Hirakata General Hospital for Developmental Disorders

Hirakata, Japan

Hirakata General Hospital for Developmental Disorders

Hirakata, Japan
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PubMed | Hirakata General Hospital for Developmental Disorders, Hyogo College of Medicine and Kouiken Co.
Type: Journal Article | Journal: PloS one | Year: 2015

Major depressive disorder (MDD) is a common psychiatric disorder that involves marked disabilities in global functioning, anorexia, and severe medical comorbidities. MDD is associated with not only psychological and sociocultural problems, but also pervasive physical dysfunctions such as metabolic, neurobiological and immunological abnormalities. Nevertheless, the mechanisms underlying the interactions between these factors have yet to be determined in detail. The aim of the present study was to identify the molecular mechanisms responsible for the interactions between MDD and dysregulation of physiological homeostasis, including immunological function as well as lipid metabolism, coagulation, and hormonal activity in the brain. We generated depression-like behavior in mice using chronic mild stress (CMS) as a model of depression. We compared the gene expression profiles in the prefrontal cortex (PFC) of CMS and control mice using microarrays. We subsequently categorized genes using two web-based bioinformatics applications: Ingenuity Pathway Analysis and The Database for Annotation, Visualization, and Integrated Discovery. We then confirmed significant group-differences by analyzing mRNA and protein expression levels not only in the PFC, but also in the thalamus and hippocampus. These web tools revealed that hepatocyte nuclear factor 4 alpha (Hnf4a) may exert direct effects on various genes specifically associated with amine synthesis, such as genes involved in serotonin metabolism and related immunological functions. Moreover, these genes may influence lipid metabolism, coagulation, and hormonal activity. We also confirmed the significant effects of Hnf4a on both mRNA and protein expression levels in the brain. These results suggest that Hnf4a may have a critical influence on physiological homeostasis under depressive states, and may be associated with the mechanisms responsible for the interactions between MDD and the dysregulation of physiological homeostasis in humans.


Ogata J.,Hirakata General Hospital for Developmental Disorders | Yamanishi H.,Hirakata General Hospital for Developmental Disorders | Ishibashi-Ueda H.,Japan National Cardiovascular Center Research Institute
Neuropathology and Applied Neurobiology | Year: 2011

J. Ogata, H. Yamanishi and H. Ishibashi-Ueda (2011) Neuropathology and Applied Neurobiology37, 40-55 Role of cerebral vessels in ischaemic injury of the brainThis review discusses the pathological changes in the heart and vessels underlying brain ischaemic injury, with a major focus on atherosclerotic disease of the brain induced by lesions of the extracranial cervical and major intracranial arteries and small-vessel disease of the brain. The carotid bifurcation is the primary site for atherosclerotic changes, for which extensive clinical trials and pathological analyses on carotid endarterectomy specimens have been performed. Plaque rupture and erosion give rise to thrombus formation, which leads to brain ischaemic injury. These changes have much in common with atherosclerotic lesions of the subepicardial coronary arteries. Emboli of various types of particles are characteristics of brain ischaemic injury. Thrombi rich in fibrin and red blood cells (red thrombi) that develop in the cardiac chambers are common sources of cerebral emboli. Small-vessel disease of the brain induces fibrinoid necrosis, microaneurysm, fibrohyalinosis, lipohyalinosis and microatheroma, changes commonly associated with hypertension. The acute hypertensive small-vessel changes organize to create segmental arterial disorganization and deep small infarcts when they escape from rupture. Some specific vascular diseases responsible for brain ischaemic injury are briefly reviewed also. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.


Li W.,Hyogo College of Medicine | Okuda A.,Hyogo College of Medicine | Yamamoto H.,Hyogo College of Medicine | Yamanishi K.,Hyogo College of Medicine | And 4 more authors.
PLoS ONE | Year: 2013

Human γδ T cells augment host defense against tumors and infections, and might have a therapeutic potential in immunotherapy. However, mechanism of γδ T cell proliferation is unclear, and therefore it is difficult to prepare sufficient numbers of γδ T cells for clinical immunotherapy. Recently, natural killer (NK)-like CD56 brightCD11c+ cells were shown to promote the proliferation of γδ T cells in an IL-18-dependent manner. In this study, we demonstrated that the NK-like CD56brightCD11c+ cells could directly interact with γδ T cells to promote their sustained expansion, while conventional dendritic cells (DCs), IFN-α-induced DCs, plasmacytoid DCs or monocytes did not. We also examined the cellular mechanism underlying the regulation of CD56brightCD11c+ cells. CD14+ monocytes pre-incubated with IL-2/IL-18 formed intensive interactions with CD56intCD11c+ cells to promote their differentiation to CD56brightCD11c+ cells with helper function. The development of CD56brightCD11c+ cells was suppressed in an IFN-α dependent manner. These results indicate that CD14+ monocytes pretreated with IL-2/IL-18, but neither DCs nor monocytes, play a determining role on the development and proliferation of CD56brightCD11c+ cells, which in turn modulate the expansion of γδ T cells. CD56brightCD11c+ NK-like cells may be a novel target for immunotherapy utilizing γδ T cells, by overcoming the limitation of γδ T cells proliferation. © 2013 Li et al.


Yoshida M.,Hirakata General Hospital for Developmental Disorders | Yoshida M.,Osaka University | Watanabe Y.,Hirakata General Hospital for Developmental Disorders | Watanabe Y.,Osaka University | And 10 more authors.
International Journal of Molecular Medicine | Year: 2014

Spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) are frequently used as rat models not only of essential hypertension and stroke, but also of attention-deficit hyperactivity disorder (ADHD). Normotensive Wistar-Kyoto rats (WKY) are used as the control rats in these cases. An increasing number of studies has demonstrated the critical role of the central nervous system in the development and maintenance of hypertension. In a previous study, we analyzed the gene expression profiles in the adrenal glands of SHR. Thus, in this study, we analyzed gene expression profiles in the brains of SHR in order to identify the genes responsible for causing hypertension and stroke, as well as those involved in ADHD. Using genome-wide microarray technology, we examined the gene expression profiles in the brains of 3 rat strains (SHR, SHRSP and WKY) when the rats were 3 and 6 weeks of age, a period in which the rats are considered to be in a pre-hypertensive state. Gene expression profiles in the brain were compared between SHR and WKY, and between SHRSP and SHR. A total of 179 genes showing a >4- or <-4-fold change in expression were isolated, and candidate genes were selected using two different web tools: the first tool was the Database for Annotation, Visualization and Integrated Discovery (DAVID), which was used to search for significantly enriched genes, and categorized them using Gene Ontology (GO) terms, and the second was the network explorer of Ingenuity Pathway Analysis (IPA), which was used to search for interaction networks among SHR- and SHRSP-specific genes. The IPA of SHR-specific genes revealed that prostaglandin E receptor 4 (Ptger4) is one of the candidate genes responsible for causing hypertension in SHR, and that albumin (Alb) and chymase 1 (Cma1) are also responsible for causing hypertension in SHR in the presence of angiotensinogen (Agt). Similar analyses of SHRSP-specific genes revealed that the angiotensin II receptor-associated gene (Agtrap) interacts with the FBJ osteosarcoma oncogene (Fos), and with the angiotensin II receptor type-1b (Agtr1b). As Agtrap and Agtr1b not only participate in the 'uptake of norepinephrine' and 'blood pressure', but also in the 'behavior' of SHRSP at 6 weeks of age, our data demonstrate a close association between hypertension and ADHD.


Hasegawa M.,Hyogo College of Medicine | Hada J.,Hirakata General Hospital for Developmental Disorders | Fujiwara M.,Hyogo College of Medicine | Honda K.,Hyogo College of Medicine
Neurological Research | Year: 2014

In this study, we examined whether tooth pulp stimulation (TPS) affects the stress responses in anesthetized rats. As for stress response indices, we monitored changes in the concentrations of plasma catecholamines (CAs) (adrenaline, noradrenaline, and dopamine), corticosterone (CS), and glucose (Glu). We observed that repeated TPS attenuated plasma adrenaline, dopamine, CS, and Glu levels compared with those of sham-TPS. After administering naloxone, an opioid antagonist, repeated TPS reversed the decreases in plasma CAs, CS, and Glu. These findings showed that the effects of repeated TPS may be mediated by endogenous opioid administration. Our findings suggest that repeated TPS can induce stress-analgesia and that an endogenous descending pain modulation system exists. © W. S. Maney & Son Ltd 2014.


Ogata J.,Hirakata General Hospital for Developmental Disorders | Yamanishi H.,Hirakata General Hospital for Developmental Disorders | Ishibashi-Ueda H.,National Cerebral and Cardiovascular Center
Brain and Nerve | Year: 2013

This review describes the principal vessel histopathology in sporadic cerebral amyloid angiopathy (CAA). In sporadic CAA, β-amyloid is deposited on the lobar intracortical and leptomeningeal vessel wall. Fibrinoid necrosis, fibrohyalinous intimal thickening, microaneurysms, luminal stenosis, and inflammatory cell infiltration of the involved vessels appear subsequent to the amyloid deposition. The histopathology of sporadic CAA is described in comparison with that of hypertensive vasculopathy, both of which are the most common forms of cerebral small vessel disease.


Li W.,Hyogo College of Medicine | Jin D.,Osaka Medical College | Hata M.,Hyogo College of Medicine | Takai S.,Osaka Medical College | And 5 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2016

Inter- leukin-18 (IL-18) was discovered as an interferon-γ-inducing factor and has been regarded as a proinflammatory cytokine. However, IL-18 is ubiquitously expressed both in immune/inflammatory cells and in nonimmune cells, and its biological roles have not been sufficiently elucidated. Here, we demonstrate that IL-18-deficient [IL-18 knockout (KO)] mice have heart abnormalities that may be related to impaired autophagy. In endurance running tests, IL-18KO mice ran significantly shorter distances compared with wild-type (WT) mice. Echocardiographs indicated disability in the systolic and diastolic functions of the IL-18KO mouse heart. Immunostaining of connexin 43 showed heterogeneous localization of gap junctions in the lateral membranes of the IL-18KO cardiac myocytes. Western blotting analysis revealed decreased phosphorylated connexin 43 in the IL-18KO heart. Electron microscopy revealed unusual localization of intercalated disks, swollen or damaged mitochondria, and broad, indistinct Z-lines in the IL-18KO heart. In accordance with the morphological observation, mitochondrial respiratory function, including that of complexes I and IV, was impaired, and production of reactive oxygen species was augmented in IL-18KO hearts. Notably, levels of LC3-II were markedly lower in the IL-18KO hearts than in WT hearts. In the culture of cardiac myocytes of IL-18KO neonates, exogenous IL-18 upregulated LC3-II and increased the number of intact mitochondria with high mitochondrial membrane potential. These results indicated that IL-18 has roles apart from those as a proinflammatory cytokine in cardiac myocytes and suggested that IL-18 contributes to the homeostatic maintenance of mitochondrial function and gap-junction turnover in cardiac myocytes, possibly by upregulating autophagy. © 2016 the American Physiological Society.


PubMed | Hirakata General Hospital for Developmental Disorders
Type: Journal Article | Journal: Brain and nerve = Shinkei kenkyu no shinpo | Year: 2013

This review describes the principal vessel histopathology in sporadic cerebral amyloid angiopathy (CAA). In sporadic CAA, -amyloid is deposited on the lobar intracortical and leptomeningeal vessel wall. Fibrinoid necrosis, fibrohyalinous intimal thickening, microaneurysms, luminal stenosis, and inflammatory cell infiltration of the involved vessels appear subsequent to the amyloid deposition. The histopathology of sporadic CAA is described in comparison with that of hypertensive vasculopathy, both of which are the most common forms of cerebral small vessel disease.


PubMed | Hirakata General Hospital for Developmental Disorders, Hyogo College of Medicine, Shanghai Key Laboratory of Hypertension and Osaka Medical College
Type: Journal Article | Journal: American journal of physiology. Heart and circulatory physiology | Year: 2016

Interleukin-18 (IL-18) was discovered as an interferon--inducing factor and has been regarded as a proinflammatory cytokine. However, IL-18 is ubiquitously expressed both in immune/inflammatory cells and in nonimmune cells, and its biological roles have not been sufficiently elucidated. Here, we demonstrate that IL-18-deficient [IL-18 knockout (KO)] mice have heart abnormalities that may be related to impaired autophagy. In endurance running tests, IL-18KO mice ran significantly shorter distances compared with wild-type (WT) mice. Echocardiographs indicated disability in the systolic and diastolic functions of the IL-18KO mouse heart. Immunostaining of connexin 43 showed heterogeneous localization of gap junctions in the lateral membranes of the IL-18KO cardiac myocytes. Western blotting analysis revealed decreased phosphorylated connexin 43 in the IL-18KO heart. Electron microscopy revealed unusual localization of intercalated disks, swollen or damaged mitochondria, and broad, indistinct Z-lines in the IL-18KO heart. In accordance with the morphological observation, mitochondrial respiratory function, including that of complexes I and IV, was impaired, and production of reactive oxygen species was augmented in IL-18KO hearts. Notably, levels of LC3-II were markedly lower in the IL-18KO hearts than in WT hearts. In the culture of cardiac myocytes of IL-18KO neonates, exogenous IL-18 upregulated LC3-II and increased the number of intact mitochondria with high mitochondrial membrane potential. These results indicated that IL-18 has roles apart from those as a proinflammatory cytokine in cardiac myocytes and suggested that IL-18 contributes to the homeostatic maintenance of mitochondrial function and gap-junction turnover in cardiac myocytes, possibly by upregulating autophagy.


PubMed | Hirakata General Hospital for Developmental Disorders, Hyogo College of Medicine and Kyoto University
Type: Journal Article | Journal: PloS one | Year: 2013

Human T cells augment host defense against tumors and infections, and might have a therapeutic potential in immunotherapy. However, mechanism of T cell proliferation is unclear, and therefore it is difficult to prepare sufficient numbers of T cells for clinical immunotherapy. Recently, natural killer (NK)-like CD56(bright)CD11c(+) cells were shown to promote the proliferation of T cells in an IL-18-dependent manner. In this study, we demonstrated that the NK-like CD56(bright)CD11c(+) cells could directly interact with T cells to promote their sustained expansion, while conventional dendritic cells (DCs), IFN--induced DCs, plasmacytoid DCs or monocytes did not. We also examined the cellular mechanism underlying the regulation of CD56(bright)CD11c(+) cells. CD14(+) monocytes pre-incubated with IL-2/IL-18 formed intensive interactions with CD56(int)CD11c(+) cells to promote their differentiation to CD56(bright)CD11c(+) cells with helper function. The development of CD56(bright)CD11c(+) cells was suppressed in an IFN- dependent manner. These results indicate that CD14(+) monocytes pretreated with IL-2/IL-18, but neither DCs nor monocytes, play a determining role on the development and proliferation of CD56(bright)CD11c(+) cells, which in turn modulate the expansion of T cells. CD56(bright)CD11c(+) NK-like cells may be a novel target for immunotherapy utilizing T cells, by overcoming the limitation of T cells proliferation.

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