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(1) is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice.[TOP]

Pubmed ID :30519364
Publication Date : //
Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus.

Authors : Sergi Domenico, Campbell Fiona M, Grant Christine, Morris Amanda C, Bachmair Eva-Maria, Koch Christiane, McLean Fiona H, Muller Aifric, Hoggard Nigel, de Roos Baukje, Porteiro Begona, Boekschoten Mark V, McGillicuddy Fiona C, Kahn Darcy, Nicol Phyllis, Benzler Jonas, Mayer Claus-Dieter, Drew Janice E, Roche Helen M, Muller Michael, Nogueiras Ruben, Dieguez Carlos, Tups Alexander, Williams Lynda M,

(2) Isolinderalactone regulates the BCL-2/caspase-3/PARP pathway and suppresses tumor growth in a human glioblastoma multiforme xenograft mouse model.[TOP]

Pubmed ID :30503550
Publication Date : //
Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which remains incurable. Plant extracts are a potential source of potent anticancer medicines. In this study, we investigated the effect of isolinderalactone from Lindera aggregata on tumor growth using U-87 human glioblastoma cells. Treatment with isolinderalactone inhibited cell viability and promoted apoptotic cell death. In addition, intraperitoneal injection of isolinderalactone significantly inhibited tumor growth in a human GBM xenograft mouse model. To identify the proteins involved in the induction of apoptosis in isolinderalactone-treated cells, we performed a human apoptosis proteome array analysis and western blotting. Isolinderalactone suppressed the expression of B-cell lymphoma 2 (BCL-2), as well as of survivin and X-linked inhibitor of apoptosis protein (XIAP), known as apoptosis inhibitors, and increased the level of cleaved caspase-3. In addition, isolinderalactone treatment increased cleaved poly(ADP-ribose) polymerase (PARP) and DNA damage. In xenograft tumor tissues, we observed high immunofluorescence of cleaved caspase-3 and TUNEL in isolinderalactone-treated group. Taken together, isolinderalactone enhances U-87 GBM cell apoptosis in vitro and in vivo and retards tumor growth, suggesting that isolinderalactone may be a potential candidate for anti-glioblastoma drug development.

Authors : Hwang Ji Young, Park Jung Hwa, Kim Min Jae, Kim Woo Jean, Ha Ki-Tae, Choi Byung Tae, Lee Seo-Yeon, Shin Hwa Kyoung,

(3) GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylation.[TOP]

Pubmed ID :30502054
Publication Date : //
Glycogen synthase kinase-3β (GSK3β) is a key regulator of cellular homeostasis. In neurons, GSK3β contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined.

Authors : Urbanska Malgorzata, Kazmierska-Grebowska Paulina, Kowalczyk Tomasz, Caban Bartosz, Nader Karolina, Pijet Barbara, Kalita Katarzyna, Gozdz Agata, Devijver Herman, Lechat Benoit, Jaworski Tomasz, Grajkowska Wieslawa, Sadowski Krzysztof, Jozwiak Sergiusz, Kotulska Katarzyna, Konopacki Jan, Van Leuven Fred, van Vliet Erwin A, Aronica Eleonora, Jaworski Jacek,

(4) Development and Characterization of a Spontaneously Metastatic Patient-Derived Xenograft Model of Human Prostate Cancer.[TOP]

Pubmed ID :30510249
Publication Date : //
Here we describe the establishment and characterization of an AR+, PSMA+, ERG+, PTEN, CHD1 patient-derived xenograft (PDX) model termed 'C5', which has been developed from a 60 years old patient suffering from castration-resistant prostate cancer (CRPC). The patient underwent radical prostatectomy, showed early tumor marker PSA recurrence and, one year after surgery, abiraterone resistance. Subcutaneous C5 tumors can be serially transplanted between mice and grow within ~90 days to 1.5-2 cm³ tumors in SCID Balb/c mice (take rate 100%), NOD-scid IL2Rg (NSG) mice (100%) and C57BL/6 pfp/rag2 mice (66%). In contrast, no tumor growth is observed in female mice. C5 tumors can be cryopreserved and show the same growth characteristics in vivo afterwards. C5 tumor cells do not grow stably in vitro, neither under two- nor three-dimensional cell culture conditions. Upon serial transplantation, some C5 tumors spontaneously disseminated to distant sites with an observable trend towards higher metastatic cell loads in scid compared to NSG mice. Lung metastases could be verified by histology by means of anti-PSMA immunohistochemistry, exclusively demonstrating single disseminated tumor cells (DTCs) and micro-metastases. Upon surgical resection of the primary tumors, such pulmonary foci rarely grew out to multi-cellular metastatic colonies despite doubled overall survival span. In the brain and bone marrow, the metastatic cell load present at surgery even disappeared during the post-surgical period. We provide shallow whole genome sequencing and whole exome sequencing data of C5 tumors demonstrating the copy number aberration/ mutation status of this PCa model and proving genomic stability over several passages. Moreover, we analyzed genomic and transcriptomic alterations during metastatic progression achieved by serial transplantation. This study describes a novel PCa PDX model that enables future research on several aspects of metastatic PCa, particularly for the AR+ , ERG+ , PTEN PCa subtype.

Authors : Lange Tobias, Oh-Hohenhorst Su Jung, Joosse Simon A, Pantel Klaus, Hahn Oliver, Gosau Tobias, Dyshlovoy Sergey A, Wellbrock Jasmin, Feldhaus Susanne, Maar Hanna, Gehrcke Renate, Kluth Martina, Simon Ronald, Schlomm Thorsten, Huland Hartwig, Schumacher Udo,

(5) Attenuation of Experimental Autoimmune Encephalomyelitis in a Common Marmoset Model by Dendritic Cell-Modulating Anti-ICAM-1 Antibody, MD-3.[TOP]

Pubmed ID :30488167
Publication Date : //
MD-3 is a novel anti-human ICAM-1 monoclonal antibody that induces T cell tolerance in humanized mice via modulation of dendritic cell differentiation and efficiently suppresses the development of collagen-induced arthritis. This effect has also been observed in xenograft rejection in nonhuman primates, where grafts survived for more than 2.5 years following MD-3 administration. Here, we show that MD-3 can attenuate experimental autoimmune encephalomyelitis (EAE) that was induced in common marmoset monkeys by immunization with human myelin oligodendrocyte glycoproteins. MD-3 administration was initiated 1 week after immunization and efficiently delayed the development of EAE phenotypes, although the disease was not completely prevented. Based on the results of histopathological examination, MD-3 treatment greatly suppressed total inflammation with respect to demyelination, as well as T cell and microglial infiltration in the brain. However, the antibody response against myelin oligodendrocyte glycoprotein was not suppressed with this treatment protocol. These observations suggest that the MD-3 antibody has beneficial effects on the treatment of EAE via the suppression of T cell-mediated cellular responses.

Authors : Lee Soon-Tae, Park Seung Pyo, Park Hi-Jung, Wicks Joan R, Lee Jae-Il, Suh Young Ho, Jung Kyeong Cheon,

(6) SAR228810: an antibody for protofibrillar amyloid β peptide designed to reduce the risk of amyloid-related imaging abnormalities (ARIA).[TOP]

Pubmed ID :30486882
Publication Date : //
Anti-amyloid β (Aβ) immunotherapy represents a major area of drug development for Alzheimer's disease (AD). However, Aβ peptide adopts multiple conformations and the pathological forms to be specifically targeted have not been identified. Aβ immunotherapy-related vasogenic edema has also been severely dose limiting for antibodies with effector functions binding vascular amyloid such as bapineuzumab. These two factors might have contributed to the limited efficacy demonstrated so far in clinical studies.

Authors : Pradier Laurent, Blanchard-Brégeon Véronique, Bohme Andrees, Debeir Thomas, Menager Jean, Benoit Patrick, Barneoud Pascal, Taupin Véronique, Bertrand Philippe, Dugay Philippe, Cameron Béatrice, Shi Yi, Naimi Souad, Duchesne Marc, Gagnaire Marie, Weeden Tim, Travaline Tara, Reczek David, Khiroug Leonard, Slaoui Mohamed, Brunel Pascale, Fukuyama Hidehiro, Ravetch Jeffrey, Canton Thierry, Cohen Caroline,

(7) [The anti-cancer effect of ZR30 protein via targeting extracellular signal proteins of different cell subpopulations of glioma].[TOP]

Pubmed ID :30481930
Publication Date : //
To investigate the roles and anti-cancer mechanism of artificially synthesized EGF-containing fibulin-like extracellular matrix protein (EFEMP1) derived tumor suppressor ZR30 protein in glioma (GBM). ZR30 protein were in vitro expressed using a wheat germ cell-free system. GBM cell lines (U251, U251NS, and U87) were cultured for 2-3 days in the presence or absence of ZR30 treatment. MMP-2 level was detected by gelatin zymography assay, moreover, the expression of EGFR, Notch-1 and p-Akt/Akt levels were determined by western blot. Additionally, MTT assay was used to measure ZR30's effect on the cell proliferation of U251 and U251NS cells. Furthermore, pre-mixed U251-GFP and U251NS-RFP cells (1∶9) were injected into the brain of nude mice, and then ZR30 or PBS was injected into the intra-tumor after 10 and 21 days, respectively. Then DNA was extracted from the right brain of nude mice in each group. Comparative quantitative polymerase chain reaction (CQ-PCR) was used to examine the copy numbers of human gene hSPAG16, mouse gene mSpag16, GFP and RFP. The survival status of each group of nude mice was also observed. The levels of activated MMP-2 in U87 and U251 cells were lower after 10, 50 and 100 ng/ml ZR30 treatment for 2-3 days. Western blot analysis showed that ZR30 treatment reduced the expression of EGFR, Notch-1 and p-Akt/Akt in U251 cells, and inhibited Notch-1 and p-Akt/Akt expression in U251NS cells, and then decreased the response of U251 cells to EGF stimulation. Moreover, ZR30 inhibited the cell proliferation of U251 and U251NS two days after exposure. The in vivo orthotopic GBM xenografts were successfully constructed. CQ-PCR results indicated that the hSPAG16/mSpag16 ratios of mice in PBS group and ZR30 treatment groups at 180, 700, and 1 800 ng dosages were 3.67±2.82, 1.18±0.97, 1.75±1.55 and 1.38±1.17, respectively, and ZR30 treatment groups showed significantly lower ratios than the PBS group (<0.05 for all). Correspondingly, the ratios of GFP/RFP in each group were 1.97±0.80, 1.97±0.85, 1.48±0.71 and 1.73±0.77, respectively, showing no statistical significance (>0.05 for all). When treatment was performed 10 d after cell implantation, and the median survival time of mice in PBS group and ZR30 group was 40.5 days and 59.0 days, respectively. When treatment was performed 21 d after cell implantation, the median survival time of mice in PBS group and ZR30 group was extended to 57.0 days and 74.5 days, respectively. The median survival time of ZR30 treatment groups significantly prolonged (<0.05 for all). ZR30 inhibits cell growth, invasion, angiogenesis and stemness maintenance in glioma via suppressing activated MMP-2, EGFR, p-Akt/Akt and Notch-1 proteins. ZR30 markedly increased survival of mice harboring glioma xenografts, even for only one intra-tumoral injection at the time of early tumor formation. Overall, the in vivo and in vitro experiments supported the therapeutic potential of ZR30 for GBM.

Authors : Li Y Y, Chen X H, Sun T, Hu Y, Zhou Y H, Zhou Y X,

(8) Histone deacetylase inhibitor ITF2357 (givinostat) reverts transformed phenotype and counteracts stemness in in vitro and in vivo models of human glioblastoma.[TOP]

Pubmed ID :30474756
Publication Date : //
Aberrant expression and activity of histone deacetylases (HDACs) sustain glioblastoma (GBM) onset and progression, and, therefore, HDAC inhibitors (HDACi) represent a promising class of anti-tumor agents. Here, we analyzed the effects of ITF2357 (givinostat), a pan-HDACi, in GBM models for its anti-neoplastic potential.

Authors : Marampon Francesco, Leoni Flavio, Mancini Andrea, Pietrantoni Ilaria, Codenotti Silvia, Letizia Ferella, Megiorni Francesca, Porro Giuliana, Galbiati Elisabetta, Pozzi Pietro, Mascagni Paolo, Budillon Alfredo, Maggio Roberto, Tombolini Vincenzo, Fanzani Alessandro, Gravina Giovanni Luca, Festuccia Claudio,

(9) Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons.[TOP]

Pubmed ID :30472681
Publication Date : //
Vagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive macrophages (mMφ) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5-HT4R) agonist prucalopride can mimic this effect in mice and human.

Authors : Stakenborg Nathalie, Labeeuw Evelien, Gomez-Pinilla Pedro J, De Schepper Sebastiaan, Aerts Raymond, Goverse Gera, Farro Giovanna, Appeltans Iris, Meroni Elisa, Stakenborg Michelle, Viola Maria Francesca, Gonzalez-Dominguez Erika, Bosmans Goele, Alpizar Yeranddy A, Wolthuis Albert, D'Hoore Andre, Van Beek Kim, Verheijden Simon, Verhaegen Marleen, Derua Rita, Waelkens Etienne, Moretti Milena, Gotti Cecilia, Augustijns Patrick, Talavera Karel, Vanden Berghe Pieter, Matteoli Gianluca, Boeckxstaens Guy E,

(10) Neuroinflammation and aberrant hippocampal plasticity in a mouse model of emotional stress evoked by exposure to ultrasound of alternating frequencies.[TOP]

Pubmed ID :30472146
Publication Date : //
Emotional stress is a form of stress evoked by processing negative mental experience rather than an organic or physical disturbance and is a frequent cause of neuropsychiatric pathologies, including depression. Susceptibility to emotional stress is commonly regarded as a human-specific trait that is challenging to model in other species. Recently, we showed that a 3-week-long exposure to ultrasound of unpredictable alternating frequencies within the ranges of 20-25 kHz and 25-45 kHz can induce depression-like characteristics in laboratory mice and rats. In an anti-depressant sensitive manner, exposure decreases sucrose preference, elevates behavioural despair, increases aggression, and alters serotonin-related gene expression. To further investigate this paradigm, we studied depression/distress-associated markers of neuroinflammation, neuroplasticity, oxidative stress and the activity of glycogen synthase kinase-3 (GSK-3) isoforms in the hippocampus of male mice. Stressed mice exhibited a decreased density of Ki67-positive and DCX-positive cells in the subgranular zone of hippocampus, and altered expression of brain-derived neurotrophic factor (BDNF), its receptor TrkB, and anti-apoptotic protein kinase B phosphorylated at serine 473 (AktpSer473). The mice also exhibited increased densities of Iba-1-positive cells, increased oxidative stress, increased levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) in the hippocampus and plasma, and elevated activity of GSK-3 isoforms. Together, the results of our investigation have revealed that unpredictable alternating ultrasound evokes behavioural and molecular changes that are characteristic of the depressive syndrome and validates this new and simple method of modeling emotional stress in rodents.

Authors : Pavlov Dmitrii, Bettendorff Lucien, Gorlova Anna, Olkhovik Andrey, Kalueff Allan V, Ponomarev Eugene D, Inozemtsev Anatoly, Chekhonin Vladimir, Lesсh Klaus-Peter, Anthony Daniel C, Strekalova Tatyana,