, China
| | - Lei Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yu Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Wenguang Chang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Moraghebi M, Maleki R, Ahmadi M, Negahi AA, Abbasi H, Mousavi P. In silico Analysis of Polymorphisms in microRNAs Deregulated in Alzheimer Disease. Front Neurosci 2021; 15:631852. [PMID: 33841080 PMCID: PMC8024493 DOI: 10.3389/fnins.2021.631852] [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] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/18/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a degenerative condition characterized by progressive cognitive impairment and dementia. Findings have revolutionized current knowledge of miRNA in the neurological conditions. Two regulatory mechanisms determine the level of mature miRNA expression; one is miRNA precursor processing, and the other is gene expression regulation by transcription factors. This study is allocated to the in-silico investigation of miRNA's SNPs and their effect on other cell mechanisms. METHODS We used databases which annotate the functional effect of SNPs on mRNA-miRNA and miRNA-RBP interaction. Also, we investigated SNPs which are located on the promoter or UTR region. RESULTS miRNA SNP3.0 database indicated several SNPs in miR-339 and miR-34a in the upstream and downstream of pre-miRNA and mature miRNAs. While, for some miRNAs miR-124, and miR-125, no polymorphism was observed, and also miR-101 with ΔG -3.1 and mir-328 with ΔG 5.8 had the highest and lowest potencies to produce mature microRNA. SNP2TFBS web-server presented several SNPs which altered the Transcription Factor Binding Sites (TFBS) or generated novel TFBS in the promoter regions of related miRNA. At last, RBP-Var database provided a list of SNPs which alter miRNA-RBP interaction pattern and can also influence other miRNAs' expression. DISCUSSION The results indicated that SNPs microRNA affects both miRNA function and miRNA expression. Our study expands molecular insight into how SNPs in different parts of miRNA, including the regulatory (promoter), the precursor (pre-miRNA), functional regions (seed region of mature miRNA), and RBP-binding motifs, which theoretically may be correlated to the Alzheimer's disease.
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Affiliation(s)
- Mahta Moraghebi
- Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Reza Maleki
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Ahmadi
- Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Ahmad Agha Negahi
- Department of Internal Medicine, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Hossein Abbasi
- Student Research Committee, Faculty of Para-Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Pegah Mousavi
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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25
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Nikolac Perkovic M, Videtic Paska A, Konjevod M, Kouter K, Svob Strac D, Nedic Erjavec G, Pivac N. Epigenetics of Alzheimer's Disease. Biomolecules 2021; 11:195. [PMID: 33573255 PMCID: PMC7911414 DOI: 10.3390/biom11020195] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/19/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
There are currently no validated biomarkers which can be used to accurately diagnose Alzheimer's disease (AD) or to distinguish it from other dementia-causing neuropathologies. Moreover, to date, only symptomatic treatments exist for this progressive neurodegenerative disorder. In the search for new, more reliable biomarkers and potential therapeutic options, epigenetic modifications have emerged as important players in the pathogenesis of AD. The aim of the article was to provide a brief overview of the current knowledge regarding the role of epigenetics (including mitoepigenetics) in AD, and the possibility of applying these advances for future AD therapy. Extensive research has suggested an important role of DNA methylation and hydroxymethylation, histone posttranslational modifications, and non-coding RNA regulation (with the emphasis on microRNAs) in the course and development of AD. Recent studies also indicated mitochondrial DNA (mtDNA) as an interesting biomarker of AD, since dysfunctions in the mitochondria and lower mtDNA copy number have been associated with AD pathophysiology. The current evidence suggests that epigenetic changes can be successfully detected, not only in the central nervous system, but also in the cerebrospinal fluid and on the periphery, contributing further to their potential as both biomarkers and therapeutic targets in AD.
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Affiliation(s)
- Matea Nikolac Perkovic
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
| | - Alja Videtic Paska
- Medical Center for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (A.V.P.); (K.K.)
| | - Marcela Konjevod
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
| | - Katarina Kouter
- Medical Center for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (A.V.P.); (K.K.)
| | - Dubravka Svob Strac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
| | - Gordana Nedic Erjavec
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
| | - Nela Pivac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
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Eyileten C, Sharif L, Wicik Z, Jakubik D, Jarosz-Popek J, Soplinska A, Postula M, Czlonkowska A, Kaplon-Cieslicka A, Mirowska-Guzel D. The Relation of the Brain-Derived Neurotrophic Factor with MicroRNAs in Neurodegenerative Diseases and Ischemic Stroke. Mol Neurobiol 2021; 58:329-347. [PMID: 32944919 PMCID: PMC7695657 DOI: 10.1007/s12035-020-02101-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 08/25/2020] [Indexed: 03/07/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that plays a crucial role in the development of the nervous system while supporting the survival of existing neurons and instigating neurogenesis. Altered levels of BDNF, both in the circulation and in the central nervous system (CNS), have been reported to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), multiple sclerosis (MS), and ischemic stroke. MicroRNAs (miRNAs) are a class of non-coding RNAs found in body fluids such as peripheral blood and cerebrospinal fluid. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of neurodegenerative and neurovascular diseases. Thus, they present as promising biomarkers and a novel treatment approach for CNS disorders. Currently, limited studies provide viable evidence of miRNA-mediated post-transcriptional regulation of BDNF. The aim of this review is to provide a comprehensive assessment of the current knowledge regarding the potential diagnostic and prognostic values of miRNAs affecting BDNF expression and its role as a CNS disorders and neurovascular disease biomarker. Moreover, a novel therapeutic approach in neurodegenerative diseases and ischemic stroke targeting miRNAs associated with BDNF will be discussed.
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Affiliation(s)
- Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097 Warsaw, Poland
| | - Lucia Sharif
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097 Warsaw, Poland
| | - Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097 Warsaw, Poland
- Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Paulo, Brazil
| | - Daniel Jakubik
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097 Warsaw, Poland
| | - Joanna Jarosz-Popek
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097 Warsaw, Poland
| | - Aleksandra Soplinska
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097 Warsaw, Poland
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097 Warsaw, Poland
| | - Anna Czlonkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
| | | | - Dagmara Mirowska-Guzel
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097 Warsaw, Poland
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Tecalco-Cruz AC, Ramírez-Jarquín JO, Alvarez-Sánchez ME, Zepeda-Cervantes J. Epigenetic basis of Alzheimer disease. World J Biol Chem 2020; 11:62-75. [PMID: 33024518 PMCID: PMC7520642 DOI: 10.4331/wjbc.v11.i2.62] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/30/2020] [Accepted: 09/10/2020] [Indexed: 02/05/2023] Open
Abstract
Alzheimer disease (AD) is the primary form of dementia that occurs spontaneously in older adults. Interestingly, the epigenetic profile of the cells forming the central nervous system changes during aging and may contribute to the progression of some neurodegenerative diseases such as AD. In this review, we present general insights into relevant epigenetic mechanisms and their relationship with aging and AD. The data suggest that some epigenetic changes during aging could be utilized as biomarkers and target molecules for the prevention and control of AD.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- Programa en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico 03100, Mexico
| | - Josué O Ramírez-Jarquín
- División de neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico 04510, Mexico
| | | | - Jesus Zepeda-Cervantes
- Biología celular y de desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico 04510, Mexico
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28
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Li X, Zhao J, Li Z, Zhang L, Huo Z. Applications of Acupuncture Therapy in Modulating the Plasticity of Neurodegenerative Disease and Depression: Do MicroRNA and Neurotrophin BDNF Shed Light on the Underlying Mechanism? Neural Plast 2020; 2020:8850653. [PMID: 33029119 PMCID: PMC7527896 DOI: 10.1155/2020/8850653] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/12/2020] [Accepted: 09/05/2020] [Indexed: 02/08/2023] Open
Abstract
As the global population ages, the incidence of neurodegenerative diseases has risen. Furthermore, it has been suggested that depression, especially in elderly people, may also be an indication of latent neurodegeneration. Stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are usually accompanied by depression. The urgent challenge is further enforced by psychiatric comorbid conditions, particularly the feeling of despair in these patients. Fortunately, as our understanding of the neurobiological substrates of maladies affecting the central nervous system (CNS) has increased, more therapeutic options and novel potential biological mechanisms have been presented: (1) Neurodegenerative diseases share some similarities in their pathological characteristics, including changes in neuron structure or function and neuronal plasticity. (2) MicroRNAs (miRNAs) are small noncoding RNAs that contribute to the pathogenesis of diverse neurological disease. (3) One ubiquitous neurotrophin, brain-derived neurotrophic factor (BDNF), is crucial for the development of the nervous system. Accumulating data have indicated that miRNAs not only are related to BDNF regulation but also can directly bind with the 3'-UTR of BDNF to regulate BDNF and participate in neuroplasticity. In this short review, we present evidence of shared biological substrates among stroke, AD, PD, and depression and summarize the possible influencing mechanisms of acupuncture on the neuroplasticity of these diseases. We discuss neuroplasticity underscored by the roles of miRNAs and BDNF, which might further reveal the potential biological mechanism of neurodegenerative diseases and depression by acupuncture.
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Affiliation(s)
- Xia Li
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jun Zhao
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zhigang Li
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Li Zhang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zejun Huo
- Department of Chinese Medicine, Peking University 3rd Hospital, Beijing 100191, China
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Ausó E, Gómez-Vicente V, Esquiva G. Biomarkers for Alzheimer's Disease Early Diagnosis. J Pers Med 2020; 10:E114. [PMID: 32899797 PMCID: PMC7563965 DOI: 10.3390/jpm10030114] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/27/2020] [Accepted: 09/01/2020] [Indexed: 12/11/2022] Open
Abstract
Alzheimer's disease (AD) is the most common cause of dementia, affecting the central nervous system (CNS) through the accumulation of intraneuronal neurofibrillary tau tangles (NFTs) and β-amyloid plaques. By the time AD is clinically diagnosed, neuronal loss has already occurred in many brain and retinal regions. Therefore, the availability of early and reliable diagnosis markers of the disease would allow its detection and taking preventive measures to avoid neuronal loss. Current diagnostic tools in the brain, such as magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and cerebrospinal fluid (CSF) biomarkers (Aβ and tau) detection are invasive and expensive. Brain-secreted extracellular vesicles (BEVs) isolated from peripheral blood have emerged as novel strategies in the study of AD, with enormous potential as a diagnostic evaluation of therapeutics and treatment tools. In addition; similar mechanisms of neurodegeneration have been demonstrated in the brain and the eyes of AD patients. Since the eyes are more accessible than the brain, several eye tests that detect cellular and vascular changes in the retina have also been proposed as potential screening biomarkers. The aim of this study is to summarize and discuss several potential markers in the brain, eye, blood, and other accessible biofluids like saliva and urine, and correlate them with earlier diagnosis and prognosis to identify individuals with mild symptoms prior to dementia.
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Affiliation(s)
| | | | - Gema Esquiva
- Department of Optics, Pharmacology and Anatomy, University of Alicante, 03690 Alicante, Spain; (E.A.); (V.G.-V.)
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30
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MicroRNAs Dysregulation and Mitochondrial Dysfunction in Neurodegenerative Diseases. Int J Mol Sci 2020; 21:ijms21175986. [PMID: 32825273 PMCID: PMC7504116 DOI: 10.3390/ijms21175986] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/12/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases are debilitating and currently incurable conditions causing severe cognitive and motor impairments, defined by the progressive deterioration of neuronal structure and function, eventually causing neuronal loss. Understand the molecular and cellular mechanisms underlying these disorders are essential to develop therapeutic approaches. MicroRNAs (miRNAs) are short non-coding RNAs implicated in gene expression regulation at the post-transcriptional level. Moreover, miRNAs are crucial for different processes, including cell growth, signal transmission, apoptosis, cancer and aging-related neurodegenerative diseases. Altered miRNAs levels have been associated with the formation of reactive oxygen species (ROS) and mitochondrial dysfunction. Mitochondrial dysfunction and ROS formation occur in many neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. The crosstalk existing among oxidative stress, mitochondrial dysfunction and miRNAs dysregulation plays a pivotal role in the onset and progression of neurodegenerative diseases. Based on this evidence, in this review, with a focus on miRNAs and their role in mitochondrial dysfunction in aging-related neurodegenerative diseases, with a focus on their potential as diagnostic biomarkers and therapeutic targets.
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31
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Improta-Caria AC, Nonaka CKV, Cavalcante BRR, De Sousa RAL, Aras Júnior R, Souza BSDF. Modulation of MicroRNAs as a Potential Molecular Mechanism Involved in the Beneficial Actions of Physical Exercise in Alzheimer Disease. Int J Mol Sci 2020; 21:E4977. [PMID: 32674523 PMCID: PMC7403962 DOI: 10.3390/ijms21144977] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/23/2020] [Accepted: 06/23/2020] [Indexed: 12/18/2022] Open
Abstract
Alzheimer disease (AD) is one of the most common neurodegenerative diseases, affecting middle-aged and elderly individuals worldwide. AD pathophysiology involves the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, along with chronic neuroinflammation and neurodegeneration. Physical exercise (PE) is a beneficial non-pharmacological strategy and has been described as an ally to combat cognitive decline in individuals with AD. However, the molecular mechanisms that govern the beneficial adaptations induced by PE in AD are not fully elucidated. MicroRNAs are small non-coding RNAs involved in the post-transcriptional regulation of gene expression, inhibiting or degrading their target mRNAs. MicroRNAs are involved in physiological processes that govern normal brain function and deregulated microRNA profiles are associated with the development and progression of AD. It is also known that PE changes microRNA expression profile in the circulation and in target tissues and organs. Thus, this review aimed to identify the role of deregulated microRNAs in the pathophysiology of AD and explore the possible role of the modulation of microRNAs as a molecular mechanism involved in the beneficial actions of PE in AD.
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Affiliation(s)
- Alex Cleber Improta-Caria
- Post-Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Bahia 40110-909, Brazil; (A.C.I.-C.); (R.A.J.)
- University Hospital Professor Edgard Santos, Bahia 40110-909, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Bahia 40110-909, Brazil; (C.K.V.N.); (B.R.R.C.)
| | - Carolina Kymie Vasques Nonaka
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Bahia 40110-909, Brazil; (C.K.V.N.); (B.R.R.C.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 20000-000, Brazil
| | - Bruno Raphael Ribeiro Cavalcante
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Bahia 40110-909, Brazil; (C.K.V.N.); (B.R.R.C.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 20000-000, Brazil
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Bahia 40110-909, Brazil
| | - Ricardo Augusto Leoni De Sousa
- Physiological Science Multicentric Program, Federal University of Valleys´ Jequitinhonha and Mucuri, Minas Gerais 30000-000, Brazil;
| | - Roque Aras Júnior
- Post-Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Bahia 40110-909, Brazil; (A.C.I.-C.); (R.A.J.)
- University Hospital Professor Edgard Santos, Bahia 40110-909, Brazil
| | - Bruno Solano de Freitas Souza
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Bahia 40110-909, Brazil; (C.K.V.N.); (B.R.R.C.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 20000-000, Brazil
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Bahia 40110-909, Brazil
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Strianese O, Rizzo F, Ciccarelli M, Galasso G, D’Agostino Y, Salvati A, Del Giudice C, Tesorio P, Rusciano MR. Precision and Personalized Medicine: How Genomic Approach Improves the Management of Cardiovascular and Neurodegenerative Disease. Genes (Basel) 2020; 11:E747. [PMID: 32640513 PMCID: PMC7397223 DOI: 10.3390/genes11070747] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
Life expectancy has gradually grown over the last century. This has deeply affected healthcare costs, since the growth of an aging population is correlated to the increasing burden of chronic diseases. This represents the interesting challenge of how to manage patients with chronic diseases in order to improve health care budgets. Effective primary prevention could represent a promising route. To this end, precision, together with personalized medicine, are useful instruments in order to investigate pathological processes before the appearance of clinical symptoms and to guide physicians to choose a targeted therapy to manage the patient. Cardiovascular and neurodegenerative diseases represent suitable models for taking full advantage of precision medicine technologies applied to all stages of disease development. The availability of high technology incorporating artificial intelligence and advancement progress made in the field of biomedical research have been substantial to understand how genes, epigenetic modifications, aging, nutrition, drugs, microbiome and other environmental factors can impact health and chronic disorders. The aim of the present review is to address how precision and personalized medicine can bring greater clarity to the clinical and biological complexity of these types of disorders associated with high mortality, involving tremendous health care costs, by describing in detail the methods that can be applied. This might offer precious tools for preventive strategies and possible clues on the evolution of the disease and could help in predicting morbidity, mortality and detecting chronic disease indicators much earlier in the disease course. This, of course, will have a major effect on both improving the quality of care and quality of life of the patients and reducing time efforts and healthcare costs.
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Affiliation(s)
- Oriana Strianese
- Clinical Research and Innovation, Clinica Montevergine S.p.A., 83013 Mercogliano, Italy; (O.S.); (C.D.G.)
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84084 Baronissi, Italy; (F.R.); (Y.D.); (A.S.)
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84084 Baronissi, Italy; (F.R.); (Y.D.); (A.S.)
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84084 Baronissi, Italy; (M.C.); (G.G.)
| | - Gennaro Galasso
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84084 Baronissi, Italy; (M.C.); (G.G.)
| | - Ylenia D’Agostino
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84084 Baronissi, Italy; (F.R.); (Y.D.); (A.S.)
| | - Annamaria Salvati
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84084 Baronissi, Italy; (F.R.); (Y.D.); (A.S.)
| | - Carmine Del Giudice
- Clinical Research and Innovation, Clinica Montevergine S.p.A., 83013 Mercogliano, Italy; (O.S.); (C.D.G.)
| | - Paola Tesorio
- Unit of Cardiology, Clinica Montevergine S.p.A., 83013 Mercogliano, Italy;
| | - Maria Rosaria Rusciano
- Clinical Research and Innovation, Clinica Montevergine S.p.A., 83013 Mercogliano, Italy; (O.S.); (C.D.G.)
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84084 Baronissi, Italy; (M.C.); (G.G.)
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Wu Y, Wu C, Ye L, Wang B, Yuan Y, Liu Y, Zheng P, Xiong J, Li Y, Jiang T, Li X, Xiao J. Exogenous fibroblast growth factor 1 ameliorates diabetes-induced cognitive decline via coordinately regulating PI3K/AKT signaling and PERK signaling. Cell Commun Signal 2020; 18:81. [PMID: 32460803 PMCID: PMC7251863 DOI: 10.1186/s12964-020-00588-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 04/29/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Diabetes induces central nervous system damage, leading to cognitive decline. Fibroblast growth factor 1 (FGF1) has dual function of neuroprotection and normalizing hyperglycemia. To date, the precise mechanisms and potential treating strategies of FGF1 for diabetes-induced cognitive decline (DICD) hasn't been fully elucidated. METHODS In this study, db/db mice were used as DICD animal model. We found that diabetes remarkably suppressed FGF1 expression in hippocampus. Thus, exogenous FGF1 had been treated for db/db mice and SH-SY5Y cells. RESULTS FGF1 significantly ameliorates DICD with better spatial learning and memory function. Moreover, FGF1 blocked diabetes-induced morphological structure change, neuronal apoptosis and Aβ1-42 deposition and synaptic dysfunction in hippocampus. But normalizing glucose may not the only contributed factor for FGF1 treating DICD with evidencing that metformin-treated db/db mice has a inferior cognitive function than that in FGF1 group. Current mechanistic study had found that diabetes inhibits cAMP-response element binding protein (CREB) activity and subsequently suppresses brain derived neurotrophic factor (BDNF) level via coordinately regulating PERK signaling and PI3K/AKT signaling in hippocampus, which were reversed by FGF1. CONCLUSION We conclude that FGF1 exerts its neuroprotective role and normalizing hyperglycemia effect, consequently ameliorates DICD, implying FGF1 holds a great promise to develop a new treatment for DICD. Video abstract.
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Affiliation(s)
- Yanqing Wu
- The Institute of Life Sciences, Engineering Laboratory of Zhejiang province for pharmaceutical development of growth factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou University, Wenzhou, 325035, China
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Chengbiao Wu
- Clinical Research Center, Affiate Xiangshang Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Libing Ye
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Beini Wang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yuan Yuan
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yaqian Liu
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Peipei Zheng
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Jun Xiong
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yiyang Li
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Ting Jiang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xiaokun Li
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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Gu WJ, Zhang C, Zhong Y, Luo J, Zhang CY, Zhang C, Wang C. Altered serum microRNA expression profile in subjects with heroin and methamphetamine use disorder. Biomed Pharmacother 2020; 125:109918. [PMID: 32036213 DOI: 10.1016/j.biopha.2020.109918] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 12/02/2019] [Accepted: 12/18/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Drug abuse is one of the most severe global social and public health problems, especially in China. However, objective blood biomarkers that are easy to detect are still in great need. This study was aim to explore the expression pattern of circulating microRNAs (miRNAs) in subjects with drug addiction and test the potential of altered serum miRNAs as noninvasive diagnostic tools for drug abuse. METHODS Serum samples were obtained from 42 heroin abusers, 42 methamphetamine (MA) abusers and 42 controls. Microarray-based miRNA analysis was first applied to screen unique serum miRNA profiles in drug abusers on a training set of serum samples from 12 heroin abusers, 12 MA abusers and 12 control subjects. The expression levels of selected candidate miRNAs were subsequently verified in individual samples of the training set and further confirmed independently in a validation set of samples from 30 heroin abusers, 30 MA abusers and 30 controls using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS Microarray analysis identified 116 and 109 significantly altered miRNAs in heroin abusers and MA abusers, respectively. Three miRNAs, including let-7b-5p, miR-206 and miR-486-5p, were verified to be significantly and steadily increased in heroin abusers, and miR-9-3p was significantly increased in MA abusers compared with normal controls. The areas under the curve (AUCs) of the ROC curve of these miRNAs ranged from 0.718 to 0.867. CONCLUSIONS Our study raises the possibility that the altered serum miRNAs could potentially be used as an auxiliary tool to identify individuals in drug abuse and addiction.
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Affiliation(s)
- Wan-Jian Gu
- Department of Clinical Laboratory, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School of Nanjing University, Nanjing, 210002, China; Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Cuiping Zhang
- Department of Clinical Laboratory, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School of Nanjing University, Nanjing, 210002, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, Nanjing, 210046, China
| | - Yujie Zhong
- Department of Clinical Laboratory, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School of Nanjing University, Nanjing, 210002, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, Nanjing, 210046, China
| | - Jun Luo
- Central Laboratory of Jiangsu Health Vocational College, Nanjing, 210029, China
| | - Chen-Yu Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, Nanjing, 210046, China
| | - Chunni Zhang
- Department of Clinical Laboratory, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School of Nanjing University, Nanjing, 210002, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, Nanjing, 210046, China.
| | - Cheng Wang
- Department of Clinical Laboratory, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science, Medical School of Nanjing University, Nanjing, 210002, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, Nanjing University School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, Nanjing, 210046, China.
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Nuzziello N, Ciaccia L, Liguori M. Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs' World. Cells 2019; 9:E75. [PMID: 31892254 PMCID: PMC7017296 DOI: 10.3390/cells9010075] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 12/22/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
: Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.
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Affiliation(s)
- Nicoletta Nuzziello
- National Research Council, Institute of Biomedical Technologies, Bari Unit, 70126 Bari, Italy
| | - Loredana Ciaccia
- Department of Biomedical Science and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Maria Liguori
- National Research Council, Institute of Biomedical Technologies, Bari Unit, 70126 Bari, Italy
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O’Meara T, Kong Y, Chiarella J, Price RW, Chaudhury R, Liu X, Spudich S, Robertson K, Emu B, Lu L. Exosomal MicroRNAs Associate With Neuropsychological Performance in Individuals With HIV Infection on Antiretroviral Therapy. J Acquir Immune Defic Syndr 2019; 82:514-522. [PMID: 31714431 PMCID: PMC6857839 DOI: 10.1097/qai.0000000000002187] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Neurocognitive dysfunction remains prevalent among people living with HIV (PLWH), even after viral suppression on combination antiretroviral therapy (cART). We investigated associations between neuropsychological performance (NP) and patterns of circulating exosomal microRNA (exo-miRNA) expression in PLWH on cART. SETTING A cross-sectional examination of plasma exo-miRNA among PLWH on cART with systemic viral suppression and volunteers without HIV infection. METHODS Thirty-one PLWH who started cART during early infection (n = 19) or chronic infection (n = 12) participated in phlebotomy and an 11-test neuropsychological battery after >1 year on treatment. NP higher- or lower-performing participants were categorized based on normalized neuropsychological scores. Total RNA was extracted from purified exosomes of 31 PLWH and 5 volunteers without HIV and subject to small RNA sequencing. Differential expression of exo-miRNAs was examined and biological functions were predicted. RESULTS Eleven exo-miRNAs were up-regulated in NP lower-performing (n = 18) relative to higher-performing PLWH (n = 13). A high proportion of the differentiating exo-miRNA target the axon guidance KEGG pathway and neurotrophin tyrosine receptor kinase signaling Gene Ontology pathway. Differential expression analysis of exo-miRNAs between NP lower- (n = 7) and higher-performing (n = 12) PLWH within the early infection group alone confirmed largely consistent findings. CONCLUSIONS Plasma exo-miRNA content differed between NP higher- and lower-performing PLWH. Several differentially expressed exo-miRNAs were predicted to be involved in inflammation and neurodegeneration pathways. Exo-miRNA in plasma may indicate cross-talk between the circulation and central nervous system and thus may be clinically relevant for neurocognitive dysfunction in PLWH.
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Affiliation(s)
| | - Yong Kong
- Yale School of Public Health, New Haven, CT
| | | | - Richard W. Price
- University of California San Francisco School of Medicine,
San Francisco, CA
| | - Rabib Chaudhury
- Yale School of Engineering and Applied Sciences, New Haven,
CT
| | | | | | - Kevin Robertson
- University of North Carolina School of Medicine, Chapel
Hill, NC
| | | | - Lingeng Lu
- Yale School of Public Health, New Haven, CT
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Zhao Y, Zhang Y, Zhang L, Dong Y, Ji H, Shen L. The Potential Markers of Circulating microRNAs and long non-coding RNAs in Alzheimer's Disease. Aging Dis 2019; 10:1293-1301. [PMID: 31788340 PMCID: PMC6844586 DOI: 10.14336/ad.2018.1105] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/05/2018] [Indexed: 12/11/2022] Open
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder and one of the leading causes of disability and mortality in the late life with no curative treatment currently. Thus, it is urgently to establish sensitive and non-invasive biomarkers for AD diagnosis, particularly in the early stage. Recently, emerging number of microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs) are considered as effective biomarkers in various diseases as they possess characteristics of stable, resistant to RNAase digestion and many extreme conditions in circulatory fluid. This review highlights recent advances in the identification of the aberrantly expressed miRNAs and lncRNAs in circulatory network for detection of AD. We summarized the abnormal expressed miRNAs in blood and cerebrospinal fluid (CSF), and detailed discussed the functions and molecular mechanism of serum or plasma miRNAs-miR-195, miR-155, miR-34a, miR-9, miR-206, miR-125b and miR-29 in the regulation of AD progression. In addition, we also elaborated the role of circulating lncRNA major including beta-site APP cleaving enzyme 1 (BACE1) and its antisense lncRNA BACE1-AS in AD pathological advancement. In brief, confirming the aberrantly expressed circulating miRNAs and lncRNAs will provide an effective testing tools for treatment of AD in the future.
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Affiliation(s)
- Yanfang Zhao
- 1Institute of Biomedical Research, Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Zibo Key Laboratory of New Drug Development of Neurodegenerative diseases, School for Life Science, Shandong University of Technology, Zibo, China
| | - Yuan Zhang
- 2Institute for Translational Medicine, Qingdao University, Qingdao, China
| | - Lei Zhang
- 2Institute for Translational Medicine, Qingdao University, Qingdao, China
| | - Yanhan Dong
- 2Institute for Translational Medicine, Qingdao University, Qingdao, China
| | - Hongfang Ji
- 1Institute of Biomedical Research, Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Zibo Key Laboratory of New Drug Development of Neurodegenerative diseases, School for Life Science, Shandong University of Technology, Zibo, China
| | - Liang Shen
- 1Institute of Biomedical Research, Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Zibo Key Laboratory of New Drug Development of Neurodegenerative diseases, School for Life Science, Shandong University of Technology, Zibo, China
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Khani-Habibabadi F, Askari S, Zahiri J, Javan M, Behmanesh M. Novel BDNF-regulatory microRNAs in neurodegenerative disorders pathogenesis: An in silico study. Comput Biol Chem 2019; 83:107153. [PMID: 31751881 DOI: 10.1016/j.compbiolchem.2019.107153] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/13/2019] [Accepted: 10/16/2019] [Indexed: 11/28/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor with various roles in the central nervous system neurogenesis, neuroprotection, and axonal guide. By attaching to Tropomyosin receptor kinase B (TrkB) receptor, this protein triggers downstream signaling pathways which lead to cellular growth, proliferation, survival, and neuroplasticity. Deregulation at mRNA level is involved in various central nervous system disorders including, Huntington, Alzheimer's, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis diseases. Considering the importance of BDNF functions, deciphering the regulatory mechanisms controlling BDNF expression level could pave the way to develop more accurate and efficient treatments for neurological diseases. Among different regulatory systems, microRNAs (miRNAs) play prominent roles by targeting genes 3' untranslated regions. In this study, 127 validated and bioinformatic-predicted miRNAs with potentially regulatory roles in BDNF expression were analyzed. Various aspects of miRNAsö possible functions were assessed by bioinformatic online tools to find their potential regulatory functions in signaling pathways, neurological disorders, expression of transcription factors and miRNAs sponge. Analyzed data led to introduce 5 newly reported miRNAs that could regulate BDNF expression level. Finally, high throughput sequencing data from different brain regions and neurological disorders were analyzed to measure correlation of candidate miRNAs with BDNF level in experimental studies. In this study, a list of novel miRNAs with possible regulatory roles in BDNF expression level involving in different neurological disorders was introduced.
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Affiliation(s)
- Fatemeh Khani-Habibabadi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Shahrzad Askari
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javad Zahiri
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Javan
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mehrdad Behmanesh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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Silvestro S, Bramanti P, Mazzon E. Role of miRNAs in Alzheimer's Disease and Possible Fields of Application. Int J Mol Sci 2019; 20:E3979. [PMID: 31443326 PMCID: PMC6720959 DOI: 10.3390/ijms20163979] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/07/2019] [Accepted: 08/14/2019] [Indexed: 01/02/2023] Open
Abstract
miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3' and 5' untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer's disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD.
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Affiliation(s)
- Serena Silvestro
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
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Liu S, Jiang T, Zhong Y, Yu Y. miR-210 inhibits cell migration and invasion by targeting the brain-derived neurotrophic factor in glioblastoma. J Cell Biochem 2019; 120:11375-11382. [PMID: 30746749 DOI: 10.1002/jcb.28414] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 11/22/2018] [Accepted: 11/29/2018] [Indexed: 01/24/2023]
Abstract
Recently, there is increasing evidence that microRNAs are related to the development, diagnosis, treatment, and prognosis of glioblastoma. microRNA-210 (miR-210) had been identified in many human cancers, but the specific function of miR-210 remains unclear in glioblastoma. The present study mainly focused on exploring its biological role and potential molecular mechanisms in glioblastoma. We found that miR-210 expression was decreased in glioblastoma, and downregulation of miR-210 was related to worse prognosis in glioblastoma patients. In addition, miR-210 overexpression inhibited the migration and invasion of human glioblastoma cells. At the same time, we found that miR-210 directly targets the brain-derived neurotrophic factor (BDNF) and reduces BDNF expression level. Consistently, BDNF silencing had the same effects as miR-210 overexpression in glioblastoma, and upregulation of BDNF counteracted the inhibitory effect of miR-210 in glioblastoma. In conclusion, miR-210 suppressed the migration and invasion of glioblastoma cells by targeting BDNF.
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Affiliation(s)
- Shouyue Liu
- Department of Neurosurgery, Second Hospital of Jilin University, Changchun, Jilin Province, People's Republic of China
| | - Tao Jiang
- Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People's Republic of China
| | - Yingjie Zhong
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People's Republic of China
| | - Yin Yu
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, People's Republic of China
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Platania CBM, Maisto R, Trotta MC, D'Amico M, Rossi S, Gesualdo C, D'Amico G, Balta C, Herman H, Hermenean A, Ferraraccio F, Panarese I, Drago F, Bucolo C. Retinal and circulating miRNA expression patterns in diabetic retinopathy: An in silico and in vivo approach. Br J Pharmacol 2019; 176:2179-2194. [PMID: 30883703 PMCID: PMC6555853 DOI: 10.1111/bph.14665] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 02/12/2019] [Accepted: 02/22/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND PURPOSE Diabetic retinopathy, a secondary complication of diabetes mellitus, can lead to irreversible vision loss. Currently, no treatment is approved for early phases of diabetic retinopathy. Modifications of the expression pattern of miRNAs could be involved in the early retinal damage of diabetic subjects. Therefore, we aimed at identification of dysregulated miRNAs-mRNA interactions that might be biomarkers and pharmacological targets for diagnosis and treatment of early diabetic retinopathy. METHODS A focused set of miRNAs was predicted through a bioinformatic analysis accessing to Gene Expression Omnibus dataset and enrichment of information approach (GENEMANIA-Cytoscape). Identification of miRNAs-mRNA interactions was carried out with miRNET analysis. Diabetes was induced in C57BL6J mice by streptozotocin and samples analysed at 5 and 10 weeks after diabetes induction. Retinal ultrastructure of diabetic mice was analysed through electron microscopy. We used Real-time PCR, western blot analysis, elisa, and immunohistochemistry to study expression of miRNAs and possible targets of dysregulated miRNAs. KEY RESULTS We found that miR-20a-5p, miR-20a-3p, miR-20b, miR-106a-5p, miR-27a-5p, miR-27b-3p, miR-206-3p, and miR-381-3p were dysregulated in the retina and serum of diabetic mice. VEGF, brain-derived neurotrophic factor (BDNF), PPAR-α, and cAMP response element-binding protein 1 (CREB1) are targets of dysregulated miRNAs, which then modulated protein expression in diabetic retina. We found structural modifications in retinas from diabetic mice. CONCLUSIONS AND IMPLICATIONS Serum and retina of diabetic mice express eight dysregulated miRNAs, which modified the expression of VEGF, BDNF, PPAR-α, and CREB1, before vasculopathy in diabetic retinas.
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Affiliation(s)
| | - Rosa Maisto
- Department of Experimental Medicine, Division of PharmacologyUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, Division of PharmacologyUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Michele D'Amico
- Department of Experimental Medicine, Division of PharmacologyUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Settimio Rossi
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental SciencesUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Carlo Gesualdo
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental SciencesUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | | | - Cornel Balta
- Institute of Life SciencesVasile Godis Western University of AradAradRomania
| | - Hildegard Herman
- Institute of Life SciencesVasile Godis Western University of AradAradRomania
| | - Anca Hermenean
- Institute of Life SciencesVasile Godis Western University of AradAradRomania
- Department of Biochemistry and Molecular BiologyUniversity of BucharestBucharestRomania
| | - Franca Ferraraccio
- Pathology Unit, Department of Mental and Physical Health and Preventive MedicineUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Iacopo Panarese
- Pathology Unit, Department of Mental and Physical Health and Preventive MedicineUniversity of Campania “Luigi Vanvitelli”NaplesItaly
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, School of MedicineUniversity of CataniaCataniaItaly
- Center for Research in Ocular Pharmacology—CERFOUniversity of CataniaCataniaItaly
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, School of MedicineUniversity of CataniaCataniaItaly
- Center for Research in Ocular Pharmacology—CERFOUniversity of CataniaCataniaItaly
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Marangon D, Raffaele S, Fumagalli M, Lecca D. MicroRNAs change the games in central nervous system pharmacology. Biochem Pharmacol 2019; 168:162-172. [PMID: 31251938 DOI: 10.1016/j.bcp.2019.06.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 06/20/2019] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) represent a class of important post-transcriptional regulators of gene expression, enabling cells to follow their intrinsic developmental program. By directly binding to their targets, miRNAs can both promote transcriptional patterns in crucial steps of cell growth, and act as powerful buffering system that titrate protein content in case of aberrant gene expression. The literature of the last decade showed that the presence of tissue-enriched miRNAs in body fluids could be reminiscent of disease state. This is particularly relevant in neurodegenerative disorders, in which peripheral biomarkers could be helpful means to detect disease onset. However, dysregulation of miRNAs is not merely a consequence of disease, but directly contributes to pathological outcomes. On this basis, increasing interest is growing in the development of pharmacological agents targeting specific miRNAs. Actually, this apparently futuristic approach is already part of the current therapies. In fact, several drugs approved for CNS disorders, such as L-Dopa or valproic acid, were also demonstrated to restore some miRNAs. Moreover, ongoing clinical trials demonstrated that miRNA-based drugs are effective against tumors, suggesting that miRNAs also represent a promising class of therapeutic molecules. However, several issues still need to be addressed, particularly in case of CNS diseases, in which stability and delivery are crucial aspects of the therapy. In this commentary, we highlighted potential advantages and limitations of miRNAs as next generation targets in CNS pharmacology, focusing on multiple sclerosis, a chronic demyelinating disease lacking specific therapeutic targets and bona-fide biomarkers.
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Affiliation(s)
- Davide Marangon
- Laboratorio di Farmacologia Molecolare e Cellulare della Trasmissione Purinergica, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy
| | - Stefano Raffaele
- Laboratorio di Farmacologia Molecolare e Cellulare della Trasmissione Purinergica, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy
| | - Marta Fumagalli
- Laboratorio di Farmacologia Molecolare e Cellulare della Trasmissione Purinergica, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy
| | - Davide Lecca
- Laboratorio di Farmacologia Molecolare e Cellulare della Trasmissione Purinergica, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Via Balzaretti, 9, 20133 Milano, Italy.
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Amakiri N, Kubosumi A, Tran J, Reddy PH. Amyloid Beta and MicroRNAs in Alzheimer's Disease. Front Neurosci 2019; 13:430. [PMID: 31130840 PMCID: PMC6510214 DOI: 10.3389/fnins.2019.00430] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 04/15/2019] [Indexed: 11/29/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive mental illness characterized by memory loss and multiple cognitive impairments. In the last several decades, significant progress has been made in understanding basic biology, molecular mechanisms, and development of biomarkers and therapeutic drugs. Multiple cellular changes are implicated in the disease process including amyloid beta and phosphorylation of tau synaptic damage and mitochondrial dysfunction in AD. Among these, amyloid beta is considered a major player in the disease process. Recent advancements in molecular biology revealed that microRNAs (miRNAs) are considered potential biomarkers in AD with a focus on amyloid beta. In this article we discussed several aspects of AD including its prevalence, classifications, risk factors, and amyloid species and their accumulation in subcellular compartments. This article also discusses the discovery and biogenesis of miRNAs and their relevance to AD. Today's research continues to add to the wealth of miRNA data that has been accumulated, however, there still lacks clear-cut understanding of the physiological relevance of miRNAs to AD. MiRNAs appear to regulate translation of gene products in AD and other human diseases. However, the mechanism of how many of these miRNAs regulate both the 5' and 3'UTR of amyloid precursor protein (APP) processing is still being extrapolated. Hence, we still need more research on miRNAs and APP/amyloid beta formation in the progression and pathogenesis of AD.
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Affiliation(s)
- Nnana Amakiri
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Aaron Kubosumi
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - James Tran
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - P. Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Garrison Institute on Aging, South West Campus, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Speech-Language and Hearing Clinics, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, United States
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Grasso M, Piscopo P, Talarico G, Ricci L, Crestini A, Tosto G, Gasparini M, Bruno G, Denti MA, Confaloni A. Plasma microRNA profiling distinguishes patients with frontotemporal dementia from healthy subjects. Neurobiol Aging 2019; 84:240.e1-240.e12. [PMID: 30826067 DOI: 10.1016/j.neurobiolaging.2019.01.024] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 12/20/2018] [Accepted: 01/27/2019] [Indexed: 12/12/2022]
Abstract
The purpose of this study was to develop an easy and minimally invasive assay to detect a plasma miRNA profile in frontotemporal dementia (FTD) patients, with the final aim of discriminating between FTD patients and healthy controls (HCs). After a global miRNA profiling, significant downregulation of miR-663a, miR-502-3p, and miR-206 (p = 0.0001, p = 0.0002, and p = 0.02 respectively) in FTD patients was confirmed when compared with HCs in a larger case-control sample. Moreover, miR-663a and miR-502-3p showed significant differences in both genders, whereas miR-206, only in male subjects. To obtain a discriminating measure between FTD patients and HCs, we calculated a combined score of the 3 miRNAs by applying a Bayesian approach and obtaining a classifier with an accuracy of 84.4%. Moreover, for men, combined miRNA levels showed an excellent sensitivity (100%) and a good specificity (87.5%) in distinguishing FTD patients from HCs. All these findings open new hypotheses in the pathophysiology and new perspectives in the diagnosis of a complex pathology as FTD.
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Affiliation(s)
- Margherita Grasso
- Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Paola Piscopo
- Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy
| | - Giuseppina Talarico
- Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Leonardo Ricci
- Department of Physics, University of Trento, Trento, Italy; CIMeC, Center for Mind/Brain Sciences, University of Trento, Rovereto, Italy
| | - Alessio Crestini
- Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy
| | - Giuseppe Tosto
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Marina Gasparini
- Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Giuseppe Bruno
- Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy
| | - Michela A Denti
- Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy.
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Afshar S, Shahidi S, Rohani AH, Komaki A, Asl SS. The effect of NAD-299 and TCB-2 on learning and memory, hippocampal BDNF levels and amyloid plaques in Streptozotocin-induced memory deficits in male rats. Psychopharmacology (Berl) 2018; 235:2809-2822. [PMID: 30027497 DOI: 10.1007/s00213-018-4973-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 07/11/2018] [Indexed: 01/08/2023]
Abstract
RATIONALE Alzheimer's disease (AD) is the most common form of dementia characterized by a progressive decline in cognitive function. The serotonergic system via the 5-HT1A receptor and 5-HT2A receptor is proposed to affect the cognitive process. OBJECTIVE In the present study, the effects of NAD-299 (5-HT1AR antagonist) and TCB-2 (5-HT2AR agonist) on learning and memory processes, hippocampal brain-derived neurotrophic factor (BDNF) levels, neuronal necrosis, and Aβ plaque production have been investigated on the intracerebroventricular (icv) injection of streptozotocin (STZ)-induced memory deficits in rats. METHODS Fifty-four adult male Wistar rats (250-300 g) were divided into six groups (n = 9 in each group): control, sham-operated, AD (icv-STZ (3 mg/kg, 10 μl)), AD+NAD-299 (5 μg/1 μl icv for 30 days), AD+TCB-2 (5 μg/1 μl icv for 30 days), and AD+NAD-299 + TCB-2 (NAD-299 (5 μg/0.5 μl icv) and TCB-2 (5 μg/0.5 μl icv) for 30 days). Following the treatment period, rats were subjected to behavioral tests of learning and memory. Then, hippocampal BDNF, amyloid-beta (Aβ) plaque, and neuronal loss were determined by ELISA Kit, Congo red staining, and Nissl staining, respectively. RESULTS The results of behavioral tests showed that icv-STZ injection decreased the discrimination index in the novel object recognition (NOR) test. In the passive avoidance learning (PAL) task, icv-STZ injection significantly decreased step-through latency (STLr) and increased time spent in dark compartment (TDC). Treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 attenuated the STZ-induced memory impairment in both NOR and PAL tasks. icv-STZ induced a decrease in hippocampal BDNF levels and increased Aβ plaques production in the brain, whereas treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 reduced Aβ plaques in the brain and increased the hippocampal BDNF level. Results of Nissl staining showed that icv-STZ injection increased neuronal loss in the hippocampus, while treatment with NAD-299, TCB-2, and NAD-299 + TCB-2 reduced hippocampal neurodegeneration. CONCLUSION These findings suggest that 5-HT1AR blockade by NAD-299 and 5-HT2AR activation by TCB-2 improve cognitive dysfunction in icv-STZ-treated rats, and these drugs may potentially prevent the progression of AD.
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Affiliation(s)
- Simin Afshar
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Siamak Shahidi
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Ali Haeri Rohani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sara Soleimani Asl
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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Amelioration by nitric oxide (NO) mimetics on neurobehavioral and biochemical changes in experimental model of Alzheimer’s disease in rats. Neurotoxicology 2018. [DOI: 10.1016/j.neuro.2018.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Wu W, He Y, Feng X, Ye S, Wang H, Tan W, Yu C, Hu J, Zheng R, Zhou Y. MicroRNA-206 is involved in the pathogenesis of ulcerative colitis via regulation of adenosine A3 receptor. Oncotarget 2018; 8:705-721. [PMID: 27893428 PMCID: PMC5352191 DOI: 10.18632/oncotarget.13525] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 11/12/2016] [Indexed: 01/18/2023] Open
Abstract
Increasing evidence suggests that miRNAs are widely dysregulated in ulcerative colitis (UC), potentially affecting UC pathogenesis, diagnosis, and therapy. microRNA (miR) -206 has been reported to be upregulated in UC; however, its function and role in UC remain unknown. Here, we elucidate the function of miR-206 in the pathogenesis of UC. In patients with active-UC, miR-206 and adenosine A3 receptor (A3AR) levels were significantly upregulated and downregulated, respectively, and were inversely correlated. A3AR was expressed in the colon mucosa (particularly in colon epithelial-cell membranes). In HT-29 cells, miR-206 downregulated A3AR mRNA/protein expression by directly targeting the A3AR 3'-UTR; miR-206 overexpression and knockdown respectively increased and decreased TNF-α-induced nuclear NF-κB/p65, p-IκB-α, IKKα, p-IKKα and IL-8/IL-1β secretion. However, A3AR-siRNA reversed the miR-206 inhibitory effect. Furthermore, miR-206 increased dextran sodium sulphate-induced colitis severity (i.e., increased bodyweight loss, DAI score, colon shrinkage, and MPO activity), which was partially ameliorated by miR-206-antagomir treatment. miR-206-agomir treatment potently suppressed A3AR expression and increased NF-κB signalling and downstream cytokine (TNF-α/IL-8/IL-1β) expression in the mouse colon, in contrast to miR-206-antagomir administration. Taken together, our results demonstrated that miR-206 has a proinflammatory role in UC by downregulating A3AR expression and activating NF-κB signalling.
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Affiliation(s)
- Weiyun Wu
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Yanting He
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Xiao Feng
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Shicai Ye
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Hao Wang
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Wenkai Tan
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Caiyuan Yu
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Juxiang Hu
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Rong Zheng
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Yu Zhou
- Department of Gastroenterology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
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Xie B, Liu Z, Jiang L, Liu W, Song M, Zhang Q, Zhang R, Cui D, Wang X, Xu S. Increased Serum miR-206 Level Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Follow-up Study. J Alzheimers Dis 2018; 55:509-520. [PMID: 27662297 DOI: 10.3233/jad-160468] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Evidence suggests that individuals with amnestic mild cognitive impairment (aMCI) tend to progress to probable Alzheimer's disease (AD) with aging. This study was performed to examine whether circulating miRNAs could be potential predictors for the progression of aMCI to AD. A total of 458 patients with aMCI were included in this study, and the clinical data were collected at two time points: the baseline and the follow-up assessment. These aMCI patients were classified into two groups after 5 years: aMCI-stable group (n = 330) and AD-conversion group (n = 128). The expression of miR-206 and miR-132 and the levels of BDNF and SIRT1 in serum were detected using a quantitative real-time RT-PCR (qPCR) and the ELISA method, respectively. Kaplan-Meier method (Log-rank test) was used for univariate survival analysis. Cox proportional hazard model was used to estimate the prognostic value of miRNAs in conversion from aMCI to AD. At the baseline, serum levels of miR-206 in aMCI-AD group were significantly elevated compared to aMCI-aMCI group and the same trend was found at 5-year follow-up time point as well. There were no significant differences in serum levels of miR-132 between the conversion and non-conversion group at both time points. Kaplan-Meier analysis showed significant correlation between AD conversion and higher serum levels of miR-206 for aMCI patients (HR = 3.60, 95% CI: 2.51- 5.36, p < 0.001). Multivariate Cox regression analysis revealed that serum miR-206 and its target BDNF were significant independent predictors for AD conversion (HR = 4.22, p < 0.001). These results suggested that increased serum miR-206 level might be a potential predictor of conversion from aMCI to AD.
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Affiliation(s)
- Bing Xie
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Zanchao Liu
- Department of Endocrinology, The Second Hospital of Shijiazhuang City, Shijiazhuang, P.R. China
| | - Lei Jiang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Wei Liu
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Mei Song
- Department of Mental Health, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China.,Institute of Mental Health, Hebei Medical University, Shijiazhuang, P.R. China
| | - Qingfu Zhang
- Department of Burns and Plastic Surgery, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China.,Burn Engineering Center of Hebei Province, Shijiazhuang, P.R. China
| | - Rui Zhang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Dongsheng Cui
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Xueyi Wang
- Department of Mental Health, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China.,Institute of Mental Health, Hebei Medical University, Shijiazhuang, P.R. China
| | - Shunjiang Xu
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China
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Pang C, Huang G, Luo K, Dong Y, He F, Du G, Xiao M, Cai W. miR-206 inhibits the growth of hepatocellular carcinoma cells via targeting CDK9. Cancer Med 2017; 6:2398-2409. [PMID: 28940993 PMCID: PMC5633544 DOI: 10.1002/cam4.1188] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Revised: 07/22/2017] [Accepted: 08/12/2017] [Indexed: 12/24/2022] Open
Abstract
miR‐206 plays an important role in regulating the growth of multiple cancer cells. Cyclin‐dependent kinase 9 (CDK9) stimulates the production of abundant prosurvival proteins, leading to impaired apoptosis of cancer cells. However, it is unknown whether CDK9 is involved in the miR‐206‐mediated growth suppression of hepatocellular carcinoma (HCC) cells. In this study, we found that the expression level of miR‐206 was significantly lower in HCC cell lines than that in normal hepatic cell line (L02). Meanwhile, CDK9 was upregulated in HCC cell lines. Moreover, miR‐206 downregulated CDK9 in HCC cells via directly binding to its mRNA 3′ UTR, which resulted in a decrease of RNA PolII Ser2 phosphorylation and Mcl‐1 level. Additionally, miR‐206 suppressed the cell proliferation, and induced cell cycle arrest and apoptosis. Similarly, silence or inhibition of CDK9 also repressed the cell proliferation, and induced cell cycle arrest and apoptosis. Taken together, the results demonstrated that miR‐206 inhibited the growth of HCC cells through targeting CDK9, suggesting that the miR‐206‐CDK9 pathway may be a novel target for the treatment of HCC.
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Affiliation(s)
- Chi Pang
- Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, 570102, China
| | - Gang Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, 400038, China
| | - Kaili Luo
- Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, 570102, China
| | - Yuying Dong
- Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, 570102, China
| | - Fengtian He
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, 400038, China
| | - Guankui Du
- Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, 570102, China
| | - Man Xiao
- Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, 570102, China
| | - Wangwei Cai
- Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, 570102, China
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Hoban AE, Stilling RM, M Moloney G, Moloney RD, Shanahan F, Dinan TG, Cryan JF, Clarke G. Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. MICROBIOME 2017; 5:102. [PMID: 28838324 PMCID: PMC5571609 DOI: 10.1186/s40168-017-0321-3] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 08/01/2017] [Indexed: 05/20/2023]
Abstract
BACKGROUND There is growing evidence for a role of the gut microbiome in shaping behaviour relevant to many psychiatric and neurological disorders. Preclinical studies using germ-free (GF) animals have been essential in contributing to our current understanding of the potential importance of the host microbiome for neurodevelopment and behaviour. In particular, it has been repeatedly demonstrated that manipulation of the gut microbiome modulates anxiety-like behaviours. The neural circuits that underlie anxiety- and fear-related behaviours are complex and heavily depend on functional communication between the amygdala and prefrontal cortex (PFC). Previously, we have shown that the transcriptional networks within the amygdala and PFC of GF mice are altered. MicroRNAs (miRNAs) act through translational repression to control gene translation and have also been implicated in anxiety-like behaviours. However, it is unknown whether these features of host post-transcriptional machinery are also recruited by the gut microbiome to exert control over CNS transcriptional networks. RESULTS We conducted Illumina® next-generation sequencing (NGS) in the amygdala and PFC of conventional, GF and germ-free colonized mice (exGF). We found a large proportion of miRNAs to be dysregulated in GF animals in both brain regions (103 in the amygdala and 31 in the PFC). Additionally, colonization of GF mice normalized some of the noted alterations. Next, we used a complementary approach to GF by manipulating the adult rat microbiome with an antibiotic cocktail to deplete the gut microbiota and found that this strategy also impacted the expression of relevant miRNAs. CONCLUSION These results suggest that the microbiome is necessary for appropriate regulation of miRNA expression in brain regions implicated in anxiety-like behaviours.
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Affiliation(s)
- Alan E Hoban
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork City, Ireland
| | - Roman M Stilling
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork City, Ireland
| | - Gerard M Moloney
- Department of Anatomy and Neuroscience, University College Cork, Cork City, Ireland
| | - Rachel D Moloney
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Psychiatry and Neurobehavioural Science, Biosciences Institute, University College Cork, Room 1.15, College Road, Cork City, Ireland
| | - Fergus Shanahan
- APC Microbiome Institute, University College Cork, Cork City, Ireland
| | - Timothy G Dinan
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Psychiatry and Neurobehavioural Science, Biosciences Institute, University College Cork, Room 1.15, College Road, Cork City, Ireland
| | - John F Cryan
- APC Microbiome Institute, University College Cork, Cork City, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork City, Ireland
| | - Gerard Clarke
- APC Microbiome Institute, University College Cork, Cork City, Ireland.
- Department of Psychiatry and Neurobehavioural Science, Biosciences Institute, University College Cork, Room 1.15, College Road, Cork City, Ireland.
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