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

We recently reported that intravenous bone marrow mononuclear cell (BM-MNC) transplantation in stroke improves neurological function through improvement of cerebral metabolism. Cerebral metabolism is known to diminish with aging, and the reduction of metabolism is one of the presumed causes of neurological decline in the elderly. We report herein that transcription of glucose transporters, monocarboxylate transporters, and Na+/K+-ATPase is downregulated in the hippocampus of aged mice with impaired neurological functions. Intravenous BM-MNC transplantation in aged mice stimulated the transcription of glucose transporter 1 and Na+/K+-ATPase α1 followed by restoration of neurological function. As glucose transporters and Na+/K+-ATPases are closely related to cerebral metabolism and neurological function, our data indicate that BM-MNC transplantation in aged mice has the potential to restore neurological function by activating transcription of glucose transporter and Na+/K+-ATPase. Furthermore, our data indicate that changes in transcription of glucose transporter and Na+/K+-ATPase could be surrogate biomarkers for age-related neurological impairment as well as quantifying the efficacy of therapies

Kinetics of phase separation and coarsening in dilute surfactant pentaethylene glycol monododecyl ether solutions

We investigated the phase separation phenomena in dilute surfactant pentaethylene glycol monodedecyl ether (C12E5) solutions focusing on the growth law of separated domains. The solutions confined between two glass plates were found to exhibit the phase inversion, characteristic of the viscoelastic phase separation; the majority phase (water-rich phase) nucleated as droplets and the minority phase (micelle-rich phase) formed a network temporarily, then they collapsed into an usual sea-island pattern where minority phase formed islands. We found from the real-space microscopic imaging that the dynamic scaling hypothesis did not hold throughout the coarsening process. The power law growth of the domains with the exponent close to 1/3 was observed even though the coarsening was induced mainly by hydrodynamic flow, which was explained by Darcy's law of laminar flow

Cadherin activity is required for activity-induced spine remodeling

Neural activity induces the remodeling of pre- and postsynaptic membranes, which maintain their apposition through cell adhesion molecules. Among them, N-cadherin is redistributed, undergoes activity-dependent conformational changes, and is required for synaptic plasticity. Here, we show that depolarization induces the enlargement of the width of spine head, and that cadherin activity is essential for this synaptic rearrangement. Dendritic spines visualized with green fluorescent protein in hippocampal neurons showed an expansion by the activation of AMPA receptor, so that the synaptic apposition zone may be expanded. N-cadherin-venus fusion protein laterally dispersed along the expanding spine head. Overexpression of dominant-negative forms of N-cadherin resulted in the abrogation of the spine expansion. Inhibition of actin polymerization with cytochalasin D abolished the spine expansion. Together, our data suggest that cadherin-based adhesion machinery coupled with the actin-cytoskeleton is critical for the remodeling of synaptic apposition zone

Myosin motor Myo1c and its receptor NEMO/IKK-γ promote TNF-α–induced serine307 phosphorylation of IRS-1

Tumor necrosis factor-α (TNF-α) signaling through the IκB kinase (IKK) complex attenuates insulin action via the phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser307. However, the precise molecular mechanism by which the IKK complex phosphorylates IRS-1 is unknown. In this study, we report nuclear factor κB essential modulator (NEMO)/IKK-γ subunit accumulation in membrane ruffles followed by an interaction with IRS-1. This intracellular trafficking of NEMO requires insulin, an intact actin cytoskeletal network, and the motor protein Myo1c. Increased Myo1c expression enhanced the NEMO–IRS-1 interaction, which is essential for TNF-α– induced phosphorylation of Ser307–IRS-1. In contrast, dominant inhibitory Myo1c cargo domain expression diminished this interaction and inhibited IRS-1 phosphorylation. NEMO expression also enhanced TNF-α–induced Ser307–IRS-1 phosphorylation and inhibited glucose uptake. In contrast, a deletion mutant of NEMO lacking the IKK-β–binding domain or silencing NEMO blocked the TNF-α signal. Thus, motor protein Myo1c and its receptor protein NEMO act cooperatively to form the IKK–IRS-1 complex and function in TNF-α–induced insulin resistance

Activation of neurogenesis in the hippocampus is a novel therapeutic target for Alzheimer's disease

Highlights: Targeting single mechanisms of physiological (aging) and pathological (neurodegeneration) loss of function in the brain may not be sufficient. Cell–cell interactions between transplanted adult stem cells and resident cells via gap junctions have the potential to support the aging or diseased brain. These cell–cell interactions can also increase hippocampal neurogenesis. This may be a novel therapeutic strategy for Alzheimer's disease and other neurodegenerative diseases that could be applied alongside any established treatments

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study

Introduction Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. Methods In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR  Results In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (− 11.6/− 5.2 mmHg, both p  Conclusion Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction

Oligodendrocyte Precursor Cells Support Blood-Brain Barrier Integrity via TGF-β Signaling

Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity

Gap junction-mediated cell-cell interaction between transplanted mesenchymal stem cells and vascular endothelium in stroke

We have shown previously that transplanted bone marrow mononuclear cells (BM‐MNC), which are a cell fraction rich in hematopoietic stem cells, can activate cerebral endothelial cells via gap junction‐mediated cell‐cell interaction. In the present study, we investigated such cell‐cell interaction between mesenchymal stem cells (MSC) and cerebral endothelial cells. In contrast to BM‐MNC, for MSC we observed suppression of vascular endothelial growth factor uptake into endothelial cells and transfer of glucose from endothelial cells to MSC in vitro. The transfer of such a small molecule from MSC to vascular endothelium was subsequently confirmed in vivo and was followed by suppressed activation of macrophage/microglia in stroke mice. The suppressive effect was absent by blockade of gap junction at MSC. Furthermore, gap junction‐mediated cell‐cell interaction was observed between circulating white blood cells and MSC. Our findings indicate that gap junction‐mediated cell‐cell interaction is one of the major pathways for MSC‐mediated suppression of inflammation in the brain following stroke and provides a novel strategy to maintain the blood‐brain barrier in injured brain. Furthermore, our current results have the potential to provide a novel insight for other ongoing clinical trials that make use of MSC transplantation aiming to suppress excess inflammation, as well as other diseases such as COVID‐19 (coronavirus disease 2019)

Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid

The predominant action of cilostazol on Aβ metabolism is likely to facilitate Aβ clearance due to the sustained cerebrovascular function in vivo. Our findings mechanistically demonstrate that cilostazol is a promising therapeutic approach for AD and CAA