Publications by authors named "Koji Shibasaki"

64 Publications

Potential prescribing omissions of anti-osteoporosis drugs is associated with rehabilitation outcomes after fragility fracture: Retrospective cohort study.

Geriatr Gerontol Int 2021 May 28;21(5):386-391. Epub 2021 Feb 28.

Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aim: We investigated the association between rehabilitation outcomes and polypharmacy, potentially inappropriate medications and potential prescribing omissions in older adults with fragility fractures.

Methods: In total, we registered 217 older adults with fragility fractures (hip or vertebral) retrospectively and examined the association between rehabilitation outcome and polypharmacy, potentially inappropriate medications and potential prescribing omissions. Polypharmacy was defined as five or more drugs. Potentially inappropriate medications and potential prescribing omissions were defined by the Beers criteria (2015) and the screening tool to alert to treatment criteria version 2, respectively. The outcome was functional independence measure gain (functional independence measure at discharge - functional independence measure at admission).

Results: Multiple regression analyses revealed no association between functional independence measure gain and polypharmacy (crude: β = 0.058, P = 0.858; adjusted model: β = 0.013, P = 0.869) or potentially inappropriate medications (crude: β = 0.100, P = 0.144; adjusted model: β = 0.084, P = 0.260). However, there was a significant association between functional independence measure gain and potential prescribing omissions (crude: β = 0.167, P = 0.014; adjusted model: β = 0.180, P = 0.016). Participants without potential prescribing omissions (in other words, participants who were prescribed anti-osteoporosis drugs) had a greater functional independence measure gain than participants with potential prescribing omissions (in other words, those that were not prescribed anti-osteoporosis drugs).

Conclusion: To the best of our knowledge, this study is the first to report that participants without potential prescribing omissions had significantly improved rehabilitation outcomes. Geriatr Gerontol Int 2021; 21: 386-391.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ggi.14145DOI Listing
May 2021

Transient Receptor Potential Melastatin 3 Is Functionally Expressed in Oligodendrocyte Precursor Cells and Is Upregulated in Ischemic Demyelinated Lesions.

Biol Pharm Bull 2021 ;44(2):181-187

Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University.

Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into oligodendrocytes and myelinate axons. The number of OPCs is reportedly increased in brain lesions in some demyelinating diseases and during ischemia; however, these cells also secrete cytokines and elicit both protective and deleterious effects in response to brain injury. The mechanism regulating the behaviors of OPCs in physiological and pathological conditions must be elucidated to control these cells and to treat demyelinating diseases. Here, we focused on transient receptor potential melastatin 3 (TRPM3), a Ca-permeable channel that is activated by the neurosteroid pregnenolone sulfate (PS) and body temperature. Trpm3/Pdgfra OPCs were detected in the cerebral cortex (CTX) and corpus callosum (CC) of P4 and adult rats by in situ hybridization. Trpm3 expression was detected in primary cultured rat OPCs and was increased by treatment with tumor necrosis factor α (TNFα). Application of PS (30-100 µM) increased the Ca concentration in OPCs and this effect was inhibited by co-treatment with the TRP channel blocker Gd (100 µM) or the TRPM3 inhibitor isosakuranetin (10 µM). Stimulation of TRPM3 with PS (50 µM) did not affect the differentiation or migration of OPCs. The number of Trpm3 OPCs was markedly increased in demyelinated lesions in an endothelin-1 (ET-1)-induced ischemic rat model. In conclusion, TRPM3 is functionally expressed in OPCs in vivo and in vitro and is upregulated in inflammatory conditions such as ischemic insults and TNFα treatment, implying that TRPM3 is involved in the regulation of specific behaviors of OPCs in pathological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.b20-00510DOI Listing
January 2021

Choroidal congestion mouse model: Could it serve as a pachychoroid model?

PLoS One 2021 28;16(1):e0246115. Epub 2021 Jan 28.

Department of Ophthalmology, Gunma University Graduate School of Medicine, Maebashi, Japan.

Pachychoroid spectrum diseases have been described as a new clinical entity within the spectrum of macular disorders. "Pachychoroid" is defined as choroidal thickening associated with dilated outer choroidal vessels often showing retinal pigment epithelium (RPE) degeneration. Although various clinical studies on the pachychoroid spectrum diseases have been conducted, the pathophysiology of pachychoroid has yet to be fully elucidated. In this study, we attempted to establish a mouse model of pachychoroid. We sutured vortex veins in eyes of wild type mice to imitate the vortex vein congestion in pachychoroid spectrum diseases. Fundus photography and ultra-widefield indocyanine green angiography showed dilated vortex veins from the posterior pole to the ampulla in eyes after induction of choroidal congestion. Optical coherence tomography and tissue sections presented choroidal thickening with dilatation of choroidal vessels. The RPE-choroid/retina thickness ratios on the tissue sections in the treated day 1 and day 7 groups were significantly greater than that in the control group (0.19±0.03 and 0.16±0.01 vs. 0.12±0.02, P<0.05 each). Moreover, immunohistochemistry using RPE flatmount revealed focal RPE degeneration in the treated eyes. Furthermore, inflammatory response-related genes were upregulated in eyes with choroidal congestion induction, and macrophages migrated into the thickened choroid. These results indicated that vortex vein congestion triggered some pachychoroid features. Thus, we have established a choroidal congestion mouse model by suturing vortex veins, which would potentially be useful for investigating the pathophysiology of pachychoroid spectrum diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246115PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843010PMC
June 2021

Transient receptor potential vanilloid 4 agonist GSK1016790A improves neurological outcomes after intracerebral hemorrhage in mice.

Biochem Biophys Res Commun 2020 08 16;529(3):590-595. Epub 2020 Jul 16.

Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.

Intracerebral hemorrhage (ICH) is one of the most severe subtypes of stroke with high morbidity and mortality. Although a lot of drug discovery studies have been conducted, the drugs with satisfactory therapeutic effects for motor paralysis after ICH have yet to reach clinical application. Transient receptor potential vanilloid 4 (TRPV4), a Ca-permeable cation channel and activated by hypoosmolarity and warm temperature, is expressed in various cell types. The present study investigated whether TRPV4 would participate in the brain damage in a mouse model of ICH. ICH was induced by intrastriatal treatment of collagenase. Administration of GSK1016790A, a selective TRPV4 agonist, attenuated neurological and motor deficits. The inhibitory effects of the TRPV4 agonist in collagenase-injected WT mice were completely disappeared in TRPV4-KO mice. The TRPV4 agonist did not alter brain injury volume and brain edema at 1 and 3 days after ICH induction. The TRPV4 agonist did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 3 days after ICH induction. Quantitative RT-PCR experiments revealed that the TRPV4 agonist significantly upregulated the expression level of c-fos, a marker of neuronal activity, while the agonist gave no effects on the expression level of cytokines/chemokines at 1 day after ICH induction, These results suggest that stimulation of TRPV4 would ameliorate ICH-induced brain injury, presumably by increased neuronal activity and TRPV4 provides a novel therapeutic target for the treatment for ICH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.06.103DOI Listing
August 2020

TRPV4 activation by thermal and mechanical stimuli in disease progression.

Authors:
Koji Shibasaki

Lab Invest 2020 02 2;100(2):218-223. Epub 2020 Jan 2.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.

Body temperature is an important determinant in regulating the activities of animals. In humans, a mild 0.5 °C hyperthermia can cause headaches, demonstrating that the maintenance of normal body temperature is a key for our health. In a more extreme example, accidental acute hypothermia can lead to severe shivering, loss of consciousness, or death, although the details of these mechanisms are poorly understood. We previously found that the TRPV4 ion channel is constitutively activated by normal body temperature. The activation threshold of TRPV4 is >34 °C in the brain, which enables TRPV4 to convert thermal information into cellular signaling. Here we review the data which describe how the deletion of TRPV4 evokes abnormal behavior in mice. These studies demonstrate that the maintenance of body temperature and the sensory system for detecting body temperature, such as via TRPV4, are critical components for normal cellular function. Moreover, abnormal TRPV4 activation exacerbates cell death, epilepsy, stroke, brain edema, or cardiac fibroblast activity. In this review, we also summarize the findings related to TRPV4 and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41374-019-0362-2DOI Listing
February 2020

TRPC5 regulates axonal outgrowth in developing retinal ganglion cells.

Lab Invest 2020 02 16;100(2):297-310. Epub 2019 Dec 16.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.

The TRPC5 ion channel is activated upon depletion of intracellular calcium stores, as well as by various stimuli such as nitric oxide (NO), membrane stretch, and cold temperatures. TRPC5 is abundantly expressed in the central nervous system where it has important neuronal functions. In the chick retina, TRPC5 expression was shown to be restricted to amacrine cells (ACs) and Müller glial cells, although its expression was also observed in the ganglion cell layer (GCL) in displaced ACs, as determined by their characteristic cell morphology. However, it is possible that this expression analysis alone might be insufficient to fully understand the expression of TRPC5 in retinal ganglion cells (RGCs). Hence, we analyzed TRPC5 expression by in situ hybridization and immunostaining in the developing mouse retina, and for the first time identified that developing and mature RGCs strongly express TRPC5. The expression begins at E14.5, and is restricted to ACs and RGCs. It was reported that TRPC5 negatively regulates axonal outgrowth in hippocampal neurons. We thus hypothesized that TRPC5 might have similar functions in RGCs since they extend very long axons toward the brain, and this characteristic significantly differs from other retinal cell types. To elucidate its possible involvement in axonal outgrowth, we inhibited TRPC5 activity in developing RGCs which significantly increased RGC axon length. In contrast, overexpression of TRPC5 inhibited axonal outgrowth in developing RGCs. These results indicate that TRPC5 is an important negative regulator of RGC axonal outgrowth. Since TRPC5 is a mechanosensor, it might function to sense abnormal intraocular pressure changes, and could contribute to the death of RGCs in diseases such as glaucoma. In this case, excessive Ca entry through TRPC5 might induce dendritic and axonal remodeling, which could lead to cell death, as our findings clearly indicate that TRPC5 is an important regulator of neurite remodeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41374-019-0347-1DOI Listing
February 2020

Temperature elevation in epileptogenic foci exacerbates epileptic discharge through TRPV4 activation.

Lab Invest 2020 02 22;100(2):274-284. Epub 2019 Oct 22.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.

Physiological brain temperature is an important determinant of brain function, and it is well established that changes in brain temperature dynamically influence hippocampal neuronal activity. We previously demonstrated that the thermosensor TRPV4 is activated at physiological brain temperature in hippocampal neurons thereby controlling neuronal excitability in vitro. Here, we examined whether TRPV4 regulates neuronal excitability through its activation by brain temperature in vivo. We locally cooled the hippocampus using our novel electrical device and demonstrated constitutive TRPV4 activation in normal mouse brain. We generated a model of partial epilepsy by utilizing kindling stimuli in the ventral hippocampus of wild type (WT) or TRPV4-deficient (TRPV4KO) mice and obtained electroencephalograms (EEG). The frequencies of epileptic EEG in WT mice were significantly larger than those in TRPV4KO mice. These results indicate that TRPV4 activation is involved in disease progression of epilepsy. We expected that disease progression would enhance hyperexcitability and lead to hyperthermia in the epileptogenic foci. To confirm this hypothesis, we developed a new device to measure exact brain temperature only in a restricted local area. From the recording results by the new device, we found that the brain temperatures in epileptogenic zones were dramatically elevated compared with normal regions. Furthermore, we demonstrated that the temperature elevation was critical for disease progression. Based on these results, we speculate that brain cooling treatment at epileptogenic foci would effectively suppress epileptic discharges through inhibition of TRPV4. Notably, the cooling treatment drastically suppressed neuronal discharges dependent on the inactivation of TRPV4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41374-019-0335-5DOI Listing
February 2020

Sex-related differences in the association between frailty and dietary consumption in Japanese older people: a cross-sectional study.

BMC Geriatr 2019 08 5;19(1):211. Epub 2019 Aug 5.

Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

Background: Female sex is an important factor predisposing individuals to frailty. Appropriate nutrition is one of the most effective ways to prevent older adults from developing frailty; Sex-related differences have also been detected in the association between nutritional intervention and health-related outcomes. However, few studies have discussed these sex-related differences. The aim of the present study was to investigate the sex-related differences in the association between frailty and dietary consumption.

Methods: We conducted a cross-sectional study which investigated community-dwelling older adults aged ≥65 years. We surveyed age, sex, body mass index, family arrangement (living alone, living with a partner or living with parent(s) and/or child (ren)), dietary consumption and frailty status. Dietary consumption was surveyed using a food frequency questionnaire that included 13 major food categories (fish, meat, eggs, dairy products, soybean products, vegetables, seaweeds, potatoes, fruits, fats or oils, snacks, salty foods and alcohol). Frailty was defined by the Kihon Checklist score. The Kihon Checklist is composed of 25 simple yes/no questions, and it has been validated as a metric for frailty. A higher score indicates a greater degree of frailty. Multinomial regression analysis was performed to clarify the association between frailty and dietary consumption for each sex.

Results: We analyzed 905 older adults (420 (46.4%) were male). After adjusting for cofounders, a low frequency of meat consumption (less than twice/week) was associated with a high prevalence of frailty in men (odds ratio: 2.76 (95%CI: 1.12-6.77), p = 0.027). In contrast, in women, low frequencies of consumption of fish, meat, vegetables, potatoes and snacks were associated with a higher prevalence of frailty compared with those who consumed foods from those categories daily (odds ratios: fish 2.45 (1.02-5.89), p = 0.045; meat 4.05 (1.67-9.86), p = 0.002; vegetables 5.03 (2.13-11.92), p < 0.001; potatoes 3.84 (1.63-9.05), p = 0.002; snacks 2.16 (1.02-4.56), p = 0.043).

Conclusions: More food categories were associated with frailty in women than in men. Nutritional intervention to prevent frailty is presumably more effective for women than for men.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12877-019-1229-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683375PMC
August 2019

Deletion of Class II ADP-Ribosylation Factors in Mice Causes Tremor by the Nav1.6 Loss in Cerebellar Purkinje Cell Axon Initial Segments.

J Neurosci 2019 08 14;39(32):6339-6353. Epub 2019 Jun 14.

Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan,

ADP-ribosylation factors (ARFs) are a family of small monomeric GTPases comprising six members categorized into three classes: class I (ARF1, 2, and 3), class II (ARF4 and 5), and class III (ARF6). In contrast to class I and III ARFs, which are the key regulators in vesicular membrane trafficking, the cellular function of class II ARFs remains unclear. In the present study, we generated class II ARF-deficient mice and found that ARF4/ARF5 mice exhibited essential tremor (ET)-like behaviors. electrophysiological recordings revealed that ARF4/ARF5 mice of both sexes exhibited abnormal brain activity when moving, raising the possibility of abnormal cerebellar excitability. Slice patch-clamp experiments demonstrated the reduced excitability of the cerebellar Purkinje cells (PCs) in ARF4/ARF5 mice. Immunohistochemical and electrophysiological analyses revealed a severe and selective decrease of pore-forming voltage-dependent Na channel subunit Nav1.6, important for maintaining repetitive action potential firing, in the axon initial segment (AIS) of PCs. Importantly, this decrease in Nav1.6 protein localized in the AIS and the consequent tremors in ARF4/ARF5 mice could be alleviated by the PC-specific expression of ARF5 using adeno-associated virus vectors. Together, our data demonstrate that the decreased expression of the class II ARF proteins in ARF4/ARF5 mice, leading to a haploinsufficiency of ARF4 in the absence of ARF5, impairs the localization of Nav1.6 to the AIS and hence reduces the membrane excitability in PCs, resulting in the ET-like movement disorder. We suggest that class II ARFs function in localizing specific proteins, such as Nav1.6, to the AIS. We found that decreasing the expression of class II ARF proteins, through the generation of ARF4/ARF5 mice, impairs Nav1.6 distribution to the axon initial segment (AIS) of cerebellar Purkinje cells (PCs), thereby resulting in the impairment of action potential firing of PCs. The ARF4/ARF5 mutant mice exhibited movement-associated essential tremor (ET)-like behavior with pharmacological profiles similar to those in ET patients. The exogenous expression of ARF5 reduced the tremor phenotype and restored the localization of Nav1.6 immunoreactivity to the AIS in ARF4/ARF5 mice. Thus, our results suggest that class II ARFs are involved in the localization of Nav1.6 to the AISs in cerebellar PCs and that the reduction of class II ARF activity leads to ET-like movement disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2002-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687904PMC
August 2019

Microglial SIRPα regulates the emergence of CD11c microglia and demyelination damage in white matter.

Elife 2019 03 26;8. Epub 2019 Mar 26.

Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma, Japan.

A characteristic subset of microglia expressing CD11c appears in response to brain damage. However, the functional role of CD11c microglia, as well as the mechanism of its induction, are poorly understood. Here we report that the genetic ablation of signal regulatory protein α (SIRPα), a membrane protein, induced the emergence of CD11c microglia in the brain white matter. Mice lacking CD47, a physiological ligand of SIRPα, and microglia-specific SIRPα-knockout mice exhibited the same phenotype, suggesting that an interaction between microglial SIRPα and CD47 on neighbouring cells suppressed the emergence of CD11c microglia. A lack of SIRPα did not cause detectable damage to the white matter, but resulted in the increased expression of genes whose expression is characteristic of the repair phase after demyelination. In addition, cuprizone-induced demyelination was alleviated by the microglia-specific ablation of SIRPα. Thus, microglial SIRPα suppresses the induction of CD11c microglia that have the potential to accelerate the repair of damaged white matter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.42025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435324PMC
March 2019

The dynamics of revascularization after white matter infarction monitored in Flt1-tdsRed and Flk1-GFP mice.

Neurosci Lett 2019 01 31;692:70-76. Epub 2018 Oct 31.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. Electronic address:

Subcortical white matter infarction causes ischemic demyelination and loss of brain functions, as the result of disturbances of the blood flow. Although angiogenesis is one of the recovery processes after cerebral infarction, the dynamics of revascularization after white matter infarction still remains unclear. We induced white matter infarction in the internal capsule of Flk1-GFP::Flt1-tdsRed double transgenic mice by injection of endothelin-1 (ET-1), a vasoconstrictor peptide, together with N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and followed the changes in Flk1 and Flt1 expression in the vascular system in the infarct area. Reduction of Flt1-tdsRed-positive blood vessels 1 day after the injection and increase of Flk1-GFP-strongly-positive blood vessels 3 days after the injection were apparent. PDGFRβ-strongly-positive (PDGFRβ+) cells appeared in the infarct area 3 days after the injection and increased their number thereafter. Three days after the injection, most of these cells were in close contact with Flk1-GFP-positive endothelial cells, indicating these cells are bona fide pericytes. Seven days after the injection, the number of PDGFRβ+ cells increased dramatically, and the vast majority of these cells were not in close contact with Flk1-GFP-positive endothelial cells. Taken together, our results suggest revascularization begins early after the ischemic insult, and the emerging pericytes first ensheath blood vessels and then produce fibroblast-like cells not directly associated with blood vessels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2018.10.057DOI Listing
January 2019

Plasma Leptin Concentration and Sympathetic Nervous Activity in Older Adults With Physical Dysfunction.

J Endocr Soc 2018 Sep 13;2(9):1040-1049. Epub 2018 Aug 13.

Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Context: Previous research has shown a positive relationship between plasma leptin and sympathetic nervous activity. High plasma leptin activate inflammatory cytokines and lead to muscle wasting. However, studies have detected low sympathetic nervous activity and high plasma leptin in older adults with muscle wasting, sarcopenia, and frailty. High plasma leptin do not seem to correlate with high sympathetic nervous activity. However, their relationship in older adults remains unclear.

Objective: We investigated the relationship between plasma leptin and sympathetic nervous activity in older adults.

Design Setting And Participants: We conducted a cross-sectional study and analyzed the results from 69 participants aged ≥75 years. Sympathetic nervous activity was measured by heart rate variability, obtained from 24-hour Holter monitoring. A functional independence measure (FIM) and Barthel index were used to assess physical function.

Results: The plasma leptin was higher in women (men, 3.4 ± 2.8 ng/mL; women, 6.6 ± 6.5 ng/mL; = 0.024). Plasma leptin was negatively and substantially related to the FIM ( = -0.233; = 0.049) and Barthel index ( = -0.298, = 0.018) after adjustment for covariates. However, the data showed no relationship between the plasma leptin and sympathetic nervous activity.

Conclusions: We could not detect an association between sympathetic nervous activity and plasma leptin in older adults. This might suggest a failure of the feedback system of the sympathetic nervous system, leading to muscle wasting in older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/js.2018-00104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117403PMC
September 2018

Retinal Detachment-Induced Müller Glial Cell Swelling Activates TRPV4 Ion Channels and Triggers Photoreceptor Death at Body Temperature.

J Neurosci 2018 10 24;38(41):8745-8758. Epub 2018 Aug 24.

Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan,

Using region-specific injection of hyaluronic acid, we developed a mouse model of acute retinal detachment (RD) to investigate molecular mechanisms of photoreceptor cell death triggered by RD. We focused on the transient receptor potential vanilloid 4 (TRPV4) ion channel, which functions as a thermosensor, osmosensor, and/or mechanosensor. After RD, the number of apoptotic photoreceptors was reduced by ∼50% in TRPV4KO mice relative to wild-type mice, indicating the possible involvement of TRPV4 activation in RD-induced photoreceptor cell death. Furthermore, TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Together, our results suggest that RD adversely impacts photoreceptor viability via TRPV4-dependent cytokine release from Müller glial cells and that TRPV4 is part of a novel molecular pathway that could exacerbate the effects of hypoxia on photoreceptor survival after RD. Identification of the mechanisms of photoreceptor death in retinal detachment is required for establishment of therapeutic targets for preventing loss of visual acuity. In this study, we found that TRPV4 expressed in Müller glial cells can be activated by mechanical stimuli caused by RD-induced swelling of these cells, resulting in release of the cytokine MCP-1, which is reported as a mediator of Müller glia-derived strong mediator for RD-induced photoreceptor death. We also found that the TRPV4 activation by the Müller glial swelling was potentiated by body temperature. Hence, TRPV4 inhibition could suppress cell death in RD pathological conditions and suggests that TRPV4 in Müller glial cells might be a novel therapeutic target for preventing photoreceptor cell death after RD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0897-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181316PMC
October 2018

Rehabilitation strategy for hip fracture, focused on behavioral psychological symptoms of dementia for older people with cognitive impairment: A nationwide Japan rehabilitation database.

PLoS One 2018 5;13(7):e0200143. Epub 2018 Jul 5.

Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

The aim is to investigate the relationship between a positive outcome on rehabilitation after hip fracture and behavioral psychological symptoms of dementia (BPSD) transition during rehabilitation. This study is a retrospective cohort study based on the Japan Rehabilitation Database. We recruited 756 subjects 65 years of age or older from 31 hospitals in the database. All subjects were in the hospital as patients undergoing rehabilitation for hip fracture. Functional independence measure (FIM), walking ability, Mini-Mental State Examination (MMSE), and BPSD were measured both at the beginning and at the end of rehabilitation. MMSE for 23 or under was defined as the cognitive-impaired group. MMSE for 24 or over was used as the cognitively intact group. Cognitive impaired participants were divided into four groups: participants presented no BPSD both at the beginning of rehabilitation and at the end of rehabilitation (Group (-/-)), participants presented BPSD at the beginning of rehabilitation but resolved at the end of rehabilitation (Group (+/-)), participants had no BPSD at the beginning of rehabilitation but appeared at the end of rehabilitation (Group (-/+)) and participants had sign of BPSD both at the beginning of rehabilitation and at the end of rehabilitation (Group (+/+)). The endpoints were waking ability, FIM gain. As results, one hundred thirty-seven cognitive-impaired older people patients out of 471 (29.1%) suffered from BPSD at the beginning of rehabilitation. FIM gains in cognitively intact group, Group (-/-), Group (+/-), Group (-/+) and Group (+/+) were 24.8 ± 18.7, 17.5 ± 16.9, 27.3 ± 19.7, 17.8 ± 12.2 and 12.2 ± 17.2, respectively. The Group (+/-) was significantly connected to a positive outcome for rehabilitation. The present study suggested that the management of BPSD can lead to better functional recovery during rehabilitation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200143PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033436PMC
January 2019

Ischemic Brain Injury Leads to Brain Edema via Hyperthermia-Induced TRPV4 Activation.

J Neurosci 2018 06 23;38(25):5700-5709. Epub 2018 May 23.

Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033 Japan,

Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain largely unclear. Here, we developed an model of ischemic stroke-induced edema in which male mouse brain slices were treated with oxygen-glucose deprivation (OGD) to mimic ischemia. We continuously measured the cross-sectional area of the brain slice for 150 min under macroscopic microscopy, finding that OGD induces swelling of brain slices. OGD-induced swelling was prevented by pharmacologically blocking or genetically knocking out the transient receptor potential vanilloid 4 (TRPV4), a member of the thermosensitive TRP channel family. Because TRPV4 is activated at around body temperature and its activation is enhanced by heating, we next elevated the temperature of the perfusate in the recording chamber, finding that hyperthermia induces swelling via TRPV4 activation. Furthermore, using the temperature-dependent fluorescence lifetime of a fluorescent-thermosensitive probe, we confirmed that OGD treatment increases the temperature of brain slices through the activation of glutamate receptors. Finally, we found that brain edema following traumatic brain injury was suppressed in TRPV4-deficient male mice Thus, our study proposes a novel mechanism: hyperthermia activates TRPV4 and induces brain edema after ischemia. Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain unclear. Here, we developed an model of ischemic stroke-induced edema in which mouse brain slices were treated with oxygen-glucose deprivation. Using this system, we showed that the increase in brain temperature and the following activation of the thermosensitive cation channel TRPV4 (transient receptor potential vanilloid 4) are involved in the pathology of edema. Finally, we confirmed that TRPV4 is involved in brain edema using TRPV4-deficient mice, concluding that hyperthermia activates TRPV4 and induces brain edema after ischemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2888-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595977PMC
June 2018

Chapter 1 Definitions and diagnosis of sarcopenia.

Geriatr Gerontol Int 2018 May;18 Suppl 1:7-12

National Center for Geriatrics and Gerontology, Obu, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ggi.13311DOI Listing
May 2018

Chapter 2 Epidemiology of sarcopenia.

Geriatr Gerontol Int 2018 May;18 Suppl 1:13-22

National Center for Geriatrics and Gerontology, Obu, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ggi.13320DOI Listing
May 2018

Role of autonomic nervous activity, as measured by heart rate variability, on the effect of mortality in disabled older adults with low blood pressure in long-term care.

Geriatr Gerontol Int 2018 Aug 11;18(8):1153-1158. Epub 2018 Apr 11.

Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aim: Previous studies have shown the relationship between low blood pressure and high mortality in frail, disabled older adults in long-term care. However, the mechanism of this relationship is still unclear. We hypothesized that autonomic nervous activity decline is involved in the relationship between low blood pressure and high mortality.

Methods: The present prospective cohort study recruited 61 participants aged ≥75 years. The data from 24-h Holter monitoring and blood pressure recorded by ambulatory blood pressure monitoring were collected. Measured data were divided into three categories: 24-h, daytime and night-time. From power spectral density in the electrocardiogram, low frequency, high frequency and low frequency/high frequency ratio were calculated. The primary end-point was death.

Results: High blood pressure was connected to both high daytime low frequency and high frequency (partial correlation coefficients: 0.42, P < 0.05 and 0.35, P < 0.05, respectively). In addition, the low blood pressure group had higher mortality than the high blood pressure group, and disabled older adults in long-term care and those with elevated daytime systolic and diastolic blood pressure had less risk of mortality compared with those without (systolic: hazard ratio 0.89, 95% confidence interval 0.83-0.96, P = 0.003; diastolic: hazard ratio 0.98, 95% confidence interval 0.79-1.00, P = 0.049). The average blood pressures in the high blood pressure groups were approximately 140/80 mmHg and were connected to low mortality.

Conclusions: Attenuated autonomic nervous activity might lead to low blood pressure in the daytime and high mortality in disabled older adults in long-term care. Geriatr Gerontol Int 2018; 18: 1153-1158.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ggi.13328DOI Listing
August 2018

TRPV4 is functionally expressed in oligodendrocyte precursor cells and increases their proliferation.

Pflugers Arch 2018 05 22;470(5):705-716. Epub 2018 Mar 22.

Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.

Oligodendrocytes, which differentiate from oligodendrocyte precursor cells (OPCs), ensheath axons with myelin, play an essential role in rapid conduction of action potentials and metabolically support neurons. Elucidation of the mechanisms underlying the proliferation, migration, differentiation, and survival of OPCs is considered indispensable for determining the causes of central nervous system diseases. However, the relationship between these functions of OPCs and their intracellular Ca signaling has not been fully elucidated. Here, we investigated the function of transient receptor potential vanilloid 4 (TRPV4), a Ca-permeable channel that responds to hypo-osmolarity, mild temperature, mechanical stimulation, and endogenous arachidonic acid metabolites, in OPCs. Trpv4 mRNA was detected in OPCs in vivo and in primary cultured rat OPCs. In Ca imaging experiments, treatment with the selective TRPV4 agonist GSK1016790A induced sustained elevation of the intracellular Ca concentration in OPCs in a concentration-dependent manner, which was almost completely suppressed by co-treatment with the selective TRPV4 antagonist HC067047. Stimulation of TRPV4 by GSK1016790A augmented OPC proliferation, which was abolished by co-treatment with HC067047, the intracellular Ca chelator BAPTA-AM, and the protein kinase C inhibitor bisindolylmaleimide II. By contrast, GSK1016790A did not significantly affect the migration or differentiation of OPCs. Taken together, these results suggest that TRPV4 is functionally expressed in OPCs and increases the proliferation of these cells without affecting their ability to differentiate into oligodendrocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00424-018-2130-3DOI Listing
May 2018

[The development of pneumothorax in an elderly woman during treatment for nontuberculous mycobacterium].

Nihon Ronen Igakkai Zasshi 2018 ;55(1):136-142

Department of Geriatric Medicine, The University of Tokyo.

We report the case of an 82-year-old woman who developed pneumothorax during treatment for nontuberculous mycobacterium (NTM). In year X, she was diagnosed with NTM at another hospital after abnormalities were pointed out on a chest X-ray. She received no treatment for NTM at that time. Antibiotic treatment was introduced at the department of respiratory medicine in our hospital in year X+15. The regimen was composed of clarithromycin (800 mg/day), ethambutol (750 mg/day) and rifampicin (600 mg/day); however, treatment with the three-drug antibiotic regimen was canceled at her request and changed to erythromycin. She was then referred to our department. However, right-side cavity wall thickening was detected on chest CT in year X+17.We resumed clarithromycin (600 mg/day), ethambutol (750 mg/day) and rifampicin (450 mg/day). On the 43rd day after treatment with three types of antibiotics, she felt dyspnea and she was admitted to the hospital and was diagnosed with right-side pneumothorax. The pneumothorax was thought to have been caused by a break in the adhesion of the cavity wall. The visceral pleura was weakened by the exacerbation of NTM and the thickness of the cavity wall was improved after the resumption of antibiotic therapy. This report is considered to be an important case in which pneumothorax developed as a complication in an elderly patient during treatment for NTM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3143/geriatrics.55.136DOI Listing
April 2019

Microglial Activation Induces Generation of Oligodendrocyte Progenitor Cells from the Subventricular Zone after Focal Demyelination in the Corpus Callosum.

Dev Neurosci 2018 25;40(1):54-63. Epub 2018 Jan 25.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Japan.

Neuroblasts derived from neural stem cells (NSCs) in the subventricular zone (SVZ) migrate along the rostral migratory stream into the olfactory bulb to generate interneurons under normal physiological conditions. When demyelination occurs, NSCs or neural progenitor cells (NPCs) in the SVZ provide newly formed oligodendrocytes to demyelinated lesions. The plasticity of NSC/NPC lineages may tend to oligodendrogenesis under the influence of demyelinated lesions. The mechanisms, however, still remain unknown. This study revealed that focal demyelination in the corpus callosum caused activation of the microglia, not only at the site of demyelination but also in the SVZ, and dramatically increased the generation of oligodendrocyte progenitor cells (OPCs) in the SVZ. Furthermore, the inhibition of microglial activation by minocycline treatment decreased OPC generation in the SVZ, suggesting that microglial activation in the SVZ, induced by the focal demyelination in the corpus callosum, regulates NSC/NPC lineage plasticity in situ. In contrast to the findings regarding demyelination in the corpus callosum, inducing focal demyelination in the internal capsule did not induce either microglial activation or OPC generation in the SVZ. These results suggest that the mechanism of OPC generation in the SVZ after inducing demyelinating lesions could be different across the demyelinated regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000486332DOI Listing
October 2018

BMP4 signaling in NPCs upregulates Bcl-xL to promote their survival in the presence of FGF-2.

Biochem Biophys Res Commun 2018 02 19;496(2):588-593. Epub 2018 Jan 19.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. Electronic address:

We previously reported that BMP4 does not promote proliferation or differentiation of CD44-positive astrocyte precursor cells (APCs) but greatly promotes their survival in the presence of fibroblast growth factor-2 (FGF-2). In this study, we examined if BMP4 acts as a survival factor also for neural stem/progenitor cells (NPCs) isolated from ganglionic eminence of neonatal mouse brain. We found BMP4 promotes survival but not proliferation or differentiation of these cells, just as in the case for CD44-positive APCs. Microarray analysis revealed some candidate molecules in the signaling pathway downstream of BMP4. Among them, we focused on Id1 (inhibitor of DNA-binding 1) and Bcl-xL in this study. Expression of both genes was promoted in the presence of BMP4, and this promotion was reduced by dorsomorphin, an inhibitor of BMP4 signaling. Furthermore, cytochrome c release from mitochondria was significantly reduced in the presence of BMP4, suggesting up-regulation of Bcl-xL activity by BMP4. Id1 siRNA reduced the expression of Bcl-xL, and negated survival promoting effect of BMP4. These data suggest that BMP4 promotes survival of NPCs by enhancing the anti-apoptotic function of Bcl-xL via BMP4-Smad1/5/8-Id1 signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2018.01.090DOI Listing
February 2018

Case of a 78-year-old woman with a neuronal intranuclear inclusion disease.

Geriatr Gerontol Int 2017 12;17(12):2623-2625

Department of Geriatric medicine, The University of Tokyo Hospital, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ggi.13174DOI Listing
December 2017

Involvement of TRPV3 and TRPM8 ion channel proteins in induction of mammalian cold-inducible proteins.

Biochem Biophys Res Commun 2018 01 21;495(1):935-940. Epub 2017 Nov 21.

Department of Urology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

Cold-inducible RNA-binding protein (CIRP), RNA-binding motif protein 3 (RBM3) and serine and arginine rich splicing factor 5 (SRSF5) are RNA-binding proteins that are transcriptionally upregulated in response to moderately low temperatures and a variety of cellular stresses in mammalian cells. Induction of these cold-inducible proteins (CIPs) is dependent on transient receptor potential (TRP) V4 channel protein, but seems independent of its ion channel activity. We herein report that in addition to TRPV4, TRPV3 and TRPM8 are necessary for the induction of CIPs. We established cell lines from the lung of TRPV4-knockout (KO) mouse, and observed induction of CIPs in them by western blot analysis. A TRPV4 antagonist RN1734 suppressed the induction in wild-type mouse cells, but not in TRPV4-KO cells. A TRPV3 channel blocker S408271 and a TRPM8 channel blocker AMTB as well as siRNAs against TRPV3 and TRPM8 suppressed the CIP induction in mouse TRPV4-KO cells and human U-2 OS cells. A TRPV3 channel agonist 2-APB induced CIP expression, but camphor did not. Neither did a TRPM8 channel agonist WS-12. These results suggest that TRPV4, TRPV3 and TRPM8 proteins, but not their ion channel activities are necessary for the induction of CIPs at 32 °C. Identification of proteins that differentially interact with these TRP channels at 37 °C and 32 °C would help elucidate the underlying mechanisms of CIP induction by hypothermia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2017.11.136DOI Listing
January 2018

Temporal Changes in Transcription Factor Expression Associated with the Differentiation State of Cerebellar Neural Stem/Progenitor Cells During Development.

Neurochem Res 2018 Jan 7;43(1):205-211. Epub 2017 Oct 7.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.

During central nervous development, multi-potent neural stem/progenitor cells located in the ventricular/subventricular zones are temporally regulated to mostly produce neurons during early developmental stages and to produce glia during later developmental stages. After birth, the rodent cerebellum undergoes further dramatic development. It is also known that neural stem/progenitor cells are present in the white matter (WM) of the postnatal cerebellum until around P10, although the fate of these cells has yet to be determined. In the present study, it was revealed that primary neurospheres generated from cerebellar neural stem/progenitor cells at postnatal day 3 (P3) mainly differentiated into astrocytes and oligodendrocytes. In contrast, primary neurospheres generated from cerebellar neural stem/progenitor cells at P8 almost exclusively differentiated into astrocytes, but not oligodendrocytes. These results suggest that the differentiation potential of primary neurospheres changes depending on the timing of neural stem/progenitor cell isolation from the cerebellum. To identify the candidate transcription factors involved in regulating this temporal change, we utilized DNA microarray analysis to compare global gene-expression profiles of primary neurospheres generated from neural stem/progenitor cells isolated from either P3 or P8 cerebellum. The expression of zfp711, zfp618, barx1 and hoxb3 was higher in neurospheres generated from P3 cerebellum than from P8 by real-time quantitative PCR. Several precursor cells were found to express zfp618, barx1 or hoxb3 in the WM of the cerebellum at P3, but these transcription factors were absent from the WM of the P8 cerebellum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-017-2405-7DOI Listing
January 2018

Mouse retinal ganglion cell signalling is dynamically modulated through parallel anterograde activation of cannabinoid and vanilloid pathways.

J Physiol 2017 10 7;595(20):6499-6516. Epub 2017 Sep 7.

Department of Ophthalmology & Visual Sciences, Moran Eye Institute, Salt Lake City, UT, USA.

Key Points: Retinal cells use vanilloid transient receptor potential (TRP) channels to integrate light-evoked signals with ambient mechanical, chemical and temperature information. Localization and function of the polymodal non-selective cation channel TRPV1 (transient receptor potential vanilloid isoform 1) remains elusive. TRPV1 is expressed in a subset of mouse retinal ganglion cells (RGCs) with peak expression in the mid-peripheral retina. Endocannabinoids directly activate TRPV1 and inhibit it through cannabinoid type 1 receptors (CB1Rs) and cAMP pathways. Activity-dependent endocannabinoid release may modulate signal gain in RGCs through simultaneous manipulation of calcium and cAMP signals mediated by TRPV1 and CB1R.

Abstract: How retinal ganglion cells (RGCs) process and integrate synaptic, mechanical, swelling stimuli with light inputs is an area of intense debate. The nociceptive cation channel TRPV1 (transient receptor potential vanilloid type 1) modulates RGC Ca signals and excitability yet the proportion of RGCs that express it remains unclear. Furthermore, TRPV1's response to endocannabinoids (eCBs), the putative endogenous retinal activators, is unknown, as is the potential modulation by cannabinoid receptors (CBRs). The density of TRPV1-expressing RGCs in the Ai9:Trpv1 reporter mouse peaked in the mid-peripheral retina. TRPV1 agonists including capsaicin (CAP) and the eCBs anandamide and N-arachidonoyl-dopamine elevated [Ca ] in 30-40% of wild-type RGCs, with effects suppressed by TRPV1 antagonists capsazepine (CPZ) and BCTC ((4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide), and lacking in Trpv1 cells. The cannabinoid receptor type 1 (CB1R) colocalized with TRPV1:tdTomato expression. Its agonists 2-arachidonoylglycerol (2-AG) and WIN55,122 inhibited CAP-induced [Ca ] signals in adult, but not early postnatal, RGCs. The suppressive effect of 2-AG on TRPV1 activation was emulated by positive modulators of the protein kinase A (PKA) pathway, inhibited by the CB1R antagonist rimonabant and G uncoupler pertussis toxin, and absent in Cnr1 RGCs. We conclude that TRPV1 is a modulator of Ca homeostasis in a subset of RGCs that show non-uniform distribution across the mouse retina. Non-retrograde eCB-mediated modulation of RGC signalling involves a dynamic push-pull between direct TRPV1 activation and PKA-dependent regulation of channel inactivation, with potential functions in setting the bandwidth of postsynaptic responses, sensitivity to mechanical/excitotoxic stress and neuroprotection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP274562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638913PMC
October 2017

TRPV4-dependent induction of a novel mammalian cold-inducible protein SRSF5 as well as CIRP and RBM3.

Sci Rep 2017 05 23;7(1):2295. Epub 2017 May 23.

Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, 606-8507, Japan.

Cold-inducible RNA-binding protein (CIRP) and RNA-binding motif protein 3 (RBM3) are two evolutionarily conserved RNA-binding proteins that are structurally related to hnRNPs and upregulated in response to moderately low temperatures in mammalian cells. Although contributions of splicing efficiency, the gene promoters activated upon mild hypothermia and the transcription factor Sp1 to induction of CIRP have been reported, precise mechanisms by which hypothermia and other stresses induce the expression of mammalian cold-inducible proteins (CIPs) are poorly understood. By screening the serine/arginine-rich splicing factors (SRSFs), we report that the transcript and protein levels of SRSF5 were increased in mammalian cells cultured at 32 °C. Expression of SRSF5 as well as CIRP and RBM3 were also induced by DNA damage, hypoxia, cycloheximide and hypotonicity. Immunohistochemical studies demonstrated that SRSF5 was constitutively expressed in male germ cells and the level was decreased in human testicular germ cell tumors. SRSF5 facilitated production of p19 H-RAS, and increased sensitivity to doxorubicin in human U-2 OS cells. Induction of CIPs was dependent on transient receptor potential vanilloid 4 (TRPV4) channel protein, but seemed independent of its ion channel activity. These findings indicate a previously unappreciated role for the TRP protein in linking environmental stress to splicing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-02473-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442135PMC
May 2017

Transient receptor potential vanilloid 2 activation by focal mechanical stimulation requires interaction with the actin cytoskeleton and enhances growth cone motility.

FASEB J 2017 04 22;31(4):1368-1381. Epub 2016 Dec 22.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, Japan;

We have previously reported that transient receptor potential vanilloid 2 (TRPV2) can be activated by mechanical stimulation, which enhances axonal outgrowth in developing neurons; however, the molecular mechanisms that govern the contribution of TRPV2 activation to axonal outgrowth remain unclear. In the present study, we examined this mechanism by using PC12 cells as a neuronal model. Overexpression of TRPV2 enhanced axonal outgrowth in a mechanical stimulus-dependent manner. Accumulation of TRPV2 at the cell surface was 4-fold greater in the growth cone compared with the soma. In the growth cone, TRPV2 is not static, but dynamically accumulates (within ∼100 ms) to the site of mechanical stimulation. The dynamic and acute clustering of TRPV2 can enhance very weak mechanical stimuli focal accumulation of TRPV2. Focal application of mechanical stimuli dramatically increased growth cone motility and caused actin reorganization activation of TRPV2. We also found that TRPV2 physically interacts with actin and that changes in the actin cytoskeleton are required for its activation. Here, we demonstrated for the first time to our knowledge that TRPV2 clustering is induced by mechanical stimulation generated by axonal outgrowth and that TRPV2 activation is triggered by actin rearrangements that result from mechanical stimulation. Moreover, TRPV2 activation enhances growth cone motility and actin accumulation to promote axonal outgrowth. Sugio, S., Nagasawa, M., Kojima, I., Ishizaki, Y., Shibasaki, K. Transient receptor potential vanilloid 2 activation by focal mechanical stimulation requires interaction with the actin cytoskeleton and enhances growth cone motility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201600686RRDOI Listing
April 2017

Effect of Rehabilitation on Recovery of Sympathetic Nervous Activity Measured According to Heart Rate Variability in Frail Elderly Adults.

J Am Geriatr Soc 2016 09 26;64(9):e15-6. Epub 2016 Aug 26.

Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.14214DOI Listing
September 2016

TRPV4 ion channel as important cell sensors.

Authors:
Koji Shibasaki

J Anesth 2016 12 9;30(6):1014-1019. Epub 2016 Aug 9.

Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.

This review provides a summary of the physiological significance of the TRPV4 ion channel. Although TRPV4 was initially characterized as an osmosensor, we found that TRPV4 can also act as a thermosensor or a mechanosensor in brain neurons or epithelial cells in the urinary bladder. Here, we summarize the newly characterized functions of TRPV4, including the research progress that has been made toward our understanding of TRPV4 physiology, and discuss other recent data pertaining to TRPV4. It is thought that TRPV4 may be an important drug target based on its broad expression patterns and important physiological functions. Possible associations between diseases and TRPV4 are also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00540-016-2225-yDOI Listing
December 2016
-->