Intravenous Bone Marrow Mononuclear Cells Transplantation in Aged Mice Increases Transcription of Glucose Transporter 1 and Na+/K+-ATPase at Hippocampus Followed by Restored Neurological Functions

Takeuchi, Kosei; Okinaka, Yuka; Ogawa, Yuko; Kikuchi-Taura, Akie; Kataoka, Yosky; Gul, Sheraz; Claussen, Carsten; Boltze, Johannes; Taguchi, Akihiko

doi:10.3389/fnagi.2020.00170

Cited by 14 publications

(23 citation statements)

References 25 publications

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“…BM-MNC transplantation promotes angiogenesis/neovascularization in the several ischemic diseases, such as limb ischemia and myocardial infarction, even if they are not in the acute phase (19,20). In addition, we demonstrated that the therapeutic mechanisms of BM-MNC include energy source to injured cells and angiogenesis activation in damaged endothelial cells (6). Therefore, we hypothesized that the therapeutic effect associated with angiogenesis may occur in chronic stroke.…”

Section: Discussionmentioning

confidence: 94%

“…In our previous study, we showed that the transfer of low molecular weight substances, including glucose, from transplanted BM-MNC to cerebral endothelial cells is the prominent pathway in the activation of endothelial cells by BM-MNC transplantation after cerebral ischemia (5). In addition, the transplant of BM-MNC restored the neurological function by activating transcription of major energy supply and consumption-related genes in the brain (6). Therefore, we hypothesized that BM-MNC might have a therapeutic effect in the case of the chronic phase of stroke.…”

Section: Introductionmentioning

confidence: 96%

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Intravenous Bone Marrow Mononuclear Cells Transplantation Improves the Effect of Training in Chronic Stroke Mice

et al. 2020

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There is no effective treatment for chronic stroke if the acute or subacute phase is missed. Rehabilitation alone cannot easily achieve a dramatic recovery in function. In contrast to significant therapeutic effects of bone marrow mononuclear cells (BM-MNC) transplantation for acute stroke, mild and non-significant effects have been shown for chronic stroke. In this study, we have evaluated the effect of a combination of BM-MNC transplantation and neurological function training in chronic stroke. The effect of BM-MNC on neurological functional was tested four weeks after permanent middle cerebral artery occlusion (MCAO) insult in mice. BM-MNC (1 × 105cells in 100 μl PBS) were injected into the vein of MCAO model mice, followed by behavioral tests as functional evaluations. Interestingly, there was a significant therapeutic effect of BM-MNC only when repeated training was performed. This suggested that cell therapy alone was not sufficient for chronic stroke treatment; however, training with cell therapy was effective. The combination of these differently targeted therapies provided a significant benefit in the chronic stroke mouse model. Therefore, targeted cell therapy via BM-MNC transplantation with appropriate training presents a promising novel therapeutic option for patients in the chronic stroke period.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 96%

Intravenous Bone Marrow Mononuclear Cells Transplantation Improves the Effect of Training in Chronic Stroke Mice

et al. 2020

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“…Recently, we showed that intravenously injected BM-MNC supplies an energy source, such as glucose, to endothelial cells via gap junction and activates injured endothelial cells by induction of hypoxia inducible factor 1-α (Hif1-α), which is one of the major activators of metabolism related genes (Kim et al, 2006), in a cerebral ischemia model (Kikuchi-Taura et al, 2020). Intravenous BM-MNC transplantation in aged mice was shown to increase transcription of glucose transporter 1 (Glut1) at hippocampus followed by improved memory functions through gap junction mediated cell-cell interaction between transplanted BM-MNC and endothelial cells (Takeuchi et al, 2020). Furthermore, we have shown that intravenously transplanted mesenchymal stem cells remove the energy source from endothelial cells via gap junction, and suppress their excessive activation in a cerebral ischemia model (Kikuchi-Taura et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Quantitative PCR (qPCR) Analysis of Circulating White Blood Cells, Hippocampus, and Human Umbilical Vein Endothelial Cells Male CB-17 mice (C.B-17/Icr-+ / + Jcl, Oriental Yeast, Tokyo, Japan) aged 5, 10, 52, and 104 weeks were used for this study (N = 5, each). Minimal variation of cerebrovascular structure is known in CB-17 mice (Taguchi et al, 2010) and CB-17 mice were used for the experiment of cerebrovascular disorders (Kasahara et al, 2013;Takeuchi et al, 2020). After deep anesthesia by pentobarbital, a blood sample was obtained by the puncture to left ventricle of heart.…”

Section: Introductionmentioning

confidence: 99%

Increased RNA Transcription of Energy Source Transporters in Circulating White Blood Cells of Aged Mice

Takeuchi

Saino

Okinaka

et al. 2022

Front. Aging Neurosci.

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Circulating white blood cells (WBC) contribute toward maintenance of cerebral metabolism and brain function. Recently, we showed that during aging, transcription of metabolism related genes, including energy source transports, in the brain significantly decreased at the hippocampus resulting in impaired neurological functions. In this article, we investigated the changes in RNA transcription of metabolism related genes (glucose transporter 1 [Glut1], Glut3, monocarboxylate transporter 4 [MCT4], hypoxia inducible factor 1-α [Hif1-α], prolyl hydroxylase 3 [PHD3] and pyruvate dehydrogenase kinase 1 [PDK1]) in circulating WBC and correlated these with brain function in mice. Contrary to our expectations, most of these metabolism related genes in circulating WBC significantly increased in aged mice, and correlation between their increased RNA transcription and impaired neurological functions was observed. Bone marrow mononuclear transplantation into aged mice decreased metabolism related genes in WBC with accelerated neurogenesis in the hippocampus. In vitro analysis revealed that cell-cell interaction between WBC and endothelial cells via gap junction is impaired with aging, and blockade of the interaction increased their transcription in WBC. Our findings indicate that gross analysis of RNA transcription of metabolism related genes in circulating WBC has the potential to provide significant information relating to impaired cell-cell interaction between WBC and endothelial cells of aged mice. Additionally, this can serve as a tool to evaluate the change of the cell-cell interaction caused by various treatments or diseases.

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“…With the resurgence of phenotypic assays in drug discovery, the observations in these systems are often complex as recently shown by cell-cell interactions in stroke models ( Kikuchi-Taura et al, 2020 ; Takeuchi et al, 2020 ; Kikuchi-Taura et al, 2021 ) and understanding the nature of the PPIs using novel technologies will allow the scientific community to better understand and unveil therapeutically relevant aspects of such PPIs to treat a variety of human diseases.…”

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confidence: 99%

Editorial: Protein–Protein Interactions: Drug Discovery for the Future

Rapposelli

Gaudio²,

Bertozzi

et al. 2021

Front. Chem.

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The human proteome is comprised of approximately 20,000 proteins and significantly more proteinprotein interactions (PPIs) that play pivotal roles in biological processes. Their dysregulation often results in the onset and progression of several diseases. PPIs therefore represent a treasure trove of disease modifying drug targets-However, targeting these is a challenging task when attempting to convert drug-like small molecules to therapeutics. When targeting PPIs, it is necessary to have a balance between the interacting proteins to provoke a therapeutic and not a significant adverse effect. This is elegantly illustrated by degradation of TP53 mediated by MDM2 which is prevented by Nutlin-3, in addition to other relevant PPIs which have been discovered (Gul and Hadian, 2014).A number of high quality articles relating to PPIs are reported in this Protein-Protein Interactions: Drug Discovery for the Future Research Topic that make use of a variety of experimental techniques. As mentioned above, the number of PPIs are vast, the methods proposed by Lawson et al. and Martino et al., allow the mapping and elucidating those PPIs that can be targeting by small molecules. This is particularly relevant in order to identify those PPIs which should be the focus of drug discovery efforts. For example, the TCL1 (T-Cell Leukemia/Lymphoma 1) oncogene and FHIT (Fragile Histidine Triad Diadenosine Triphosphatase) are relevant drug targets in cancer and their interacting partners have been studied extensively (Gaudio et al., 2012;Gaudio et al., 2013a;Gaudio et al., 2013b;Paduano et al., 2018). In many cases the interacting partners in PPIs are poorly understood and González-Avendaño et al. used proteomics approaches based on mass spectrometry to resolve complex interacting partners of well characterized proteins. Each novel PPI was further investigated with the aim of understanding its importance in the biology and biochemistry of cancer. It was also shown as PPIs are functional to signaling pathways that are up-regulated in cancer, such as PI3K-AKT, NFκB and drug resistance.Liang et al. used a drug discovery approach to consider not only drug activity and selectivity, but also drug-like properties and the associated primarily toxicity. To this end, the synthesis of new druglike small molecules or the design of close analogues, starting from natural products was undertaken in order to allow for suitable compound optimization. Chemical modifications, starting from the planar marine natural product fascaplysin, led to the identification of nonplanar tetrahydroβ-carboline analogs with conserved capability to bind selectively its target CDK4. The synthetically modified derivatives of the natural product resulted reduced toxicity using in vitro models.Parate et al. used a combination of the computational methods, biological and biophysical validations allow the realization of compelling studies of both drug-target and protein-protein interactions. By applying computational chemistry and Molecular Dynamics Simulations, the most relevant...

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Intravenous Bone Marrow Mononuclear Cells Transplantation in Aged Mice Increases Transcription of Glucose Transporter 1 and Na+/K+-ATPase at Hippocampus Followed by Restored Neurological Functions

Cited by 14 publications

References 25 publications

Intravenous Bone Marrow Mononuclear Cells Transplantation Improves the Effect of Training in Chronic Stroke Mice

Intravenous Bone Marrow Mononuclear Cells Transplantation Improves the Effect of Training in Chronic Stroke Mice

Increased RNA Transcription of Energy Source Transporters in Circulating White Blood Cells of Aged Mice

Editorial: Protein–Protein Interactions: Drug Discovery for the Future

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