|
1
|
Choi J, Jang E, Jeong H, Hwang J, Cho HH, Kim BC, Jang G, Jeong HS, Jang S. Novel miRNAs, miR-937-3p, miR-4536-3p, and miR-4650-5p, can Modulate Neuronal Differentiation via the Wnt/MAPK Pathway in SH-SY5Y Cells. Mol Neurobiol 2025:10.1007/s12035-025-05002-4. [PMID: 40316877 DOI: 10.1007/s12035-025-05002-4] [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: 09/05/2024] [Accepted: 04/24/2025] [Indexed: 05/04/2025]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate various biological processes, including cell differentiation. Despite their potential, their role in promoting neuronal differentiation by targeting neuronal genes and modulating signaling pathways is poorly understood. In this study, we aimed to elucidate the functions of miR-937-3p-, miR-4536-3p-, and miR-4650-5p-inhibitors in the neuronal differentiation of SH-SY5Y cells. We also aimed to determine the underlying mechanisms via qPCR, luciferase assay, immunocytochemistry, and western blotting analysis. Our findings confirmed that miRNAs participated in neuronal differentiation and regulated the Wnt/MAPK signaling pathway. Specifically, we identified Netrin1 (NTN1), Drebrin1 (DBN1), and Netrin-G1 (NTNG1) as target genes of miR-937-3p, miR-4536-3p, and miR-4650-5p, respectively. The treatment with the miRNA inhibitors increased the expression levels of neuronal markers such as TUBB3, NEFH, NEFM, NEFL, and MAP2. It also enhanced the protein expression levels of Wnt and MAPK signaling. Therefore, the inhibitors of miR-937-3p, miR-4536-3p, and miR-4650-5p could promote neuronal differentiation by targeting neuronal genes and activating the Wnt/MAPK signaling pathway.
Collapse
Affiliation(s)
- Jiyun Choi
- Department of Physiology, Chonnam National University Medical School, Hwasun-Gun, Jeollanamdo, 58128, Republic of Korea
| | - Eunjae Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun-Gun, Jeollanamdo, 58128, Republic of Korea
- Jeonnam Bioindustry Foundation Biopharmaceutical Research Center, Hwasun-Gun, Jeollanamdo, 58141, Republic of Korea
| | - Haewon Jeong
- Department of Physiology, Chonnam National University Medical School, Hwasun-Gun, Jeollanamdo, 58128, Republic of Korea
| | - Jinsu Hwang
- Department of Physiology, Chonnam National University Medical School, Hwasun-Gun, Jeollanamdo, 58128, Republic of Korea
| | - Hyong-Ho Cho
- Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea
| | - Byeong C Kim
- Department of Neurology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea
| | - Geupil Jang
- School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Han-Seong Jeong
- Department of Physiology, Chonnam National University Medical School, Hwasun-Gun, Jeollanamdo, 58128, Republic of Korea.
| | - Sujeong Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun-Gun, Jeollanamdo, 58128, Republic of Korea.
| |
Collapse
|
|
2
|
Swanson K, Bell J, Hendrix D, Jiang D, Kutzler M, Batty B, Hanlon M, Bionaz M. Bovine milk consumption affects the transcriptome of porcine adipose stem cells: Do exosomes play any role? PLoS One 2024; 19:e0302702. [PMID: 39705291 DOI: 10.1371/journal.pone.0302702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 12/03/2024] [Indexed: 12/22/2024] Open
Abstract
The potential association of milk with childhood obesity has been widely debated and researched. Milk is known to contain many bioactive compounds as well as bovine exosomes rich in micro-RNA (miR) that can have effects on various cells, including stem cells. Among them, adipose stem cells (ASC) are particularly interesting due to their role in adipose tissue growth and, thus, obesity. The objective of this study was to evaluate the effect of milk consumption on miR present in circulating exosomes and the transcriptome of ASC in piglets. Piglets were supplemented for 11 weeks with 750 mL of whole milk (n = 6; M) or an isocaloric maltodextrin solution (n = 6; C). After euthanasia, ASC were isolated, quantified, and characterized. RNA was extracted from passage 1 ASC and sequenced. Exosomes were isolated and quantified from the milk and plasma of the pigs at 6-8 hours after milk consumption, and miRs were isolated from exosomes and sequenced. The transfer of exosomes from milk to porcine plasma was assessed by measuring bovine milk-specific miRs and mRNA in exosomes isolated from the plasma of 3 piglets during the first 6h after milk consumption. We observed a higher proportion of exosomes in the 80 nM diameter, enriched in milk, in M vs. C pigs. Over 500 genes were differentially expressed (DEG) in ASC isolated from M vs. C pigs. Bioinformatic analysis of DEG indicated an inhibition of the immune, neuronal, and endocrine systems and insulin-related pathways in ASC of milk-fed pigs compared with maltodextrin-fed pigs. Of the 900 identified miRs in porcine plasma exosomes, only 3 miRs were differentially abundant between the two groups and could target genes associated with neuronal functions. We could not detect exosomal miRs or mRNA transfer from milk to porcine-circulating plasma exosomes. Our data highlights the significant nutrigenomic role of milk consumption on ASC, a finding that does not appear to be attributed to miRs in bovine milk exosomes. The downregulation of insulin resistance and inflammatory-related pathways in the ASC of milk-fed pigs should be further explored in relation to milk and human health. In conclusion, the bioinformatic analyses and the absence of bovine exosomal miRs in porcine plasma suggest that miRs are not vertically transferred from milk exosomes.
Collapse
Affiliation(s)
- Katherine Swanson
- Animal and Rangeland Sciences, Oregon State University, Corvallis, Oregon, United States of America
| | - Jimmy Bell
- Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, United States of America
| | - David Hendrix
- Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon, United States of America
| | - Duo Jiang
- Statistics, Oregon State University, Corvallis, Oregon, United States of America
| | - Michelle Kutzler
- Animal and Rangeland Sciences, Oregon State University, Corvallis, Oregon, United States of America
| | - Brandon Batty
- Animal and Rangeland Sciences, Oregon State University, Corvallis, Oregon, United States of America
| | - Melanie Hanlon
- Food Science and Technology, Oregon State University, Corvallis, Oregon, United States of America
| | - Massimo Bionaz
- Animal and Rangeland Sciences, Oregon State University, Corvallis, Oregon, United States of America
| |
Collapse
|
|
3
|
Zheng Y, Yu X, Wei L, Chen Q, Xu Y, Ni P, Deng W, Guo W, Hu X, Qi X, Li T. LT-102, an AMPA receptor potentiator, alleviates depression-like behavior and synaptic plasticity impairments in prefrontal cortex induced by sleep deprivation. J Affect Disord 2024; 367:18-30. [PMID: 39214374 DOI: 10.1016/j.jad.2024.08.176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 08/25/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Sleep loss is closely related to the onset and development of depression, and the mechanisms involved may include impaired synaptic plasticity. Considering the important role of glutamate α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) in synaptic plasticity as well as depression, we introduce LT-102, a novel AMPARs potentiator, to evaluate the potential of LT-102 in treating sleep deprivation-induced depression-like behaviors. METHODS We conducted a comprehensive behavioral assessment to evaluate the effects of LT-102 on depression-like symptoms in male C57BL/6J mice. This assessment included the open field test to measure general locomotor activity and anxiety-like behavior, the forced swimming test and tail suspension test to assess despair behaviors indicative of depressive states, and the sucrose preference test to quantify anhedonia, a core symptom of depression. Furthermore, to explore the impact of LT-102 on synaptic plasticity, we utilized a combination of Western blot analysis to detect protein expression levels, Golgi-Cox staining to visualize neuronal morphology, and immunofluorescence to examine the localization of synaptic proteins. Additionally, we utilized primary cortical neurons to delineate the signaling pathway modulated by LT-102. RESULTS Treatment with LT-102 significantly reduced depression-like behaviors associated with sleep deprivation. Quantitative Western blot (WB) analysis revealed a significant increase in GluA1 phosphorylation in the prefrontal cortex (PFC), triggering the Ca2+/calmodulin-dependent protein kinase II/cAMP response element-binding protein/brain-derived neurotrophic factor (CaMKII/CREB/BDNF) and forkhead box protein P2/postsynaptic density protein 95 (FoxP2/PSD95) signaling pathways. Immunofluorescence imaging confirmed that LT-102 treatment increased spine density and co-labeling of PSD95 and vesicular glutamate transporter 1 (VGLUT1) in the PFC, reversing the reductions typically observed following sleep deprivation. Golgi staining further validated these results, showing a substantial increase in neuronal dendritic spine density in sleep-deprived mice treated with LT-102. Mechanistically, application of LT-102 to primary cortical neurons, resulted in elevated levels of phosphorylated AKT (p-AKT) and phosphorylated glycogen synthase kinase-3 beta (p-GSK3β), key downstream molecules in the BDNF signaling pathway, which in turn upregulated FoxP2 and PSD95 expression. LIMITATIONS In our study, we chose to exclusively use male mice to eliminate potential influences of the estrous cycle on behavior and physiology. As there is no widely accepted positive drug control for sleep deprivation studies, we did not include one in our research. CONCLUSION Our results suggest that LT-102 is a promising therapeutic agent for counteracting depression-like behaviors and synaptic plasticity deficits induced by sleep deprivation, primarily through the activation of CaMKII/CREB/BDNF and AKT/GSK3β/FoxP2/PSD95 signaling pathways.
Collapse
Affiliation(s)
- Yanghao Zheng
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China
| | - Xueli Yu
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
| | - Long Wei
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qiyuan Chen
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yan Xu
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Peiyan Ni
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China
| | - Wei Deng
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China
| | - Wanjun Guo
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China
| | - Xun Hu
- The Clinical Research Center and Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xueyu Qi
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
| | - Tao Li
- Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
| |
Collapse
|
|
4
|
Chen WJ, Zhu BL, Qian JJ, Zhao J, Zhang F, Jiang B, Zhao HY. Hippocampal SorCS2 overexpression represses chronic stress-induced depressive-like behaviors by promoting the BDNF-TrkB system. Pharmacol Biochem Behav 2024; 242:173820. [PMID: 38996926 DOI: 10.1016/j.pbb.2024.173820] [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: 05/30/2024] [Revised: 07/04/2024] [Accepted: 07/09/2024] [Indexed: 07/14/2024]
Abstract
BACKGROUND Emerging data has demonstrated that in mature neurons, SorCS2 localizes to the postsynaptic density of dendritic spines and facilitates plasma membrane sorting of TrkB by interacting with it, transmitting positive signaling from BDNF on neurons. Thus, it is possible that SorCS2 plays a role in the pathophysiology of depression by regulating the BDNF-TrkB system. METHODS In the present study, SorCS2 expression in different brain regions [hippocampus, medial prefrontal cortex (mPFC), hypothalamus, amygdala, ventral tegmental area (VTA), and nucleus accumbens (NAc)] was thoroughly investigated in the chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression. The changes in depressive-like behaviors, the hippocampal BDNF signaling cascade, and amounts of hippocampal immature neurons were further investigated after SorCS2 overexpression by microinjection of the adenovirus associated virus vector containing the coding sequence of mouse SorCS2 (AAV-SorCS2) into the hippocampus of mice exposed to CSDS or CUMS. RESULTS It was found that both CSDS and CUMS significantly decreased the protein and mRNA expression of SorCS2 in the hippocampus but not in other brain regions. Chronic stress also notably downregulated the level of hippocampal SorCS2-TrkB binding in mice. In contrast, AAV-based genetic overexpression of hippocampal SorCS2 fully reversed the chronic stress-induced not only depressive-like behaviors but also decreased SorCS2-TrkB binding, BDNF signaling pathway, and amounts of immature neurons in the hippocampus of mice. CONCLUSION All these results suggest that enhancing the hippocampal SorCS2 expression protects against chronic stress, producing antidepressant-like actions. Hippocampal SorCS2 may participate in depression neurobiology and be a potential antidepressant target. SIGNIFICANCE STATEMENT Targeting of proteins to distinct subcellular compartments is essential for neuronal activity and modulated by VPS10P domain receptors which include SorCS2. In mature neurons, SorCS2 localizes to the postsynaptic density of dendritic spines and facilitates plasma membrane sorting of TrkB by interacting with it, transmitting positive signaling from BDNF on neurons. Our study is the first direct evidence preliminarily showing that SorCS2 plays a role in depression neurobiology. It was found that chronic stress induced not only depressive-like behaviors but also decreased SorCS2 expression in the hippocampus. Chronic stress did not affect SorCS2 expression in the mPFC, hypothalamus, amygdala, VTA, or NAc. In contrast, genetic overexpression of hippocampal SorCS2 prevented against chronic stress, producing antidepressant-like actions in mice. Thus, hippocampal SorCS2 is a potential participant underlying depression neurobiology and may be a novel antidepressant target. Our study may also extend the knowledge of the neurotrophic hypothesis of depression.
Collapse
Affiliation(s)
- Wei-Jia Chen
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Bao-Lun Zhu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China
| | - Jun-Jie Qian
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Department of Anatomy, Medical School, Nantong University, Nantong 226001, Jiangsu, China
| | - Jie Zhao
- Department of Pharmacy, The Sixth People's Hospital of Nantong, Nantong, 226011, Jiangsu, China
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China; Department of Anatomy, Medical School, Nantong University, Nantong 226001, Jiangsu, China
| | - Bo Jiang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China.
| | - He-Yan Zhao
- Department of Anatomy, Medical School, Nantong University, Nantong 226001, Jiangsu, China.
| |
Collapse
|
|
5
|
Lee DH, Lee EC, Lee JY, Lee MR, Shim JW, Oh JS. Neuronal Cell Differentiation of iPSCs for the Clinical Treatment of Neurological Diseases. Biomedicines 2024; 12:1350. [PMID: 38927557 PMCID: PMC11201423 DOI: 10.3390/biomedicines12061350] [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: 04/20/2024] [Revised: 06/05/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Current chemical treatments for cerebrovascular disease and neurological disorders have limited efficacy in tissue repair and functional restoration. Induced pluripotent stem cells (iPSCs) present a promising avenue in regenerative medicine for addressing neurological conditions. iPSCs, which are capable of reprogramming adult cells to regain pluripotency, offer the potential for patient-specific, personalized therapies. The modulation of molecular mechanisms through specific growth factor inhibition and signaling pathways can direct iPSCs' differentiation into neural stem cells (NSCs). These include employing bone morphogenetic protein-4 (BMP-4), transforming growth factor-beta (TGFβ), and Sma-and Mad-related protein (SMAD) signaling. iPSC-derived NSCs can subsequently differentiate into various neuron types, each performing distinct functions. Cell transplantation underscores the potential of iPSC-derived NSCs to treat neurodegenerative diseases such as Parkinson's disease and points to future research directions for optimizing differentiation protocols and enhancing clinical applications.
Collapse
Affiliation(s)
- Dong-Hun Lee
- Industry-Academic Cooperation Foundation, The Catholic University of Korea, 222, Banpo-daro, Seocho-gu, Seoul 06591, Republic of Korea
| | - Eun Chae Lee
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Ji young Lee
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Man Ryul Lee
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Republic of Korea
| | - Jae-won Shim
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Republic of Korea
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Republic of Korea
| | - Jae Sang Oh
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| |
Collapse
|
|
6
|
Choudhary P, Gupta A, Gupta SK, Dwivedi S, Singh S. Comparative evaluation of divergent concoction of NGF, BDNF, EGF, and FGF growth factor's role in enhancing neuronal differentiation of adipose-derived mesenchymal stem cells. Int J Biol Macromol 2024; 260:129561. [PMID: 38246449 DOI: 10.1016/j.ijbiomac.2024.129561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 01/13/2024] [Accepted: 01/15/2024] [Indexed: 01/23/2024]
Abstract
MSCs (Mesenchymal Stem Cells) can differentiate into various lineages, including neurons and glial cells. In the past few decades, MSCs have been well explored in the context of neuronal differentiation and have been reported to have the immense potential to form distinct kinds of neurons. The distinguishing features of MSCs make them among the most desired cell sources for stem cell therapy. This study involved the trans-differentiation of Adipose-derived human Mesenchymal Stem Cells (ADMSCs) into neurons. The protocol employs a cocktail of chemical inducers in different combinations, including Brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), and Nerve growth factor (NGF) Fibroblastic growth factor (FGF), in induction media. Both types have been successfully differentiated into neurons, confirmed by morphological aspects and the presence of neural-specific markers through RT-PCR (Reverse transcription polymerase chain reaction) studies and immunocytochemistry assay. They have shown excellent morphology with long neurites, synaptic connections, and essential neural markers to validate their identity. The results may significantly contribute to cell replacement therapy for neurological disorders.
Collapse
Affiliation(s)
- Princy Choudhary
- Department of Applied Science, Indian Institute of Information Technology, Allahabad Devghat, Jhalwa, Prayagraj 211015, U.P., India
| | - Ayushi Gupta
- Department of Applied Science, Indian Institute of Information Technology, Allahabad Devghat, Jhalwa, Prayagraj 211015, U.P., India
| | - Saurabh Kumar Gupta
- Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela, Odisha 769008, India
| | - Shrey Dwivedi
- Department of Applied Science, Indian Institute of Information Technology, Allahabad Devghat, Jhalwa, Prayagraj 211015, U.P., India
| | - Sangeeta Singh
- Department of Applied Science, Indian Institute of Information Technology, Allahabad Devghat, Jhalwa, Prayagraj 211015, U.P., India.
| |
Collapse
|
|
7
|
Boukhatem I, Fleury S, Jourdi G, Lordkipanidzé M. The intriguing role of platelets as custodians of brain-derived neurotrophic factor. Res Pract Thromb Haemost 2024; 8:102398. [PMID: 38706782 PMCID: PMC11066552 DOI: 10.1016/j.rpth.2024.102398] [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: 12/22/2023] [Revised: 02/26/2024] [Accepted: 03/18/2024] [Indexed: 05/07/2024] Open
Abstract
A State of the Art lecture titled "Platelets and neurotrophins" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Neurotrophins, a family of neuronal growth factors known to support cognitive function, are increasingly recognized as important players in vascular health. Indeed, along with their canonical receptors, neurotrophins are expressed in peripheral tissues, particularly in the vasculature. The better-characterized neurotrophin in vascular biology is the brain-derived neurotrophic factor (BDNF). Its largest extracerebral pool resides within platelets, partly inherited from megakaryocytes and also likely internalized from circulation. Activation of platelets releases vast amounts of BDNF into their milieu and interestingly leads to platelet aggregation through binding of its receptor, the tropomyosin-related kinase B, on the platelet surface. As BDNF is readily available in plasma, a mechanism to preclude excessive platelet activation and aggregation appears critical. As such, binding of BDNF to α2-macroglobulin hinders its ability to bind its receptor and limits its platelet-activating effects to the site of vascular injury. Altogether, addition of BDNF to a forming clot facilitates not only paracrine platelet activation but also binding to fibrinogen, rendering the resulting clot more porous and plasma-permeable. Importantly, release of BDNF into circulation also appears to be protective against adverse cardiovascular and cerebrovascular outcomes, which has been reported in both animal models and epidemiologic studies. This opens an avenue for platelet-based strategies to deliver BDNF to vascular lesions and facilitate wound healing through its regenerative properties. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.
Collapse
Affiliation(s)
- Imane Boukhatem
- Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
| | - Samuel Fleury
- Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
| | - Georges Jourdi
- Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
- Université Paris Cité, Institut National de la Santé Et de la Recherche Médicale, Innovative Therapies in Haemostasis, Paris, France
- Service d’Hématologie Biologique, Assistance Publique : Hôpitaux de Paris, Hôpital Lariboisière, Paris, France
| | - Marie Lordkipanidzé
- Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
| |
Collapse
|
|
8
|
Khodabakhsh P, Asgari Taei A, Shafaroodi H, Pournajaf S, Dargahi L. Effect of Metformin on Epidermal Neural Crest Stem Cells and Their Potential Application in Ameliorating Paclitaxel-induced Neurotoxicity Phenotype. Stem Cell Rev Rep 2024; 20:394-412. [PMID: 37924435 DOI: 10.1007/s12015-023-10642-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2023] [Indexed: 11/06/2023]
Abstract
AIMS Epidermal Neural Crest Stem Cells (EPI-NCSCs) have emerged as prospective ideal candidates to meet the fundamental requirements of cell-based therapies in neurodegenerative disorders. The present study aimed to identify the potential of metformin in driving EPI-NCSCs to neuronal/glial differentiation and express neurotrophic factors as well as assess their therapeutic potential for mitigating the main behavioral manifestations of chemotherapy-induced neurotoxicity (CIN). MAIN METHODS EPI-NCSCs were extracted from the bulge region of hair follicle. Following expansion, transcript and protein expression profiles of key markers for stemness (Nestin, EGR-1, SOX-2 and 10), neurotrophic activity (BDNF, GDNF, NGF, FGF-2, and IL-6), and neuronal (TUB3, DCX, NRF and NeuN) and glial (PDGFRα, NG2, GFAP, and MBP) differentiation were determined on days 1 and 7 post-treatment with 10 and 100 μM metformin using real time-PCR and immunocytochemistry methods. Then, the in vivo function of metformin-treated stem cells was evaluated in the context of paclitaxel CIN. To do so, thermal hyperalgesia, mechanical allodynia, and spatial learning and memory tests were evaluated by Hotplate, Von Frey, and Morris water maze tests. KEY FINDINGS Our result indicated that exposure of EPI-NCSCs to metformin was associated with progressive decline in stemness markers and enhanced expression levels of several neurotrophic, neuron and oligodendrocyte-specific markers. Further, it was observed that intranasal metformin-treated EPI-NCSCs improved the cognitive impairment, and mechanical and thermal hypersensitivity induced by paclitaxel in rats. SIGNIFICANCE Collectively, we reasoned that metformin pretreatment of EPI-NCSCs might further enhance their therapeutic benefits against CIN.
Collapse
Affiliation(s)
- Pariya Khodabakhsh
- Institute of Physiology, Department Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Afsaneh Asgari Taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shafaroodi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Safura Pournajaf
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Leila Dargahi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
9
|
Kao Y, Zhu H, Yang Y, Shen W, Song W, Zhang R, Liu Y, Liu H, Kong X. CREB1 Facilitates GABAergic Neural Differentiation of Human Mesenchymal Stem Cells through BRN2 for Pain Alleviation and Locomotion Recovery after Spinal Cord Injury. Cells 2023; 13:67. [PMID: 38201271 PMCID: PMC10778540 DOI: 10.3390/cells13010067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/28/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
The transplantation of GABAergic neuron cells has been reported to alleviate nerve pain and improve motor function after spinal cord injury (SCI). However, human mesenchymal stem cell (hMSC) differentiation into GABAergic neuron cells in a sufficient quantity remains to be accomplished. From a database screening, cAMP-responsive element-binding protein 1 (CREB1) was chosen as a potential modulator due to its critical role in the protein-protein interaction of genes related to GABAergic neural differentiation. Here, CREB1 was overexpressed in transfected hMSCs, where CREB1 could induce differentiation into GABAergic neuron cells with an upregulation of Map2 and GAD1 by 2- and 3.4-fold, respectively. Additionally, GABAergic neural differentiation was enhanced, while Notch signaling was inhibited, and BRN2 transcriptional activation played an important role in neuronal maturation. Moreover, transfected hMSCs injected into immunocompromised mice caused by CsA exhibited the neuronal markers Tuj1 and Map2 via the intraspinal route, suggesting an improvement in survival and neural differentiation. Significantly, improvement in both BMS scores (6.2 ± 1.30 vs. 4 ± 0) and thermal hyperalgesia latency (7.74 ± 2.36 s vs. 4.52 ± 0.39 s) was seen compared with the SCI naïve treatment at 4 weeks post-transplantation. Our study demonstrates that CREB1 is crucial in generating induced GABAergic neuron cells (iGNs) originating from hMSCs. Transplanting iGNs to injured spinal cord provides a promising strategy for alleviating neuropathic pain and locomotion recovery after SCI.
Collapse
Affiliation(s)
- Yanbing Kao
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| | - Hanming Zhu
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| | - Yu Yang
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| | - Wenyuan Shen
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| | - Wei Song
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| | - Renjie Zhang
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| | - Yanchun Liu
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| | - Haoyun Liu
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| | - Xiaohong Kong
- Orthopedic Research Center of Qilu Hospital, Shandong University, Jinan 250100, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250100, China
| |
Collapse
|
|
10
|
Jin Y, Mikhailova E, Lei M, Cowley SA, Sun T, Yang X, Zhang Y, Liu K, Catarino da Silva D, Campos Soares L, Bandiera S, Szele FG, Molnár Z, Zhou L, Bayley H. Integration of 3D-printed cerebral cortical tissue into an ex vivo lesioned brain slice. Nat Commun 2023; 14:5986. [PMID: 37794031 PMCID: PMC10551017 DOI: 10.1038/s41467-023-41356-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 09/01/2023] [Indexed: 10/06/2023] Open
Abstract
Engineering human tissue with diverse cell types and architectures remains challenging. The cerebral cortex, which has a layered cellular architecture composed of layer-specific neurons organised into vertical columns, delivers higher cognition through intricately wired neural circuits. However, current tissue engineering approaches cannot produce such structures. Here, we use a droplet printing technique to fabricate tissues comprising simplified cerebral cortical columns. Human induced pluripotent stem cells are differentiated into upper- and deep-layer neural progenitors, which are then printed to form cerebral cortical tissues with a two-layer organization. The tissues show layer-specific biomarker expression and develop a structurally integrated network of processes. Implantation of the printed cortical tissues into ex vivo mouse brain explants results in substantial structural implant-host integration across the tissue boundaries as demonstrated by the projection of processes and the migration of neurons, and leads to the appearance of correlated Ca2+ oscillations across the interface. The presented approach might be used for the evaluation of drugs and nutrients that promote tissue integration. Importantly, our methodology offers a technical reservoir for future personalized implantation treatments that use 3D tissues derived from a patient's own induced pluripotent stem cells.
Collapse
Affiliation(s)
- Yongcheng Jin
- Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK
| | | | - Ming Lei
- Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK
| | - Sally A Cowley
- James and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Tianyi Sun
- Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK
| | - Xingyun Yang
- Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK
| | - Yujia Zhang
- Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK
| | - Kaili Liu
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK
| | | | - Luana Campos Soares
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK
| | - Sara Bandiera
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK
| | - Francis G Szele
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
| | - Zoltán Molnár
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
| | - Linna Zhou
- Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK.
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
| | - Hagan Bayley
- Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK.
| |
Collapse
|
|
11
|
Al-Maswary AA, O’Reilly M, Holmes AP, Walmsley AD, Cooper PR, Scheven BA. Exploring the neurogenic differentiation of human dental pulp stem cells. PLoS One 2022; 17:e0277134. [PMID: 36331951 PMCID: PMC9635714 DOI: 10.1371/journal.pone.0277134] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Human dental pulp stem cells (hDPSCs) have increasingly gained interest as a potential therapy for nerve regeneration in medicine and dentistry, however their neurogenic potential remains a matter of debate. This study aimed to characterize hDPSC neuronal differentiation in comparison with the human SH-SY5Y neuronal stem cell differentiation model. Both hDPSCs and SH-SY5Y could be differentiated to generate typical neuronal-like cells following sequential treatment with all-trans retinoic acid (ATRA) and brain-derived neurotrophic factor (BDNF), as evidenced by significant expression of neuronal proteins βIII-tubulin (TUBB3) and neurofilament medium (NF-M). Both cell types also expressed multiple neural gene markers including growth-associated protein 43 (GAP43), enolase 2/neuron-specific enolase (ENO2/NSE), synapsin I (SYN1), nestin (NES), and peripherin (PRPH), and exhibited measurable voltage-activated Na+ and K+ currents. In hDPSCs, upregulation of acetylcholinesterase (ACHE), choline O-acetyltransferase (CHAT), sodium channel alpha subunit 9 (SCN9A), POU class 4 homeobox 1 (POU4F1/BRN3A) along with a downregulation of motor neuron and pancreas homeobox 1 (MNX1) indicated that differentiation was more guided toward a cholinergic sensory neuronal lineage. Furthermore, the Extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126 significantly impaired hDPSC neuronal differentiation and was associated with reduction of the ERK1/2 phosphorylation. In conclusion, this study demonstrates that extracellular signal-regulated kinase/Mitogen-activated protein kinase (ERK/MAPK) is necessary for sensory cholinergic neuronal differentiation of hDPSCs. hDPSC-derived cholinergic sensory neuronal-like cells represent a novel model and potential source for neuronal regeneration therapies.
Collapse
Affiliation(s)
- Arwa A. Al-Maswary
- School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- * E-mail: , (AAA-M); (BAS)
| | - Molly O’Reilly
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Andrew P. Holmes
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - A. Damien Walmsley
- School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Paul R. Cooper
- School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- Faculty of Dentistry, Sir John Walsh Research Institute, University of Otago, Dunedin, New Zealand
| | - Ben A. Scheven
- School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
- * E-mail: , (AAA-M); (BAS)
| |
Collapse
|
|
12
|
Luteolin-7- O-Glucuronide Improves Depression-like and Stress Coping Behaviors in Sleep Deprivation Stress Model by Activation of the BDNF Signaling. Nutrients 2022; 14:nu14163314. [PMID: 36014820 PMCID: PMC9412559 DOI: 10.3390/nu14163314] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 11/16/2022] Open
Abstract
Stress exposure is a major risk factor for mental disorders such as depression. Because of the limitations of classical antidepressants such as side effects, low efficacy, and difficulty in long-term use, new natural medicines and bioactive molecules from plants with greater safety and efficacy have recently attracted attention. Luteolin-7-O-glucuronide (L7Gn), a bioactive molecule present in Perilla frutescens, is known to alleviate severe inflammatory responses and oxidative stress in macrophages. However, its antistress and antidepressant effects have not been elucidated. The present study aims to explore the antidepressant the effect of L7Gn on stress-induced behaviors and the underlying mechanism in a mouse sleep deprivation (SD) model. L7Gn treatment improved depression-like and stress coping behaviors induced by SD stress, as confirmed by the tail suspension test and forced swimming test. Furthermore, L7Gn treatment reduced the blood corticosterone and hippocampal proinflammatory cytokine levels which were increased by SD stress, and L7Gn also increased the mRNA and protein levels of hippocampal brain-derived neurotrophic factor (BDNF) which were reduced by SD stress. Additionally, treatment with L7Gn resulted in increases in the phosphorylation of tropomyosin-related kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB), which are downstream molecules of BDNF signaling. These findings suggest that L7Gn have therapeutic potential for SD-induced stress, via activating the BDNF signaling.
Collapse
|
|
13
|
Karimi-Haghighi S, Chavoshinezhad S, Safari A, Razeghian-Jahromi I, Jamhiri I, Khodabandeh Z, Khajeh S, Zare S, Borhani-Haghighi A, Dianatpour M, Pandamooz S, Salehi MS. Preconditioning with secretome of neural crest-derived stem cells enhanced neurotrophic expression in mesenchymal stem cells. Neurosci Lett 2022; 773:136511. [PMID: 35143889 DOI: 10.1016/j.neulet.2022.136511] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/01/2022] [Accepted: 02/04/2022] [Indexed: 12/16/2022]
Abstract
During the last 20 years, stem cell therapy has been considered as an effective approach for regenerative medicine. Due to poor ability of stem cells to survive following transplantation, it has been proposed that beneficial effects of stem cells mainly depend on paracrine function. Therefore, the present study was designed to reinforce mesenchymal stem cells (MSCs) to express higher levels of trophic factors especially the ones with the neurotrophic properties. Here, bone marrow (BM)-MSCs and adipose-MSCs were treated with conditioned medium (CM) of dental pulp stem cells (DPSCs) or hair follicle stem cells (HFSCs) for up to three days. The relative expression of five key trophic factors that have critical effects on the central nervous system regeneration were evaluated using qRT-PCR technique. Furthermore, to assess the impacts of conditioned mediums on the fate of MSCs, expression of seven neuronal/glial markers were evaluated 3 days after the treatments. The obtained data revealed priming of BM-MSCs with HFSC-CM or DPSC-CM increases the BDNF expression over time. Such effect was also observed in adipose-MSCs following DPSC-CM treatment. Secretome preconditioning remarkably increased NGF expression in the adipose-MSCs. In addition, although priming of adipose-MSCs with HFSC-CM increased GDNF expression one day after the treatment, DPSC-CM enhanced GDNF mRNA in BM-MSCs at a later time point. It seemed priming of BM-MSCs with HFSC-CM, promoted differentiation into the glial lineage. Our findings showed that MSCs preconditioning with secretome of neural crest-derived stem cells could be a promising approach to enhance the neurotrophic potential of these stem cells.
Collapse
Affiliation(s)
| | - Sara Chavoshinezhad
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Anahid Safari
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Iman Jamhiri
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Khodabandeh
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sahar Khajeh
- Bone and Joint Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahrokh Zare
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mehdi Dianatpour
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sareh Pandamooz
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohammad Saied Salehi
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| |
Collapse
|
|
14
|
Lu J, Wang X, Wu A, Cao Y, Dai X, Liang Y, Li X. Ginsenosides in central nervous system diseases: Pharmacological actions, mechanisms, and therapeutics. Phytother Res 2022; 36:1523-1544. [PMID: 35084783 DOI: 10.1002/ptr.7395] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 01/04/2022] [Accepted: 01/08/2022] [Indexed: 12/11/2022]
Abstract
The nervous system is one of the most complex physiological systems, and central nervous system diseases (CNSDs) are serious diseases that affect human health. Ginseng (Panax L.), the root of Panax species, are famous Chinese herbs that have been used for various diseases in China, Japan, and Korea since ancient times, and remain a popular natural medicine used worldwide in modern times. Ginsenosides are the main active components of ginseng, and increasing evidence has demonstrated that ginsenosides can prevent CNSDs, including neurodegenerative diseases, memory and cognitive impairment, cerebral ischemia injury, depression, brain glioma, multiple sclerosis, which has been confirmed in numerous studies. Therefore, this review summarizes the potential pathways by which ginsenosides affect the pathogenesis of CNSDs mainly including antioxidant effects, anti-inflammatory effects, anti-apoptotic effects, and nerve protection, which provides novel ideas for the treatment of CNSDs.
Collapse
Affiliation(s)
- Jing Lu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xian Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Anxin Wu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi Cao
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolin Dai
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Youdan Liang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
15
|
Pandey A, Sarkar S, Yadav SK, Yadav SS, Srikrishna S, Siddiqui MH, Parmar D, Yadav S. Studies on Regulation of Global Protein Profile and Cellular Bioenergetics of Differentiating SH-SY5Y Cells. Mol Neurobiol 2022; 59:1799-1818. [PMID: 35025051 DOI: 10.1007/s12035-021-02667-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/25/2021] [Indexed: 01/07/2023]
Abstract
The SH-SY5Y cells differentiated by sequential exposure of retinoic acid (RA) and brain-derived neurotrophic growth factor (BDNF) are a well-employed cellular model for studying the mechanistic aspects of neural development and neurodegeneration. Earlier studies from our lab have identified dramatic upregulation (77 miRNAs) and downregulation (17 miRNAs) of miRNAs in SH-SY5Y cells differentiated with successive exposure of RA + BDNF and demonstrated the essential role of increased levels of P53 proteins in coping with the differentiation-induced changes in protein levels. In continuation to our earlier studies, we have performed unbiased LC-MS/MS global protein profiling of naïve and differentiated SH-SY5Y cells and analyzed the identified proteins in reference to miRNAs identified in our earlier studies to identify the cellular events regulated by both identified miRNAs and proteins. Analysis of LC-MS/MS data has shown a significant increase and decrease in levels of 215 and 163 proteins, respectively, in differentiated SH-SY5Y cells. Integrative analysis of miRNA identified in our previous studies and protein identified in the present study is carried out to discover novel miRNA-protein regulatory modules to elucidate miRNA-protein regulatory relationships of differentiating neurons. In silico network analysis of miRNAs and proteins deregulated upon SH-SY5Y differentiation identified cell cycle, synapse formation, axonogenesis, differentiation, neuron projection, and neurotransmission, as the topmost involved pathways. Further, measuring mitochondrial dynamics and cellular bioenergetics using qPCR and Seahorse XFp Flux Analyzer, respectively, showed that differentiated cells possess increased mitochondrial dynamics and OCR relative to undifferentiated cells. In summary, our studies have identified a novel set of proteins deregulated during neuronal differentiation and establish the role of miRNAs identified in earlier studies in the regulation of proteins identified by LC-MS/MS-based global profiling of differentiating neurons, which will help in future studies related to neural development and neurodegeneration.
Collapse
Affiliation(s)
- Anuj Pandey
- Systems Toxicology and Health Risk Assessment Group, , CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Uttar Pradesh, Vishvigyan Bhawan, Lucknow, India.,Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sana Sarkar
- Systems Toxicology and Health Risk Assessment Group, , CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Uttar Pradesh, Vishvigyan Bhawan, Lucknow, India.,Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, India
| | - Sanjeev Kumar Yadav
- Systems Toxicology and Health Risk Assessment Group, , CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Uttar Pradesh, Vishvigyan Bhawan, Lucknow, India
| | - Smriti Singh Yadav
- Systems Toxicology and Health Risk Assessment Group, , CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Uttar Pradesh, Vishvigyan Bhawan, Lucknow, India
| | - Saripella Srikrishna
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India
| | | | - Devendra Parmar
- Systems Toxicology and Health Risk Assessment Group, , CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Uttar Pradesh, Vishvigyan Bhawan, Lucknow, India.
| | - Sanjay Yadav
- Systems Toxicology and Health Risk Assessment Group, , CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Uttar Pradesh, Vishvigyan Bhawan, Lucknow, India. .,All India Institute of Medical Sciences (AIIMS), Uttar Pradesh, Raebareli, India.
| |
Collapse
|
|
16
|
Kou RW, Xia B, Han R, Li ZQ, Yang JR, Yin X, Gao YQ, Gao JM. Neuroprotective effects of a new triterpenoid from edible mushroom on oxidative stress and apoptosis through the BDNF/TrkB/ERK/CREB and Nrf2 signaling pathway in vitro and in vivo. Food Funct 2022; 13:12121-12134. [DOI: 10.1039/d2fo02854a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Inonotus obliquus (Fr.) Pilat is an edible mushroom which is used to produce tea and syrup due to its medicinal properties.
Collapse
Affiliation(s)
- Rong-Wei Kou
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Bing Xia
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Rui Han
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Zhi-Qing Li
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Jun-Ren Yang
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Xia Yin
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| | - Yu-Qi Gao
- College of Food Science and Technology, Northwest University, Xi'an, 710069, Shaanxi, People's Republic of China
| | - Jin-Ming Gao
- Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China
| |
Collapse
|
|
17
|
Electroacupuncture and Moxibustion Modulate the BDNF and TrkB Expression in the Colon and Dorsal Root Ganglia of IBS Rats with Visceral Hypersensitivity. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:8137244. [PMID: 34621325 DOI: 10.1155/2021/8137244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/11/2021] [Indexed: 12/27/2022]
Abstract
Objective To evaluate the effects of electroacupuncture and moxibustion on brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase receptor B (TrkB) protein and mRNA expressions in the colon and dorsal root ganglia of IBS rats with visceral hypersensitivity and to explore their underlying therapeutic mechanisms. Method Forty Sprague Dawley rats were randomly divided into normal, model, model + mild moxibustion (MM), model + electroacupuncture (EA), and model + pinaverium bromide (PB) groups, with eight rats in each group. Chronic visceral hypersensitive IBS rat models were established by colorectal distension (CRD) with mustard oil clyster. Rats in the MM and EA groups, respectively, received moxibustion and electroacupuncture treatments on the Tianshu (ST25) and Shangjuxu (ST37) acupoints once daily for 7 days, and rats in the PB group received pinaverium bromide by oral gavage once daily for 7 consecutive days. After treatment, rats underwent abdominal withdrawal reflex (AWR) scoring under CRD and colon histopathological examination. Immunohistochemistry and real-time quantitative PCR (RT-qPCR) were used to study the protein and mRNA expressions of BDNF and TrkB in the rat colon and dorsal root ganglia. Results Compared with the normal group, AWR scores and body weight were clearly increased in the model group rats (both P < 0.01). The body weights were significantly elevated (P < 0.01, P < 0.05), but the AWR scores were reduced (P < 0.05, P < 0.01), after electroacupuncture and mild moxibustion treatment. Compared with levels in normal rats, BDNF and TrkB protein and mRNA expressions were significantly elevated in the IBS model rats (P < 0.01) but were downregulated after mild moxibustion, electroacupuncture, and Western medicine treatment (P < 0.01). Conclusion Electroacupuncture and moxibustion improved visceral hypersensitivity of IBS rats possibly by reducing BDNF and TrkB protein and mRNA expressions in the colon and dorsal root ganglia.
Collapse
|
|
18
|
The Role of Exercise in Reducing Hyperlipidemia-Induced Neuronal Damage in Apolipoprotein E-Deficient Mice. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5512518. [PMID: 34409103 PMCID: PMC8367587 DOI: 10.1155/2021/5512518] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 06/13/2021] [Accepted: 07/16/2021] [Indexed: 12/14/2022]
Abstract
Hyperlipidemia causes nervous system-related diseases. Exercise training has developed into an established evidence-based treatment strategy that is beneficial for neuronal injury. This study investigated the effect of exercise on hyperlipidemia-induced neuronal injury in apolipoprotein E-deficient (ApoE-/-) mice. Male ApoE-/- mice (age: 8 weeks) were randomly divided into four groups as follows: mice fed a normal diet (ND), normal diet+swimming training (ND+S), high-fat diet (HD), and high-fat diet+swimming (HD+S). Exercise training consisted of swimming for 40 min/day, 5 days/week for 12 weeks. After 12 weeks, we measured serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c). We also evaluated glial fibrillary acidic protein (GFAP) expression levels using immunohistochemistry, real-time PCR, and immunoblotting. In addition, NLR family pyrin domain-containing 3 (NLRP3), interleukin- (IL-) 18, caspase-1, Bax, Bcl-2, and phosphorylated extracellular signal-regulated kinase (p-ERK) expression levels were measured using immunoblotting. Serum levels of TG, TC, and LDL-c were lower in ApoE-/- HD+S mice than in ApoE-/- HD mice. Immunohistochemistry, real-time PCR, and immunoblotting showed increased levels of GFAP in the ApoE-/- HD group. Immunoblotting revealed increased levels of NLRP3, IL-18, caspase-1, Bax, Bcl-2, and p-ERK in the ApoE-/- HD group; however, they were significantly suppressed in the ApoE-/- HD+S group. Therefore, exercise has protective effects against neuronal injury caused by hyperlipidemia.
Collapse
|
|
19
|
Hamblin MH, Lee JP. Neural Stem Cells for Early Ischemic Stroke. Int J Mol Sci 2021; 22:ijms22147703. [PMID: 34299322 PMCID: PMC8306669 DOI: 10.3390/ijms22147703] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022] Open
Abstract
Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially therapeutic actions against neurovascular injury. Currently, tissue plasminogen activator (tPA) is the only FDA-approved clot-dissolving agent. While tPA’s thrombolytic role within the vasculature is beneficial, tPA’s non-thrombolytic deleterious effects aggravates neurovascular injury, restricting the treatment time window (time-sensitive) and tPA eligibility. Thus, new strategies are needed to mitigate tPA’s detrimental effects and quickly mediate vascular repair after stroke. Up to date, clinical trials focus on the impact of stem cell therapy on neuro-restoration by delivering cells during the chronic stroke stage. Also, NSCs secrete factors that stimulate endogenous repair mechanisms for early-stage ischemic stroke. This review will present an integrated view of the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury, with an emphasis on early-stage ischemic stroke. Further, this will highlight the impact of early sub-acute NSC delivery on improving short-term and long-term stroke outcomes.
Collapse
Affiliation(s)
- Milton H. Hamblin
- Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA
- Correspondence: (M.H.H.); (J.-P.L.)
| | - Jean-Pyo Lee
- Department of Physiology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA
- Tulane Brain Institute, Tulane University, 1430 Tulane Ave, New Orleans, LA 70112, USA
- Correspondence: (M.H.H.); (J.-P.L.)
| |
Collapse
|
|
20
|
Huang S, Chen T, Suo Q, Shi R, Khan H, Ma Y, Tang Y, Yang GY, Zhang Z. BK Channel-Mediated Microglial Phagocytosis Alleviates Neurological Deficit After Ischemic Stroke. Front Cell Neurosci 2021; 15:683769. [PMID: 34276309 PMCID: PMC8281043 DOI: 10.3389/fncel.2021.683769] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/25/2021] [Indexed: 11/16/2022] Open
Abstract
Microglial phagocytosis benefits neurological recovery after stroke. Large-conductance Ca2+-activated K+ currents are expressed in activated microglia, and BK channel knockout aggravates cerebral ischemic injury. However, the effect of BK channels on microglial phagocytosis after ischemic stroke remains unknown. Here, we explored whether BK channel activation is beneficial for neurological outcomes through microglial phagocytosis after ischemic stroke. ICR mice after transient middle cerebral artery occlusion (tMCAO) were treated with dimethyl sulfoxide (DMSO), BK channel activator NS19504, and inhibitor Paxilline. The results showed a decrease in BK channel expression after tMCAO. BK channel activator NS19504 alleviates neurological deficit after experimental modeling of tMCAO in mice compared to the control. Furthermore, we treated primary microglia with DMSO, NS19504, and Paxilline after oxygen glucose deprivation (OGD). NS19504 promoted primary microglial phagocytosing fluorescent beads and neuronal debris, which reduced neuronal apoptosis after stroke. These effects could be reversed by BK channel inhibitor Paxilline. Finally, NS19504 increased relative phosphorylated extracellular signal-regulated kinase 1/2 expression compared to the Paxilline group at the third day after stroke. Our findings indicate that microglial BK channels are a potential target for acute stage of ischemic stroke therapy.
Collapse
Affiliation(s)
- Shuxian Huang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Tingting Chen
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Suo
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Rubing Shi
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Haroon Khan
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yuanyuan Ma
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yaohui Tang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Guo-Yuan Yang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhijun Zhang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
21
|
Jiang N, Huang H, Wang H, Lv J, Zeng G, Wang Q, Bao Y, Chen Y, Liu XM. The antidepressant-like effects of Shen Yuan: Dependence on hippocampal BDNF-TrkB signaling activation in chronic social defeat depression-like mice. Phytother Res 2021; 35:2711-2726. [PMID: 33474783 DOI: 10.1002/ptr.7017] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 11/30/2023]
Abstract
The Shen Yuan prescription (SY) comprises Panax ginseng (GT) and Polygala tenuifolia (YT), elicited superior antidepressant activity compared with that of GT or YT alone. The aim of this paper is to elucidate the effects of SY treatment on chronic social defeat stress (CSDS)-induced depression-like symptoms and the related mechanism. Our results indicated that SY treatment reverses the depressive-like behaviors induced by CSDS as measured by the social interaction test, sucrose preference test, forced swim test, and tail suspension test. SY decreased the serum levels of CORT and increased hippocampal neurotransmitters (5-HT, DA, and NE) in CSDS mice. Meanwhile, SY upregulated the brain-derived neurotrophic factor (BDNF) signaling pathway and reversed the decreased hippocampal neurogenesis caused by CSDS. In addition, we found that the TrkB antagonist K252a fully blocked the SY effects on behavioral improvement and eliminated the promoting effects of SY on hippocampal neurogenesis and BDNF-TrkB signaling (including the downstream ERK and Akt pathways) activation, thus further demonstrating that BDNF-TrkB signaling was necessary for the SY effects. In conclusion, our study showed that SY acted as an antidepressant in mice exhibiting CSDS-induced depression-like symptoms, and its effect was facilitated by promoting hippocampal neurogenesis and BDNF signaling pathway activation.
Collapse
Affiliation(s)
- Ning Jiang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Huang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haixia Wang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | - Guirong Zeng
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiong Wang
- Affiliated TCM Hospital/School of Pharmacy/Sino-Portugal TCM International Cooperation Center, Southwest Medical University, Luzhou, China
| | - Yu Bao
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Chen
- Institute of Chinese Materia Medical, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xin-Min Liu
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
22
|
Jiang N, Wang H, Li C, Zeng G, Lv J, Wang Q, Chen Y, Liu X. The antidepressant-like effects of the water extract of Panax ginseng and Polygala tenuifolia are mediated via the BDNF-TrkB signaling pathway and neurogenesis in the hippocampus. JOURNAL OF ETHNOPHARMACOLOGY 2021; 267:113625. [PMID: 33248184 DOI: 10.1016/j.jep.2020.113625] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 10/04/2020] [Accepted: 11/23/2020] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGY RELEVANCE The water extract of Panax ginseng (GT) and Polygala tenuifolia (YT), the main constituents of the commonly used kai-xin-san formula of traditional Chinese medicine, represents SY. It possesses strong neuroprotective effects. Using behavioural tests, we have previously established that the SY formulation exerts superior antidepressant activity than that of GT or YT. AIM To elucidate the impact of SY treatment on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviours and the prospective mechanism related to hippocampal neurogenesis and the BDNF signaling pathway. METHODS We exposed Sprague-Dawley rats (male; 180-200 g) to CUMS for 35 days. The rats in the experimental treatment groups were daily treated with either fluoxetine (10 mg kg-1d-1) or SY (67.5, 135, or 270 mg kg-1d-1) orally until the behavioural tests (tail suspension test [TST], novelty-suppressed feeding test [NSFT], sucrose preference test [SPT], and forced swim test [FST]) were completed. We assessed the modifications in the hippocampal neurogenesis and the BDNF signaling pathway post-treatment with CUMS and SY. Additionally, K252a, a tyrosine protein kinase inhibitor, was utilized to evaluate the antidepressant mechanisms of SY. RESULT s: The results of SPT, NSFT, FST, and TST in CUMS-exposed rats confirmed the antidepressant actions of SY. Additionally, SY treatment induced the BDNF signaling pathway and reversed the hippocampal neurogenesis caused by CUMS. Moreover, we found that the TrkB antagonist K252a blocked SY effects on behavioural improvement, inhibited the incremental effects of SY on hippocampal neurogenesis, and eliminated the impact of SY on BDNF-TrkB signaling activation. Thus, the impact of SY treatment on BDNF signaling molecules (pAkt, pERK1/2, and pCREB) were significantly inhibited by K252a. CONCLUSIONS This study showed that SY acted as an antidepressant in rats exhibiting CUMS-induced depressive-like behaviours, and was facilitated by promoting hippocampal neurogenesis and the BDNF signaling pathway activation. Thus, SY could act as a potential novel supplement or adjuvant to prevent or treat clinical depressive disorders.
Collapse
Affiliation(s)
- Ning Jiang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Haixia Wang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenchen Li
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guirong Zeng
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingwei Lv
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiong Wang
- Affiliated TCM Hospital/School of Pharmacy/Sino-Portugal TCM International Cooperation Center, Southwest Medical University, Luzhou, 646000, China
| | - Yin Chen
- Institute of Chinese Materia Medical, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xinmin Liu
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
23
|
Xiong S, Ma M, Xu Y, Wei F, Gu Q, He X, Xu X. Protective effects of peptide FK18 against neuro-excitotoxicity in SH-SY5Y cells. Exp Ther Med 2021; 21:451. [PMID: 33747186 DOI: 10.3892/etm.2021.9880] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 10/08/2020] [Indexed: 12/12/2022] Open
Abstract
Excitotoxic neuronal injury is associated with numerous acute and chronic neurological disorders, such as Alzheimer's disease and glaucoma. Neuroprotection is a direct and effective therapeutic approach, with small-molecule bioactive peptides displaying certain advantages, including high membrane permeability, low immunogenicity and convenient synthesis and modification. FK18 is a novel peptide derived from basic fibroblast growth factor, which is a protein with neuroprotective effects. The present study aims to evaluate the neuroprotective effect of FK18 against excitotoxic injury. For this purpose, cell viability was determined by the MTS assay, cell apoptosis was assessed by flow cytometry and the TUNEL assay; expression of antiapoptotic proteins Bcl-2, proapoptotic protein Bax and caspase-3 as well as the phosphorylation of Akt and Erk was estimated by western blotting. The results of the present study demonstrated that FK18 effectively increased the viability of, and attenuated glutamate-induced apoptosis of SH-SY5Y cells. In addition, FK18 significantly increased Akt phosphorylation and decreased Erk phosphorylation in SH-SY5Y cells. FK18 also increased the Bcl-2/Bax ratio and decreased the level of cleaved-caspase-3 in SY5Y cells, which was reversed by the Akt pathway inhibitor LY294002, but not by the Erk pathway inhibitor U0126. The findings of the present study suggested that FK18 may be a promising therapeutic agent for the inhibition of neuronal cell death in multiple neurological diseases involving excitotoxicity.
Collapse
Affiliation(s)
- Shuyu Xiong
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.,Shanghai Key Laboratory of Ocular Fundus Disease, Shanghai 200080, P.R. China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, P.R. China.,National Clinical Research Center for Eye Diseases, Shanghai 200080, P.R. China
| | - Mingming Ma
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.,Shanghai Key Laboratory of Ocular Fundus Disease, Shanghai 200080, P.R. China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, P.R. China.,National Clinical Research Center for Eye Diseases, Shanghai 200080, P.R. China
| | - Yupeng Xu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.,Shanghai Key Laboratory of Ocular Fundus Disease, Shanghai 200080, P.R. China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, P.R. China.,National Clinical Research Center for Eye Diseases, Shanghai 200080, P.R. China
| | - Fang Wei
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.,Shanghai Key Laboratory of Ocular Fundus Disease, Shanghai 200080, P.R. China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, P.R. China.,National Clinical Research Center for Eye Diseases, Shanghai 200080, P.R. China
| | - Qing Gu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.,Shanghai Key Laboratory of Ocular Fundus Disease, Shanghai 200080, P.R. China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, P.R. China.,National Clinical Research Center for Eye Diseases, Shanghai 200080, P.R. China
| | - Xiangui He
- Department of Preventative Ophthalmology, Shanghai Eye Disease Prevention and Treatment Center, Shanghai Eye Hospital, Shanghai 200040, P.R. China
| | - Xun Xu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.,Shanghai Key Laboratory of Ocular Fundus Disease, Shanghai 200080, P.R. China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, P.R. China.,National Clinical Research Center for Eye Diseases, Shanghai 200080, P.R. China
| |
Collapse
|
|
24
|
Wang G, Li Y, Lei C, Lei X, Zhu X, Yang L, Zhang R. Quercetin exerts antidepressant and cardioprotective effects in estrogen receptor α-deficient female mice via BDNF-AKT/ERK1/2 signaling. J Steroid Biochem Mol Biol 2021; 206:105795. [PMID: 33246157 DOI: 10.1016/j.jsbmb.2020.105795] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 10/13/2020] [Accepted: 11/17/2020] [Indexed: 12/23/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is the potential link between depression and cardiovascular disease and estrogen receptor α (ERα), an estrogen-mediated major regulator, plays an important role in protecting against depression and cardiovascular disease. However, the relationship between BDNF and ERα remains obscure. Herein, quercetin (QUE), a kind of plant flavonoids and existed in many vegetables and fruits, was found to simultaneously reverse ERα-/--induced depression-like and cardiac dysfunction by reducing immobility time in the tail suspension test (TST) and forced swimming test (FST), and decreasing systolic blood pressure and activating the apoptosis-related proteins, BDNF, tropomyosin-related kinase B (TrkB), protein kinase B (AKT), and extracellular regulatory protein kinase (ERK1/2) in the hippocampal and cardiac tissues of female mice. These findings suggested that ERα might be involved in the regulation of BDNF activity, thereby regulating depression-like and cardiovascular responses in female mice, and QUE exerted significant antidepressant and cardioprotective effects, at least in part, through BDNF-TrkB-AKT/ERK1/2 to effectively inhibit ERα-/--induced hippocampal and cardiac dysfunction.
Collapse
Affiliation(s)
- Guoli Wang
- College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yunchuan Li
- College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Cong Lei
- College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiaotong Lei
- College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiaofeng Zhu
- Department of the First Affiliated Hospital, Jinan University, Guangzhou 510632, China; College of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China
| | - Li Yang
- College of Pharmacy, Jinan University, Guangzhou 510632, China.
| | - Ronghua Zhang
- College of Pharmacy, Jinan University, Guangzhou 510632, China.
| |
Collapse
|
|
25
|
Zhao J, Zhang Y, Liu Y, Tang WQ, Ji CH, Gu JH, Jiang B. Antidepressant-like effects of 1-methylnicotinamide in a chronic unpredictable mild stress model of depression. Neurosci Lett 2021; 742:135535. [PMID: 33248165 DOI: 10.1016/j.neulet.2020.135535] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 11/04/2020] [Accepted: 11/20/2020] [Indexed: 12/22/2022]
Abstract
Depression is one of the most common psychiatric disorders, and there is strong demand for developing novel antidepressants with better efficacy and less adverse effects. 1-Methylnicotinamide (MNA) is a main metabolite of nicotinamide and has been demonstrated to possess biological effects in the brain. This study aimed to evaluate the antidepressant-like effects of MNA in mice, and the possible antidepressant mechanism was also determined. The forced swim test (FST), tail suspension test (TST), chronic unpredictable mild stress (CUMS) model of depression, western blotting method and K252a (a pharmacological inhibitor of the BDNF receptor) were used together in the present study. It was found that a single injection of MNA (100 and 200 mg/kg) displayed notable antidepressant-like potential in the FST and TST without affecting the locomotor activity of mice. Repeated administration of MNA (100 and 200 mg/kg) for 2 weeks fully reversed not only the CUMS-induced depressive-like symptoms in mice but also the CUMS-induced decrease in the hippocampal BDNF signaling pathway. Furthermore, the usage of K252a fully blocked the antidepressant-like effects of MNA in the FST, TST and CUMS model of depression. Collectively, MNA possess an antidepressant-like effect in mice which is mediated, at least in part, through promoting the hippocampal BDNF signaling pathway.
Collapse
Affiliation(s)
- Jie Zhao
- Department of Pharmacy, The Sixth People's Hospital of Nantong, Nantong, 226011 Jiangsu, China
| | - Yin Zhang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001 Jiangsu, China
| | - Yue Liu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001 Jiangsu, China; Provincial Key Laboratory of Inflammation and Molecular Drug Target, Nantong, 226001 Jiangsu, China
| | - Wen-Qian Tang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001 Jiangsu, China; Provincial Key Laboratory of Inflammation and Molecular Drug Target, Nantong, 226001 Jiangsu, China
| | - Chun-Hui Ji
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001 Jiangsu, China; Provincial Key Laboratory of Inflammation and Molecular Drug Target, Nantong, 226001 Jiangsu, China
| | - Jiang-Hong Gu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001 Jiangsu, China; Provincial Key Laboratory of Inflammation and Molecular Drug Target, Nantong, 226001 Jiangsu, China
| | - Bo Jiang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, 226001 Jiangsu, China; Provincial Key Laboratory of Inflammation and Molecular Drug Target, Nantong, 226001 Jiangsu, China.
| |
Collapse
|
|
26
|
Ataei A, Poorebrahim M, Rajabpour A, Rizvanov A, Shahriar Arab S. Topological Analysis of Regulatory Networks Reveals Functionally Key Genes and miRNAs Involved in the Differentiation of Mesenchymal Stem Cells. IRANIAN JOURNAL OF BIOTECHNOLOGY 2021; 19:e2565. [PMID: 34179189 PMCID: PMC8217530 DOI: 10.30498/ijb.2021.2565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Background The details of molecular mechanisms underlying the differentiation of Mesenchymal Stem Cells (MSCs) into specific lineages are not well understood. Objectives We aimed to construct the interactome network and topology analysis of bone marrow mesenchymal stem cell of CAGE data. Applying the enrichment results, we wanted to introduce the common genes and hub-microRNA and hub-genes of these giant network. Materials and Methods In this study, we constructed gene regulatory networks for each non-mesenchymal cell lineage according to their gene expression profiles obtained from FANTOM5 database. The putative interactions of TF-gene and protein-protein were determined using TRED, STRING, HPRD and GeneMANIA servers. In parallel, a regulatory network including corresponding miRNAs and total differentially expressed genes (DEGs) was constructed for each cell lineage. Results The results indicated that analysis of networks' topology can significantly distinguish the hub regulatory genes and miRNAs involved in the differentiation of MSCs. The functional annotation of identified hub genes and miRNAs revealed that several signal transduction pathways i.e. AKT, WNT and TGFβ and cell proliferation related pathways play a pivotal role in the regulation of MSCs differentiation. We also classified cell lineages into two groups based on their predicted miRNA profiles. Conclusions In conclusion, we found a number of hub genes and miRNAs which seem to have key regulatory functions during differentiation of MSCs. Our results also introduce a number of new regulatory genes and miRNAs which can be considered as the new candidates for genetic manipulation of MSCs in vitro.
Collapse
Affiliation(s)
- Atousa Ataei
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Equal contribution
| | - Mansour Poorebrahim
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, University of Medical Sciences, Tehran, Iran.,Equal contribution
| | - Azam Rajabpour
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Seyed Shahriar Arab
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| |
Collapse
|
|
27
|
Um S, Ha J, Choi SJ, Oh W, Jin HJ. Prospects for the therapeutic development of umbilical cord blood-derived mesenchymal stem cells. World J Stem Cells 2020; 12:1511-1528. [PMID: 33505598 PMCID: PMC7789129 DOI: 10.4252/wjsc.v12.i12.1511] [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: 06/30/2020] [Revised: 10/23/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord blood (UCB) is a primitive and abundant source of mesenchymal stem cells (MSCs). UCB-derived MSCs have a broad and efficient therapeutic capacity to treat various diseases and disorders. Despite the high latent self-renewal and differentiation capacity of these cells, the safety, efficacy, and yield of MSCs expanded for ex vivo clinical applications remains a concern. However, immunomodulatory effects have emerged in various disease models, exhibiting specific mechanisms of action, such as cell migration and homing, angiogenesis, anti-apoptosis, proliferation, anti-cancer, anti-fibrosis, anti-inflammation and tissue regeneration. Herein, we review the current literature pertaining to the UCB-derived MSC application as potential treatment strategies, and discuss the concerns regarding the safety and mass production issues in future applications.
Collapse
Affiliation(s)
- Soyoun Um
- Research Team for Immune Cell Therapy, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Jueun Ha
- Research Team for Osteoarthritis, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| |
Collapse
|
|
28
|
Lin CW, Fan CH, Chang YC, Hsieh-Li HM. ERK activation precedes Purkinje cell loss in mice with Spinocerebellar ataxia type 17. Neurosci Lett 2020; 738:135337. [PMID: 32877710 DOI: 10.1016/j.neulet.2020.135337] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/27/2020] [Accepted: 08/26/2020] [Indexed: 12/18/2022]
Abstract
Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant neurodegenerative disease caused by CAG expansion in the gene encoding the TATA-binding protein (TBP). The neurological features of SCA17 are Purkinje cell loss and gliosis. We have generated SCA17 transgenic mice which recapitulate the patients' phenotypes and are suitable for the study of the SCA17 pathomechanism. Our previous study identified the activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) occurred in the SCA17 cerebella, this study aims to study the role of ERK activation in SCA17. The levels of pERK, calbindin, and gliosis markers on the mouse cerebellum at 4-8 weeks old were analyzed to elucidate the correlation among behavioral performance, ERK activation and Purkinje cell degeneration. The motor incoordination was initiated in SCA17 mice at 6 weeks old. We found that the presence of TBP nuclear aggregation and microglia activation were observed at 4 weeks old. Gliosis of astrocytes and Bergmann glia, pERK, Bax/Bcl2 ratio, and caspase-3 were significantly increased in the 6-week-old SCA17 mouse cerebellum. In addition to the polyglutamine-protein aggregation in Purkinje cells caused apoptosis cell-autonomously, a significant body of evidence have shown that ERK pathways involves in neuronal apoptosis. Our study showed that the activation of ERK in the astrocytes and Bergmann glia was identified as preceding motor deficits, which suggest the elevated gliosis by ERK activation may contribute to neuronal apoptosis in SCA17 mice.
Collapse
Affiliation(s)
- Chia-Wei Lin
- Department of Life Science, National Taiwan Normal University, Taiwan
| | - Chia-Hao Fan
- Department of Life Science, National Taiwan Normal University, Taiwan
| | - Ya-Chin Chang
- Department of Pharmacy, Taiwan Adventist Hospital, Taiwan
| | - Hsiu Mei Hsieh-Li
- Department of Life Science, National Taiwan Normal University, Taiwan.
| |
Collapse
|
|
29
|
Mehri Ghahfarrokhi A, Jami MS, Hashemzadeh Chaleshtori M. Upregulation of Neuroprogenitor and Neural Markers via Enforced miR-124 and Growth Factor Treatment. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2020; 9:62-70. [PMID: 32832485 PMCID: PMC7422846 DOI: 10.22088/ijmcm.bums.9.1.62] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Previous studies have shown that miR-124 plays an important role in the development of auditory neurons, which are degenerated in the sensorineural hearing loss. However, whether the combined use of miR-124 and growth factors can increase the expression of neural related markers in human dental pulp stem cells has been remained unknown so far. In this study, human dental pulp stem cells were transfected with miR-124 following treatment with brain-derived neurotrophic factor or epidermal growth factor/basic fibroblast growth factor. The expression of some neural related markers (nestin, SOX2, β-tubulin III, MAP2, and peripherin) was analyzed in two groups by qRT-PCR or immunofluorescence. Cellular treatment resulted in morphological changes including neurosphere-like colonies formation. Nestin and SOX2 were up-regulated, and MAP2 and peripherin were down-regulated in dental pulp stem cells transfected by miR-124 following treatment with brain-derived neurotrophic factor. Replacement of brain-derived neurotrophic factor with epidermal growth factor/ basic fibroblast growth factor resulted in the up-regulation of nestin, MAP2, peripherin, and β-tubulin III and down-regulation of SOX2. The expression of SOX2 and nestin was also confirmed by immunofluorescence. The combination of miR-124 and growth factors would provide a promising starting point for upregulating the neural progenitor markers in human dental pulp stem cells.
Collapse
Affiliation(s)
- Ameneh Mehri Ghahfarrokhi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad Saeid Jami
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Department of Neurology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Morteza Hashemzadeh Chaleshtori
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| |
Collapse
|
|
30
|
Guo M, Wu L, Song Z, Yang B. Enhancement of Neural Stem Cell Proliferation in Rats with Spinal Cord Injury by a Combination of Repetitive Transcranial Magnetic Stimulation (rTMS) and Human Umbilical Cord Blood Mesenchymal Stem Cells (hUCB-MSCs). Med Sci Monit 2020; 26:e924445. [PMID: 32814758 PMCID: PMC7453755 DOI: 10.12659/msm.924445] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND This study was designed to explore the combined effects of repetitive transcranial magnetic stimulation (rTMS) and human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) transplantation on neural stem cell proliferation in rats with spinal cord injury (SCI). MATERIAL AND METHODS SCI was induced in 90 rats by laminectomy at T10. Fifteen rats each were treated with 0.5 Hz rTMS or 10 Hz rTMS or underwent hUCB-MSC transplantation; 15 each were treated with 0.5 Hz rTMS+hUCB-MSCs or 10 Hz rTMS+hUCB-MSCs; and 15 were untreated (control group). The Basso, Beattie, and Bresnahan (BBB) scores and motor evoked potentials (MEPs) were measured, and all rats underwent biotin dextran-amine (BDA) tracing of the corticospinal tract (CST). The levels of expression of neural stem cell proliferation related proteins, including BrdU, nestin, Tuj1, Ng2+ and GFAP, were measured, and the levels of bFGF and EGF determined by Western blotting. RESULTS BBB scores and MEPs were increased after rTMS and hUCB-MSC transplantation, while histologically determined SCI-induced neuron apoptosis was attenuated. The numbers of BDA-positive fibers and Brdu-, nestin- and Tuj1-positive cells were markedly increased and the numbers of Ng2+- and GFAP-positive cells were markedly decreased following treatment with rTMS alone or rTMS plus hUCB-MSC transplantation. The levels of expression of bFGF and EGF were significantly upregulated following rTMS treatment and hUCB-MSC transplantation. Higher performance was observed after combined treatment with rTMS and hUCB-MSC transplantation than after either alone. CONCLUSIONS The combination of rTMS treatment and hUCB-MSC transplantation could attenuate SCI-induced neural stem cell apoptosis and motor dysfunction in rats.
Collapse
Affiliation(s)
- Mengguo Guo
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| | - Lixin Wu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| | - Zhenyu Song
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| | - Bo Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| |
Collapse
|
|
31
|
Singh M, Pandey PK, Bhasin A, Padma MV, Mohanty S. Application of Stem Cells in Stroke: A Multifactorial Approach. Front Neurosci 2020; 14:473. [PMID: 32581669 PMCID: PMC7296176 DOI: 10.3389/fnins.2020.00473] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/16/2020] [Indexed: 12/21/2022] Open
Abstract
Stroke has a debilitating effect on the human body and a serious negative effect on society, with a global incidence of one in every six people. According to the World Health Organization, 15 million people suffer stroke worldwide each year. Of these, 5 million die and another 5 million are permanently disabled. Motor and cognitive deficits like hemiparesis, paralysis, chronic pain, and psychomotor and behavioral symptoms can persist long term and prevent the patient from fully reintegrating into society, therefore continuing to add to the costly healthcare burden of stroke. Regenerative medicine using stem cells seems to be a panacea for sequelae after stroke. Stem cell-based therapy aids neuro-regeneration and neuroprotection for neurological recovery in patients. However, the use of stem cells as a therapy in stroke patients still needs a lot of research at both basic and translational levels. As well as the mode of action of stem cells in reversing the symptoms not being clear, there are several clinical parameters that need to be addressed before establishing stem cell therapy in stroke, such as the type of stem cells to be administered, the number of stem cells, the timing of dosage, whether dose-boosters are required, the route of administration, etc. There are upcoming prospects of cell-free therapy also by using exosomes derived from stem cells. There are several ongoing pre-clinical studies aiming to answer these questions. Despite still being in the development stage, stem cell therapy holds great potential for neurological rehabilitation in patients suffering from stroke.
Collapse
Affiliation(s)
- Manisha Singh
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, India
- Dr. Solomon H. Snyder Department of Neurosciences, Johns Hopkins University, Baltimore, MD, United States
| | - Pranav K. Pandey
- Dr. R.P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Ashu Bhasin
- Department of Neurosciences, All India Institute of Medical Sciences, New Delhi, India
| | - M. V. Padma
- Department of Neurosciences, All India Institute of Medical Sciences, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
32
|
Arctigenin Enhances the Cytotoxic Effect of Doxorubicin in MDA-MB-231 Breast Cancer Cells. Int J Mol Sci 2020; 21:ijms21082997. [PMID: 32340377 PMCID: PMC7215735 DOI: 10.3390/ijms21082997] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/21/2020] [Accepted: 04/21/2020] [Indexed: 12/23/2022] Open
Abstract
Several reports have described the anti-cancer activity of arctigenin, a lignan extracted from Arctium lappa L. Here, we investigated the effect of arctigenin (ATG) on doxorubicin (DOX)-induced cell death using MDA-MB-231 human breast cancer cells. The results showed that DOX-induced cell death was enhanced by ATG/DOX co-treatment in a concentration-dependent manner and that this was associated with increased DOX uptake and the suppression of multidrug resistance-associated protein 1 (MRP1) gene expression in MDA-MB-231 cells. ATG enhanced DOX-induced DNA damage and decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expressions of RAD51 and survivin. Cell death caused by ATG/DOX co-treatment was mediated by the nuclear translocation of apoptosis inducing factor (AIF), reductions in cellular and mitochondrial Bcl-2 and Bcl-xL, and increases in mitochondrial BAX levels. However, caspase-3 and -7 did not participate in DOX/ATG-induced cell death. We also found that DOX/ATG-induced cell death was linked with activation of the p38 signaling pathway and suppressions of the phosphorylations and expressions of Akt and c-Jun N-terminal kinase. Taken together, these results show that ATG enhances the cytotoxic activity of DOX in MDA-MB-231 human breast cancer cells by inducing prolonged p21 expression and p38-mediated AIF-dependent cell death. In conclusion, our findings suggest that ATG might alleviate the side effects and improve the therapeutic efficacy of DOX.
Collapse
|
|
33
|
Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample. J Mol Neurosci 2019; 70:219-229. [PMID: 31838722 PMCID: PMC7018782 DOI: 10.1007/s12031-019-01456-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. Whole-exome sequencing studies have shown that de novo single-nucleotide variations (SNVs) play an important role in sporadic ASD. The present study aimed to search for de novo SNVs using whole-exome sequencing in 59 unrelated Chinese ASD sporadic trios, and found 24 genes (including five reported ASD candidate genes CACNA1D, ACHE, YY1, TTN, and FBXO11) with de novo harmful SNVs. Five genes (CACNA1D, JAK2, ACHE, MAPK7, and PRKAG2) classified as “medium-confidence” genes were found to be related to ASD using the Phenolyzer gene analysis tool, which predicts the correlation between the candidate genes and the ASD phenotype. De novo SNVs in JAK2, MAPK7, and PRKAG2 were first found in ASD. Both JAK2 and MAPK7 were involved in the regulation of the MAPK signaling pathway. Gene co-expression and inter-gene interaction networks were constructed and gene expression data in different brain regions were further extracted, revealing that JAK2 and MAPK7 genes were associated with certain previously reported ASD genes and played an important role in early brain development. The findings of this study suggest that the aforementioned five reported ASD genes and JAK2 and MAPK7 may be related to ASD susceptibility. Further investigations of expression studies in cellular and animal models are needed to explore the mechanism underlying the involvement of JAK2 and MAPK7 in ASD.
Collapse
|
|
34
|
Baruch-Eliyahu N, Rud V, Braiman A, Priel E. Telomerase increasing compound protects hippocampal neurons from amyloid beta toxicity by enhancing the expression of neurotrophins and plasticity related genes. Sci Rep 2019; 9:18118. [PMID: 31792359 PMCID: PMC6889131 DOI: 10.1038/s41598-019-54741-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 10/03/2019] [Indexed: 12/31/2022] Open
Abstract
The telomerase reverse transcriptase protein, TERT, is expressed in the adult brain and its exogenic expression protects neurons from oxidative stress and from the cytotoxicity of amyloid beta (Aβ). We previously showed that telomerase increasing compounds (AGS) protected neurons from oxidative stress. Therefore, we suggest that increasing TERT by AGS may protect neurons from the Aβ-induced neurotoxicity by influencing genes and factors that participate in neuronal survival and plasticity. Here we used a primary hippocampal cell culture exposed to aggregated Aβ and hippocampi from adult mice. AGS treatment transiently increased TERT gene expression in hippocampal primary cell cultures in the presence or absence of Aβ and protected neurons from Aβ induced neuronal degradation. An increase in the expression of Growth associated protein 43 (GAP43), and Feminizing locus on X-3 genes (NeuN), in the presence or absence of Aβ, and Synaptophysin (SYP) in the presence of Aβ was observed. GAP43, NeuN, SYP, Neurotrophic factors (NGF, BDNF), beta-catenin and cyclin-D1 expression were increased in the hippocampus of AGS treated mice. This data suggests that increasing TERT by pharmaceutical compounds partially exerts its neuroprotective effect by enhancing the expression of neurotrophic factors and neuronal plasticity genes in a mechanism that involved Wnt/beta-catenin pathway.
Collapse
Affiliation(s)
- Natalie Baruch-Eliyahu
- The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Vladislav Rud
- The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Alex Braiman
- The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Esther Priel
- The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
| |
Collapse
|
|
35
|
George S, Hamblin MR, Abrahamse H. Differentiation of Mesenchymal Stem Cells to Neuroglia: in the Context of Cell Signalling. Stem Cell Rev Rep 2019; 15:814-826. [PMID: 31515658 PMCID: PMC6925073 DOI: 10.1007/s12015-019-09917-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The promise of engineering specific cell types from stem cells and rebuilding damaged or diseased tissues has fascinated stem cell researchers and clinicians over last few decades. Mesenchymal Stem Cells (MSCs) have the potential to differentiate into non-mesodermal cells, particularly neural-lineage, consisting of neurons and glia. These multipotent adult stem cells can be used for implementing clinical trials in neural repair. Ongoing research identifies several molecular mechanisms involved in the speciation of neuroglia, which are tightly regulated and interconnected by various components of cell signalling machinery. Growing MSCs with multiple inducers in culture media will initiate changes on intricately interlinked cell signalling pathways and processes. Net result of these signal flow on cellular architecture is also dependent on the type of ligands and stem cells investigated in vitro. However, our understanding about this dynamic signalling machinery is limited and confounding, especially with spheroid structures, neurospheres and organoids. Therefore, the results for differentiating neurons and glia in vitro have been inconclusive, so far. Added to this complication, we have no convincing evidence about the electrical conductivity and functionality status generated in differentiating neurons and glia. This review has taken a step forward to tailor the information on differentiating neuroglia with the common methodologies, in practice.
Collapse
Affiliation(s)
- Sajan George
- Laser Research Centre, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa
| | - Michael R Hamblin
- Laser Research Centre, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa
- Wellman Centre for Photomedicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA
| | - Heidi Abrahamse
- Laser Research Centre, University of Johannesburg, P.O. Box 17011, Doornfontein, 2028, South Africa.
| |
Collapse
|
|
36
|
Jiang N, Lv JW, Wang HX, Lu C, Wang Q, Xia TJ, Bao Y, Li SS, Liu XM. Dammarane sapogenins alleviates depression-like behaviours induced by chronic social defeat stress in mice through the promotion of the BDNF signalling pathway and neurogenesis in the hippocampus. Brain Res Bull 2019; 153:239-249. [PMID: 31542427 DOI: 10.1016/j.brainresbull.2019.09.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/04/2019] [Accepted: 09/17/2019] [Indexed: 12/21/2022]
Abstract
Chronic social defeat stress (CSDS) is a widely used behavioural paradigm of psychosocial stress that can be used to research the pathogenesis of depression and seek antidepressant drugs. Dammarane sapogenins (DS), the deglycosylated product of ginsenosides, has a wide range of biological activities, including immunomodulatory, antifatigue, antitumour and antidepressant activities. However, whether DS has antidepressant-like effects in a CSDS mouse model remains unknown. Therefore, the present study was conducted to evaluate the antidepressant properties of DS in CSDS mice and its underlying mechanisms. The results showed that the oral administration of DS (40 and 80 mg/kg) increased the time spent in the interaction zone in the social interaction test and the sucrose intake in the sucrose preference test, decreased the latency in the novelty-suppressed feeding test, and reduced the immobility time in both the tail suspension test and forced swimming test. Biochemical analyses of brain tissue and serum showed that DS treatment significantly decreased serum corticosterone levels and enhanced brain monoamine neurotransmitter levels in CSDS mice. In addition, an impairment in hippocampal neurogenesis that paralleled a reduced BDNF level in the hippocampus was observed in the mice that were subjected with CSDS for 3 weeks, while treatment with DS reversed these changes. Moreover, DS treatment significantly upregulated BDNF, pTrkB/TrkB, pAkt/Akt, pPI3K/PI3K, pCREB/CREB, pERK1/2/ERK1/2 and pmTOR/mTOR protein expression in the hippocampus. In conclusion, our results showed that DS exerts antidepressant-like effects in mice with CSDS-induced depression, that the effects may be mediated by the normalization of monoamine neurotransmitter levels, the prevention of HPA axis dysfunction and the impairment of hippocampal neurogenesis, and that this occurs partly through the ability of DS to enhance BDNF expression by increasing the TrkB/CREB/ERK pathway and the PI3K/AKT/mTOR pathway.
Collapse
Affiliation(s)
- Ning Jiang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing-Wei Lv
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hai-Xia Wang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Cong Lu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China
| | - Qiong Wang
- Affiliated TCM Hospital/School of Pharmacy/Sino-Portugal TCM International Cooperation Center, Southwest Medical University, Luzhou 646000, China
| | - Tian-Ji Xia
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Bao
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shan-Shan Li
- Affiliated TCM Hospital/School of Pharmacy/Sino-Portugal TCM International Cooperation Center, Southwest Medical University, Luzhou 646000, China
| | - Xin-Min Liu
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
37
|
Wang G, Lei C, Tian Y, Wang Y, Zhang L, Zhang R. Rb1, the Primary Active Ingredient in Panax ginseng C.A. Meyer, Exerts Antidepressant-Like Effects via the BDNF-Trkb-CREB Pathway. Front Pharmacol 2019; 10:1034. [PMID: 31572200 PMCID: PMC6753202 DOI: 10.3389/fphar.2019.01034] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 08/14/2019] [Indexed: 12/18/2022] Open
Abstract
Panax ginseng C.A. Meyer (Araliaceae), a popular tonic and dietetic herbal medicine, has been traditionally prescribed in China and other countries to treat affective disorders. The medicinal parts of ginseng, the roots and flower buds, have become increasingly popular as dietary supplements due to the current holistic healthcare trend. We have investigated for the first time the antidepressive actions of the different medicinal parts, namely, the main roots, fibrous roots, and flower buds (in water extract and powder), of garden-cultivated ginseng through behavioral and drug-induced tests in mice. The water extracts, but not the powders of ginseng fibrous roots, flower buds, and main roots (1.5 g of crude drug per kilogram, p.o.), significantly reduced the immobility time in the forced swim test (FST) and tail suspension test (TST); moreover, the water extracts enhanced the 5-hydroxytryptophan (5-HTP)-induced head-twitch response and antagonized the action of reserpine in the mouse. We then explored the antidepressive mechanism of action of the ginsenoside Rb1 (Rb1) related to the brain-derived neurotrophic factor (BDNF) and its downstream proteins in mice exposed to chronic unpredictable mild stress (CUMS). Treatment with Rb1 (20 mg/kg, p.o.) for 21 days significantly attenuated the CUMS-induced decrease in the activities of BDNF, tropomyosin-related kinase B (TrkB), protein kinase B (AKT), extracellular regulatory protein kinase (ERK), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) in the mouse hippocampal CA3 region and prefrontal cortex (PFC). Interestingly, treatment with the novel TrkB antagonist ANA-12 (0.5 mg/kg, i.p.) did not alter the level of BDNF but significantly blocked the antidepressive effects of Rb1 on proteins downstream of BDNF in CUMS-treated mice. These results suggest that BDNF–TrkB–CREB signaling may be involved in the antidepressive mechanism of the action of Rb1.
Collapse
Affiliation(s)
- Guoli Wang
- College of Pharmacy, Jinan University, Guangzhou, China.,College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Cong Lei
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Ya Tian
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Yingping Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Lianxue Zhang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China
| | - Ronghua Zhang
- College of Pharmacy, Jinan University, Guangzhou, China
| |
Collapse
|
|
38
|
Lang C, Shu X, Peng L, Yu X. The ERK signaling pathway is involved in cardiotrophin-1-induced neural differentiation of human umbilical cord blood mesenchymal stem cells in vitro. Cytotechnology 2019; 71:977-988. [PMID: 31489528 DOI: 10.1007/s10616-019-00339-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: 10/16/2018] [Accepted: 08/20/2019] [Indexed: 11/29/2022] Open
Abstract
Central nervous system diseases remain the most challenging pathologies, with limited or even no therapeutic possibilities and a poor prognosis. This study aimed to investigate the differentiation properties of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) transfected with recombinant adenovirus expressing enhanced green fluorescence protein cardiotrophin-1 (Adv-EGFP-CT-1) and the possible mechanisms involved. Cells were isolated, and MSC immunophenotypes were confirmed. The resulting differentiated cells treated with Adv-EGFP-CT-1 and cultured in neural induction medium (NIM) expressed higher levels of Nestin, neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) markers than cells in other treatments. Expression of glycoprotein 130/leukemia inhibitory factor receptor β (gp130/LiFRβ), Raf-1, phosphorylated Raf-1 (p-Raf-1), extracellular signal-regulated kinase 1/2 (ERK1/2) and phospho-ERK1/2 (p-ERK1/2) increased gradually within 72 h after transfection with Adv-EGFP-CT-1 and NIM culture. Additionally, inhibition of extracellular signal-regulated kinase kinase (MEK) abrogated expression of p-ERK1/2, Nestin, GFAP and NeuN. Thus, the ERK1/2 pathway may contribute to CT1-stimulated neural differentiation of hUCB-MSCs.
Collapse
Affiliation(s)
- Changhui Lang
- Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Xiaomei Shu
- Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China.
| | - Longying Peng
- Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Xiaohua Yu
- Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| |
Collapse
|
|
39
|
Cui D, Xiao J, Zhou Y, Zhou X, Liu Y, Peng Y, Yu Y, Li H, Zhou X, Yuan Q, Wan M, Zheng L. Epiregulin enhances odontoblastic differentiation of dental pulp stem cells via activating MAPK signalling pathway. Cell Prolif 2019; 52:e12680. [PMID: 31454111 PMCID: PMC6869433 DOI: 10.1111/cpr.12680] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 07/18/2019] [Accepted: 07/23/2019] [Indexed: 02/05/2023] Open
Abstract
Objectives The odontoblastic differentiation of dental pulp stem cells (DPSCs) contributes to tertiary dentin formation. Our previous study indicated that epiregulin (EREG) enhanced odontogenesis potential of dental pulp. Here, we explored the effects of EREG during DPSC odontoblastic differentiation. Methods The changes in EREG were detected during tertiary dentin formation. DPSCs were treated with recombinant human EREG (rhEREG), EREG receptor inhibitor gefitinib and short hairpin RNAs. The odontoblastic differentiation was assessed with ALP staining, ALP activity assay, alizarin red S staining and real‐time RT‐PCR of DSPP, OCN, RUNX2 and OSX. Western blot was conducted to examine the levels of p38 mitogen‐activated protein kinase (p38 MAPK), c‐Jun N‐terminal kinase (JNK) and extracellular signal‐regulated kinase 1/2 (Erk1/2). The expression of EREG and odontoblastic differentiation‐related markers was investigated in human dental pulp from teeth with deep caries and healthy teeth. Results Epiregulin was upregulated during tertiary dentin formation. rhEREG enhanced the odontoblastic differentiation of DPSCs following upregulated p38 MAPK and Erk1/2 phosphorylation, but not JNK, whereas depletion of EREG suppressed DPSC differentiation. Gefitinib decreased odontoblastic differentiation with decreased phosphorylation of p38 MAPK and Erk1/2. And suppression of p38 MAPK and Erk1/2 pathways attenuated DPSC differentiation. In human dental pulp tissue, EREG upregulation in deep caries correlates with odontoblastic differentiation enhancement. Conclusion Epiregulin is released during tertiary dentin formation. And EREG enhanced DPSC odontoblastic differentiation via MAPK pathways.
Collapse
Affiliation(s)
- Dixin Cui
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Jiani Xiao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yachuan Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xin Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Ying Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yiran Peng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yi Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Hongyu Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Quan Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Mian Wan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Liwei Zheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
|
40
|
The antidepressant-like effects of sinomenine in mice: a behavioral and neurobiological characterization. Behav Pharmacol 2019; 29:306-315. [PMID: 29035920 DOI: 10.1097/fbp.0000000000000350] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Sinomenine is a bioactive alkaloid extracted from Sinomenium acutum. Here, we investigated the antidepressant effects of sinomenine in mice. The antidepressant actions of sinomenine were first examined in the forced-swim test and the tail-suspension test, and then assessed in the chronic social defeat stress (CSDS) model of depression. Changes in the brain-derived neurotrophic factor (BDNF) signaling pathway after CSDS and sinomenine treatment were also investigated. A tryptophan hydroxylase inhibitor and a BDNF signaling inhibitor were also used to determine the pharmacological mechanisms of sinomenine. It was found that sinomenine induced antidepressant-like effects in the forced-swim test and tail-suspension test without affecting the locomotor activity of mice. Sinomenine also prevented the CSDS-induced depressive-like symptoms. Moreover, sinomenine fully restored the CSDS-induced decrease in the hippocampal BDNF signaling pathway, whereas a BDNF signaling inhibitor, but not a tryptophan hydroxylase inhibitor, blocked the antidepressant effects of sinomenine. In conclusion, sinomenine exerts antidepressant effects in mice by promoting the hippocampal BDNF signaling pathway.
Collapse
|
|
41
|
Jiang B, Wang H, Wang JL, Wang YJ, Zhu Q, Wang CN, Song L, Gao TT, Wang Y, Meng GL, Wu F, Ling Y, Zhang W, Li JX. Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1-cAMP Response Element Binding-Brain-Derived Neurotrophic Factor Pathway. Biol Psychiatry 2019; 85:650-666. [PMID: 30503507 DOI: 10.1016/j.biopsych.2018.10.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 10/03/2018] [Accepted: 10/04/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND Developing novel pharmacological targets beyond monoaminergic systems is now a popular strategy for finding new ways to treat depression. Salt-inducible kinase (SIK) is a kinase that regulates the nuclear translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator (CRTC) by phosphorylation. Here, we hypothesize that dysfunction of the central SIK-CRTC system may contribute to the pathogenesis of depression. METHODS Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, viral-mediated gene transfer, Western blotting, coimmunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunohistochemistry were used in this study (for in vivo studies, n = 10; for in vitro studies, n = 5). RESULTS Both CSDS and CUMS markedly increased the expression of hippocampal SIK2, which reduced CRTC1 nuclear translocation and binding of CRTC1 and CREB in the hippocampus. Genetic overexpression of hippocampal SIK2 in naïve mice simulated chronic stress, inducing depressive-like behaviors in the forced swim test, tail suspension test, sucrose preference test, and social interaction test, as well as decreasing the brain-derived neurotrophic factor signaling cascade and neurogenesis in the hippocampus. In contrast, genetic knockdown and knockout of hippocampal SIK2 protected against CSDS and CUMS, exerting significant antidepressant-like effects that were mediated via the downstream CRTC1-CREB-brain-derived neurotrophic factor pathway. Moreover, fluoxetine, venlafaxine, and mirtazapine all significantly restored the effects of CSDS and CUMS on the hippocampal SIK2-CRTC1 pathway, which was necessary for their antidepressant actions. CONCLUSIONS The hippocampal SIK2-CRTC1 pathway is involved in the pathogenesis of depression, and hippocampal SIK2 could be a novel target for the development of antidepressants.
Collapse
Affiliation(s)
- Bo Jiang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China.
| | - Hao Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Jin-Liang Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Ying-Jie Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Qing Zhu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Cheng-Niu Wang
- Basic Medical Research Centre, Medical College, Nantong University, Nantong, Jiangsu, China
| | - Lu Song
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Ting-Ting Gao
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Yuan Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Guo-Liang Meng
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Feng Wu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Yong Ling
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Wei Zhang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China; Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, Jiangsu, China
| | - Jun-Xu Li
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
| |
Collapse
|
|
42
|
Preclinical Evaluation of Long-Term Neuroprotective Effects of BDNF-Engineered Mesenchymal Stromal Cells as Intravitreal Therapy for Chronic Retinal Degeneration in Rd6 Mutant Mice. Int J Mol Sci 2019; 20:ijms20030777. [PMID: 30759764 PMCID: PMC6387230 DOI: 10.3390/ijms20030777] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/03/2019] [Accepted: 02/10/2019] [Indexed: 12/13/2022] Open
Abstract
This study aimed to investigate whether the transplantation of genetically engineered bone marrow-derived mesenchymal stromal cells (MSCs) to overexpress brain-derived neurotrophic factor (BDNF) could rescue the chronic degenerative process of slow retinal degeneration in the rd6 (retinal degeneration 6) mouse model and sought to identify the potential underlying mechanisms. Rd6 mice were subjected to the intravitreal injection of lentivirally modified MSC-BDNF or unmodified MSC or saline. In vivo morphology, electrophysiological retinal function (ERG), and the expression of apoptosis-related genes, as well as BDNF and its receptor (TrkB), were assessed in retinas collected at 28 days and three months after transplantation. We observed that cells survived for at least three months after transplantation. MSC-BDNF preferentially integrated into the outer retinal layers and considerably rescued damaged retinal cells, as evaluated by ERG and immunofluorescence staining. Additionally, compared with controls, the therapy with MSC-BDNF was associated with the induction of molecular changes related to anti-apoptotic signaling. In conclusion, BDNF overexpression observed in retinas after MSC-BDNF treatment could enhance the neuroprotective properties of transplanted autologous MSCs alone in the chronically degenerated retina. This research provides evidence for the long-term efficacy of genetically-modified MSC and may represent a strategy for treating various forms of degenerative retinopathies in the future.
Collapse
|
|
43
|
Comparison between Polybutylcyanoacrylate Nanoparticles with Either Surface-Adsorbed or Encapsulated Brain-Derived Neurotrophic Factor on the Neural Differentiation of iPSCs. Int J Mol Sci 2019; 20:ijms20010182. [PMID: 30621332 PMCID: PMC6337453 DOI: 10.3390/ijms20010182] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 12/22/2018] [Accepted: 12/31/2018] [Indexed: 01/18/2023] Open
Abstract
The brain-derived neurotrophic factor (BDNF) is vital in the neural differentiation of neural stem/progenitor cells, and together may have therapeutic potential for neural regeneration. In this study, a multiplexed polybutylcyanoacrylate nanoparticle (PBCA NP) delivery platform was constructed, incorporating either surface-adsorbed or encapsulated BDNF for the induction of neural differentiation in induced pleuripotent stem cells (iPSCs), where tween 80 (T80) and superparamagnetic iron oxide (SPIO) were added for central nervous system (CNS) targeting and magnetic resonance (MR) image tracking, respectively. Both methods by which the BDNF was carried resulted in loading efficiencies greater than 95%. The nanoparticle-mediated delivery of BDNF resulted in neural differentiation of iPSCs detected on immunofluorescence staining as early as 7 days, with enhanced differentiation efficiency by 1.3-fold compared to the control on flow cytometry; the delivery system of surface-adsorbed BDNF gave rise to cells that had the best neural development than the encapsulated formulation. T80-coating disrupted the in vitro blood–brain barrier model with a corresponding 1.5- to two-fold increase in permeability. SPIO-loaded PBCA NPs exhibited a concentration-dependent, rapid decay in signal intensity on the phantom MR experiment. This study demonstrates the versatility of the PBCA NP, and the surface-adsorption of BDNF is the preferred method of delivery for the differentiation of iPSCs.
Collapse
|
|
44
|
Differentiation of eye field neuroectoderm from human adipose-derived stem cells by using small-molecules and hADSC-conditioned medium. Ann Anat 2019; 221:17-26. [DOI: 10.1016/j.aanat.2018.08.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 08/11/2018] [Accepted: 08/21/2018] [Indexed: 12/19/2022]
|
|
45
|
Cunha MP, Pazini FL, Lieberknecht V, Rodrigues ALS. Subchronic administration of creatine produces antidepressant-like effect by modulating hippocampal signaling pathway mediated by FNDC5/BDNF/Akt in mice. J Psychiatr Res 2018; 104:78-87. [PMID: 30005372 DOI: 10.1016/j.jpsychires.2018.07.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 06/18/2018] [Accepted: 07/05/2018] [Indexed: 12/22/2022]
Abstract
Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1-10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1α induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1α, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC-1α, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt phosphorylation (Ser 473), and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD.
Collapse
Affiliation(s)
- Mauricio P Cunha
- Universidade Federal de Santa Catarina, Department of Biochemistry, Florianópolis, Brazil.
| | - Francis L Pazini
- Universidade Federal de Santa Catarina, Department of Biochemistry, Florianópolis, Brazil
| | - Vicente Lieberknecht
- Universidade Federal de Santa Catarina, Department of Biochemistry, Florianópolis, Brazil
| | - Ana Lúcia S Rodrigues
- Universidade Federal de Santa Catarina, Department of Biochemistry, Florianópolis, Brazil
| |
Collapse
|
|
46
|
Lanza Cariccio V, Scionti D, Raffa A, Iori R, Pollastro F, Diomede F, Bramanti P, Trubiani O, Mazzon E. Treatment of Periodontal Ligament Stem Cells with MOR and CBD Promotes Cell Survival and Neuronal Differentiation via the PI3K/Akt/mTOR Pathway. Int J Mol Sci 2018; 19:ijms19082341. [PMID: 30096889 PMCID: PMC6121255 DOI: 10.3390/ijms19082341] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 07/31/2018] [Accepted: 08/06/2018] [Indexed: 12/31/2022] Open
Abstract
Periodontal ligament mesenchymal stem cells (hPDLSCs), as well as all mesenchymal stem cells, show self-renewal, clonogenicity, and multi-tissue differentiation proprieties and can represent a valid support for regenerative medicine. We treated hPDLSCs with a combination of Moringin (MOR) and Cannabidiol (CBD), in order to understand if treatment could improve their survival and their in vitro differentiation capacity. Stem cells survival is fundamental to achieve a successful therapy outcome in the re-implanted tissue of patients. Through NGS transcriptome analysis, we found that combined treatment increased hPDLSCs survival, by inhibition of apoptosis as demonstrated by enhanced expression of anti-apoptotic genes and reduction of pro-apoptotic ones. Moreover, we investigated the possible involvement of PI3K/Akt/mTOR pathway, emphasizing a differential gene expression between treated and untreated cells. Furthermore, hPDLSCs were cultured for 48 h in the presence or absence of CBD and MOR and, after confirming the cellular viability through MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide) assay, we examined the presence of neuronal markers, through immunofluorescence analysis. We found an increased expression of Nestin and GAP43 (growth associated protein 43) in treated cells. In conclusion, hPDLSCs treated with Moringin and Cannabidiol showed an improved survival capacity and neuronal differentiation potential.
Collapse
Affiliation(s)
- Veronica Lanza Cariccio
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
| | - Domenico Scionti
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
| | - Antonio Raffa
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
| | - Renato Iori
- Consiglio per la Ricerca in Agricoltura e L'analisi Dell'economia Agraria, Centro di Ricerca Agricoltura e Ambiente (CREA-AA), Via di Corticella 133, 40128 Bologna, Italy.
| | - Federica Pollastro
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
| | - Francesca Diomede
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy.
| | - Placido Bramanti
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
| | - Oriana Trubiani
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara, 66100 Chieti, Italy.
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy.
| |
Collapse
|
|
47
|
Oh DR, Yoo JS, Kim Y, Kang H, Lee H, Lm SJ, Choi EJ, Jung MA, Bae D, Oh KN, Hong JA, Jo A, Shin J, Kim J, Kim YR, Cho SS, Lee BJ, Choi CY. Vaccinium bracteatum Leaf Extract Reverses Chronic Restraint Stress-Induced Depression-Like Behavior in Mice: Regulation of Hypothalamic-Pituitary-Adrenal Axis, Serotonin Turnover Systems, and ERK/Akt Phosphorylation. Front Pharmacol 2018; 9:604. [PMID: 30038568 PMCID: PMC6047486 DOI: 10.3389/fphar.2018.00604] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 05/21/2018] [Indexed: 01/02/2023] Open
Abstract
The leaves of Vaccinium bracteatum Thunb. are a source of traditional herbal medicines found in East Asia. The present study aimed to evaluate the mechanisms underlying the antidepressant-like effects of water extract of V. bracteatum Thunb. leaves (VBLW) in a mouse model of chronic restraint stress (CRS) and to identify the possible molecular in vitro mechanisms of the neuroprotective effects. The CRS-exposed mice were orally administered VBLW (100 and 200 mg/kg) daily for 21 days consecutively. The behavioral effects of VBLW were assessed through the forced swim test (FST) and the open field test (OFT). The levels of serum corticosterone (CORT), corticotropin releasing hormone (CRH), and adrenocorticotropin hormone (ACTH), brain monoamines, such as serotonin, dopamine, and norepinephrine, and serotonin turnover by tryptophan hydroxylase 2 (TPH2), serotonin reuptake (SERT), and monoamine oxidase A (MAO-A) were evaluated, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway. CRS-exposed mice treated with VBLW (100 and 200 mg/kg) showed significantly reduced immobility time and increased swimming and climbing times in the FST, and increased locomotor activity in the OFT. Moreover, CRS mice treated with VBLW exhibited significantly decreased CORT and ACTH, but enhanced brain monoamine neurotransmitters. In addition, CRS mice treated with VBLW had dramatically decreased protein levels of MAO-A and SERT, but increased TPH2 protein levels in the hippocampus and the PFC. Similarly, VBLW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and the PFC. Furthermore, VBLW showed neuroprotective effects via increased CREB phosphorylation in CORT-induced cell injury that were mediated through the ERK/Akt/mTOR signaling pathways. These results suggested that the antidepressant-like effects of VBLW might be mediated by the regulation of the HPA axis, glucocorticoids, and serotonin turnover, such as TPH2, SERT, and MAO-A, as well as the concentration of monoamine neurotransmitters, and the activities of ERK and Akt phosphorylation, which were possibly associated with neuroprotective effects.
Collapse
Affiliation(s)
- Dool-Ri Oh
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea.,College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, South Korea
| | - Ji-Seok Yoo
- Bioavailability Control Laboratory, College of Pharmacy, Ajou University, Suwon, South Korea
| | - Yujin Kim
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Huwon Kang
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Hunmi Lee
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - So J Lm
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Eun-Jin Choi
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Myung-A Jung
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Donghyuck Bae
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Kyo-Nyeo Oh
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Ji-Ae Hong
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Ara Jo
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Jawon Shin
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Jaeyong Kim
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| | - Young R Kim
- College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, South Korea
| | - Seung S Cho
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan, South Korea
| | - Beom-Jin Lee
- Bioavailability Control Laboratory, College of Pharmacy, Ajou University, Suwon, South Korea
| | - Chul Yung Choi
- Jeonnam Bioindustry Foundation, Jeonnam Institute of Natural Resources Research, Jeollanamdo, South Korea
| |
Collapse
|
|
48
|
Boese AC, Le QSE, Pham D, Hamblin MH, Lee JP. Neural stem cell therapy for subacute and chronic ischemic stroke. Stem Cell Res Ther 2018; 9:154. [PMID: 29895321 PMCID: PMC5998588 DOI: 10.1186/s13287-018-0913-2] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Neural stem cells (NSCs) play vital roles in brain homeostasis and exhibit a broad repertoire of potentially therapeutic actions following neurovascular injury. One such injury is stroke, a worldwide leading cause of death and disability. Clinically, extensive injury from ischemic stroke results from ischemia-reperfusion (IR), which is accompanied by inflammation, blood-brain barrier (BBB) damage, neural cell death, and extensive tissue loss. Tissue plasminogen activator (tPA) is still the only US Food and Drug Administration-approved clot-lysing agent. Whereas the thrombolytic role of tPA within the vasculature is beneficial, the effects of tPA (in a non-thrombolytic role) within the brain parenchyma have been reported as harmful. Thus, new therapies are needed to reduce the deleterious side effects of tPA and quickly facilitate vascular repair following stroke. The Stroke Treatment Academic Industry Roundtable (STAIR) recommends that stroke therapies "focus on drugs/devices/treatments with multiple mechanisms of action and that target multiple pathways". Thus, based on multifactorial ischemic cascades in various stroke stages, effective stroke therapies need to focus on targeting and ameliorating early IR injury as well as facilitating angiogenesis, neurogenesis, and neurorestorative mechanisms following stroke. This review will discuss the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury and will emphasize both the subacute and chronic phase of ischemic stroke.
Collapse
Affiliation(s)
- Austin C Boese
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Quan-Son Eric Le
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Dylan Pham
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Milton H Hamblin
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Jean-Pyo Lee
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA. .,Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
| |
Collapse
|
|
49
|
Moon GJ, Cho YH, Kim DH, Sung JH, Son JP, Kim S, Cha JM, Bang OY. Serum-mediated Activation of Bone Marrow-derived Mesenchymal Stem Cells in Ischemic Stroke Patients: A Novel Preconditioning Method. Cell Transplant 2018; 27:485-500. [PMID: 29774769 PMCID: PMC6038038 DOI: 10.1177/0963689718755404] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Stroke induces complex and dynamic, local and systemic changes including inflammatory
reactions, immune responses, and repair and recovery processes. Mesenchymal stem cells
(MSCs) have been shown to enhance neurological recovery after stroke. We hypothesized that
serum factors play a critical role in the activation of bone marrow (BM) MSCs after stroke
such as by increasing proliferation, paracrine effects, and rejuvenation. Human MSCs
(hMSCs) were grown in fetal bovine serum (FBS), normal healthy control serum (NS), or
stroke patient serum (SS). MSCs cultured in growth medium with 10% SS or NS exhibited
higher proliferation indices than those cultured with FBS (P < 0.01).
FBS-, NS-, and SS-hMSCs showed differences in the expression of trophic factors; vascular
endothelial growth factor, glial cell–derived neurotrophic factor, and fibroblast growth
factor were densely expressed in samples cultured with SS (P < 0.01).
In addition, SS-MSCs revealed different cell cycle– or aging-associated messenger RNA
expression in a later passage, and β-galactosidase staining showed the senescence of MSCs
observed during culture expansion was lower in MSCs cultured with SS than those cultured
with NS or FBS (P < 0.01). Several proteins related to the activity of
receptors, growth factors, and cytokines were more prevalent in the serum of stroke
patients than in that of normal subjects. Neurogenesis and angiogenesis were markedly
increased in rats that had received SS-MSCs (P < 0.05), and these rats
showed significant behavioral improvements (P < 0.01). Our results
indicate that stroke induces a process of recovery via the activation of MSCs. Culture
methods for MSCs using SS obtained during the acute phase of a stroke could constitute a
novel MSC activation method that is feasible and efficient for the neurorestoration of
stroke.
Collapse
Affiliation(s)
- Gyeong Joon Moon
- 1 Translational and Stem Cell Research Laboratory on Stroke, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.,2 Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Gangnam-gu, Seoul, South Korea.,3 School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Buk-gu, Daegu, South Korea
| | - Yeon Hee Cho
- 1 Translational and Stem Cell Research Laboratory on Stroke, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.,4 Samsung Biomedical Research Institute, Samsung Medical Center, Gangnam-gu, Seoul, South Korea
| | - Dong Hee Kim
- 1 Translational and Stem Cell Research Laboratory on Stroke, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.,5 Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Jongno-gu, Seoul, South Korea
| | - Ji Hee Sung
- 1 Translational and Stem Cell Research Laboratory on Stroke, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.,4 Samsung Biomedical Research Institute, Samsung Medical Center, Gangnam-gu, Seoul, South Korea
| | - Jeong Pyo Son
- 1 Translational and Stem Cell Research Laboratory on Stroke, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.,5 Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Jongno-gu, Seoul, South Korea
| | - Sooyoon Kim
- 1 Translational and Stem Cell Research Laboratory on Stroke, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.,4 Samsung Biomedical Research Institute, Samsung Medical Center, Gangnam-gu, Seoul, South Korea
| | - Jae Min Cha
- 6 Medical Device Research Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Oh Young Bang
- 1 Translational and Stem Cell Research Laboratory on Stroke, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.,5 Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Jongno-gu, Seoul, South Korea.,7 Department of Neurology, Samsung Medical Center, Sungkyunkwan University, Jongno-gu, Seoul, South Korea
| |
Collapse
|
|
50
|
Ni YF, Wang H, Gu QY, Wang FY, Wang YJ, Wang JL, Jiang B. Gemfibrozil has antidepressant effects in mice: Involvement of the hippocampal brain-derived neurotrophic factor system. J Psychopharmacol 2018. [PMID: 29534628 DOI: 10.1177/0269881118762072] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Major depressive disorder has become one of the most serious neuropsychiatric disorders worldwide. However, currently available antidepressants used in clinical practice are ineffective for a substantial proportion of patients and always have side effects. Besides being a lipid-regulating agent, gemfibrozil is an agonist of peroxisome proliferator-activated receptor-α (PPAR-α). We investigated the antidepressant effects of gemfibrozil on C57BL/6J mice using the forced swim test (FST) and tail suspension test (TST), as well as the chronic unpredictable mild stress (CUMS) model of depression. The changes in brain-derived neurotrophic factor (BDNF) signaling cascade in the brain after CUMS and gemfibrozil treatment were further assessed. Pharmacological inhibitors and lentivirus-expressed short hairpin RNA (shRNA) were also used to clarify the antidepressant mechanisms of gemfibrozil. Gemfibrozil exhibited significant antidepressant actions in the FST and TST without affecting the locomotor activity of mice. Chronic gemfibrozil administration fully reversed CUMS-induced depressive-like behaviors in the FST, TST and sucrose preference test. Gemfibrozil treatment also restored CUMS-induced inhibition of the hippocampal BDNF signaling pathway. Blocking PPAR-α and BDNF but not the serotonergic system abolished the antidepressant effects of gemfibrozil on mice. Gemfibrozil produced antidepressant effects in mice by promoting the hippocampal BDNF system.
Collapse
Affiliation(s)
- Yu-Fei Ni
- 1 Nantong Maternal and Child Health Care Hospital, China
| | - Hao Wang
- 2 Department of Pharmacology, School of Pharmacy, Nantong University, China
| | - Qiu-Yan Gu
- 1 Nantong Maternal and Child Health Care Hospital, China
| | - Fei-Ying Wang
- 1 Nantong Maternal and Child Health Care Hospital, China
| | - Ying-Jie Wang
- 2 Department of Pharmacology, School of Pharmacy, Nantong University, China
| | - Jin-Liang Wang
- 2 Department of Pharmacology, School of Pharmacy, Nantong University, China
| | - Bo Jiang
- 2 Department of Pharmacology, School of Pharmacy, Nantong University, China
| |
Collapse
|