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(1) Neuroinflammation and ER-stress are key mechanisms of acute bilirubin toxicity and hearing loss in a mouse model.[TOP]

Pubmed ID :30106954
Publication Date : //
Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.

Authors : Schiavon Emanuele, Smalley Joshua L, Newton Sherylanne, Greig Nigel H, Forsythe Ian D,

(2) Cell-specific gene therapy driven by an optimized hypoxia-regulated vector reduces choroidal neovascularization.[TOP]

Pubmed ID :30105447
Publication Date : //
Aberrant growth of blood vessels in the choroid layer of the eye, termed choroidal neovascularization (CNV), is the pathological hallmark of exudative age-related macular degeneration (AMD), causing irreversible blindness among the elderly. Co-localization of proangiogenic factors and hypoxia inducible factors (HIF) in neovascular membranes from AMD eyes suggests the role of hypoxia in pathogenesis of CNV. In order to utilize hypoxic conditions in RPE for therapeutic purposes, we developed an optimized hypoxia regulated, RPE cell-specific gene therapy to inhibit choroidal neovascularization. An adeno-associated virus (AAV2) vector comprising a RPE-specific promoter and HIF-1 response elements (HRE) was designed to regulate production of human endostatin (a powerful angiostatic protein) in RPE. The vector was tested in a mouse model of laser-induced CNV using subretinal delivery. Spectral domain optical coherence tomography (SD-OCT) images from live mice and confocal images from lectin stained RPE flat mount sections demonstrated reduction in CNV areas by 80% compared to untreated eyes. Quantitative real-time polymerase chain reaction (qPCR) confirmed exogenous endostatin mRNA expression from the regulated vector that was significantly elevated 3, 7, and 14 days following laser treatment, but its expression was completely shut off after 45 days. Thus, RPE-specific, hypoxia-regulated delivery of anti-angiogenic proteins could be a valuable therapeutic approach to treat neovascular AMD at the time and in the ocular space where it arises.

Authors : Biswal Manas R, Prentice Howard M, Smith George W, Zhu Ping, Tong Yao, Dorey C Kathleen, Lewin Alfred S, Blanks Janet C,

(3) Enriched environment enhances β-adrenergic signaling to prevent microglia inflammation by amyloid-β.[TOP]

Pubmed ID :30093491
Publication Date : //
Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE's anti-inflammatory protection of brain microglia against soluble oligomers of human amyloid β-protein (oAβ). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced β-adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the β-adrenergic agonist isoproterenol experienced similar protection of microglia against oAβ-induced inflammation as did mice in EE Conversely, mice in EE fed the β-adrenergic antagonist propranolol lost microglial protection against oAβ. Mice lacking β1/β2-adrenergic receptors showed no protection of microglia by EE In SH mice, quantification of norepinephrine in hippocampus and interstitial fluid showed that oAβ disrupted norepinephrine homeostasis, and microglial-specific analysis of β2-adrenergic receptors indicated a decreased receptor level. Both features were rescued by EE Thus, enhanced β-adrenergic signaling at the ligand and receptor levels mediates potent benefits of EE on microglial inflammation induced by human Aβ oligomers .

Authors : Xu Huixin, Rajsombath Molly M, Weikop Pia, Selkoe Dennis J,

(4) Progress of studies on the systemic toxicities induced by titanium dioxide nanoparticles.[TOP]

Pubmed ID :30090482
Publication Date : //
Titanium dioxide nanoparticles (TiO NPs) are inorganic materials with a diameter of 1-100 nm. In recent years, TiO NPs have been used in a wide range of products, including food, toothpaste, cosmetics, medicine, paints and printing materials, due to their unique properties (high stability, anti-corrosion, and efficient photocatalysis). Following exposure various routes including inhalation, injection, dermal deposition and gastrointestinal tract absorption, NPs can be found in various organs in the body potentially inducing toxic effects. Thus more attention to the safety of TiO NPs is necessary. Therefore, the present review aims to provide a comprehensive evaluation of the toxic effects induced by TiO NPs in the lung, liver, stomach, intestine, kidney, spleen, brain, hippocampus, heart, blood vessels, ovary and testis of mice and rats in experiments, and evaluate their potential toxic mechanisms. The findings will provide an important reference for human risk evaluation and management following TiO NP exposure.

Authors : Hong Fashui, Yu Xiaohong, Wu Nan, Zhang Yu-Qing,

(5) Biochemical and Morphological Characterization of a Guanine Nucleotide Exchange Factor ARHGEF9 in Mouse Tissues.[TOP]

Pubmed ID :30083020
Publication Date : //
ARHGEF9, also known as Collybistin, a guanine nucleotide exchange factor for Rho family GTPases, is thought to play an essential role in the mammalian brain. In this study, we prepared a specific polyclonal antibody against ARHGEF9, anti-ARHGEF9, and carried out expression analyses with mouse tissues especially brain. Western blotting analyses demonstrated tissue-dependent expression profiles of ARHGEF9 in the young adult mouse, and strongly suggested a role during brain development. Immunohistochemical analyses revealed developmental stage-dependent expression profiles of ARHGEF9 in cerebral cortex, hippocampus and cerebellum. ARHGEF9 exhibited partial localization at dendritic spines in cultured hippocampal neurons. From the obtained results, anti-ARHGEF9 was found to be a useful tool for biochemical and cell biological analyses of ARHGEF9.

Authors : Ibaraki Kyoko, Mizuno Makoto, Aoki Hitomi, Niwa Ayumi, Iwamoto Ikuko, Hara Akira, Tabata Hidenori, Ito Hidenori, Nagata Koh-Ichi,

(6) Phosphoproteomic approach for agonist-specific signaling in mouse brains: mTOR pathway is involved in κ opioid aversion.[TOP]

Pubmed ID :30082888
Publication Date : //
Kappa opioid receptor (KOR) agonists produce analgesic and anti-pruritic effects, but their clinical application was limited by dysphoria and hallucinations. Nalfurafine, a clinically used KOR agonist, does not cause dysphoria or hallucinations at therapeutic doses in humans. We found that in CD-1 mice nalfurafine produced analgesic and anti-scratch effects dose-dependently, like the prototypic KOR agonist U50,488H. In contrast, unlike U50,488H, nalfurafine caused no aversion, anhedonia, or sedation or and a low level of motor incoordination at the effective analgesia and anti-scratch doses. Thus, we established a mouse model that recapitulated important aspects of the clinical observations. We then employed a phosphoproteomics approach to investigate mechanisms underlying differential KOR-mediated effects. A large-scale mass spectrometry (MS)-based analysis on brains revealed that nalfurafine perturbed phosphoproteomes differently from U50,488H in a brain-region specific manner after 30-min treatment. In particular, U50,488H and nalfurafine imparted phosphorylation changes to proteins found in different cellular components or signaling pathways in different brain regions. Notably, we observed that U50,488H, but not nalfurafine, activated the mammalian target of rapamycin (mTOR) pathway in the striatum and cortex. Inhibition of the mTOR pathway by rapamycin abolished U50,488H-induced aversion, without affecting analgesic, anti-scratch, and sedative effects and motor incoordination. The results indicate that the mTOR pathway is involved in KOR agonist-induced aversion. This is the first demonstration that phosphoproteomics can be applied to agonist-specific signaling of G protein-coupled receptors (GPCRs) in mouse brains to unravel pharmacologically important pathways. Furthermore, this is one of the first two reports that the mTOR pathway mediates aversion caused by KOR activation.

Authors : Liu Jeffrey J, Chiu Yi-Ting, DiMattio Kelly M, Chen Chongguang, Huang Peng, Gentile Taylor A, Muschamp John W, Cowan Alan, Mann Matthias, Liu-Chen Lee-Yuan,

(7) Imaging of Microglia With Multiphoton Microscopy.[TOP]

Pubmed ID :30072888
Publication Date : //
Neuroimaging has become an unparalleled tool to understand the central nervous system (CNS) anatomy, physiology and neurological diseases. While an altered immune function and microglia hyperactivation are common neuropathological features for many CNS disorders and neurodegenerative diseases, direct assessment of the role of microglial cells remains a challenging task. Non-invasive neuroimaging techniques, including magnetic resonance imaging (MRI), positron emission tomography (PET) and single positron emission computed tomography (SPECT) are widely used for human clinical applications, and a variety of ligands are available to detect neuroinflammation. In animal models, intravital imaging has been largely used, and minimally invasive multiphoton microcopy (MPM) provides high resolution detection of single microglia cells, longitudinally, in living brain. In this study, we review real-time MPM approaches to assess microglia in preclinical studies, including individual cell responses in surveillance, support, protection and restoration of brain tissue integrity, synapse formation, homeostasis, as well as in different pathological situations. We focus on studies that assess the role of microglia in mouse models of Alzheimer's disease (AD), analyzing microglial motility and recruitment, as well as the role of microglia in anti-amyloid-β treatment, as a key therapeutic approach to treat AD. Altogether, MPM provides a high contrast and high spatial resolution approach to follow microglia chronically in complex models, supporting MPM as a powerful tool for deep intravital tissue imaging.

Authors : Hierro-Bujalance Carmen, Bacskai Brian J, Garcia-Alloza Monica,

(8) Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors.[TOP]

Pubmed ID :30071868
Publication Date : //
Reprogramming of cancers into normal-like tissues is an innovative strategy for cancer treatment. Recent reports demonstrate that defined factors can reprogram cancer cells into pluripotent stem cells. Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor. Therefore, developing novel therapeutic strategy is a critical requirement.

Authors : Yuan Jie, Zhang Fan, Hallahan Dennis, Zhang Zhen, He Liming, Wu Ling-Gang, You Meng, Yang Qin,

(9) Dendritic cell-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites elicits enhanced anti-cancer immune response in glioblastoma.[TOP]

Pubmed ID :30071380
Publication Date : //
Glioblastoma (GBM) is the deadliest and most common type of primary brain tumor in adults with a grim prognosis despite multimodal treatments. Dendritic cell (DC)-based immunotherapy has emerged as a promising therapeutic modality for GBM, whose efficacy is nonetheless fundamentally undermined by GBM-induced immunosuppression. Inducing emission of damage associated molecular patterns (DAMPs) is a highly effective strategy to subvert tumor-associated immunosuppression. The present work was carried out to explore the idea of subverting the GBM immunosuppressive microenvironment through DC-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites (Nano-DOX), a potent DAMPs inducer demonstrated by our previous study, and thereby eliciting enhanced DC-driven anti-GBM immune response. In the in-vitro work on human cell models, Nano-DOX-loaded DC were shown to be functionally viable and release cargo drug to co-cultured GBM cells (GC). Nano-DOX-treated GC displayed not only profuse DAMPs emission but also antigen release. Enhanced activation and acquisition and presentation of GC-derived antigen were then demonstrated in DC in co-culture with GC and Nano-DOX. Consistently, co-culture with GC and Nano-DOX also activated mouse bone marrow-derived DC (mDC) which in turn stimulated mouse spleen-derived lymphocytes which ultimately suppressed co-cultured GC. Next, athymic mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mDC and, 48 h later, spleen-derived lymphocytes. The presence of Nano-DOX, DAMPs emission and enhanced infiltration and activation of mDC and lymphocytes were detected in the GBM xenografts. Taken together, our results demonstrate the efficacy of DC-mediated delivery of Nano-DOX to stimulate GC immunogenicity and elicit anti-cancer immune response in the GBM. By this work, we present a novel approach with great application potential to subverting the GBM immunosuppressive microenvironment and to anti-GBM immunotherapy. Investigation has also been conducted probing the mechanisms by which Nano-DOX stimulates GC immunogenicity, which is described in a follow-up paper.

Authors : Li Tong-Fei, Li Ke, Zhang Quan, Wang Chao, Yue Yuan, Chen Zhuo, Yuan Shen-Jun, Liu Xin, Wen Yu, Han Min, Komatsu Naoki, Xu Yong-Hong, Zhao Li, Chen Xiao,

(10) Adenosine Promotes the Recovery of Mice from the Cuprizone-Induced Behavioral and Morphological Changes while Effecting on Microglia and Inflammatory Cytokines in the Brain.[TOP]

Pubmed ID :30069711
Publication Date : //
Recent studies have shown that multiple sclerosis (MS) and schizophrenia share similarities in some respects, including white matter damage and neuroinflammation. On the other hand, adenosine was reported to promote oligodendrocyte precursor maturation and remyelinating while influencing microglia activation. The aim of the present study was to examine possible beneficial effects of adenosine on the recovery of cuprizone (CPZ)-exposed mouse which has been used as an animal model of MS and schizophrenia as the CPZ-exposed mouse presents demyelination, oligodendrocyte loss, microglia accumulation, as well as behavioral changes. As reported previously, C57BL/6 mice, after fed CPZ for 5 weeks, showed salient demyelination and oligodendrocyte loss in the cerebral cortex (CTX) and hippocampus, in addition to displaying anxiety-like behavior, spatial working memory deficit, and social interaction impairment. Administration of adenosine for 7 days during the recovery period after CPZ withdrawal promoted the behavioral recovery of CPZ-exposed mice and accelerated the remyelinating process in the brains of mice after CPZ withdrawal in a dose-dependent manner. In addition, the effective dose (10 mg/kg) of adenosine inhibited microglia activation and suppressed abnormal elevation of the pro-inflammatory cytokines IL-1β and TNF-α in CTX and hippocampus, but increased levels of the anti-inflammatory cytokines IL-4 or IL-10 in the same brain regions during the remyelinating process. These results provided an evidence-based rationale for the application of adenosine or its analogues as add-on therapy for schizophrenia.

Authors : Zhang Jinling, Yang Liu, Fang Zeman, Kong Jiming, Huang Qingjun, Xu Haiyun,