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(1) Simulated microgravity culture enhances the neuroprotective effects of human cranial bone-derived mesenchymal stem cells in traumatic brain injury.[TOP]

Pubmed ID :29790427
Publication Date : //
Fundamental cures of central nervous system (CNS) diseases are rarely achieved due to the low regenerative ability of the CNS. Recently, cell-based therapy using mesenchymal stem cells (MSCs) has been explored as effective treatments for CNS diseases. Among the various tissue-derived MSCs, we have isolated human cranial bone-derived MSCs (cMSCs) in our laboratory. In addition, we have focused on simulated microgravity (MG) as a valuable culture environment of MSCs. However, the detailed mechanisms underlying functional recovery from the transplantation of MSCs cultured under MG conditions remain unclear. In this study, we investigated the therapeutic mechanisms of cMSCs transplantation cultured under MG conditions in traumatic brain injury (TBI) model mice. Human cMSCs were cultured under 1G and MG conditions, and cMSCs cultured under MG conditions expressed significantly higher mRNA levels of hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-β). In TBI model mice, the transplantation of cMSCs cultured under MG conditions (group MG) showed greater motor functional improvement compared to the only phosphate buffered saline administration (group PBS). Moreover, the protein expressions of tumor necrosis factor alpha (TNF-α) and the Bax/Bcl-2 ratio were significantly lower at brain injury sites in mice of group MG than those of group PBS. In addition, an in vitro study showed that the conditioned medium of the cMSCs cultured under MG conditions significantly suppressed the cell death of NG108-15 cells exposed to oxidative or inflammatory stress through anti-inflammatory and anti-apoptosis effects. These findings demonstrate that culturing cMSCs under simulated microgravity increases the neuroprotective effects, suggesting that simulated microgravity cultures may be a useful method for cell-based therapy strategies for CNS diseases.

Authors : Otsuka Takashi, Imura Takeshi, Nakagawa Kei, Shrestha Looniva, Takahashi Shinya, Kawahara Yumi, Sueda Taijiro, Kurisu Kaoru, Yuge Louis,

(2) Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease.[TOP]

Pubmed ID :29784049
Publication Date : //
Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery.

Authors : Rangaraju Srikant, Dammer Eric B, Raza Syed Ali, Rathakrishnan Priyadharshini, Xiao Hailian, Gao Tianwen, Duong Duc M, Pennington Michael W, Lah James J, Seyfried Nicholas T, Levey Allan I,

(3) The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model.[TOP]

Pubmed ID :29781813
Publication Date : //
NOTCH1 is a prevalent signaling pathway in T cell acute lymphoblastic leukemia (T-ALL), but crucial NOTCH1 downstream signals and target genes contributing to T-ALL pathogenesis cannot be retrospectively analyzed in patients and thus remain ill defined. This information is clinically relevant, as initiating lesions that lead to cell transformation and leukemia-initiating cell (LIC) activity are promising therapeutic targets against the major hurdle of T-ALL relapse. Here, we describe the generation in vivo of a human T cell leukemia that recapitulates T-ALL in patients, which arises de novo in immunodeficient mice reconstituted with human hematopoietic progenitors ectopically expressing active NOTCH1. This T-ALL model allowed us to identify CD44 as a direct NOTCH1 transcriptional target and to recognize CD44 overexpression as an early hallmark of preleukemic cells that engraft the BM and finally develop a clonal transplantable T-ALL that infiltrates lymphoid organs and brain. Notably, CD44 is shown to support crucial BM niche interactions necessary for LIC activity of human T-ALL xenografts and disease progression, highlighting the importance of the NOTCH1/CD44 axis in T-ALL pathogenesis. The observed therapeutic benefit of anti-CD44 antibody administration in xenotransplanted mice holds great promise for therapeutic purposes against T-ALL relapse.

Authors : García-Peydró Marina, Fuentes Patricia, Mosquera Marta, García-León María J, Alcain Juan, Rodríguez Antonio, de Miguel Purificación García, Menéndez Pablo, Weijer Kees, Spits Hergen, Scadden David T, Cuesta-Mateos Carlos, Muñoz-Calleja Cecilia, Sánchez-Madrid Francisco, Toribio María L,

(4) Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery.[TOP]

Pubmed ID :29767307
Publication Date : //
The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively. Delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells may provide a more stable and localized reservoir of therapy as they are more differentiated than fast-dividing tumor cells. Reactive astrocytes and tumor-associated macrophage/microglia (TAMs) are stromal cells that comprise a large portion of the tumor mass and are associated with tumorigenesis. In mouse models of GBM, we used IV delivery of exosome-associated AAV vectors driving green fluorescent protein expression by specific promoters (NF-κB-responsive promoter and a truncated glial fibrillary acidic protein promoter), to obtain targeted transduction of TAMs and reactive astrocytes, respectively, while avoiding transgene expression in the periphery. We used our approach to express the potent, yet toxic anti-tumor cytokine, interferon beta, in tumor stroma of a mouse model of GBM, and achieved a modest, yet significant enhancement in survival compared to controls. Noninvasive genetic modification of tumor microenvironment represents a promising approach for therapy against cancers. Additionally, the vectors described here may facilitate basic research in the study of tumor stromal cells in situ.

Authors : Volak Adrienn, LeRoy Stanley G, Natasan Jeya Shree, Park David J, Cheah Pike See, Maus Andreas, Fitzpatrick Zachary, Hudry Eloise, Pinkham Kelsey, Gandhi Sheetal, Hyman Bradley T, Mu Dakai, GuhaSarkar Dwijit, Stemmer-Rachamimov Anat O, Sena-Esteves Miguel, Badr Christian E, Maguire Casey A,

(5) Pharmacopuncture with Scolopendra subspinipes suppresses mechanical allodynia in oxaliplatin-induced neuropathic mice and potentiates clonidine-induced anti-allodynia without hypotension or motor impairment.[TOP]

Pubmed ID :29758357
Publication Date : //
Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of anticancer drugs but lacks an effective treatment strategy. Scolopendra subspinipes (SS) has been used in traditional medicine to treat chronic neuronal diseases. Moreover, pharmacopuncture with SS (SSP) produces potent analgesia in humans and experimental animals. In this study, we examined the effect of SSP into the ST36 acupoint on oxaliplatin-induced mechanical allodynia in mice. Acupoint treatment with SSP (0.5%/20 μL) significantly reduced mechanical allodynia produced by a single oxaliplatin injection (10 mg/kg, i.p.), which was completely prevented by acupoint pre-injection of lidocaine. Intrathecal treatment with yohimbine (25 μg/5 μL), an α-adrenoceptor antagonist, prevented the anti-allodynic effect of SSP. On the other hand, a high dose (0.1 mg/kg, i.p.) of clonidine, an α-adrenoceptor agonist, suppressed oxaliplatin-induced mechanical allodynia, but produced severe side effects including hypotension, bradycardia, and motor impairment. Combination of SSP with a lower dose (0.03 mg/kg) of clonidine produced a comparable analgesic effect without side effects. Collectively, our findings demonstrate that SSP produces an analgesic effect in oxaliplatin-induced pain via neuronal conduction at the acupoint and activation of spinal α-adrenoceptors. Moreover, a combination of low-dose clonidine with SSP represents a novel and safe therapeutic strategy for chemotherapy-induced chronic pain.

Authors : Yoon Seo-Yeon, Lee Jeong-Yun, Roh Dae-Hyun, Oh Seog Bae,

(6) Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment.[TOP]

Pubmed ID :29753658
Publication Date : //
There is an urgent need for strategies to combat dengue virus (DENV) infection; a major global threat. We reported that the cellular kinases AAK1 and GAK regulate intracellular trafficking of multiple viruses and that sunitinib and erlotinib, approved anticancer drugs with potent activity against these kinases, protect DENV-infected mice from mortality. Nevertheless, further characterization of the therapeutic potential and underlying mechanism of this approach is required prior to clinical evaluation. Here, we demonstrate that sunitinib/erlotinib combination achieves sustained suppression of systemic infection at approved dose in DENV-infected IFN-α/β and IFN-γ receptor-deficient mice. Nevertheless, treatment with these blood-brain barrier impermeable drugs delays, yet does not prevent, late-onset paralysis; a common manifestation in this immunodeficient mouse model but not in humans. Sunitinib and erlotinib treatment also demonstrates efficacy in human primary monocyte-derived dendritic cells. Additionally, DENV infection induces expression of AAK1 transcripts, but not GAK, via single-cell transcriptomics, and these kinases are important molecular targets underlying the anti-DENV effect of sunitinib and erlotinib. Lastly, sunitinib/erlotinib combination alters inflammatory cytokine responses in DENV-infected mice. These findings support feasibility of repurposing sunitinib/erlotinib combination as a host-targeted antiviral approach and contribute to understanding its mechanism of antiviral action.

Authors : Pu Szu-Yuan, Xiao Fei, Schor Stanford, Bekerman Elena, Zanini Fabio, Barouch-Bentov Rina, Nagamine Claude M, Einav Shirit,

(7) IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination that involves the down-regulation of the IL-4 receptor in the hippocampus.[TOP]

Pubmed ID :29751176
Publication Date : //
We have previously verified that neonatal hepatitis B vaccination induced hippocampal neuroinflammation and behavior impairments in mice. However, the exact mechanism of these effects remain unclear. In this study, we observed that neonatal hepatitis B vaccination induced an anti-inflammatory cytokine response lasting for 4-5 weeks in both the serum and the hippocampus, primarily indicated by elevated IL-4 levels. Three weeks after the vaccination schedule, however, hepatitis B vaccine (HBV)-mice showed delayed hippocampal neuroinflammation. In periphery, IL-4 is the major cytokine induced by this vaccine. Correlation analyses showed a positive relationship in the IL-4 levels between serum and hippocampus in HBV-mice. Thus, we investigated whether neonatal over-exposure to systemic IL-4 influences brain and behavior. We observed that mice injected intraperitoneally with recombinant mouse IL-4 (mIL-4) during early life had similar neuroinflammation and cognition impairment similar to those induced by neonatal hepatitis B vaccination. Next, the mechanism underlying the effects of IL-4 on brain in mice was explored using a series of experiments. In brief, these experiments showed that IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination, which involves the permeability of neonatal blood-brain barrier and the down-regulation of IL-4 receptor. This finding suggests that clinical events concerning neonatal IL-4 over-exposure, including neonatal hepatitis B vaccination and allergic asthma in human infants, may have adverse implications for brain development and cognition.

Authors : Wang Xiao, Yang Junhua, Xing Zhiwei, Zhang Hongyang, Wen Yaru, Qi Fangfang, Zuo Zejie, Xu Jie, Yao Zhibin,

(8) An Immunocompetent Mouse Model of Zika Virus Infection.[TOP]

Pubmed ID :29746837
Publication Date : //
Progress toward understanding Zika virus (ZIKV) pathogenesis is hindered by lack of immunocompetent small animal models, in part because ZIKV fails to effectively antagonize Stat2-dependent interferon (IFN) responses in mice. To address this limitation, we first passaged an African ZIKV strain (ZIKV-Dak-41525) through Rag1 mice to obtain a mouse-adapted virus (ZIKV-Dak-MA) that was more virulent than ZIKV-Dak-41525 in mice treated with an anti-Ifnar1 antibody. A G18R substitution in NS4B was the genetic basis for the increased replication, and resulted in decreased IFN-β production, diminished IFN-stimulated gene expression, and the greater brain infection observed with ZIKV-Dak-MA. To generate a fully immunocompetent mouse model of ZIKV infection, human STAT2 was introduced into the mouse Stat2 locus (hSTAT2 KI). Subcutaneous inoculation of pregnant hSTAT2 KI mice with ZIKV-Dak-MA resulted in spread to the placenta and fetal brain. An immunocompetent mouse model of ZIKV infection may prove valuable for evaluating countermeasures to limit disease.

Authors : Gorman Matthew J, Caine Elizabeth A, Zaitsev Konstantin, Begley Matthew C, Weger-Lucarelli James, Uccellini Melissa B, Tripathi Shashank, Morrison Juliet, Yount Boyd L, Dinnon Kenneth H, Rückert Claudia, Young Michael C, Zhu Zhe, Robertson Shelly J, McNally Kristin L, Ye Jing, Cao Bin, Mysorekar Indira U, Ebel Gregory D, Baric Ralph S, Best Sonja M, Artyomov Maxim N, Garcia-Sastre Adolfo, Diamond Michael S,

(9) Absence of Gene Predisposes Mice to Mild Social Isolation - Chronic Stress, Leading to Depression-Like Phenotype Associated With Differential Expression of Synaptic Proteins.[TOP]

Pubmed ID :29743870
Publication Date : //
We earlier reported that the male mice lacking the gene () showed mild anxiety, better memory retention, and up-regulation of synaptic proteins in the hippocampus. With increasing evidences from parallel studies in our laboratory about the possible role of in stress response, we investigated its role in brain. We observed that transcript gets up-regulated in the hippocampus of the wild-type mice exposed to stress. To further dissect its function, we analyzed the behavioral and molecular phenotypes of mice when subjected to mild chronic psychological stress, namely; mild (attenuated) social isolation. We employed iTRAQ based quantitative proteomics, real time PCR and western blotting to investigate molecular changes. Three weeks of social isolation predisposed mice to anhedonia, heightened anxiety-measured by Open field test (OFT), increased behavior despair- measured by Forced swim test (FST) and reduced dendritic branching along with decreased spine density of hippocampal CA1 neurons as compared to wild-type counterparts. This depression-like-phenotype was however ameliorated when treated with anti-depressant imipramine. Molecular analysis revealed that out of 1002 quantified proteins [1% False discovery rate (FDR), at-least two unique peptides], strikingly, a significant proportion of synaptic proteins including, SYN1, CAMK2A, and RAB3A were down-regulated in the socially isolated mice as compared to its wild-type counterparts. This was in contrast to the elevated levels of these proteins in non-stressed mutants as compared to the controls. We hypothesized that a de-regulated transcription factor upstream of the synaptic genes might be responsible for the observed phenotype. Indeed, in the socially isolated mice, there was an up-regulation of GATA1 - a transcription factor that negatively regulates synaptic genes and has been associated with Major Depression (MD) in humans. The present study demonstrates significant genotype × enviornment interaction for gene as shown by the reversal in the expression levels of several synaptic proteins in the mutant vis-à-vis wild-type mouse when exposed to social isolation stress.

Authors : Mitra Shiladitya, Sameer Kumar Ghantasala S, Jyothi Lakshmi B, Thakur Suman, Kumar Satish,

(10) Loss of Tctn3 causes neuronal apoptosis and neural tube defects in mice.[TOP]

Pubmed ID :29725084
Publication Date : //
Tctn3 belongs to the Tectonic (Tctn) family and is a single-pass membrane protein localized at the transition zone of primary cilia as an important component of ciliopathy-related protein complexes. Previous studies showed that mutations in Tctn1 and Tctn2, two members of the tectonic family, have been reported to disrupt neural tube development in humans and mice, but the functions of Tctn3 in brain development remain elusive. In this study, Tctn3 knockout (KO) mice were generated by utilizing the piggyBac (PB) transposon system. We found that Tctn3 KO mice exhibited abnormal global development, including prenatal lethality, microphthalmia, polysyndactyly, and abnormal head, sternum, and neural tube, whereas Tctn3 heterozygous KO mice did not show abnormal development or behaviors. Further, we found that the mRNA levels of Gli1 and Ptch1, downstream signaling components of the Shh pathway, were significantly reduced. Likewise, neural tube patterning-related proteins, such as Shh, Foxa2, and Nkx2.2, were altered in their distribution. Interestingly, Tctn3 KO led to significant changes in apoptosis-related proteins, including Bcl-2, Bax, and cleaved PARP1, resulting in reduced numbers of neuronal cells in embryonic brains. Tctn3 KO inhibited the PI3K/Akt signaling pathway but not the mTOR-dependent pathway. The small molecule SC79, a specific Akt activator, blocked apoptotic cell death in primary mouse embryonic fibroblasts from Tctn3 KO mice. Finally, NPHP1, a protein with anti-apoptotic ability, was found to form a complex with Tctn3, and its levels were decreased in Tctn3 KO mice. In conclusion, our results show that Tctn3 KO disrupts the Shh signaling pathway and neural tube patterning, resulting in abnormal embryonic development, cellular apoptosis, and prenatal death in mice.

Authors : Wang Bin, Zhang Yingying, Dong Hongli, Gong Siyi, Wei Bin, Luo Man, Wang Hongyan, Wu Xiaohui, Liu Wei, Xu Xingshun, Zheng Yufang, Sun Miao,