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Hsin-Yun Cheng, Yung-Song Wang, Po-Yuan Hsu, Chien-Yuan Chen, Yi-Chu Liao, Suh-Hang H Juo
Tissue plasminogen activator is the only U.S. FDA-approved therapy for ischemic stroke, while there is no specific medication for hemorrhagic stroke. Therefore, the treatment of acute stroke continues to be a major unmet clinical need. We explored the effects of miR-195 on neurovascular protection and its potential in treating acute stroke. Using both cellular and animal studies, we showed that miR-195's beneficial effects are mediated by four mechanisms: (1) anti-apoptosis for injured neural cells by directly suppressing Sema3A/Cdc42/JNK signaling, (2) neural regeneration by promoting neural stem cell proliferation and migration, (3) anti-inflammation by directly blocking the NF-kB pathway, and (4) improvement of endothelial functions...
June 14, 2019: Molecular Therapy. Methods & Clinical Development
Xiangdong Liu, Wenzhong Zhu, Lei Wang, Jin Wu, Feng Ding, Yingliang Song
Adipose-derived stem cells (ADSCs) provide a novel method for bone tissue regeneration, but their adipogenic tendency limits their therapeutic efficacy. MicroRNAs (miRNAs) have been reported to regulate stem cell differentiation and bone tissue regeneration, but the detailed mechanism is poorly investigated. Our study indicated that inhibition of miR-145-5p enhanced the osteogenic potential of ADSCs and reduced the adipogenic differentiation. Osteogenesis- and adipogenesis-associated genes were detected by qRT-PCR indicating a corresponding result...
February 11, 2019: In Vitro Cellular & Developmental Biology. Animal
André Varcianna, Monika A Myszczynska, Lydia M Castelli, Brendan O'Neill, Yeseul Kim, Jordan Talbot, Sophie Nyberg, Immanuelle Nyamali, Paul R Heath, Matthew J Stopford, Guillaume M Hautbergue, Laura Ferraiuolo
BACKGROUND: Astrocytes regulate neuronal function, synaptic formation and maintenance partly through secreted extracellular vesicles (EVs). In amyotrophic lateral sclerosis (ALS) astrocytes display a toxic phenotype that contributes to motor neuron (MN) degeneration. METHODS: We used human induced astrocytes (iAstrocytes) from 3 ALS patients carrying C9orf72 mutations and 3 non-affected donors to investigate the role of astrocyte-derived EVs (ADEVs) in ALS astrocyte toxicity...
January 30, 2019: EBioMedicine
Victor S C Wong, Marc Meadows, David Goldberg, Dianna E Willis
The development and survival of spiral ganglion neurons (SGNs) are dependent on multiple trophic factors as well as membrane electrical activity. Semaphorins (Sema) constitute a family of membrane-associated and secreted proteins that have garnered significant attention as a potential SGN "navigator" during cochlea development. Previous studies using mutant mice demonstrated that Sema3A plays a role in the SGN pathfinding. The mechanisms, however, by which Sema3A shapes SGNs firing behaviour are not known...
January 31, 2019: European Journal of Neuroscience
Elena Maria Boggio, Erich M Ehlert, Leonardo Lupori, Elizabeth B Moloney, Fred De Winter, Craig W Vander Kooi, Laura Baroncelli, Vasilis Mecollari, Bas Blits, James W Fawcett, Joost Verhaagen, Tommaso Pizzorusso
Perineuronal nets (PNNs) are condensed structures in the extracellular matrix that mainly surround GABA-ergic parvalbumin-positive interneurons in the adult brain. Previous studies revealed a parallel between PNN formation and the closure of the critical period. Moreover, ocular dominance plasticity is enhanced in response to PNN manipulations in adult animals. However, the mechanisms through which perineuronal nets modulate plasticity are still poorly understood. Recent work indicated that perineuronal nets may convey molecular signals by binding and storing proteins with important roles in cellular communication...
January 31, 2019: Molecular Neurobiology
Rodrigo Carlini Fernando, Diego Robles Mazzotti, Hatylas Azevedo, Alex Freire Sandes, Edgar Gil Rizzatti, Mariana Bleker de Oliveira, Veruska Lia Fook Alves, Angela Isabel Pereira Eugênio, Fabrício de Carvalho, Maria Aparecida Dalboni, David Correa Martins, Gisele Wally Braga Colleoni
A growing body of evidence suggests a key role of tumor microenvironment, especially for bone marrow mesenchymal stem cells (MSC), in the maintenance and progression of multiple myeloma (MM), through direct and indirect interactions with tumor plasma cells. Thus, this study aimed to investigate the gene expression and functional alterations of MSC from MM patients (MM-MSC) in comparison with their normal counterparts from normal donors (ND-MSC). Gene expression analysis (Affymetrix) was performed in MM-MSC and ND-MSC after in vitro expansion...
January 31, 2019: Scientific Reports
Mahmoud M Mostafa, Christopher F Rider, Suharsh Shah, Suzanne L Traves, Paul M K Gordon, Anna Miller-Larsson, Richard Leigh, Robert Newton
BACKGROUND: Glucocorticoids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and, as inhaled corticosteroids (ICS), are the cornerstone of treatment for asthma. However, reduced efficacy in severe disease or exacerbations indicates a need to improve ICS actions. METHODS: Glucocorticoid-driven transcriptomes were compared using PrimeView microarrays between primary human bronchial epithelial (HBE) cells and the model cell lines, pulmonary type II A549 and bronchial epithelial BEAS-2B cells...
January 31, 2019: BMC Medical Genomics
Toru Nakanishi, Yuki Fujita, Toshihide Yamashita
Following incomplete spinal cord injury (SCI), reorganization of the corticospinal tract (CST) contributes to spontaneous motor recovery. Axotomized CST fibers form collaterals and make synapses with interneurons, followed by pruning of excess fibers. Although axonal pruning is involved in refinement of neural circuits, its molecular mechanisms and functional roles remain poorly understood. To address these questions, we performed dorsal hemisections of mouse thoracic spinal cord. We observed that Neuropilin-1 (Nrp1) mRNA was upregulated in layer 5 pyramidal neurons in the motor cortex 14 days after SCI, when the pruning occurred...
January 25, 2019: Cell Death & Disease
Patrick Shean-Young Lee, Nan Gao, Mamata Dike, Olga Shkilnyy, Rao Me, Yangyang Zhang, Fu-Shin X Yu
The diabetic cornea exhibits pathological alterations such as delayed epithelial wound healing and nerve regeneration. We sought to investigate the role of Semaphorin (SEMA) 3C in corneal wound healing and re-innervation in normal and diabetic B6 mice. Wounding induced the expression of SEMA3A, 3C and their receptor Neuropilin (NRP) 2, but not NRP1 in normal corneal epithelial cells (CECs); this upregulation was suppressed for SEMA3C and NRP2 in diabetic corneas. Injections of Sema3C- specific siRNA and NRP2 neutralizing antibodies in wounded mice resulted in a decrease in the rate of wound healing and regenerating nerve fibers, while exogenous SEMA3C had opposing effects in diabetic corneas...
January 24, 2019: Diabetes
Mikihito Hayashi, Tomoki Nakashima, Noriko Yoshimura, Kazuo Okamoto, Sakae Tanaka, Hiroshi Takayanagi
Osteocyte survival is key to bone homeostasis and is perturbed in menopause and aging. However, it remains unknown how osteocyte-mediated maintenance of the skeleton is regulated by the osteoprotective factor semaphorin 3A (Sema3A), a secreted protein that is known to reduce bone resorption and enhance bone formation. Here, we show that estrogen induces osteocyte expression of Sema3A, which acts on its receptor on osteocytes to promote their survival and maintain bone homeostasis. Postnatal global and conditional deletion of Sema3a in osteoblastic cells resulted in a severe osteoporotic phenotype marked by fewer osteocytes...
January 17, 2019: Cell Metabolism
Agatha A van der Klaauw, Sophie Croizier, Edson Mendes de Oliveira, Lukas K J Stadler, Soyoung Park, Youxin Kong, Matthew C Banton, Panna Tandon, Audrey E Hendricks, Julia M Keogh, Susanna E Riley, Sofia Papadia, Elana Henning, Rebecca Bounds, Elena G Bochukova, Vanisha Mistry, Stephen O'Rahilly, Richard B Simerly, James E N Minchin, Inês Barroso, E Yvonne Jones, Sebastien G Bouret, I Sadaf Farooqi
Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls...
January 14, 2019: Cell
Seigo Usuki, Noriko Tamura, Tomohiro Tamura, Shigeki Higashiyama, Kunikazu Tanji, Susumu Mitsutake, Asuka Inoue, Junken Aoki, Katsuyuki Mukai, Yasuyuki Igarashi
Previously, we proposed the following mechanism for konjac ceramide (kCer)-mediated neurite outgrowth inhibition: kCer binds to Nrp as a Sema3A agonist, resulting in Nrp1/PlexA complex formation and activation of the Sema3A signaling pathway to induce phosphorylation of CRMP2 and microtubule depolymerization. The Sema3A/Nrp1 signaling pathway is known to be also expressed in normal human keratinocytes. To determine whether kCer can function in human keratinocytes as it does in neurites, that is, if it can bind to Nrp1 in place of Sema3A, we studied the effect of kCer on HaCaT cell migration activity...
March 2019: Biochemistry and Biophysics Reports
Rong Xiang, Yu Xu, Wei Zhang, Yong-Gang Kong, Lu Tan, Shi-Ming Chen, Yu-Qin Deng, Ze-Zhang Tao
BACKGROUND: It has been reported that semaphorin 3A (sema3A) could improve allergic symptoms in allergic rhinitis (AR) mice. However, the immunomodulatory roles of sema3A in AR remain unclear. This study was performed to determine the immunoregulatory effects of sema3A on airway inflammation in an AR mice model. METHODS: First, sema3A expression was measured in the serum of AR patients and also in a mice model. Then, nasal symptoms, ovalbumin (OVA)-specific immunoglobulin E (IgE) production, cytokine levels, and histologic structure were analyzed in OVA-sensitized mice, sema3A mice, mice given saline, and controls...
December 31, 2018: International Forum of Allergy & Rhinology
Roberta Cagnetta, Hovy Ho-Wai Wong, Christian K Frese, Giovanna R Mallucci, Jeroen Krijgsveld, Christine E Holt
Local translation is rapidly regulated by extrinsic signals during neural wiring, but its control mechanisms remain elusive. Here we show that the extracellular cue Sema3A induces an initial burst in local translation that precisely controls phosphorylation of the translation initiation factor eIF2α via the unfolded protein response (UPR) kinase PERK. Strikingly, in contrast to canonical UPR signaling, Sema3A-induced eIF2α phosphorylation bypasses global translational repression and underlies an increase in local translation through differential activity of eIF2B mediated by protein phosphatase 1...
December 4, 2018: Molecular Cell
Neven Papic, Snjezana Zidovec Lepej, Lana Gorenec, Ivana Grgic, Slavko Gasparov, Tajana Filipec Kanizaj, Adriana Vince
Semaphorins are a diverse family of immunoregulators recently recognized to play a major role in various phases of immune responses. Their role in chronic viral hepatitis C (CHC) and contribution to the progression of liver disease is unknown. The aim of this study was to analyse the association of secreted semaphorins with the severity of liver disease in patients with CHC. Serum concentrations of semaphorins were measured in 114 treatment-naive CHC patients and 36 healthy controls. Serum concentrations of SEMA3A, SEMA3C, SEMA5A, SEMA6B and SEMA6D were significantly increased in patients with CHC compared to controls...
2018: PloS One
Jie-Hong Wu, Yi-Fan Zhou, Can-Dong Hong, An-Qi Chen, Yan Luo, Ling Mao, Yuan-Peng Xia, Quan-Wei He, Hui-Juan Jin, Ming Huang, Ya-Nan Li, Bo Hu
BACKGROUND: Neointimal hyperplasia is a prominent pathological event during in-stent restenosis. Phenotype switching of vascular smooth muscle cells (VSMCs) from a differentiated/contractile to a dedifferentiated/synthetic phenotype, accompanied by migration and proliferation of VSMCs play an important role in neointimal hyperplasia. However, the molecular mechanisms underlying phenotype switching of VSMCs have yet to be fully understood. METHODS: The mouse carotid artery ligation model was established to evaluate Sema3A expression and its role during neointimal hyperplasia in vivo...
December 19, 2018: EBioMedicine
Raquel Escrich, Irmgard Costa, Montserrat Moreno, Marta Cubedo, Elena Vela, Eduard Escrich, Raquel Moral
Breast cancer is the most common malignancy in women worldwide, and dietary lipids are important environmental factors influencing its etiology. We have investigated the effects, and the mechanisms associated, of high-fat diets on 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Animals were fed a low-fat, a high-corn-oil (HCO) or a high-extra-virgin-olive-oil (HOO) diet from weaning or after induction. The HCO diet had a clear stimulating effect on mammary carcinogenesis, especially when dietary intervention started after induction, whereas the tumors from HOO diet groups exhibited clinical and morphological characteristics similar to those from low-fat controls...
November 17, 2018: Journal of Nutritional Biochemistry
You-Jung Ha, Dong Woo Han, Ji Hyoun Kim, Sang Wan Chung, Eun Ha Kang, Yeong Wook Song, Yun Jong Lee
Semaphorin 3A (Sema3A) and semaphorin 4D (Sema4D) are molecules which regulate immune responses as well as bone remodeling process. The aim of this study was to evaluate the serum levels of Sema3A and Sema4D and to investigate their clinical significance in rheumatoid arthritis (RA). The serum levels of Sema3A and Sema4D were measured in 130 patients with RA and 65 sex- and age-matched healthy individuals. Circulating levels of biomarkers of RA-related inflammation and bone turnover such as tumor necrosis factor- (TNF-) α , interleukin- (IL-) 6, IL-22, IL-34, osteopontin, Dkk-1, and sclerostin were also measured...
2018: Disease Markers
Jung-Hyun Choi, Sung-Hoon Kim, Young-Hun Jeong, Sung Wook Kim, Kyung-Tai Min, Kyong-Tai Kim
Fragile X syndrome (FXS) caused by loss of fragile X mental retardation protein (FMRP) is the most common cause of inherited intellectual disability. Numerous studies show that FMRP is a RNA binding protein that regulates translation of its binding targets and plays key roles in neuronal functions. However, the regulatory mechanism for FMRP expression is incompletely understood. Conflicting results regarding internal ribosome entry site (IRES)-mediated fmr1 translation were reported. Here, we unambiguously demonstrated that the fmr1 gene, which encodes FMRP, exploits both IRES-mediated translation and canonical cap-dependent translation...
November 26, 2018: Molecular and Cellular Biology
Chun-Wai Ma, Pui-Yi Kwan, Kenneth Lap-Kei Wu, Daisy Kwok-Yan Shum, Ying-Shing Chan
Perineuronal nets (PN) restrict neuronal plasticity in the adult brain. We hypothesize that activity-dependent consolidation of PN is required for functional maturation of behavioral circuits. Using the postnatal maturation of brainstem vestibular nucleus (VN) circuits as a model system, we report a neonatal period in which consolidation of central vestibular circuitry for graviception is accompanied by activity-dependent consolidation of chondroitin sulfate (CS)-rich PN around GABAergic neurons in the VN. Postnatal onset of negative geotaxis was used as an indicator for functional maturation of vestibular circuits...
November 20, 2018: Brain Structure & Function
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