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Dive into the research topics where Hiroko Nobuta is active.

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Featured researches published by Hiroko Nobuta.


Neuroscience | 2008

IMPAIRED NERVE REGENERATION AND ENHANCED NEUROINFLAMMATORY RESPONSE IN MICE LACKING PITUITARY ADENYLYL CYCLASE ACTIVATING PEPTIDE

Brian D. Armstrong; Catalina Abad; Seririthanar Chhith; Gardenia Cheung-Lau; O.E. Hajji; Hiroko Nobuta; James A. Waschek

Peripheral nerve injury models are used to investigate processes that can potentially be exploited in CNS injury. A consistent change that occurs in injured peripheral neurons is an induction in expression of pituitary adenylyl cyclase activating peptide (PACAP), a neuropeptide with putative neuroprotective and neuritogenic actions. PACAP-deficient mice were used here to investigate actions of endogenous PACAP after facial nerve injury. Although motor neuron survival after axotomy was not significantly different in PACAP deficient vs. wild type mice, recovery of axon regeneration after crush injury was significantly delayed. The impaired regeneration was associated with 8- to 12-fold increases in gene expression of proinflammatory cytokines tumor necrosis factor-alpha, interferon-gamma, interleukin (IL) -6, and a 90% decrease in the anti-inflammatory cytokine IL-4 at the injury site. Similar cytokine changes and an increased microglial response were observed in the brainstem facial motor nucleus. Because immunocompromised animals such as SCID mice are known to exhibit peripheral nerve regeneration defects, the observations raise the novel hypothesis that PACAP is critically involved in a carefully controlled immune response that is necessary for proper nerve regeneration after injury.


Annals of Neurology | 2012

STAT3-mediated astrogliosis protects myelin development in neonatal brain injury.

Hiroko Nobuta; Cristina A. Ghiani; Pablo M. Paez; Vilma Spreuer; Hongmei Dong; Rose A. Korsak; Armine Manukyan; Jiaxi Li; Harry V. Vinters; Eric J. Huang; David H. Rowitch; Michael V. Sofroniew; Anthony T. Campagnoni; Jean de Vellis; James A. Waschek

Pathological findings in neonatal brain injury associated with preterm birth include focal and/or diffuse white matter injury (WMI). Despite the heterogeneous nature of this condition, reactive astrogliosis and microgliosis are frequently observed. Thus, molecular mechanisms by which glia activation contribute to WMI were investigated.


International Journal of Cancer | 2007

Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP

Nicole Nemetz; Catalina Abad; Greg Lawson; Hiroko Nobuta; Seririthanar Chhith; Lucy Duong; Gary Tse; Jonathan Braun; James A. Waschek

Pituitary adenylyl cyclase activating peptide (PACAP) is expressed in central, sensory, autonomic, and enteric neurons. Although it classically acts as a neurotransmitter/neuromodulator, recent studies indicate that PACAP can also regulate immune function. To this effect, PACAP has been shown to reduce clinical symptoms and inflammation in mouse models of human immune‐based diseases such as rheumatoid arthritis, Crohns Disease, septic shock and multiple sclerosis. Despite these findings, the role of the endogenous peptide in regulating immune function is unknown. To determine if endogenous PACAP plays a protective role in inflammatory bowel disease (IBD) and IBD‐associated colorectal cancer in mice, PACAP‐deficient (KO) mice were subjected to 3 cycles of dextran sulfate sodium (DSS) in drinking water over 2 months, an established mouse model for colitis. Compared to wild type (WT) controls, PACAP KO mice exhibited more severe clinical symptoms of colitis and had significantly higher colonic inflammation on pathological examination. Moreover, 60% of the PACAP KO mice developed colorectal tumors with an aggressive‐appearing pathology. Consistent with published data, DSS‐treated WT mice did not develop such tumors. The results demonstrate a new mouse model which rapidly develops inflammation‐associated colorectal cancer in the absence of a carcinogen.


Asn Neuro | 2011

Early Effects of Lipopolysaccharide-Induced Inflammation on Foetal Brain Development in Rat

Cristina A. Ghiani; Natalia S. Mattan; Hiroko Nobuta; Jemily Malvar; Julie Boles; Michael G. Ross; James A. Waschek; Ellen M. Carpenter; Robin S. Fisher; Jean de Vellis

Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide)/kg to timed-pregnant rats at GD15 (gestational day 15) and GD16. Increased thickness of the CP (cortical plate) and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter), and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.


Proceedings of the National Academy of Sciences of the United States of America | 2010

Vasoactive intestinal peptide loss leads to impaired CNS parenchymal T-cell infiltration and resistance to experimental autoimmune encephalomyelitis

Catalina Abad; Yossan-Var Tan; Robert Lopez; Hiroko Nobuta; Hongmei Dong; Phu Phan; Ji-Ming Feng; Anthony T. Campagnoni; James A. Waschek

The neuropeptide vasoactive intestinal peptide (VIP) has been shown to inhibit macrophage proinflammatory actions, promote a positive Th2/Th1 balance, and stimulate regulatory T-cell production. The fact that this peptide is highly efficacious in animal models of inflammatory diseases such as collagen-induced arthritis and experimental autoimmune encephalomyelitis (EAE) suggests that the endogenous peptide might normally provide protection against such pathologies. We thus studied the response of VIP-deficient (i.e., VIP KO) mice to myelin oligodendrocyte protein-induced EAE. Surprisingly, VIP KO mice were almost completely resistant to EAE, with delayed onset and mild or absent clinical profile. Despite this, flow cytometric analyses and antigen-rechallenge experiments indicated that myelin oligodendrocyte protein-treated VIP KO mice exhibited robust Th1/Th17 cell inductions and antigen-specific proliferation and cytokine responses. Moreover, adoptive transfer of lymphocytes from immunized VIP KO mice to WT recipients resulted in full-blown EAE, supporting their encephalitogenic potential. In contrast, transfer of encephalitogenic WT cells to VIP KO hosts did not produce EAE, suggesting that loss of VIP specifically affected the effector phase of the disease. Histological analyses indicated that CD4 T cells entered the meningeal and perivascular areas of VIP-deficient mice, but that parenchymal infiltration was strongly impaired. Finally, VIP pretreatment of VIP KO mice before immunization was able to restore their sensitivity to EAE. These results indicate that VIP plays an unanticipated permissive and/or proinflammatory role in the propagation of the inflammatory response in the CNS, a finding with potential therapeutic relevance in autoimmune neuroinflammatory diseases such as multiple sclerosis.


The Lancet | 2017

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

Ari J. Green; Jeffrey M. Gelfand; Bruce Ac Cree; Carolyn Bevan; W. John Boscardin; Feng Mei; Justin Inman; Sam Arnow; Michael P. Devereux; Aya Abounasr; Hiroko Nobuta; Alyssa H. Zhu; Matt Friessen; Roy Gerona; Hans Christian Von Büdingen; Roland G. Henry; Stephen L. Hauser; Jonah R. Chan

BACKGROUND Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis. METHODS We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298. FINDINGS Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported. INTERPRETATION To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage. FUNDING University of California, San Francisco and the Rachleff Family.


The Journal of Neuroscience | 2016

Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination

Feng Mei; Sonia R. Mayoral; Hiroko Nobuta; Fei Wang; Caroline Desponts; Daniel S. Lorrain; Lan Xiao; Ari J. Green; David H. Rowitch; Jennifer L. Whistler; Jonah R. Chan

Remyelinating therapies seek to promote restoration of function and normal cellular architecture following demyelination in diseases, such as multiple sclerosis (MS). Functional screening for small molecules or novel targets for remyelination is a major hurdle to the identification and development of rational therapeutics for MS. Recent findings and technical advances provide us with a unique opportunity to provide insight into the cell autonomous mechanisms for remyelination and address this unmet need. Upon screening a G-protein-coupled receptor small-molecule library, we report the identification of a cluster of κ-opioid receptor (KOR) agonists that significantly promotes oligodendrocyte differentiation and myelination. KOR agonists were validated in purified rat oligodendroglial cultures, and the (±)U-50488 compound proved to be most effective for differentiation. (±)U-50488 treatment significantly enhances differentiation and myelination in purified oligodendroglial cocultures and greatly accelerates the kinetics of remyelination in vivo after focal demyelination with lysolecithin. The effect of (±)U-50488 is attenuated by KOR antagonists and completely abolished in KOR-null oligodendroglia. Conditional deletion of KOR in murine oligodendrocyte precursor cells (OPCs) greatly inhibits remyelination after focal demyelination lacking any response to (±)U-50488 treatment. To determine whether agonism of KOR represents a feasible therapeutic approach, human induced pluripotent stem cell-derived OPCs were treated with (±)U-50488. Consistent with findings, differentiation of human OPCs into mature oligodendrocytes was significantly enhanced. Together, KOR is a therapeutic target to consider for future remyelination therapy. SIGNIFICANCE STATEMENT Remyelination represents a promising strategy to achieve functional recovery in demyelinating diseases, like MS. Thus, identification of potent compounds and targets that promote remyelination represents a critically unmet need. This study reports a cluster of compounds that are highly effective in enhancing remyelination and identifies κ-opioid receptor (KOR) as a positive regulator for oligodendroglial differentiation, implicating KOR agonism as a potential strategy to accelerate remyelination.


Journal of Leukocyte Biology | 2014

Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma

Catalina Abad; Hiroko Nobuta; Jiaxi Li; Atsushi Kasai; William H. Yong; James A. Waschek

Although the immune system may provide early protection against cancer, tumors may exploit the healing arm of the immune system to enhance their growth and metastasis. For example, myeloid derived suppressor cells (MDSCs) are thought to promote tumor growth by several mechanisms, including the suppression of T cell activity. It has been suggested that STAT3 activation in myeloid cells modulates multiple aspects of MDSC physiology, including their expansion and activity. Whereas most animal studies investigating tumor immunology have used tumor implants, we used transgenic mice (Smo*) that spontaneously develop medulloblastoma brain tumors to investigate the temporal accumulation of MDSCs within tumors and how myeloid STAT3 disruption affects MDSC and other immune cell types. We found distinct populations of MDSC in medulloblastoma tumors, with a high prevalence of CD11b+Ly6G+Ly6Clow/− cells, described previously by others as G‐MDSCs. These were found early in tumor development, in premalignant lesions located on the surface of the cerebellum of 28‐day‐old mice. In fully developed tumors, pSTAT3 was found in the majority of these cells. Conditional STAT3 gene disruption in myeloid cells resulted in an enhanced proinflammatory phenotype of macrophages in Smo* mice. Moreover, a significant reduction in the abundance of G‐MDSCs and Tregs was observed within tumors along with an increased presence of CD4+ and CD8+ cells. Despite these alterations in immune cells induced by myeloid STAT3 disruption, we found no effect on tumor incidence in Smo* mice with this deletion.


Neuroscience | 2013

PACAP deficiency sensitizes nigrostriatal dopaminergic neurons to paraquat-induced damage and modulates central and peripheral inflammatory activation in mice

Melanie B. Watson; Hiroko Nobuta; Catalina Abad; Soo Kyung Lee; Noor Bala; Chunni Zhu; Franziska Richter; Marie-Françoise Chesselet; James A. Waschek

Exposure to the pesticide paraquat (PQ) increases the risk of Parkinsons disease (PD), and its effect may be modulated by genetic or other environmental factors. The neuropeptide PACAP (pituitary adenylyl cyclase-activating polypeptide, Adcyap1) has been shown to enhance tyrosine hydroxylase (TH) and VMAT2 expression, protect dopaminergic (DA) neurons against the neurotoxin 6-hydroxydopamine, regulate neuronal mitochondria, and inhibit inflammation. Decreased expression of PACAP may thus interact with environmental factors such as PQ to increase the risk of PD. To mimic a low level environmental exposure to PQ, wild type (WT) and PACAP knockout (KO) mice were given a single [10 mg/kg] dose of PQ, a regimen that did not induce the loss of TH expression or DA neurons in WT mice. This treatment selectively reduced the number of TH-positive cell bodies in the substantia nigra pars compacta (SNpc) selectively in PACAP KO mice. Because inflammation is also a risk factor for PD, we performed a quantitative analysis of SNpc Iba⁺ microglia. As expected, PQ increased the number of larger microglial profiles, indicative of activation, in WT mice. Strikingly, microglial activation was already evident in PACAP KO mice in the basal state. PQ caused no further activation in these mice, although tumor necrosis factor-α gene expression was enhanced. In the periphery, PQ had no effects on the abundance of proinflammatory Th1 or Th17 cells in WT mice, but increased the numbers of anti-inflammatory regulatory T cells (Tregs). PACAP KO mice, in contrast, had elevated numbers of Th17 cells after PQ, and the induction of Tregs was impaired. The results indicate that endogenous PACAP acts to maintain the integrity of DA neurons during exposure to PQ, an action that may be linked to its ability to regulate microglia and/or other immune cells.


Acta Neuropathologica | 2015

Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome

Hiroko Nobuta; Maria Roberta Cilio; Olivier Danhaive; Hui-Hsin Tsai; Srinivasan Tupal; Sandra Chang; Alice T. Murnen; Faith Kreitzer; Verenice Bravo; Catherine Czeisler; Hamza Numan Gokozan; Patrick Gygli; Sean Bush; Debra E. Weese-Mayer; Bruce R. Conklin; Siu-Pok Yee; Eric J. Huang; Paul A. Gray; David H. Rowitch; Jose Otero

Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆8 mutation, we found that early embryonic expression (<E10.5) caused failure of LC neuronal specification and perinatal respiratory lethality. In contrast, later onset (E11.5) of PHOX2B∆8 expression was not deleterious to LC development and perinatal respiratory lethality was rescued, despite failure of chemosensor retrotrapezoid nucleus formation. Our findings indicate that early-onset mutant PHOX2B expression inhibits LC neuronal development in CCHS. They further suggest that such mutations result in dysregulation of central noradrenergic signaling, and therefore, potential for early pharmacologic intervention in humans with CCHS.

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Catalina Abad

University of California

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Hongmei Dong

University of California

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Ari J. Green

University of California

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Eric J. Huang

University of California

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Hui-Hsin Tsai

University of California

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Jean de Vellis

University of California

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